79C3C34C52B45572883A05D425EB0F82
Pharmacological Trials on Women
http://bioetica.governo.it/media/3514/5_doc_pharmacological_trials_on_women_28nov2008.pdf
http://leaux.net/URLS/ConvertAPI Text Files/E395F64B30D41AD08182DEAA82F8429B.en.txt
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| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / political affiliation
Searching for indicator political:
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p.000007: 601-615; M. Gandhi, F. Aweeka, R.M. Greenblatt, T. Blaschke, Sex Differences in Pharmacokinetics and
p.000007: Pharmacodynamics, “Ann. Rev. Pharmacol. Toxicol.”, 2004, 44, pages 499-523, A.D.M. Kashuba, A.N. Nafzinger
p.000007: Physiological Changes during the Menstrual Cycle and their Effects on the Pharmacokinetics and Pharmacodynamics
p.000007: of Drugs, “Clinical Pharmacokinetics”, 1998, 34 (3), pages 203-218; P.A. Thuermann, B.C. Hompesch,
p.000007: Influence on Gender on the Pharmacokinetics and Pharmacodynamics of Drugs,“International Journal of Clinical
p.000007: Pharmacology and Therapeutics”, 1998, 36 (11), pages 586-590.
p.000007: 18 Cf. A. Holdcroft, Gender Bias in Research: How does it affect Evidence Based Medicine?, editorial “J. Royal Soc.
p.000007: Med.”, p. 100.
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p.000008: 8
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p.000008: qualified workers); the change in the participation in the work-market (many traditionally male jobs are open to
p.000008: women), the strong female push towards a career, but the persistent difficulties in the work-market (the participation
p.000008: of women is nevertheless inferior to that of men, with greater unemployment problems or relinquishment of work
p.000008: places due to maternity and lack of working facilitations and social aids); the increase of the public
p.000008: participation on a social, political, economic basis, but the persistent marginalisation (there are still few
p.000008: women in positions of power and responsibility); the behavioural traits generally more frequent in women (e.g.
p.000008: the inclination to take care of others and the selflessness). The change of women’s conditions from
p.000008: a historical, cultural and psychological point of view has relevant implications on their conditions of illness
p.000008: and health, on the way women perceive them and live through them. We highlight how, many pathologies traditionally
p.000008: attributed to the male gender because of their physical structure or their behavioural habits on an individual and
p.000008: social basis, are also widespread – and at times more greatly – in the female sex, due to the change in lifestyles and
p.000008: risk factors and/or to a lack of an adequate prevention, diagnosis and cure.
p.000008: The research on women’s health, elaborated by NOWH (National Observatory on Women’s Health) in collaboration with
p.000008: the National Observatory of Health in Italian Regions, part of the Catholic University of the Sacred Heart19,
p.000008: highlights (in the second part: “Health needs and health assistance”) the condition of women’s health and
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Political / vulnerable
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p.000045: La sperimentazione farmacologica
p.000045: sulle donne
p.000045: (26 nove »bt e 2008)
p.000045: VEBStONElTALlAM& E )NG6ESE
p.000045:
p.000045: NATIONAL BIOETHICS COMMITTEE
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p.000045: PI1àIJHàC0L0GIC࣠HIàLS
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p.000045: 28ih Noember 2008
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p.000045: DEPARTMENT OF INROMATION AND PUBLISHING
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p.000045: TABLE OF CONTENTS
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p.000045: l'rosentntion
p.000045: 45
p.000045: 1. Introduction
p.000047: 47
p.000047: 2. Clinieal experimentation 50
p.000047: 3. Clinical experimentation on women: under-representation in the enlistment
p.000047: and shortcomings in the differentiated analysis of the data 51
p.000047: 4. New needs of experimentation differentiated by sex:
p.000047: the changes of health/illness in women 53
p.000047: 5. Women as drug users and the problem
p.000047: of the side-effects 55
p.000047: 6. Female vulnerability in clinical trails: women
p.000047: as “weak subjects” 56
p.000047: 7. The exclusion/inclusion of women of childbearing
p.000047: age in trials protocols 58
p.000047: 8. Female presence in medical teams and in ethical committees 60
p.000047: 9. International bioethical guidelines 60
p.000047: 10. National legislation 64
p.000047: 11. Bioethical recommendations 65
p.000047: Bibliography
p.000069: 69
p.000069: l‘ei•s‹i›snl remark
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p.000076: ITALIAN NATIONAL BIOETHICS COMMITTEE
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p.000076: PHARMACOLOGICAL TRIALS ON WOMEN
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p.000076: 28th November 2008
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p.000001: PRESENTATION
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...
p.000009: appear to be the greatest consumers of drugs, in particular within the ages of 15 and 54 (cf. tab. 5). The
p.000009: reasons of the difference in the consumption of drugs, with regard to gender, would require
p.000009: complex pharmacoepidemiological analysis: some hypothesis have been formulated, according to which women take better
p.000009: care of themselves in comparison to men, they have better awareness of their pathological condition,
p.000009: but also undergo a greater number of treatments due to their reproductive state and to the fact that they
p.000009: are more easily affected by chronic but non-lethal pathologies22.
p.000009: But if women, in greater quantities, use drugs that have not been adequately tested on them, the result is inevitably a
p.000009: higher frequency and seriousness of adverse reactions, often due to overdosing or polytherapies23. In
p.000009: 2007 the national Net of pharmacovigilance highlighted that spontaneous reports of adverse
p.000009: reactions in women constitute 57% of the total (cf. tab. 6). Examples of adverse reactions in women
p.000009: are: serious arrhythmia, cardiac imbalances and breaking of limbs due to drugs, even when commonly consumed24. In the
p.000009: United States some drugs have been withdrawn from the market because of the high number of side effects reported in
p.000009: women25.
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p.000009: 6. Female vulnerability in clinical trails: women as “weak subjects”
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p.000009: The lower number of women participating in experimental studies is due to a variety of reasons26.
p.000009:
p.000009: 21 Cf. National Observatory on the use of drugs, L’uso dei farmaci in Italia, 2006.
p.000009: 22 Arno Project, Donne e farmaci. Rapporto 2003, vol. VII, Ed. Centauro, Bologna 2004.
p.000009: 23 International analysis report a frequency 1,7 times higher and they highlight the gravity, including even hospital
p.000009: admissions, of 59% of women. Cf. M. Pirmohamed, S. Meakin, C. Green, et. Al., Adverse Drug Reactions as cause of
p.000009: Admission to Hospital: Prospective Analysis of 18.820 Patients, “British Medical Journal”, 2004, 329, pages
p.000009: 15-19.
p.000009: 24 An example of this is aspirin, which is used by both men and women as prevention for cardiovascular pathologies. It
p.000009: induces adverse reactions in higher percentage in women, due to a difference in blood coagulation. Cf.
p.000009: The Puzzle of Aspirin and Sex, “New England Journal of Medicine”, 2005, 352, pages 1366-1368. A case that
p.000009: caused the interest of public opinion is represented by the events linked to Digoxin; the analysis, mentioned in a
p.000009: prestigious, international journal, highlighted that the drug, when given to men, protected them from the risk of
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Health / Drug Dependence
Searching for indicator dependency:
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p.000008: the National Observatory of Health in Italian Regions, part of the Catholic University of the Sacred Heart19,
p.000008: highlights (in the second part: “Health needs and health assistance”) the condition of women’s health and
p.000008: the quality of health assistance. In the pathologies most common in women – where the frequency of the
p.000008: pathologies is linked to age and social condition – we can find some relevant elements: an increase in
p.000008: cardiac pathologies (arterial hypertension, coronary cardiomyopathy, peripheral arteriopathy and cardiac
p.000008: imbalance, thromboembolic pathologies); an increment in the oncological field, as well as “female cancers” (breast
p.000008: cancer, carcinoma of the uterine cervix, endometrial tumours, ovarian neoplasia), also of trachea-bronchi-lungs
p.000008: tumours, due to the spread of nicotine addition even during adolescence; an increase in psychological
p.000008: pathologies (anxiety and depressive syndromes, eating disorders, psychotic syndromes); a tendency to an increase
p.000008: in obesity, due to the lack of physical activity and sedentary life, with an increase in the risk of
p.000008: cardiovascular illnesses and diabetes; an increase in alcohol abuse (with nutritional imbalances and
p.000008: dependency); an increase in neurodegenerative illnesses (Alzheimer’s illness, Parkinson disease, multiple
p.000008: sclerosis, senile dementia); an increase in problems linked to infertility, caused by the postponement of the decision
p.000008: to have children or by the protracted use of contraceptives; problems and pathologies linked with the
p.000008: non- acceptance of aging also emerge20.
p.000008: These changes in the conditions of women’s health and illness emphasise even more the lack of an
p.000008: adequately differentiated trails for the care of women’s health, beyond traditional areas.
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p.000008: 19 La salute della donna. Stato di salute a assistenza nelle regioni italiane. Libro bianco, Franco Angeli, Milano
p.000008: 2007.
p.000008: 20 Different the causes: the problems of the substitutive hormonal therapy; the possibility to postpone for decades
p.000008: physical aging, extending the menstrual cycle for years as well as intervening with plastic surgery, with possible
p.000008: dangers for women’s health, and not only because of the bad quality of the treatments – as in the case of deaths
p.000008: due to routing operations, like liposuction – but also because of extended negative effects, injected
p.000008: liquids and stress, due to the effort of not showing their real age.
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Health / Drug Usage
Searching for indicator drug:
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p.000045: N. 4
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p.000045: Comitato Nazionale per la Bioetica
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p.000045:
p.000045: La sperimentazione farmacologica
p.000045: sulle donne
p.000045: (26 nove »bt e 2008)
p.000045: VEBStONElTALlAM& E )NG6ESE
p.000045:
p.000045: NATIONAL BIOETHICS COMMITTEE
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p.000045:
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p.000045: PI1àIJHàC0L0GIC࣠HIàLS
p.000045:
p.000045: 28ih Noember 2008
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p.000045:
p.000045:
p.000045:
p.000045:
p.000045: DEPARTMENT OF INROMATION AND PUBLISHING
p.000045:
p.000045: TABLE OF CONTENTS
p.000045:
p.000045:
p.000045: l'rosentntion
p.000045: 45
p.000045: 1. Introduction
p.000047: 47
p.000047: 2. Clinieal experimentation 50
p.000047: 3. Clinical experimentation on women: under-representation in the enlistment
p.000047: and shortcomings in the differentiated analysis of the data 51
p.000047: 4. New needs of experimentation differentiated by sex:
p.000047: the changes of health/illness in women 53
p.000047: 5. Women as drug users and the problem
p.000047: of the side-effects 55
p.000047: 6. Female vulnerability in clinical trails: women
p.000047: as “weak subjects” 56
p.000047: 7. The exclusion/inclusion of women of childbearing
p.000047: age in trials protocols 58
p.000047: 8. Female presence in medical teams and in ethical committees 60
p.000047: 9. International bioethical guidelines 60
p.000047: 10. National legislation 64
p.000047: 11. Bioethical recommendations 65
p.000047: Bibliography
p.000069: 69
p.000069: l‘ei•s‹i›snl remark
p.000076: 76
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p.000076: ITALIAN NATIONAL BIOETHICS COMMITTEE
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p.000076: PHARMACOLOGICAL TRIALS ON WOMEN
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p.000076: 28th November 2008
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p.000003: it appears
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p.000003: 1 This is true in almost all Countries although there are great differences in the life expectancy of men and women.
p.000003: A. Barford, D. Dorling, G Davey Smith, M. Shaw, Life Expectancy: Women Now on Top Everywhere, “British
p.000003: Medical Journal”, 2006, 332, p. 808.
p.000003: 2 On this topic cf Regulation (CE) number 190/2006 of the European Parliament and of the Council of
p.000003: Europe regarding drugs for paediatric use, which ends the marketing of drugs tested almost exclusively on adult
p.000003: subjects.
p.000003: 3 In Italy the greater consumption of drugs by women is per-capita data, therefore normalised. Cf.
p.000003: paragraph 5.
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p.000004: 4
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p.000004: that the effects of drugs on women are less studied or not adequately studied with regard to female specificity4. Women
p.000004: are more exposed to possible side-effects when
p.000004: they take drugs after their introduction on the market and we highlight less efficacy in the use of the drugs, with
p.000004: more frequent unwanted side-effects, which are also more serious compared to those experienced by men5.
p.000004: It is a bioethical problem that has emerged in international literature, in particular in the United States. It must be
p.000004: taken into account that the Food and Drug Administration (FDA) currently has an office that takes care specifically of
p.000004: women’s health and of their participation in clinical trials6 (the CDs “clinical trials gender oriented”)7. The
p.000004: European debate generally refers to the guidelines set by the United States; in Europe, until today, no National
p.000004: Bioethics Committee has chosen this theme as an object for reflection8. In Italy, studies regarding this field are
p.000004: still few, even if we can report recent initiatives in the direction of a greater consideration of the female
p.000004: specificity in pharmacological experimentation. In 2005 the Ministry of Health created the workbench on
p.000004: “Women’s health and drugs for women” (with the participation of the Superior Institute for Health, of the Italian
p.000004: Drug Agency, of the Regional Health Service Agency and of the Italian Society of Pharmacology). In 2007
p.000004: a working group was created “Gender approach to health” within the Women’s Health Commission, part of the
p.000004: Ministry of Health, with the primary objective of implementing the gathering of statistical data about female health,
p.000004: of promoting research and training in this field. In 2008, the Report on the “State of women’s health
p.000004: in Italy” was published, which, in the context of the general consideration of female health, also
p.000004: touches on the problem of drugs. Also in 2008, the Italian Drug Agency (IDA) introduced the equality between men and
p.000004: women as one of the criteria of the Evaluation of the Agreements’ Plan Commission to assign funds to
p.000004: industries which invest in Italy in pharmacological research. The Italian Society of Pharmacology (ISP) has
p.000004: in recent years started a working group that has the objective of motivating pharmacological research on sexual
p.000004: differences, through a campaign of information aimed at health workers, with the purpose of boosting the
p.000004: formation of experts in this sector and to raise awareness in health authorities.
p.000004: Awareness is growing – at a time in which we are trying to achieve the individualization of the cure,
p.000004: working on the genetic or immunity component – that the analysis of the data stratified by sex can give indications on
p.000004: the best therapy to follow and supply useful information for deeper studies with a scientific basis on the illnesses
p.000004: that
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p.000004: 4 E. Annandale, K. Hunt, Gender Inequalities in Health, Open University Press, Buckingham 2000; F.
p.000004: Franconi, S. Canu, I. Campasi, working group “Approccio di genere alla salute”, Approccio di genere nella ricerca,
p.000004: nelle sperimentazioni e nei trattamenti farmacologici, in Lo Stato di Salute delle donne in Italia. Primo rapporto sui
p.000004: lavori della Commissione Salute delle Donne, Rome 2008, pages 39-53.
p.000004: 5 Cf. paragraph 5.
p.000004: 6 Cf. http://www.fda.gov/womens/trials.html. In some North American Universities, like the Columbia
p.000004: University in New York, there are activities entirely dedicated to these problems. In the last few years the
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p.000005: the introduction of new drugs will benefit the greatest amount of patients. We must remember that this
p.000005: is not the only possible model, but it is the one that is generally considered the most suitable because
p.000005: of the needs of modern medicine and because of its impact on the population’s health.
p.000005: Drugs’ experimentation, before the authorisation to market them, makes provisions, after the pre-clinical phase, for
p.000005: phase I, essentially about safety, and phases II and III, in which
p.000005:
p.000005: 9 With regards to experimentation which is not directly therapeutic in the interest of the pregnant woman or of the
p.000005: breast feeder, aiming to achieve effective protection of the health of the woman, of the embryo and of the foetus, and
p.000005: of the child after birth, the additional conditions anticipated in ch. VI of article 18 of the additional Protocol to
p.000005: the Convention of human rights and biomedicine are applied, relative to biomedical research, approved in Strasbourgh on
p.000005: the 25th of January 2005, which indicate particular precautions.
p.000005: 10 The “Good Clinical Practices” constitute an international standard of ethics and quality of planning,
p.000005: managing and recording clinical studies. In Italy they were first adopted as part of the national legislation with the
p.000005: ministerial decree of the 15th of July 1997.
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p.000006: 6
p.000006:
p.000006: the efficacy of the drug on a growing number of patients is established. Subsequently the drug is authorised by the
p.000006: health authorities and becomes part of the clinical practice. Other phase IV studies can take place,
p.000006: always with experimental characteristics and therefore with the enlistment of a certain number of patients, aimed
p.000006: at better establishing the efficacy of a new drug with regards to the safety of use, even for longer periods of time.
p.000006: The whole process is under the control of health authorities, primarily of the Italian Drug Agency (IDA), which is
p.000006: called to supervise and if necessary direct, through its funding, drug research11.
p.000006:
p.000006: 3. Clinical experimentation on women: under-representation in the enlistment and shortcomings in the
p.000006: differentiated analysis of the data
p.000006:
p.000006: Within clinical drugs experimentation, women appear to be “weak subjects”, or at least they appear to be not subjected
p.000006: to adequate consideration, which should take into account their specificity both from a quantitative point of
p.000006: view (number of enlisted women in comparison to the number of men) and a qualitative point of view (analysis of the
p.000006: data with regards to sexual difference).
p.000006: In Italy numerous studies are carried out on female pathologies: in this case the enlistment of the patients is
p.000006: determined by the pathology. Analysing the data reported by the IDA, we can see that on a total of 4,196
p.000006: experimentations from 2000 to 2006, there is a progressive increase of studies specifically carried out on women (cf.
p.000006: tab.1). Analysing the data of these trials, what emerges is a greater attention to phases II and III, an absence of
p.000006: phase I and a scarce emphasis on phase IV (cf. tab. 2). But what emerges the most is that such experimentations are
p.000006: mostly dedicated to therapeutic strategies for female pathologies, like the breast cancer and the control of the
p.000006: post-menopausal osteoporosis12. Studies are also carried out on the genitourinary field, the musculoskeletal
p.000006: system, connective tissue, the endocrinal system, in the context of the pregnancy, the labour and the time immediately
p.000006: after giving birth and in the context of the disorders of the nervous system. There are many studies on female
p.000006: fertilization with regards to ovarian stimulation as well as assisted fecundation; others are aimed at
p.000006: controlling incontinence in post- menopausal women (cf. tab. 3)13. We highlight that there are specific trials on
p.000006: women in the field of cardiovascular pathologies especially after the menopause, thanks to national studies on the
p.000006: incidence of these illnesses, in which the data is stratified by sex as well as age14. There are areas in which
p.000006: we notice a lack of pharmacological trials on female pathologies as well: in particular with regards to the
p.000006: substitutive hormonal treatment in post-menopausal women, where there are many risks of heart attack or breast cancer
p.000006: or cardiovascular toxicity of the chemotherapy drugs used to treat breast cancer.
p.000006:
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p.000006: 11 Part of the IDA is the Observatory on drug experimentation, which collects the data of all the
p.000006: experimentation conducted in Italy, periodically published in their bulletins. The data of the Observatory can be found
p.000006: on http://oss-sper-clin.agenziafarmaco.it.
p.000006: 12 J.E. Rossouw, G.L. Anderson, R.L. Prentice, A.Z. LaCroix, et al. (Group for the Women’s Health
p.000006: Initiative Investigators), Risks and Benefits of Estrogen plus Progestin in Healthy Postmenopausal Women, “JAMA”, 2002,
p.000006: 288, pages 321-332.
p.000006: 13 On the site of the Observatory we can search for current studies, using the key word “women”: the
p.000006: studies which specifically involve women, in relation to female pathologies, are almost 60.
p.000006: 14 An example of this is the “CUORE” (heart) project, coordinated by the Higher Institute of Health.
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p.000007: The areas of criticality and disadvantage for women are highlighted, in particular, with regard to the experimentation
p.000007: of drugs on pathologies that are not specifically and traditionally female15 (even if few data is reported, as
p.000007: confirmation of such lack of interest). The majority of trials do not allow for a difference between men and women
p.000007: at the moment of enlistment and of the analysis of the data. The percentage of women (if compared to that of men)
p.000007: recruited in the experimentation is still low: it is referred to as “representative inappropriateness” or
p.000007: “under-representation” of women16. Drug dosage is generally measured on men (70 Kg. in weight) and women are considered
p.000007: a “variation” of the male model: but the weight difference between men and women, as well as the
p.000007: morphological and physiological difference, determines a considerable difference in the pharmacokinetics, that is
p.000007: the different way in which the drug is absorbed, distributed, metabolised and eliminated, and in the
p.000007: pharmacodynamics, that is in the response of the body to a certain concentration of drug in the blood or in the
p.000007: tissue17. Despite the fact that the knowledge of the specificity of the female body has matured,
p.000007: experimentation protocols have not been modified, therefore the enlistment without distinction between men
p.000007: and women persists and so does a consequent undifferentiated analysis of the data. Women are generally included (if
p.000007: they are) in phase III of the enlistment in the trails, but not in phases I and II of the trails (important phases, as
p.000007: already mentioned, to establish dosage, side-effects and safety in the drug’s use). The lack of specific studies on
p.000007: women, especially in the early phases of the research, does not make it possible to measure the real efficacy of the
p.000007: drugs on women, but could even have limited the identification of specifically female drugs (cf. tab. 4)18.
p.000007:
p.000007: 4. New needs of experimentation differentiated by sex: the changes of health/illness in women
p.000007:
p.000007: The fact that there’s a lack of studies which take into account the sex difference within pharmacological
p.000007: experimentation, is even more problematic, given the recent change in the conditions of women’s
p.000007: health/illness within the context of the general change in the female condition. Some of the illnesses considered
p.000007: “male”, today tend to be more frequent in women.
p.000007: There are many factors, as we know, that have contributed to a change in the conditions of women, at
p.000007: least with regard to western societies. We need to consider: the increase in education (in latest years women exceed
p.000007: men in the number of graduates and
p.000007:
p.000007: 15 That is male/female pathologies.
p.000007: 16 F. Franconi, S. Canu, I. Campasi, Working Group “Approccio di genere alla salute”. Approccio di
...
p.000008: sclerosis, senile dementia); an increase in problems linked to infertility, caused by the postponement of the decision
p.000008: to have children or by the protracted use of contraceptives; problems and pathologies linked with the
p.000008: non- acceptance of aging also emerge20.
p.000008: These changes in the conditions of women’s health and illness emphasise even more the lack of an
p.000008: adequately differentiated trails for the care of women’s health, beyond traditional areas.
p.000008:
p.000008:
p.000008:
p.000008: 19 La salute della donna. Stato di salute a assistenza nelle regioni italiane. Libro bianco, Franco Angeli, Milano
p.000008: 2007.
p.000008: 20 Different the causes: the problems of the substitutive hormonal therapy; the possibility to postpone for decades
p.000008: physical aging, extending the menstrual cycle for years as well as intervening with plastic surgery, with possible
p.000008: dangers for women’s health, and not only because of the bad quality of the treatments – as in the case of deaths
p.000008: due to routing operations, like liposuction – but also because of extended negative effects, injected
p.000008: liquids and stress, due to the effort of not showing their real age.
p.000008:
p.000009: 9
p.000009:
p.000009: 5. Women as drug users and the problem of the side-effects
p.000009:
p.000009: The fact that women are not adequately taken into consideration within clinical trails is penalising, given the
p.000009: increase in the consumption of drugs on their part.
p.000009: As we can see from the data on territorial assistance in relation to the consumption and the
p.000009: gross public expense per capita for reimbursed drugs (class A) of the Italian National Health Service21, women
p.000009: appear to be the greatest consumers of drugs, in particular within the ages of 15 and 54 (cf. tab. 5). The
p.000009: reasons of the difference in the consumption of drugs, with regard to gender, would require
p.000009: complex pharmacoepidemiological analysis: some hypothesis have been formulated, according to which women take better
p.000009: care of themselves in comparison to men, they have better awareness of their pathological condition,
p.000009: but also undergo a greater number of treatments due to their reproductive state and to the fact that they
p.000009: are more easily affected by chronic but non-lethal pathologies22.
p.000009: But if women, in greater quantities, use drugs that have not been adequately tested on them, the result is inevitably a
p.000009: higher frequency and seriousness of adverse reactions, often due to overdosing or polytherapies23. In
p.000009: 2007 the national Net of pharmacovigilance highlighted that spontaneous reports of adverse
p.000009: reactions in women constitute 57% of the total (cf. tab. 6). Examples of adverse reactions in women
p.000009: are: serious arrhythmia, cardiac imbalances and breaking of limbs due to drugs, even when commonly consumed24. In the
p.000009: United States some drugs have been withdrawn from the market because of the high number of side effects reported in
p.000009: women25.
p.000009:
p.000009: 6. Female vulnerability in clinical trails: women as “weak subjects”
p.000009:
p.000009: The lower number of women participating in experimental studies is due to a variety of reasons26.
p.000009:
p.000009: 21 Cf. National Observatory on the use of drugs, L’uso dei farmaci in Italia, 2006.
p.000009: 22 Arno Project, Donne e farmaci. Rapporto 2003, vol. VII, Ed. Centauro, Bologna 2004.
p.000009: 23 International analysis report a frequency 1,7 times higher and they highlight the gravity, including even hospital
p.000009: admissions, of 59% of women. Cf. M. Pirmohamed, S. Meakin, C. Green, et. Al., Adverse Drug Reactions as cause of
p.000009: Admission to Hospital: Prospective Analysis of 18.820 Patients, “British Medical Journal”, 2004, 329, pages
p.000009: 15-19.
p.000009: 24 An example of this is aspirin, which is used by both men and women as prevention for cardiovascular pathologies. It
p.000009: induces adverse reactions in higher percentage in women, due to a difference in blood coagulation. Cf.
p.000009: The Puzzle of Aspirin and Sex, “New England Journal of Medicine”, 2005, 352, pages 1366-1368. A case that
p.000009: caused the interest of public opinion is represented by the events linked to Digoxin; the analysis, mentioned in a
p.000009: prestigious, international journal, highlighted that the drug, when given to men, protected them from the risk of
p.000009: death, however it did not protect female patients. Cf. R. Short, Fracture Risk is a Class Effect of Glitazones,
p.000009: “British Medical Journal”, 2007, 334, p. 551; S. Saif Rathore, M.P.H. Yongfei Wang, H.M. Krumholtz, Sex-Based
p.000009: Differences in the Effect of Diagoxin for the Treatment of Heart Failure, “NEJM”, 2002, 347, pages. 1403-1411.
p.000009: 25 Cf. Withdrawn Drugs Posed Greater Health Risk for Women then Man, GAO says, “American Journal of Health-System
p.000009: Pharmacy”, March 15, 2001, 58 (6), pages 458-462; United States General Accounting Office, Drug Safety:
p.000009: Most Drugs Withdrawn in Recent Years had Greater Health Risk for Women, Washington D.C. 2001.
p.000009: 26 D. Wrigt, N.J. Chew, Women as Subjects in Clinical Research, “Applied Clinical Trials”, 1996, 5 (9), pages 44-54; E.
p.000009: Shuster, For her Own Good: Protecting (and Neglecting) Women in Research, “Cambridge Quarterly of Healthcare Ethics”,
p.000009: 1996, 5, pages 346-361.
p.000009:
p.000010: 10
p.000010:
p.000010: a) Social reasons. Some sociological studies highlight women’s difficulties in becoming part of clinical
p.000010: studies due to the lack of time (mainly because of their role of carers within the family or, in the case of
p.000010: working women, due to their double obligation at home and at work) or due to their low income (because of the not
p.000010: yet adequate participation of women in the work-market and because of their lower wages). In part the reticence to
p.000010: participate is also due to the recruiters’ lack of attention to the practical and psychological needs of women.
p.000010: b) External environmental reasons. There are also other factors linked with lifestyle or exposure to substances
...
p.000010: influence the clinical response to the pharmacological experimentation. Women are generally more inclined to
p.000010: use natural substances or home remedies consolidated in the cultural tradition of the family. Even if in
p.000010: clinical experimentation the treatment in the various experimental branches is the same, it is not always
p.000010: possible to keep under control lifestyle differences and external factors that can affect the experimentation in a
p.000010: different way for men and women.
p.000010: c) Economic reasons. The pharmaceutical industry prefers not to invest in the experimentation on women
p.000010: due to the inevitable rise in costs. The enlistment should necessarily be multiplied: to stratify the data
p.000010: according to gender, men and women should be recruited, doubling or quadrupling the amount of enlistments, increasing
p.000010: time and cost, trails costs and insurance costs to cover eventual negative effects. Even the use of
p.000010: female and male animals in the pre-clinical phase increases the time and the cost of the research. As the
p.000010: authorisation for the introduction of the drug on the market does not require it, the pharmaceutical
p.000010: industry is not motivated to undertake such studies, as they are seen as economically
p.000010: disadvantageous. On the other hand public funding chooses typically female pathologies (like osteoporosis
p.000010: during the menopause), to be able to better tackle the health policies of a country where women live
p.000010: longer, overlooking those pathologies traditionally considered not typical of the female population.
p.000010: d) Biological reasons. Women have always been considered “difficult” subjects for trials, due to their biological and
p.000010: physiological differences, but especially for their enzymatic and hormonal differences, due to the variations
p.000010: during childbearing and non-childbearing age (menstrual cycle, pregnancy, breast feeding,
p.000010: menopause) and to the possible consumption of contraceptives for contraceptive or therapeutic reasons (estrogens and
p.000010: progestin modify women’s metabolism; the estrogens also affect the way genes work). This kind of variability does not
p.000010: allow the collection of “clean data” in mixed sex trials and lowers the statistical relevance of the
p.000010: experimentation. Even when there are women involved in the trial, it is not certain that the enlisted
p.000010: number can allow us to see significant events.
p.000010:
p.000010:
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: e) Possible pregnancy during childbearing age27. One of the reasons that have led the pharmaceutical
p.000011: industry to exclude women from trials is connected to the possibility that the trial of a new drug
p.000011: could damage the foetus28 in case of pregnancy. There is also the possibility that the studied drug could have
p.000011: negative effects even after the end of the trial, months later. This explains why in general the pharmaceutical
p.000011: industry imposes the use of specific hormonal contraceptives29 as condition for the participation in a research
p.000011: that can be considered “without risk” for the foetus.
p.000011:
p.000011: 7. The exclusion/inclusion of women of childbearing age in trials protocols
p.000011:
p.000011: Regarding the problem of pharmacological experimentation on women of childbearing age, the literature
p.000011: presents a variety of positions: within those, we report the most spread ones.
p.000011: Some affirm that the inclusion of women of childbearing age in the trails is ethically of the outmost
p.000011: importance, when balancing the possible damage to the foetus (considered not yet to have dignity in a strong sense)
p.000011: with the predictable direct benefits to women and in general to society30. From this point of view, the a priori
p.000011: exclusion of women of childbearing age from trails (to protect the possible foetus) results in injustice in the
p.000011: biomedical research, as women do not have the same opportunities as men with regards to the cure of certain
p.000011: illnesses. The particular physio-psychological and social conditions of women should not justify their exclusion,
p.000011: but, on the contrary, motivate a differentiated study in comparison to men. The expectation of the
p.000011: pharmaceutical industry that women should use hormonal contraceptives is also criticised as restrictive of women’s
p.000011: freedom intended as self-determination.
p.000011: Others maintain that where clinical trials, even only hypothetically and probably, poses a danger to the foetus’ life
p.000011: and health (here the foetus is recognised as a subject
p.000011:
p.000011: 27 U. Halbreich, S.W. Carson, Drug Studies in Women of Childbearing Age: Ethical and Methodological Considerations, “J.
p.000011: Clin. Pharmacol.”, 1989, 9, pages 328-333.
p.000011: 28 The risks of teratogenicity for the foetus are classified as follows by the Food and Drug Administration:
p.000011: “controlled study without risk” when the safety of the drug in all stages of pregnancy has been
p.000011: demonstrated; “remote but possible risk” when in the studies on animals an increase in foetal anomalies has not been
p.000011: demonstrated but the risk is possible; “no chance to exclude risk” when the risks have been demonstrated
p.000011: by teratogen effects in the studies on animals and there are few studies on humans; “positive evidence of risk” when
p.000011: the teratogen effect has been demonstrated; “contraindicated during pregnancy” when there is positive
p.000011: evidence, in both studies on animals and humans, of the risk for the foetus. Even the potential benefits for women are
p.000011: variable and oscillate from the therapy for deadly illnesses that cannot be cured in any other way (for instance,
p.000011: cancer cures) to the cure of non-deadly pathologies (take into account the cure of acne).
p.000011: 29 We refer to the use of hormonal contraceptives, as with the use of barrier contraceptives (e.g.
p.000011: preservatives), even if they do not interact with the drugs, there is a percentage of risk of pregnancy. The need for
p.000011: the use of contraceptives is functional to the experimentation to protect the foetus as well as to guarantee the
p.000011: conditions of homogeneity.
...
p.000012: present in the medical teams that plan and define the trials’ development and present in the ethical
p.000012: committees that evaluate the trials protocols. The presence of women could contribute to a greater focus on the
p.000012: relevance of women’s participation to the trials and could allow greater sensitivity with regards to female needs, from
p.000012: a psychological and social point of view.
p.000012: There is no data regarding the presence of women in medical teams, however, it is possible to verify the presence of
p.000012: women in ethical Committees through an analysis of the committees’ composition, as reported by the data of the
p.000012: Observatory on trials. Generally women’s presence, although often linked to the nursing sector and to
p.000012: the representative of patients, is consistent, even if almost always inferior to that of men, and is strongly dependent
p.000012: on local circumstances.
p.000012:
p.000012: 9. International bioethical guidelines
p.000012:
p.000012: In the ‘70s explicit instructions emerged, that made rules for the exclusion of women from clinical studies
p.000012: with the aim of protecting the health of the future child, as dramatic cases of foetal death and severe damage
p.000012: to the infants had occurred, due to indiscriminate trials32. In 1977 the Food and Drug Administration (FDA) in
p.000012: the General Considerations for the Clinical Evaluation of Drugs recommended the exclusion from
p.000012: experimentation of women of childbearing age, especially in phases I and II, as the data on teratogenicity was not
p.000012: known, with the exception of women with deadly pathologies;
p.000012:
p.000012: 31 This is the position that refers to the inseparability of the uniting and the procreating dimension of the marital
p.000012: act. Cf. R. Minacori, D. Sacchini, A.G. Spagnolo, Women of Childbearing Potential as Research Subjects in Clinical
p.000012: Trials: Ethical Issues, in A.G. Spagnolo, G. Gambino (edited by), Women’s Health Issues, Societa’ Editrice
p.000012: Universo, Roma 2003, pages 123-129; A.G. Spagnolo, M. Cicerone, Sperimantazione farmacologica e donne
p.000012: in eta’ fertile, “Medicina e Morale”, from international literature, 2005, 3, pages 667-670; Catholic University
p.000012: of the Sacred Heart, ethical Committee, Raccomandazioni riguardo alla inclusione di donne in eta’ fertile
p.000012: nei protocolli di sperimentazione clinica, “Medicina e Morale”, 1996, 46, pages 141-143. Cf. for a historical
p.000012: reconstruction M. Pelaja, L. Scaraffia, Due in una carne. Chiesa e sessualita’ nella storia, Laterza, Bari 2008, page
p.000012: 261 and following.
p.000012: 32 S. Cagliano, Dieci farmaci che sconvolsero il mondo, Laterza, Rome-Bari 1994, pages 43-68.
p.000012:
p.000013: 13
p.000013:
p.000013: women of childbearing age could participate to the studies in phases II and III only if sufficient
p.000013: information on the drug’s safety and efficacy, even in the studies on animals, had been collected, which excluded
p.000013: interferences with the reproductive functions. In 1982 the World Health Organisation promulgated the Proposed
p.000013: International Guidelines which affirmed the duty to exclude women from non-therapeutic experimentations on
p.000013: healthy volunteers33.
p.000013: In 1988 we register a radical change in the direction of the FDA that, with the publication of the document Guideline
p.000013: for the Format and Content of the Clinical and Statistical Sections of the New Drug Application, highlights the
p.000013: under-representation of women in pharmacological trial and recommends the analysis of sex-differentiated data in
p.000013: clinical trials34. In 1993 the FDA again issued the Guidelines for the Study and Evaluation of gender
p.000013: Differences in the Clinical Evaluation of Drugs, recognising that the percentage of the participation of women to
p.000013: clinical experimentations in pathologies not typically female is inferior to that of men and hoping for the inclusion
p.000013: of women in the trials protocols with the aim to guarantee equal representation. The FDA accepts that such exclusion
p.000013: could have, in subtle ways, caused the impression that men are the “primary focus” of medicine and of
p.000013: pharmacological development, with women being of secondary consideration; it therefore recommends the removal of the
p.000013: prohibition of the participation of women of childbearing age to the first phases of trial, with the aim
p.000013: to prevent forms of discrimination, avoiding a paternalistic attitude. The FDA believes that it is not necessary to
p.000013: exclude women because of the potential risks to the foetus, as the risks can be minimised with an explicit commitment
p.000013: of the woman to avoid pregnancy, as well as through the use of laboratory tests which can ascertain such behaviours.
...
p.000013: International Ethical Guidelines for Biomedical Research Involving Human Subjects (revised in 2002),
p.000013: recommending the researchers, the sponsors and the ethical committees to avoid excluding women of
p.000013: childbearing age from trials, as they do not believe the possibility of a pregnancy is sufficient reason
p.000013: to preclude or limit their participation and recognising that women have the ability to take a “rational decision” in
p.000013: participating in research (guideline number 16). In the case of risk to the foetus’ health, women have to accept to
p.000013: undertake a pregnancy
p.000013:
p.000013:
p.000013: 33 K.L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice,
p.000013: “Journal of Health Politics, Politics and Law”, 1999, 24 (3), pages 531-566.
p.000013: 34 R.B. Merkatz, Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, “Acad
p.000013: Med”, 1994, 69, pages 703-707; R.B. Merkatz, R. Temple, S. Sobel, Women in Clinical Trials of new Drugs. A Change in
p.000013: Food and Drug Administration Policy, “The New England Journal of Medicine”, 1993, 329 (4), pages 292-296.
p.000013:
p.000014: 14
p.000014:
p.000014: test and to use an “effective contraceptive method”, allowing, with such procedures, their enlistment also in the first
p.000014: phases of the trials with controlled doses of the new substance; we highlight that the informed consent must be
p.000014: guaranteed offering women a fair amount of time and adequate environmental conditions to decide, believing
p.000014: that an individual consent is a must, and that it cannot be substituted by the partner’s consent. In addition, CIOMS
p.000014: recommends that even pregnant women are acceptable (guideline number 17) as trials subjects, provided that the risks
p.000014: (for the woman and for the foetus) are minimised, leaving the decision to the individual woman, even in the
p.000014: case of uncertainty and ambiguity about the definition of risk; the research can be promoted only if it is relevant
p.000014: to the health of the woman who is subjected to the trials and to other women in the same condition; it is believed that
p.000014: women can be recruited into the research only in case there are pre-clinical studies which state the drug’s
p.000014: teratogenity.
p.000014: In 1994 in the United States, a dedicated office called “Office of Women’s Health” was created as part of
p.000014: the FDA, with the objective of boosting the inclusion of women in clinical studies, evaluating the different
p.000014: responses for the safety and the efficacy of drugs. In 1995 the previous instructions were strengthened
p.000014: further in the document Investigational New Drug Applications, which explicitly demands an end to any
p.000014: discrimination due to sexual difference, as well as age and race, in trials. In 1998 the FDA promulgates the Final Rule
p.000014: on the Investigational Drug Applications with the aim of actively intervening with sponsors who do not respect
p.000014: the instructions of fairness within sexual difference. In 1999 the working group “FDA-MA Women and Minorities
p.000014: Working Group” was created, with the aim of drawing up specific guidelines to boost the correct inclusion of women and
p.000014: of weak subjects in clinical trials. In 2001 the National Institute of Health in the USA issued the document
p.000014: Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research to promote a policy
p.000014: of women’s inclusion in the enlistment for pharmacological trials. It is important to highlight that the
p.000014: Department of Health and Human Services in issuing the Regulations for the Protection of Human Subjects in 2001,
p.000014: does not take explicitely into account tendencies and directives for the researchers, the doctors and IRBs on the
p.000014: specific theme of trials on women of childbearing age.
p.000014: Within the European biolegislation we highlight the focus on female specificity within the general area of
p.000014: health35, but lacking specific provisions of policies of non- exclusion or inclusion of women in clinical
p.000014: studies (simply highlighting the lack of data in such field)36. There are however some initiatives of awareness. In
p.000014: 1998, the EMEA
p.000014:
...
p.000015: which would promote the comparison between sexes, with the guarantee of a statistically significant participation of
p.000015: women and adequate medical training. In the document Gender Considerations in the Conduct of Clinical Trials
p.000015: issued by the Committee for Medical Products for Human Use (CHMP) of the European Drugs’ Agency (EMEA) in January
p.000015: 2005, the lack of need for the elaboration of specific European guidelines on pharmacological trials on
p.000015: women is explicitely stated (differently to what occurred in reference to age difference, with regards to
p.000015: underage and elderly patients) considering as sufficient the international guidelines on the issue.
p.000015:
p.000015: 10. National legislation
p.000015:
p.000015: In the Italian legal system there is no explicit reference to the female condition within clinical trials. In the
p.000015: legislative decree of the 24th of June 2003 number 211 Carrying out of the directive 2001/20/CE in relation to
p.000015: the application of good clinical practice in the execution of clinical trials of drugs for clinical use to the article
p.000015: 1 c. 2 “The respect of good practice guarantees the protection of the rights, safety and wellbeing of the subjects and
p.000015: ensures the credibility of the data regarding the same clinical trials”, we refer to the “subject” intended as “person
p.000015: who participates to the clinical trials, both as the target for the experimented drug as well as its test” (art. 2.
p.000015: i.), without distinction between men and women. We speak of protection of the trials’ subjects, with particular
p.000015: reference to adults unable to give their informed consent and to minors, but no explicit reference to women.
p.000015: The new regulation on Minimum requiremenst for the creation, the organisation and the functioning of ethical Committees
p.000015: for the trials of drugs (ministerial decree of the 12th of May 2006) does not specify that there must be a balanced
p.000015: representation of both sexes.
p.000015:
p.000015:
p.000015:
p.000015: intergovernamental body responsible for the definition and the implementation of the actions of the Council of Europe
p.000015: that aim to promote equality between men and women. The Report was supposed to provide the conceptual basis, where
p.000015: the need to take into consideration sexual differences in the context of their differing social roles was
p.000015: highlighted, for any future action that would be recommended to all the States members of the Council of Europe. The
p.000015: European Health Committee (CDSP-European Council), starting with a careful evaluation of the current situation with
p.000015: regards to the theme “women and health" and with an insufficient analysis in the European countries, highlights the
p.000015: lack of detailed information about the access to cures by men and women, the necessity to pre-empt discriminations in
...
p.000016: of social and cultural factors and their interaction with female health.
p.000016: 3. The NBC deems the increase of bioethically relevant clinical trials on women, as an important step towards
p.000016: guaranteeing the effective conditions of equality of care in comparison to men: the scarse
p.000016: representativeness of women and the lack of sex- differentiatied data constitute a discriminatory element
p.000016: for women’s health. The increase in clinical trials must be promoted not just with regard to traditionally female
p.000016: pathologies but also for new pathologies, hoping for a link between the results of sex differentiated medical
p.000016: research and pharmacological trials. To this end, we recommend an increase of women’s enlistment in
p.000016: clinical trials at every phase, even when studying the drugs’ efficacy and their effect, promoting a sex
p.000016: differentiated analysis of the data. Trials should take into account sexual differences even at the pre- clinical
p.000016: level, in order to evaluate the toxicity of drugs in animal experimentation, but also in the research of alternative
p.000016: methodologies. The stratification of data according to sexual difference should also be boosted after the authorisation
p.000016: to market has been granted, in order to highlight the negative effects on women, which can contribute to an improvement
p.000016: in the planning of the course of the trials.
p.000016: 4. The NBC believes that drug’s labels should indicate whether the drug has been specifically tested on
p.000016: women or not and that they should clarify and highlight any element that could generate a different response
p.000016: in men and women. The lack of such references presumes an improper assimilation of women to men, with
p.000016: possible negative effects on women but also on men.
p.000016: 5. The NBC believes that the way to increase sex differentiated pharmacological trials can be indicated as follows:
p.000016: a) raise awareness in the local health authorities and motivate the pharmaceutical industry to support sex
p.000016: differentiated trials, even if not very lucrative, promoting research projects on the issue, showing
p.000016: its social importance in the achievement of a real equality between men and women in their
p.000016:
p.000016:
p.000017: 17
p.000017:
p.000017: accessXtoXhealthcare; b) promote the participation of women to clinical trials, giving adequate information (even
p.000017: through the media) on the negative consequences of the lack of differentiated trials and on the social importance of
p.000017: female trials, guaranteeing support and specific attention to women’s psychological and practical needs; c)
p.000017: ensure a greater presence of women as experimenters and as members of ethical committees in order to
...
p.000017: d) boost health training which focuses on the female dimension within pharmacological
p.000017: trials, as well as within research and cure; e) increase international cooperation, as well as national and
p.000017: local, with the focus on the female condition within clinical trials, involving health authorities and the
p.000017: pharmaceutical industry.
p.000017: 6. The NBC believes that even the participation of women of childbearing age in pharmacological trials is
p.000017: ethically and socially important, provided that an adequate protection of the future child can be guaranteed. The NBC
p.000017: highlights the importance of a preliminary consultation about the intended trials, including adequate
p.000017: information, clear and in full, according to an objective, technical-scientific classification of the
p.000017: risks and benefits that the study involves for the patient, but that also taking into account the risks for the foetus
p.000017: in case of pregnancy37. We must also take into account that the exclusion of women of childbearing age from trials does
p.000017: not allow, in practice, to protect the foetus, as women could take the experimented drug (but not tested on them) on
p.000017: the market with similar risks in case of pregnancy and, to make it worse, without adequate protection. The NBC believes
p.000017: that the inclusion of women of childbearing age in pharmacological trials that poses risks to the foetus
p.000017: needs, unavoidably, the woman’s clear statement of a conscious and responsible commitment to avoid
p.000017: intercourse that could lead to pregnancy. If it is not possible to exclude a risk to the foetus’ life and
p.000017: health within the trials, but there are possible benefits to women in general and in particular in the
p.000017: cure of illnesses, the NBC believes that requesting the commitment to take contraceptives as a safety measure
p.000017: believed necessary by the study’s sponsor – to avoid pregnancy, as the trials could be damaging to the foetus – can be
p.000017: included in the criteria to participate in the study.
p.000017: In addition, the NBC believes that it is important that the woman’s husband or partner is also involved in the
p.000017: informative counselling, as the choices being made involve them as a couple.
p.000017: The trial of drugs that can make hormonal contraceptives ineffective is an open problem, so it is the fact
p.000017: that there might be interactions between the treatments being studied and the contraceptive methods being used: in this
...
p.000018: the conditions of safety to proceed. The informed consent and the committment to avoid procreation applies also to men
p.000018: who enter a trial protocol which presents the risk of damage to the foetus through their gametes.
p.000018:
p.000018:
p.000018: Bibliography38
p.000018:
p.000018: Bennett J.C., Inclusion of Women in Clinical Trials. Policies for Population Subgroups, “New England
p.000018: Journal of Medicine”, 1993, 329 (4), pp. 288-292
p.000018:
p.000018: Borgia L.M. (a cura di), Manuale di bioetica per la sperimentazione clinica e i comitati etici,
p.000018: Edizioni Medico Scientifiche, Torino 2008 (cfr. pp. 36-45)
p.000018:
p.000018: Buffoni F., Donne nella ricerca farmacologica italiana, Quaderni della SIF, marzo 2006, 5, pp. 6-7
p.000018:
p.000018: Ceci A., Legislazione e criticità nella sperimentazione dei farmaci, Agenzia Sanitaria Servizi Sanitari
p.000018: Monitor ASSR, 2005, 12, pp. 67-71
p.000018:
p.000018: Commissione Nazionale per la parità e le pari opportunità tra uomo e donna, Presidenza del Consiglio dei Ministri,
p.000018: Guida alla salute delle donne, a cura di E. Reale, Dipartimento per l’Informazione e l’Editoria, 2003
p.000018:
p.000018: Fleisch J., Fleisch M.C., Thurmann P.A., Women in Early-Phase Clinical Drugs Trials: Have Things Changed
p.000018: over the Past 20 Years?, “Clinical Pharmacology and Therapeutics”, 2005, 78 (5), pp. 445-452
p.000018:
p.000018: Food and Drug Administration, Department of Health and Human Services, FDA Scholarship in Women’s Health Program,
p.000018: Participation of Females in Clinical Trials and Gender Analysis of Data in Biologic Product Application,
p.002001: 2001
p.002001:
p.002001: Franconi F., Brunelleschi S., Steardo L., Cuomo G., Gender Differences in Drug Responses,
p.002001: “Pharmacological Research”, 2007, 55 (2), pp. 81-97
p.002001:
p.002001: Healy B., The Yentl Sindrome, “The New England Journal of Medicine”, 1991, 25, pp. 274-276 Holden C., Women Abound in
p.002001: NIH Trials, “Science”, 2008, 322, p. 219
p.002001: Kaiser J., Gender in the Pharmacy: Does it Matter?, “Science”, 2005, 308, pp. 1572-1574
p.002001:
p.002001: Keitt S.K., Wagner C.R., Marts S.A., Understanding the Biology of Sex and Gender Differences: Using Subgroup Analysis
p.002001: and Statistical Design to Detect Sex Differences in Clinical Trials, “Medscape General Medicine”, 2003, 5 (2)
p.002001:
p.002001: Louis M., J. Sieczkiewicz, Law, Ethics, and Gender Impact of the US Patent System on the Promise of
p.002001: Personalized Medicine, “Gender Medicine”, 2007; 4, 187–192; 1550-8579
p.002001:
p.002001:
p.002001: 38 For the bibliographical research we thank Dr. Vanna Pistotti and Dr. Cinzia Colombo of the Mario Negri Institute.
p.002001:
p.000019: 19
p.000019:
p.000019: Mastroianni A.C., Faden R., Federman D. (eds.), Women and Health Research: Ethical and Legal Issues of Including Women
p.000019: in Clinical Studies, vol. I e vol. II, National Academy Press, Washington D.C. 1994
p.000019:
p.000019: Mattison D.R., Sex Matters in Pharmacology: Principles of Pharmacology for Women, in Leppert P.C., Peipert
p.000019: J.F. (eds.), Primary Care for Women, Lippincot Williams and Wilkins, Philadelphia 2004, pp. 112- 117
p.000019:
p.000019: McCarthy C.R., Historical Background of Clinical Trials Involving Women and Minorities, “Academic Medicine”,
p.000019: 1994, 69 (9), pp. 695-698
p.000019:
p.000019: McCullough L., Coverdale J.H., Chervenak F.A., Preventive Ethics for Including Women of Childbearing Potential in
p.000019: Clinical Trials, “Americal Journal of Obstetrics & Gynecology”, 2006, 194, pp. 1221-1227
p.000019:
p.000019: McCullough L., Coverdale J.H., Chervenak F.A, A Comprehensive Ethical Framework for Responsibly Designing
p.000019: and Conducting Pharmacologic Research Involving Pregnant Women, “Americal Journal of Obstetrics & Gynecology”,
p.000019: 2005, 193, pp. 901-907
p.000019:
p.000019: Meinert C.L., Gilpin A.K., Unalp A., Dawson C., Gender Representation in Trials, “Controlled Clinical Trials”, 2000,
p.000019: 21, pp. 462-475
p.000019:
p.000019: Merton V., The Exclusion of Pregnant, Pregnable, and Once-Pregnable People (a.k.a. Women) from Biomedical
p.000019: Research, “Am. J. Law Med.”, 1993, 19, pp. 369-451
p.000019:
p.000019: Miller M.A., Gender-Based Differences in the Toxicity of Pharmaceutical, the Food and Drug
p.000019: Administration’s Perspective, “International Journal of Toxicology”, 2001, 20 (3), pp. 149-152
p.000019:
p.000019: Ministero della salute, Lo stato di salute delle donne in Italia, Primo rapporto sui lavori della Commissione “Salute
p.000019: delle donne”, Roma, marzo 2008 (www.ministerosalute.it): F. Franconi in collaborazione con S. Canu, I. Campasi (a
p.000019: cura di), Approccio di genere nella ricerca, nelle sperimentazioni e nei trattamenti farmacologici, pp. 39-53
p.000019:
p.000019: Mordacci R., Bioetica della sperimentazione. Fondamenti e linee guida, Franco Angeli, Milano 1997, pp. 208-214
p.000019:
p.000019: Osservatorio Nazionale sull’impiego dei medicinali, Istituto Superiore di Sanità, Agenzia Italiana del
p.000019: Farmaco, L’uso dei farmaci in Italia. Rapporto nazionale anno 2006, Il Pensiero Scientifico, Roma 2006
p.000019:
p.000019: Prout M.N., Fish S.S., Participation of Women in Clinical Trials of Drug Therapies: a Context for the
p.000019: Controversies, “Medscape Women’s Health Journal”, 2001, 6 (5)
p.000019:
p.000019: Rosser S.V., Re-visioning Clinical Research: Gender and the Ethics of Experiment Design, “Hypatia”, 1989, 4
p.000019: (2)
p.000019:
p.000019: Schonfeld T.L., Gordon B.G., Contraception in Research: a Policy Suggestion, IRB Ethics & Human Research,
p.000019: 2005, 27 (2), pp. 15-20
p.000019:
p.000019: Schwartz J.B., The Current State of Knowledge on Age, Sex, and the Interactions on Clinical
p.000019: Pharmacology, “Clinical Parmacol. Ter.”, 2007, 82, pp. 87-96
p.000019:
p.000019: Uhl K., Parekh A., Kweder S., Females in Clinical Studies: Where are we Going?, “Clin. Pharmacol.
p.000019: Ther.”, 2007, 81, pp. 600-602
p.000019:
p.000019: United States General Accounting Office, Women’s Health: FDA Needs to Censure More Study of Gender Differences in
p.000019: Prescription Drug Testing, Washington D.C. 1992
p.000019:
p.000019:
p.000019:
p.000019:
p.000020: 20
p.000020:
p.000020: US National Institute of Health, NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in
p.000020: Clinical Research, October, 2001
p.000020:
p.000020: Wizemann T.M., Pardue M.L., Exploring the Biological Contributions to Human Health: Does Sex Matter?,
p.000020: Committee on Understanding the biology of sex and gender differences, National Academy Press, Washington D.C. 2001
p.000020:
p.000020:
p.000020: Table 1
p.000020:
p.000020:
p.000020: Year Clinical Trials
p.000020: 2000 55
p.000020: 2001 45
p.000020: 2002 62
p.000020: 2003 57
p.000020: 2004 51
p.000020: 2005 66
p.000020: 2006 76
p.000020: Total 412
p.000020: Clinical trials on women within all clinical trials – Observatory for clinical trials (data AIFA 01/01/2000 -
p.000020: 31/12/2006)
p.000020: Table 2
p.000020:
p.000020: Year Number of Clinical
p.000020: Trials
p.000020: % Phase II
p.000020: %
p.000020: Phase III
p.000020: %
p.000020: Phase IV
p.000020: % Bioeq
p.000020: / Biod
p.000020: %
p.000020: Tot.
p.000020: 2000 55 45,5 47,3 5,5 1,8
p.000020: 100,0
p.000020: 2001 45 42,2 55,6 2,2 0,0
p.000020: 100,0
p.000020: 2002 62 48,4 50,0 1,6 0,0
p.000020: 100,0
p.000020:
...
p.000021: 279.179 24.1
p.000021: Antithrombotics 103 167.878 27.0
p.000021: Antiarrhythmics 80 45.430 22.6
p.000021: Beta blockers 70 56.517 20.6
p.000021: Antiaggregants 69 91.172 24.0
p.000021:
p.000021: Data on the participation of women to clinical trial in the principal therapeutic classas (80% of trials). The table is
p.000021: part of a more extensive table: not all therapeutic classes have been referred to (the others cover 20% of the trials).
p.000021: In the original version RCT stands for ‘Randomized Controlled Trials’. Data taken by
p.000021: P.Y. Lee, K.P. Alexander, B.G. Hammill et al., Representation of Elderly Persons and Women in Published Randomized
p.000021: Trials of Acute Coronary Syndromes, JAMA, 2001, 286(6), pages 708-713
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000022: 22
p.000022:
p.000022:
p.000022:
p.000022: Table 5
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022: Drug consumption by age and sex (DDD – Defined Daily Dose per day per 1000 inhabitants)- AIFA (National Drug Agency)
p.000022: data regarding 2006.
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000023: 23
p.000023:
p.000023:
p.000023: Table 6
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023: Reported cases of adverse reactions to drugs (Adrs – Adverse Drug ReactionS) by sex and age – AIFA data regarding 2007.
p.000023:
p.000023:
p.000023:
p.000023: Personal remark by Prof. Adriano Bompiani, Bruno Dallapiccola, Maria Luisa Di Pietro, Rodolfo Proietti
p.000023:
p.000023: The “abstension” vote – and not a “contrary vote” – on the document “Pharmacological trials on
p.000023: women”, approved by the National Bioethics Committee on the 28th of November 2008, is dictated by the awareness of the
p.000023: importance of a bioethical reflection on the question of the inclusion of women of childbearing
p.000023: age in pharmacological clinical trials. It is about – in this case – putting together important points
p.000023: for the progress of medical research and the marketing of new drugs, respecting the fundamental rights of the patients,
p.000023: if involved as trial subjects.
p.000023: On the one hand we must, in fact, consider the need to include women in clinical trials in order to properly evaluate –
p.000023: in relation to the particular differences of the female organism – the pharmacokinetics, the pharmacodynamics, the
p.000023: toxicity, the efficacy and the safety of the new pharmacological treatments. This represents an unavoidable medical
p.000023: need, with regards to the therapeutic advantage that results from the evaluation of the therapeutic
p.000023: efficacy and of the side effects. In addition, the possibility to have access to a
p.000023:
p.000023:
p.000024: 24
p.000024:
p.000024: clinical trial can constitute, especially for some situations of particular gravity (for example in the case
p.000024: of phatologies indifferent to standard treatments or of rare diseases) another opportunity of therapy – even if
p.000024: uncertain in outcome -, that can be a priori precluded to women because of their fertile condition. On
p.000024: the other hand, is equally important, for those who promote and conduct a clinical trial, to always
p.000024: consider the potential risk of teratogenicity in case of pregnancy, especially if there is already previous evidence
p.000024: from the studies on animals. From this, comes the absolute need, for potentially fertile subjects (even men carry
p.000024: such risk, when the drug can produce pathological changes of the spermatozoons), to avoid conception during the
p.000024: trial treatment and until the cessation of its effects.
p.000024: We believe that these aspects have been well identified in the document and we agree with the arguments put forward in
p.000024: it.
p.000024: We don’t think, however, that it is ethically acceptable or justifiable from a medical point of view,
p.000024: to force the inclusion of potentially fertile patients in pharmacological clinical trials to use
p.000024: contraceptive methods chosen and imposed by the sponsor and supported by binding clauses from insurance companies, in
p.000024: order to give the necessary economical guarantees to cover possible damages. This request, independently from ethical
p.000024: and religious positions, is not in fact in keeping with the responsible freedom of choice that – within completely
p.000024: personal choices like those regarding married life and the responsibility to procreate – the patient applying to enlist
p.000024: in clinical trials must take on in a personal and independent way, after an exhaustive conversation with the doctor
p.000024: experimentator.
p.000024: In addition, we highlight that contractual imposition from the sponsor of the trials to use contraceptive
p.000024: methods, gives ethical committees, which operate in health institutions regulated by particular
p.000024: rules, some evident difficulties in evaluating and accepting the protocols.
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
...
Searching for indicator influence:
(return to top)
p.000007: “male”, today tend to be more frequent in women.
p.000007: There are many factors, as we know, that have contributed to a change in the conditions of women, at
p.000007: least with regard to western societies. We need to consider: the increase in education (in latest years women exceed
p.000007: men in the number of graduates and
p.000007:
p.000007: 15 That is male/female pathologies.
p.000007: 16 F. Franconi, S. Canu, I. Campasi, Working Group “Approccio di genere alla salute”. Approccio di
p.000007: genere nella ricerca, nelle sperimentazioni e nei trattamenti farmacologici, cited.
p.000007: 17 M. Anthony, M.J. Berg, Biological and Molecular Mechanism for Sex Differences in Pharmacokinetics, Pharmacodynamics,
p.000007: and Pharmacogenetics: part I, “Journal of Women’s Health and Gender-Based Medicine”, 2002, 11 (7), pages
p.000007: 601-615; M. Gandhi, F. Aweeka, R.M. Greenblatt, T. Blaschke, Sex Differences in Pharmacokinetics and
p.000007: Pharmacodynamics, “Ann. Rev. Pharmacol. Toxicol.”, 2004, 44, pages 499-523, A.D.M. Kashuba, A.N. Nafzinger
p.000007: Physiological Changes during the Menstrual Cycle and their Effects on the Pharmacokinetics and Pharmacodynamics
p.000007: of Drugs, “Clinical Pharmacokinetics”, 1998, 34 (3), pages 203-218; P.A. Thuermann, B.C. Hompesch,
p.000007: Influence on Gender on the Pharmacokinetics and Pharmacodynamics of Drugs,“International Journal of Clinical
p.000007: Pharmacology and Therapeutics”, 1998, 36 (11), pages 586-590.
p.000007: 18 Cf. A. Holdcroft, Gender Bias in Research: How does it affect Evidence Based Medicine?, editorial “J. Royal Soc.
p.000007: Med.”, p. 100.
p.000007:
p.000008: 8
p.000008:
p.000008: qualified workers); the change in the participation in the work-market (many traditionally male jobs are open to
p.000008: women), the strong female push towards a career, but the persistent difficulties in the work-market (the participation
p.000008: of women is nevertheless inferior to that of men, with greater unemployment problems or relinquishment of work
p.000008: places due to maternity and lack of working facilitations and social aids); the increase of the public
p.000008: participation on a social, political, economic basis, but the persistent marginalisation (there are still few
p.000008: women in positions of power and responsibility); the behavioural traits generally more frequent in women (e.g.
p.000008: the inclination to take care of others and the selflessness). The change of women’s conditions from
...
p.000009: Shuster, For her Own Good: Protecting (and Neglecting) Women in Research, “Cambridge Quarterly of Healthcare Ethics”,
p.000009: 1996, 5, pages 346-361.
p.000009:
p.000010: 10
p.000010:
p.000010: a) Social reasons. Some sociological studies highlight women’s difficulties in becoming part of clinical
p.000010: studies due to the lack of time (mainly because of their role of carers within the family or, in the case of
p.000010: working women, due to their double obligation at home and at work) or due to their low income (because of the not
p.000010: yet adequate participation of women in the work-market and because of their lower wages). In part the reticence to
p.000010: participate is also due to the recruiters’ lack of attention to the practical and psychological needs of women.
p.000010: b) External environmental reasons. There are also other factors linked with lifestyle or exposure to substances
p.000010: that can interact with the experimental drugs. In external working environments, generally any substances
p.000010: present should be known; in less controlled working environments however, risky conditions can occur. Even
p.000010: lifestyle, which includes dietary habits or the use of natural remedies, exposes the patients to substances that can
p.000010: influence the clinical response to the pharmacological experimentation. Women are generally more inclined to
p.000010: use natural substances or home remedies consolidated in the cultural tradition of the family. Even if in
p.000010: clinical experimentation the treatment in the various experimental branches is the same, it is not always
p.000010: possible to keep under control lifestyle differences and external factors that can affect the experimentation in a
p.000010: different way for men and women.
p.000010: c) Economic reasons. The pharmaceutical industry prefers not to invest in the experimentation on women
p.000010: due to the inevitable rise in costs. The enlistment should necessarily be multiplied: to stratify the data
p.000010: according to gender, men and women should be recruited, doubling or quadrupling the amount of enlistments, increasing
p.000010: time and cost, trails costs and insurance costs to cover eventual negative effects. Even the use of
p.000010: female and male animals in the pre-clinical phase increases the time and the cost of the research. As the
p.000010: authorisation for the introduction of the drug on the market does not require it, the pharmaceutical
p.000010: industry is not motivated to undertake such studies, as they are seen as economically
...
Searching for indicator substance:
(return to top)
p.000013: childbearing age from trials, as they do not believe the possibility of a pregnancy is sufficient reason
p.000013: to preclude or limit their participation and recognising that women have the ability to take a “rational decision” in
p.000013: participating in research (guideline number 16). In the case of risk to the foetus’ health, women have to accept to
p.000013: undertake a pregnancy
p.000013:
p.000013:
p.000013: 33 K.L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice,
p.000013: “Journal of Health Politics, Politics and Law”, 1999, 24 (3), pages 531-566.
p.000013: 34 R.B. Merkatz, Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, “Acad
p.000013: Med”, 1994, 69, pages 703-707; R.B. Merkatz, R. Temple, S. Sobel, Women in Clinical Trials of new Drugs. A Change in
p.000013: Food and Drug Administration Policy, “The New England Journal of Medicine”, 1993, 329 (4), pages 292-296.
p.000013:
p.000014: 14
p.000014:
p.000014: test and to use an “effective contraceptive method”, allowing, with such procedures, their enlistment also in the first
p.000014: phases of the trials with controlled doses of the new substance; we highlight that the informed consent must be
p.000014: guaranteed offering women a fair amount of time and adequate environmental conditions to decide, believing
p.000014: that an individual consent is a must, and that it cannot be substituted by the partner’s consent. In addition, CIOMS
p.000014: recommends that even pregnant women are acceptable (guideline number 17) as trials subjects, provided that the risks
p.000014: (for the woman and for the foetus) are minimised, leaving the decision to the individual woman, even in the
p.000014: case of uncertainty and ambiguity about the definition of risk; the research can be promoted only if it is relevant
p.000014: to the health of the woman who is subjected to the trials and to other women in the same condition; it is believed that
p.000014: women can be recruited into the research only in case there are pre-clinical studies which state the drug’s
p.000014: teratogenity.
p.000014: In 1994 in the United States, a dedicated office called “Office of Women’s Health” was created as part of
...
Health / HIV/AIDS
Searching for indicator HIV:
(return to top)
p.000014: with the aim of identifying the inequalities (the disadvantages of women in comparison to men) and of
p.000014: elaborating active responses to promote equality in the Health System with regards to the policies, the
p.000014: organisation of the services and the access to cures, adequate to the different needs determined by sexual difference.
p.000014: In 1999, in the document Highlights on Women’s Health in Europe, the WHO lists Italy amongst the European countries
p.000014: lacking in the supplying specific data on female health in comparison to data on the population in general. Due to the
p.000014: position of the Committee of Ministers of the Council of Europe, in 1998 the Report Mainstreaming:
p.000014: Conceptual Framework Methodology and Presentation of Good Practice was elaborated by the Comité Directeur pour
p.000014: l'égalitée de gendre (CDEG),
p.000014:
p.000015: 15
p.000015:
p.000015: (European Agency for the Evaluation of Pharmaceutical Products) issued the Note for Guidance on General
p.000015: Considerations for Clinical Trials allowing women of childbearing age to be part of clinical studies only if they were
p.000015: using contraceptives. Again the EMEA in 2003, after the contribution of a working group that included female
p.000015: researchers and representatives of the pharmaceutical industries from the whole of Europe (XX group), published the
p.000015: Note for Guidance on the Clinical Development of HIV-Medical Products recommending the elaboratation of study protocols
p.000015: which would promote the comparison between sexes, with the guarantee of a statistically significant participation of
p.000015: women and adequate medical training. In the document Gender Considerations in the Conduct of Clinical Trials
p.000015: issued by the Committee for Medical Products for Human Use (CHMP) of the European Drugs’ Agency (EMEA) in January
p.000015: 2005, the lack of need for the elaboration of specific European guidelines on pharmacological trials on
p.000015: women is explicitely stated (differently to what occurred in reference to age difference, with regards to
p.000015: underage and elderly patients) considering as sufficient the international guidelines on the issue.
p.000015:
p.000015: 10. National legislation
p.000015:
p.000015: In the Italian legal system there is no explicit reference to the female condition within clinical trials. In the
p.000015: legislative decree of the 24th of June 2003 number 211 Carrying out of the directive 2001/20/CE in relation to
p.000015: the application of good clinical practice in the execution of clinical trials of drugs for clinical use to the article
p.000015: 1 c. 2 “The respect of good practice guarantees the protection of the rights, safety and wellbeing of the subjects and
p.000015: ensures the credibility of the data regarding the same clinical trials”, we refer to the “subject” intended as “person
...
Health / Mentally Disabled
Searching for indicator disability:
(return to top)
p.000003: influences. The changes that women have lived through and are still living through are profound, especially in
p.000003: western civilizations, with consequent changes regarding the relationship between health and illness.
p.000003: Some illnesses traditionally considered typical of the male population are now statistically more
p.000003: widespread in women, but medicine – in some of the specializations in which it is developed – does not seem to take
p.000003: into adequate account such changes in their policies of prevention, diagnosis and cure.
p.000003: Biomedical research – in general and in past decades – tended to reflect predominantly a male
p.000003: perspective, according to some, assimilating women to men (except in some particular specializations): many
p.000003: researchers and doctors in some fields of human pathology have not adequately taken into account sexual
p.000003: differences with regards to the study of the symptoms, the assessment of the diagnosis and the efficacy of the
p.000003: treatments. The lack of consideration of sexual differences is part of a research that tends to the generalisation of
p.000003: any organic phenomenon (although this is necessary), not always paying enough attention to differences due to
p.000003: sex, as well as those due to age (taking into account under-age patients2 and the elderly), disability and
p.000003: ethnicity.
p.000003: However it is fair to indicate that not only a more “mature” clinic, but also a more careful research, have in recent
p.000003: time offered, and continue to offer more and more today, examples of greater balance in the formulation of protocols
p.000003: and the relative “enlistments” of the subjects.
p.000003: Medicine’s “neutral” approach, “in-different” to sex differences, has come to light for a long time in the
p.000003: experimentation of medicines, for reasons that will be subsequently clarified. As a consequence, although on one
p.000003: hand we highlight an increase in the consumption of medicines by women in comparison to men3, on the other hand
p.000003: it appears
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003: 1 This is true in almost all Countries although there are great differences in the life expectancy of men and women.
p.000003: A. Barford, D. Dorling, G Davey Smith, M. Shaw, Life Expectancy: Women Now on Top Everywhere, “British
p.000003: Medical Journal”, 2006, 332, p. 808.
p.000003: 2 On this topic cf Regulation (CE) number 190/2006 of the European Parliament and of the Council of
p.000003: Europe regarding drugs for paediatric use, which ends the marketing of drugs tested almost exclusively on adult
p.000003: subjects.
p.000003: 3 In Italy the greater consumption of drugs by women is per-capita data, therefore normalised. Cf.
p.000003: paragraph 5.
p.000003:
p.000004: 4
p.000004:
...
Health / Motherhood/Family
Searching for indicator family:
(return to top)
p.000009: “British Medical Journal”, 2007, 334, p. 551; S. Saif Rathore, M.P.H. Yongfei Wang, H.M. Krumholtz, Sex-Based
p.000009: Differences in the Effect of Diagoxin for the Treatment of Heart Failure, “NEJM”, 2002, 347, pages. 1403-1411.
p.000009: 25 Cf. Withdrawn Drugs Posed Greater Health Risk for Women then Man, GAO says, “American Journal of Health-System
p.000009: Pharmacy”, March 15, 2001, 58 (6), pages 458-462; United States General Accounting Office, Drug Safety:
p.000009: Most Drugs Withdrawn in Recent Years had Greater Health Risk for Women, Washington D.C. 2001.
p.000009: 26 D. Wrigt, N.J. Chew, Women as Subjects in Clinical Research, “Applied Clinical Trials”, 1996, 5 (9), pages 44-54; E.
p.000009: Shuster, For her Own Good: Protecting (and Neglecting) Women in Research, “Cambridge Quarterly of Healthcare Ethics”,
p.000009: 1996, 5, pages 346-361.
p.000009:
p.000010: 10
p.000010:
p.000010: a) Social reasons. Some sociological studies highlight women’s difficulties in becoming part of clinical
p.000010: studies due to the lack of time (mainly because of their role of carers within the family or, in the case of
p.000010: working women, due to their double obligation at home and at work) or due to their low income (because of the not
p.000010: yet adequate participation of women in the work-market and because of their lower wages). In part the reticence to
p.000010: participate is also due to the recruiters’ lack of attention to the practical and psychological needs of women.
p.000010: b) External environmental reasons. There are also other factors linked with lifestyle or exposure to substances
p.000010: that can interact with the experimental drugs. In external working environments, generally any substances
p.000010: present should be known; in less controlled working environments however, risky conditions can occur. Even
p.000010: lifestyle, which includes dietary habits or the use of natural remedies, exposes the patients to substances that can
p.000010: influence the clinical response to the pharmacological experimentation. Women are generally more inclined to
p.000010: use natural substances or home remedies consolidated in the cultural tradition of the family. Even if in
p.000010: clinical experimentation the treatment in the various experimental branches is the same, it is not always
p.000010: possible to keep under control lifestyle differences and external factors that can affect the experimentation in a
p.000010: different way for men and women.
p.000010: c) Economic reasons. The pharmaceutical industry prefers not to invest in the experimentation on women
p.000010: due to the inevitable rise in costs. The enlistment should necessarily be multiplied: to stratify the data
p.000010: according to gender, men and women should be recruited, doubling or quadrupling the amount of enlistments, increasing
p.000010: time and cost, trails costs and insurance costs to cover eventual negative effects. Even the use of
p.000010: female and male animals in the pre-clinical phase increases the time and the cost of the research. As the
p.000010: authorisation for the introduction of the drug on the market does not require it, the pharmaceutical
p.000010: industry is not motivated to undertake such studies, as they are seen as economically
p.000010: disadvantageous. On the other hand public funding chooses typically female pathologies (like osteoporosis
p.000010: during the menopause), to be able to better tackle the health policies of a country where women live
p.000010: longer, overlooking those pathologies traditionally considered not typical of the female population.
...
Health / Physically Disabled
Searching for indicator illness:
(return to top)
p.000045:
p.000045: N. 4
p.000045:
p.000045:
p.000045:
p.000045:
p.000045: Comitato Nazionale per la Bioetica
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045: La sperimentazione farmacologica
p.000045: sulle donne
p.000045: (26 nove »bt e 2008)
p.000045: VEBStONElTALlAM& E )NG6ESE
p.000045:
p.000045: NATIONAL BIOETHICS COMMITTEE
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045: PI1àIJHàC0L0GIC࣠HIàLS
p.000045:
p.000045: 28ih Noember 2008
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045: DEPARTMENT OF INROMATION AND PUBLISHING
p.000045:
p.000045: TABLE OF CONTENTS
p.000045:
p.000045:
p.000045: l'rosentntion
p.000045: 45
p.000045: 1. Introduction
p.000047: 47
p.000047: 2. Clinieal experimentation 50
p.000047: 3. Clinical experimentation on women: under-representation in the enlistment
p.000047: and shortcomings in the differentiated analysis of the data 51
p.000047: 4. New needs of experimentation differentiated by sex:
p.000047: the changes of health/illness in women 53
p.000047: 5. Women as drug users and the problem
p.000047: of the side-effects 55
p.000047: 6. Female vulnerability in clinical trails: women
p.000047: as “weak subjects” 56
p.000047: 7. The exclusion/inclusion of women of childbearing
p.000047: age in trials protocols 58
p.000047: 8. Female presence in medical teams and in ethical committees 60
p.000047: 9. International bioethical guidelines 60
p.000047: 10. National legislation 64
p.000047: 11. Bioethical recommendations 65
p.000047: Bibliography
p.000069: 69
p.000069: l‘ei•s‹i›snl remark
p.000076: 76
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: ITALIAN NATIONAL BIOETHICS COMMITTEE
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
...
p.000002: Prof. Adriano Bompiani, Prof. Roberto Colombo, Prof. Francesco D’Agostino, Prof. Bruno Dallapiccola, Prof. Maria
p.000002: Luisa Di Pietro, Prof. Emma Fattorini.
p.000002: Prof. Adriano Bompiani, Prof. Bruno Dallapiccola, Prof. Maria Luisa Di Pietro, Prof. Rodolfo Proietti
p.000002: clarified their abstention with additional note, cited at the end of the text. Prof. Luisella Battaglia, Prof.
p.000002: Romano Forleo, Prof. Claudia Mancina, Prof. Vittorio Possenti and Prof. Grazia Zuffa, absent from the meeting,
p.000002: expressed their agreement.
p.000002: Rome, 28th November 2008 The President
p.000002: Prof. Francesco Paolo Casavola
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000002:
p.000003: 3
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003: 1.Introduction
p.000003:
p.000003: Recent studies highlight how women, in today’s society, have a longer life expectancy in
p.000003: comparison to men in the same socio-economic circumstances, but their life seems to have “less health”1.
p.000003: An apparent paradox – women live longer, but with more health problems in comparison to men – it can be
p.000003: explained also on the basis that the conditions of health and illness depend on complex relationships between
p.000003: the biological dimension, the psychic as well as symbolic component and the historical- social-cultural
p.000003: influences. The changes that women have lived through and are still living through are profound, especially in
p.000003: western civilizations, with consequent changes regarding the relationship between health and illness.
p.000003: Some illnesses traditionally considered typical of the male population are now statistically more
p.000003: widespread in women, but medicine – in some of the specializations in which it is developed – does not seem to take
p.000003: into adequate account such changes in their policies of prevention, diagnosis and cure.
p.000003: Biomedical research – in general and in past decades – tended to reflect predominantly a male
p.000003: perspective, according to some, assimilating women to men (except in some particular specializations): many
p.000003: researchers and doctors in some fields of human pathology have not adequately taken into account sexual
p.000003: differences with regards to the study of the symptoms, the assessment of the diagnosis and the efficacy of the
p.000003: treatments. The lack of consideration of sexual differences is part of a research that tends to the generalisation of
p.000003: any organic phenomenon (although this is necessary), not always paying enough attention to differences due to
p.000003: sex, as well as those due to age (taking into account under-age patients2 and the elderly), disability and
p.000003: ethnicity.
p.000003: However it is fair to indicate that not only a more “mature” clinic, but also a more careful research, have in recent
p.000003: time offered, and continue to offer more and more today, examples of greater balance in the formulation of protocols
p.000003: and the relative “enlistments” of the subjects.
...
p.000007: morphological and physiological difference, determines a considerable difference in the pharmacokinetics, that is
p.000007: the different way in which the drug is absorbed, distributed, metabolised and eliminated, and in the
p.000007: pharmacodynamics, that is in the response of the body to a certain concentration of drug in the blood or in the
p.000007: tissue17. Despite the fact that the knowledge of the specificity of the female body has matured,
p.000007: experimentation protocols have not been modified, therefore the enlistment without distinction between men
p.000007: and women persists and so does a consequent undifferentiated analysis of the data. Women are generally included (if
p.000007: they are) in phase III of the enlistment in the trails, but not in phases I and II of the trails (important phases, as
p.000007: already mentioned, to establish dosage, side-effects and safety in the drug’s use). The lack of specific studies on
p.000007: women, especially in the early phases of the research, does not make it possible to measure the real efficacy of the
p.000007: drugs on women, but could even have limited the identification of specifically female drugs (cf. tab. 4)18.
p.000007:
p.000007: 4. New needs of experimentation differentiated by sex: the changes of health/illness in women
p.000007:
p.000007: The fact that there’s a lack of studies which take into account the sex difference within pharmacological
p.000007: experimentation, is even more problematic, given the recent change in the conditions of women’s
p.000007: health/illness within the context of the general change in the female condition. Some of the illnesses considered
p.000007: “male”, today tend to be more frequent in women.
p.000007: There are many factors, as we know, that have contributed to a change in the conditions of women, at
p.000007: least with regard to western societies. We need to consider: the increase in education (in latest years women exceed
p.000007: men in the number of graduates and
p.000007:
p.000007: 15 That is male/female pathologies.
p.000007: 16 F. Franconi, S. Canu, I. Campasi, Working Group “Approccio di genere alla salute”. Approccio di
p.000007: genere nella ricerca, nelle sperimentazioni e nei trattamenti farmacologici, cited.
p.000007: 17 M. Anthony, M.J. Berg, Biological and Molecular Mechanism for Sex Differences in Pharmacokinetics, Pharmacodynamics,
p.000007: and Pharmacogenetics: part I, “Journal of Women’s Health and Gender-Based Medicine”, 2002, 11 (7), pages
p.000007: 601-615; M. Gandhi, F. Aweeka, R.M. Greenblatt, T. Blaschke, Sex Differences in Pharmacokinetics and
p.000007: Pharmacodynamics, “Ann. Rev. Pharmacol. Toxicol.”, 2004, 44, pages 499-523, A.D.M. Kashuba, A.N. Nafzinger
p.000007: Physiological Changes during the Menstrual Cycle and their Effects on the Pharmacokinetics and Pharmacodynamics
p.000007: of Drugs, “Clinical Pharmacokinetics”, 1998, 34 (3), pages 203-218; P.A. Thuermann, B.C. Hompesch,
...
p.000007: Pharmacology and Therapeutics”, 1998, 36 (11), pages 586-590.
p.000007: 18 Cf. A. Holdcroft, Gender Bias in Research: How does it affect Evidence Based Medicine?, editorial “J. Royal Soc.
p.000007: Med.”, p. 100.
p.000007:
p.000008: 8
p.000008:
p.000008: qualified workers); the change in the participation in the work-market (many traditionally male jobs are open to
p.000008: women), the strong female push towards a career, but the persistent difficulties in the work-market (the participation
p.000008: of women is nevertheless inferior to that of men, with greater unemployment problems or relinquishment of work
p.000008: places due to maternity and lack of working facilitations and social aids); the increase of the public
p.000008: participation on a social, political, economic basis, but the persistent marginalisation (there are still few
p.000008: women in positions of power and responsibility); the behavioural traits generally more frequent in women (e.g.
p.000008: the inclination to take care of others and the selflessness). The change of women’s conditions from
p.000008: a historical, cultural and psychological point of view has relevant implications on their conditions of illness
p.000008: and health, on the way women perceive them and live through them. We highlight how, many pathologies traditionally
p.000008: attributed to the male gender because of their physical structure or their behavioural habits on an individual and
p.000008: social basis, are also widespread – and at times more greatly – in the female sex, due to the change in lifestyles and
p.000008: risk factors and/or to a lack of an adequate prevention, diagnosis and cure.
p.000008: The research on women’s health, elaborated by NOWH (National Observatory on Women’s Health) in collaboration with
p.000008: the National Observatory of Health in Italian Regions, part of the Catholic University of the Sacred Heart19,
p.000008: highlights (in the second part: “Health needs and health assistance”) the condition of women’s health and
p.000008: the quality of health assistance. In the pathologies most common in women – where the frequency of the
p.000008: pathologies is linked to age and social condition – we can find some relevant elements: an increase in
p.000008: cardiac pathologies (arterial hypertension, coronary cardiomyopathy, peripheral arteriopathy and cardiac
p.000008: imbalance, thromboembolic pathologies); an increment in the oncological field, as well as “female cancers” (breast
p.000008: cancer, carcinoma of the uterine cervix, endometrial tumours, ovarian neoplasia), also of trachea-bronchi-lungs
p.000008: tumours, due to the spread of nicotine addition even during adolescence; an increase in psychological
p.000008: pathologies (anxiety and depressive syndromes, eating disorders, psychotic syndromes); a tendency to an increase
p.000008: in obesity, due to the lack of physical activity and sedentary life, with an increase in the risk of
p.000008: cardiovascular illnesses and diabetes; an increase in alcohol abuse (with nutritional imbalances and
p.000008: dependency); an increase in neurodegenerative illnesses (Alzheimer’s illness, Parkinson disease, multiple
p.000008: sclerosis, senile dementia); an increase in problems linked to infertility, caused by the postponement of the decision
p.000008: to have children or by the protracted use of contraceptives; problems and pathologies linked with the
p.000008: non- acceptance of aging also emerge20.
p.000008: These changes in the conditions of women’s health and illness emphasise even more the lack of an
p.000008: adequately differentiated trails for the care of women’s health, beyond traditional areas.
p.000008:
p.000008:
p.000008:
p.000008: 19 La salute della donna. Stato di salute a assistenza nelle regioni italiane. Libro bianco, Franco Angeli, Milano
p.000008: 2007.
p.000008: 20 Different the causes: the problems of the substitutive hormonal therapy; the possibility to postpone for decades
p.000008: physical aging, extending the menstrual cycle for years as well as intervening with plastic surgery, with possible
p.000008: dangers for women’s health, and not only because of the bad quality of the treatments – as in the case of deaths
p.000008: due to routing operations, like liposuction – but also because of extended negative effects, injected
p.000008: liquids and stress, due to the effort of not showing their real age.
p.000008:
p.000009: 9
p.000009:
p.000009: 5. Women as drug users and the problem of the side-effects
p.000009:
p.000009: The fact that women are not adequately taken into consideration within clinical trails is penalising, given the
p.000009: increase in the consumption of drugs on their part.
p.000009: As we can see from the data on territorial assistance in relation to the consumption and the
p.000009: gross public expense per capita for reimbursed drugs (class A) of the Italian National Health Service21, women
...
Health / Pregnant
Searching for indicator pregnant:
(return to top)
p.000004: women. This is not the place to tackle the problem of the identity of gender and of other meanings of the expression,
p.000004: on which the NBC intends to return in another document.
p.000004: 8 In the same month and year, the Austrian Committee for Bioethics issued “Recommendations with Gender
p.000004: Reference for Ethics Committees and Clinical Studies (15th November 2009),
p.000004:
p.000005: 5
p.000005:
p.000005: affect both men and women. Adequate participation of women in experimentation, would allow us to understand if in
p.000005: therapies there are significant differences that can be attributed to sex, even to be able to consider
p.000005: the different incidence or relapse of the pathology.
p.000005: The NBC has already looked at the general problem in pharmacological experimentation (The experimentation of drugs,
p.000005: 17th November 1992), but has not specifically analysed this problem in reference to women. The objective of this
p.000005: document is to reflect on the current state of pharmacological experimentation within sexual difference
p.000005: and on emerging bioethical problems, aiming to avoid any form of discrimination and to promote sexual
p.000005: equality in healthcare.
p.000005: In here, the document does not intend to look at the problem of the pharmacological
p.000005: experimentation on pregnant women, reserving the right to discuss the topic in a future document9.
p.000005:
p.000005: 2. Clinical experimentation
p.000005:
p.000005: When we speak of clinical trial, we generally refer to the process of verification of the safety and efficacy of a
p.000005: medicine in relation to therapeutic properties after a phase of laboratory research and pre-clinical experimentation on
p.000005: appropriate subjects. Clinical trial can in reality involve other therapeutic instruments, different from
p.000005: drugs, like medical devices, or diagnostic instruments, including genetic tests. However, as both the regulations and
p.000005: the ethical approach have essentially been developed for drugs, generally we refer to this sector of biomedical
p.000005: research, eventually transferring to the other sectors the models and the procedures that have been developed,
p.000005: especially with regard to the protection of the patients.
p.000005: Clinical experimentation in order to develop new drugs in Italy, as in the rest of Europe, takes place with common
p.000005: methods, through various experimental phases, in accordance with the norms of “Good Clinical Practices”10.
p.000005: This allows homogeneity from a scientific point of view as well as from an ethical point of view, with regards to the
p.000005: respect due to the rights of the patients involved. The regulations make provisions for the verification of the safety
p.000005: and the efficacy of the new drugs before their introduction on the market. This verification applies the methods of
p.000005: evidence based medicine (EBM), which at the moment is considered the most adequate model to guarantee that
p.000005: the introduction of new drugs will benefit the greatest amount of patients. We must remember that this
p.000005: is not the only possible model, but it is the one that is generally considered the most suitable because
p.000005: of the needs of modern medicine and because of its impact on the population’s health.
p.000005: Drugs’ experimentation, before the authorisation to market them, makes provisions, after the pre-clinical phase, for
p.000005: phase I, essentially about safety, and phases II and III, in which
p.000005:
p.000005: 9 With regards to experimentation which is not directly therapeutic in the interest of the pregnant woman or of the
p.000005: breast feeder, aiming to achieve effective protection of the health of the woman, of the embryo and of the foetus, and
p.000005: of the child after birth, the additional conditions anticipated in ch. VI of article 18 of the additional Protocol to
p.000005: the Convention of human rights and biomedicine are applied, relative to biomedical research, approved in Strasbourgh on
p.000005: the 25th of January 2005, which indicate particular precautions.
p.000005: 10 The “Good Clinical Practices” constitute an international standard of ethics and quality of planning,
p.000005: managing and recording clinical studies. In Italy they were first adopted as part of the national legislation with the
p.000005: ministerial decree of the 15th of July 1997.
p.000005:
p.000006: 6
p.000006:
p.000006: the efficacy of the drug on a growing number of patients is established. Subsequently the drug is authorised by the
p.000006: health authorities and becomes part of the clinical practice. Other phase IV studies can take place,
p.000006: always with experimental characteristics and therefore with the enlistment of a certain number of patients, aimed
p.000006: at better establishing the efficacy of a new drug with regards to the safety of use, even for longer periods of time.
...
p.000013: undertake a pregnancy
p.000013:
p.000013:
p.000013: 33 K.L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice,
p.000013: “Journal of Health Politics, Politics and Law”, 1999, 24 (3), pages 531-566.
p.000013: 34 R.B. Merkatz, Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, “Acad
p.000013: Med”, 1994, 69, pages 703-707; R.B. Merkatz, R. Temple, S. Sobel, Women in Clinical Trials of new Drugs. A Change in
p.000013: Food and Drug Administration Policy, “The New England Journal of Medicine”, 1993, 329 (4), pages 292-296.
p.000013:
p.000014: 14
p.000014:
p.000014: test and to use an “effective contraceptive method”, allowing, with such procedures, their enlistment also in the first
p.000014: phases of the trials with controlled doses of the new substance; we highlight that the informed consent must be
p.000014: guaranteed offering women a fair amount of time and adequate environmental conditions to decide, believing
p.000014: that an individual consent is a must, and that it cannot be substituted by the partner’s consent. In addition, CIOMS
p.000014: recommends that even pregnant women are acceptable (guideline number 17) as trials subjects, provided that the risks
p.000014: (for the woman and for the foetus) are minimised, leaving the decision to the individual woman, even in the
p.000014: case of uncertainty and ambiguity about the definition of risk; the research can be promoted only if it is relevant
p.000014: to the health of the woman who is subjected to the trials and to other women in the same condition; it is believed that
p.000014: women can be recruited into the research only in case there are pre-clinical studies which state the drug’s
p.000014: teratogenity.
p.000014: In 1994 in the United States, a dedicated office called “Office of Women’s Health” was created as part of
p.000014: the FDA, with the objective of boosting the inclusion of women in clinical studies, evaluating the different
p.000014: responses for the safety and the efficacy of drugs. In 1995 the previous instructions were strengthened
p.000014: further in the document Investigational New Drug Applications, which explicitly demands an end to any
p.000014: discrimination due to sexual difference, as well as age and race, in trials. In 1998 the FDA promulgates the Final Rule
...
p.002001: Personalized Medicine, “Gender Medicine”, 2007; 4, 187–192; 1550-8579
p.002001:
p.002001:
p.002001: 38 For the bibliographical research we thank Dr. Vanna Pistotti and Dr. Cinzia Colombo of the Mario Negri Institute.
p.002001:
p.000019: 19
p.000019:
p.000019: Mastroianni A.C., Faden R., Federman D. (eds.), Women and Health Research: Ethical and Legal Issues of Including Women
p.000019: in Clinical Studies, vol. I e vol. II, National Academy Press, Washington D.C. 1994
p.000019:
p.000019: Mattison D.R., Sex Matters in Pharmacology: Principles of Pharmacology for Women, in Leppert P.C., Peipert
p.000019: J.F. (eds.), Primary Care for Women, Lippincot Williams and Wilkins, Philadelphia 2004, pp. 112- 117
p.000019:
p.000019: McCarthy C.R., Historical Background of Clinical Trials Involving Women and Minorities, “Academic Medicine”,
p.000019: 1994, 69 (9), pp. 695-698
p.000019:
p.000019: McCullough L., Coverdale J.H., Chervenak F.A., Preventive Ethics for Including Women of Childbearing Potential in
p.000019: Clinical Trials, “Americal Journal of Obstetrics & Gynecology”, 2006, 194, pp. 1221-1227
p.000019:
p.000019: McCullough L., Coverdale J.H., Chervenak F.A, A Comprehensive Ethical Framework for Responsibly Designing
p.000019: and Conducting Pharmacologic Research Involving Pregnant Women, “Americal Journal of Obstetrics & Gynecology”,
p.000019: 2005, 193, pp. 901-907
p.000019:
p.000019: Meinert C.L., Gilpin A.K., Unalp A., Dawson C., Gender Representation in Trials, “Controlled Clinical Trials”, 2000,
p.000019: 21, pp. 462-475
p.000019:
p.000019: Merton V., The Exclusion of Pregnant, Pregnable, and Once-Pregnable People (a.k.a. Women) from Biomedical
p.000019: Research, “Am. J. Law Med.”, 1993, 19, pp. 369-451
p.000019:
p.000019: Miller M.A., Gender-Based Differences in the Toxicity of Pharmaceutical, the Food and Drug
p.000019: Administration’s Perspective, “International Journal of Toxicology”, 2001, 20 (3), pp. 149-152
p.000019:
p.000019: Ministero della salute, Lo stato di salute delle donne in Italia, Primo rapporto sui lavori della Commissione “Salute
p.000019: delle donne”, Roma, marzo 2008 (www.ministerosalute.it): F. Franconi in collaborazione con S. Canu, I. Campasi (a
p.000019: cura di), Approccio di genere nella ricerca, nelle sperimentazioni e nei trattamenti farmacologici, pp. 39-53
p.000019:
p.000019: Mordacci R., Bioetica della sperimentazione. Fondamenti e linee guida, Franco Angeli, Milano 1997, pp. 208-214
p.000019:
p.000019: Osservatorio Nazionale sull’impiego dei medicinali, Istituto Superiore di Sanità, Agenzia Italiana del
p.000019: Farmaco, L’uso dei farmaci in Italia. Rapporto nazionale anno 2006, Il Pensiero Scientifico, Roma 2006
p.000019:
p.000019: Prout M.N., Fish S.S., Participation of Women in Clinical Trials of Drug Therapies: a Context for the
p.000019: Controversies, “Medscape Women’s Health Journal”, 2001, 6 (5)
p.000019:
...
Health / of childbearing age/fertile
Searching for indicator childbearing age:
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p.000010: menopause) and to the possible consumption of contraceptives for contraceptive or therapeutic reasons (estrogens and
p.000010: progestin modify women’s metabolism; the estrogens also affect the way genes work). This kind of variability does not
p.000010: allow the collection of “clean data” in mixed sex trials and lowers the statistical relevance of the
p.000010: experimentation. Even when there are women involved in the trial, it is not certain that the enlisted
p.000010: number can allow us to see significant events.
p.000010:
p.000010:
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: e) Possible pregnancy during childbearing age27. One of the reasons that have led the pharmaceutical
p.000011: industry to exclude women from trials is connected to the possibility that the trial of a new drug
p.000011: could damage the foetus28 in case of pregnancy. There is also the possibility that the studied drug could have
p.000011: negative effects even after the end of the trial, months later. This explains why in general the pharmaceutical
p.000011: industry imposes the use of specific hormonal contraceptives29 as condition for the participation in a research
p.000011: that can be considered “without risk” for the foetus.
p.000011:
p.000011: 7. The exclusion/inclusion of women of childbearing age in trials protocols
p.000011:
p.000011: Regarding the problem of pharmacological experimentation on women of childbearing age, the literature
p.000011: presents a variety of positions: within those, we report the most spread ones.
p.000011: Some affirm that the inclusion of women of childbearing age in the trails is ethically of the outmost
p.000011: importance, when balancing the possible damage to the foetus (considered not yet to have dignity in a strong sense)
p.000011: with the predictable direct benefits to women and in general to society30. From this point of view, the a priori
p.000011: exclusion of women of childbearing age from trails (to protect the possible foetus) results in injustice in the
p.000011: biomedical research, as women do not have the same opportunities as men with regards to the cure of certain
p.000011: illnesses. The particular physio-psychological and social conditions of women should not justify their exclusion,
p.000011: but, on the contrary, motivate a differentiated study in comparison to men. The expectation of the
p.000011: pharmaceutical industry that women should use hormonal contraceptives is also criticised as restrictive of women’s
p.000011: freedom intended as self-determination.
p.000011: Others maintain that where clinical trials, even only hypothetically and probably, poses a danger to the foetus’ life
p.000011: and health (here the foetus is recognised as a subject
p.000011:
p.000011: 27 U. Halbreich, S.W. Carson, Drug Studies in Women of Childbearing Age: Ethical and Methodological Considerations, “J.
p.000011: Clin. Pharmacol.”, 1989, 9, pages 328-333.
p.000011: 28 The risks of teratogenicity for the foetus are classified as follows by the Food and Drug Administration:
p.000011: “controlled study without risk” when the safety of the drug in all stages of pregnancy has been
p.000011: demonstrated; “remote but possible risk” when in the studies on animals an increase in foetal anomalies has not been
p.000011: demonstrated but the risk is possible; “no chance to exclude risk” when the risks have been demonstrated
p.000011: by teratogen effects in the studies on animals and there are few studies on humans; “positive evidence of risk” when
p.000011: the teratogen effect has been demonstrated; “contraindicated during pregnancy” when there is positive
p.000011: evidence, in both studies on animals and humans, of the risk for the foetus. Even the potential benefits for women are
p.000011: variable and oscillate from the therapy for deadly illnesses that cannot be cured in any other way (for instance,
p.000011: cancer cures) to the cure of non-deadly pathologies (take into account the cure of acne).
p.000011: 29 We refer to the use of hormonal contraceptives, as with the use of barrier contraceptives (e.g.
p.000011: preservatives), even if they do not interact with the drugs, there is a percentage of risk of pregnancy. The need for
p.000011: the use of contraceptives is functional to the experimentation to protect the foetus as well as to guarantee the
p.000011: conditions of homogeneity.
p.000011: 30 This is also the theory supported by the feminist circle. Cf. D.A. DeBruin, Justice and the Inclusion of Women in
p.000011: Clinical Studies: an Argument for Further Reform, “Kennedy of Institute of Ethics Journal”, 1994, 3,
p.000011: pages 533-538; Id., No Longer Patient. Feminist Ethics and Health Care, Temple University Press,
p.000011: Philadelphia 1992, pages 158-175; V. Merton, Ethical Obstacles to the Participation of Women in Biomedical Research,
p.000011: in Wolf S.M. (ed.), Feminism and Bioethics. Beyond Reproduction, Oxford University Press, Oxford-New York
p.000011: 1996.
p.000011:
p.000012: 12
p.000012:
p.000012: having dignity in the strong sense), it is ethically advisable to women of childbearing age to avoid participating in
p.000012: clinical studies, as the risk to the new life overrides the potential benefits to women. However, it is accepted that
p.000012: women could decide to be part of the trials for social reasons or for personal health needs. In such cases,
p.000012: however, the imposition by the pharmaceutical industry to use hormonal contraceptives is not
p.000012: considered morally acceptable as, even for those who support this point of view this imposition is seen
p.000012: as detrimental to the freedom and the responsibility of those who choose to be subjected to the trials.
p.000012: It is felt that the woman’s explicit commitment to avoid pregnancy is sufficient, and that it is up
p.000012: to her to choose the methods of birth control which coincide with her lifestyle and values, including
p.000012: abstaining from sexual intercourse31.
p.000012:
p.000012: 8. Female presence in medical teams and in ethical committees
p.000012:
p.000012: An important aspect of protecting women during the trials is the participation of women not only as “object” of the
p.000012: trials (that is as individuals enlisted in the trials), but also as trials’ “subject”, in the sense of active subjects,
p.000012: present in the medical teams that plan and define the trials’ development and present in the ethical
p.000012: committees that evaluate the trials protocols. The presence of women could contribute to a greater focus on the
p.000012: relevance of women’s participation to the trials and could allow greater sensitivity with regards to female needs, from
p.000012: a psychological and social point of view.
p.000012: There is no data regarding the presence of women in medical teams, however, it is possible to verify the presence of
p.000012: women in ethical Committees through an analysis of the committees’ composition, as reported by the data of the
p.000012: Observatory on trials. Generally women’s presence, although often linked to the nursing sector and to
p.000012: the representative of patients, is consistent, even if almost always inferior to that of men, and is strongly dependent
p.000012: on local circumstances.
p.000012:
p.000012: 9. International bioethical guidelines
p.000012:
p.000012: In the ‘70s explicit instructions emerged, that made rules for the exclusion of women from clinical studies
p.000012: with the aim of protecting the health of the future child, as dramatic cases of foetal death and severe damage
p.000012: to the infants had occurred, due to indiscriminate trials32. In 1977 the Food and Drug Administration (FDA) in
p.000012: the General Considerations for the Clinical Evaluation of Drugs recommended the exclusion from
p.000012: experimentation of women of childbearing age, especially in phases I and II, as the data on teratogenicity was not
p.000012: known, with the exception of women with deadly pathologies;
p.000012:
p.000012: 31 This is the position that refers to the inseparability of the uniting and the procreating dimension of the marital
p.000012: act. Cf. R. Minacori, D. Sacchini, A.G. Spagnolo, Women of Childbearing Potential as Research Subjects in Clinical
p.000012: Trials: Ethical Issues, in A.G. Spagnolo, G. Gambino (edited by), Women’s Health Issues, Societa’ Editrice
p.000012: Universo, Roma 2003, pages 123-129; A.G. Spagnolo, M. Cicerone, Sperimantazione farmacologica e donne
p.000012: in eta’ fertile, “Medicina e Morale”, from international literature, 2005, 3, pages 667-670; Catholic University
p.000012: of the Sacred Heart, ethical Committee, Raccomandazioni riguardo alla inclusione di donne in eta’ fertile
p.000012: nei protocolli di sperimentazione clinica, “Medicina e Morale”, 1996, 46, pages 141-143. Cf. for a historical
p.000012: reconstruction M. Pelaja, L. Scaraffia, Due in una carne. Chiesa e sessualita’ nella storia, Laterza, Bari 2008, page
p.000012: 261 and following.
p.000012: 32 S. Cagliano, Dieci farmaci che sconvolsero il mondo, Laterza, Rome-Bari 1994, pages 43-68.
p.000012:
p.000013: 13
p.000013:
...
p.000014: further in the document Investigational New Drug Applications, which explicitly demands an end to any
p.000014: discrimination due to sexual difference, as well as age and race, in trials. In 1998 the FDA promulgates the Final Rule
p.000014: on the Investigational Drug Applications with the aim of actively intervening with sponsors who do not respect
p.000014: the instructions of fairness within sexual difference. In 1999 the working group “FDA-MA Women and Minorities
p.000014: Working Group” was created, with the aim of drawing up specific guidelines to boost the correct inclusion of women and
p.000014: of weak subjects in clinical trials. In 2001 the National Institute of Health in the USA issued the document
p.000014: Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research to promote a policy
p.000014: of women’s inclusion in the enlistment for pharmacological trials. It is important to highlight that the
p.000014: Department of Health and Human Services in issuing the Regulations for the Protection of Human Subjects in 2001,
p.000014: does not take explicitely into account tendencies and directives for the researchers, the doctors and IRBs on the
p.000014: specific theme of trials on women of childbearing age.
p.000014: Within the European biolegislation we highlight the focus on female specificity within the general area of
p.000014: health35, but lacking specific provisions of policies of non- exclusion or inclusion of women in clinical
p.000014: studies (simply highlighting the lack of data in such field)36. There are however some initiatives of awareness. In
p.000014: 1998, the EMEA
p.000014:
p.000014: 35 M.T. Ruiz Cantero, M.A. Pardo, European Medicines Agency Policies for Clinical Trials Leave Women Unprotected,
p.000014: “Journal Epidemiol. Community Health”, 2006, 60, pages 911-913.
p.000014: 36 The World Health Organization, Regional Office for Europe, specifically focused on the issue of the
p.000014: difference between sexes within Health System in general, without explicit reference to the issue of trial. Starting
p.000014: with highlighting the differences in social roles and in male and female behaviours, the WHO states that
p.000014: the health risk factors are inevitably different. For this reason it promoted the program “Gender and Health Program”
p.000014: with the aim of identifying the inequalities (the disadvantages of women in comparison to men) and of
p.000014: elaborating active responses to promote equality in the Health System with regards to the policies, the
p.000014: organisation of the services and the access to cures, adequate to the different needs determined by sexual difference.
p.000014: In 1999, in the document Highlights on Women’s Health in Europe, the WHO lists Italy amongst the European countries
p.000014: lacking in the supplying specific data on female health in comparison to data on the population in general. Due to the
p.000014: position of the Committee of Ministers of the Council of Europe, in 1998 the Report Mainstreaming:
p.000014: Conceptual Framework Methodology and Presentation of Good Practice was elaborated by the Comité Directeur pour
p.000014: l'égalitée de gendre (CDEG),
p.000014:
p.000015: 15
p.000015:
p.000015: (European Agency for the Evaluation of Pharmaceutical Products) issued the Note for Guidance on General
p.000015: Considerations for Clinical Trials allowing women of childbearing age to be part of clinical studies only if they were
p.000015: using contraceptives. Again the EMEA in 2003, after the contribution of a working group that included female
p.000015: researchers and representatives of the pharmaceutical industries from the whole of Europe (XX group), published the
p.000015: Note for Guidance on the Clinical Development of HIV-Medical Products recommending the elaboratation of study protocols
p.000015: which would promote the comparison between sexes, with the guarantee of a statistically significant participation of
p.000015: women and adequate medical training. In the document Gender Considerations in the Conduct of Clinical Trials
p.000015: issued by the Committee for Medical Products for Human Use (CHMP) of the European Drugs’ Agency (EMEA) in January
p.000015: 2005, the lack of need for the elaboration of specific European guidelines on pharmacological trials on
p.000015: women is explicitely stated (differently to what occurred in reference to age difference, with regards to
p.000015: underage and elderly patients) considering as sufficient the international guidelines on the issue.
p.000015:
p.000015: 10. National legislation
p.000015:
p.000015: In the Italian legal system there is no explicit reference to the female condition within clinical trials. In the
p.000015: legislative decree of the 24th of June 2003 number 211 Carrying out of the directive 2001/20/CE in relation to
...
p.000017: associations) to the elaboration of the procedures for the protocols and for the relevant informed consent;
p.000017: to promote greater attention from ethical committees to sexual difference in research protocols;
p.000017: d) boost health training which focuses on the female dimension within pharmacological
p.000017: trials, as well as within research and cure; e) increase international cooperation, as well as national and
p.000017: local, with the focus on the female condition within clinical trials, involving health authorities and the
p.000017: pharmaceutical industry.
p.000017: 6. The NBC believes that even the participation of women of childbearing age in pharmacological trials is
p.000017: ethically and socially important, provided that an adequate protection of the future child can be guaranteed. The NBC
p.000017: highlights the importance of a preliminary consultation about the intended trials, including adequate
p.000017: information, clear and in full, according to an objective, technical-scientific classification of the
p.000017: risks and benefits that the study involves for the patient, but that also taking into account the risks for the foetus
p.000017: in case of pregnancy37. We must also take into account that the exclusion of women of childbearing age from trials does
p.000017: not allow, in practice, to protect the foetus, as women could take the experimented drug (but not tested on them) on
p.000017: the market with similar risks in case of pregnancy and, to make it worse, without adequate protection. The NBC believes
p.000017: that the inclusion of women of childbearing age in pharmacological trials that poses risks to the foetus
p.000017: needs, unavoidably, the woman’s clear statement of a conscious and responsible commitment to avoid
p.000017: intercourse that could lead to pregnancy. If it is not possible to exclude a risk to the foetus’ life and
p.000017: health within the trials, but there are possible benefits to women in general and in particular in the
p.000017: cure of illnesses, the NBC believes that requesting the commitment to take contraceptives as a safety measure
p.000017: believed necessary by the study’s sponsor – to avoid pregnancy, as the trials could be damaging to the foetus – can be
p.000017: included in the criteria to participate in the study.
p.000017: In addition, the NBC believes that it is important that the woman’s husband or partner is also involved in the
...
Searching for indicator fertile:
(return to top)
p.000012: on local circumstances.
p.000012:
p.000012: 9. International bioethical guidelines
p.000012:
p.000012: In the ‘70s explicit instructions emerged, that made rules for the exclusion of women from clinical studies
p.000012: with the aim of protecting the health of the future child, as dramatic cases of foetal death and severe damage
p.000012: to the infants had occurred, due to indiscriminate trials32. In 1977 the Food and Drug Administration (FDA) in
p.000012: the General Considerations for the Clinical Evaluation of Drugs recommended the exclusion from
p.000012: experimentation of women of childbearing age, especially in phases I and II, as the data on teratogenicity was not
p.000012: known, with the exception of women with deadly pathologies;
p.000012:
p.000012: 31 This is the position that refers to the inseparability of the uniting and the procreating dimension of the marital
p.000012: act. Cf. R. Minacori, D. Sacchini, A.G. Spagnolo, Women of Childbearing Potential as Research Subjects in Clinical
p.000012: Trials: Ethical Issues, in A.G. Spagnolo, G. Gambino (edited by), Women’s Health Issues, Societa’ Editrice
p.000012: Universo, Roma 2003, pages 123-129; A.G. Spagnolo, M. Cicerone, Sperimantazione farmacologica e donne
p.000012: in eta’ fertile, “Medicina e Morale”, from international literature, 2005, 3, pages 667-670; Catholic University
p.000012: of the Sacred Heart, ethical Committee, Raccomandazioni riguardo alla inclusione di donne in eta’ fertile
p.000012: nei protocolli di sperimentazione clinica, “Medicina e Morale”, 1996, 46, pages 141-143. Cf. for a historical
p.000012: reconstruction M. Pelaja, L. Scaraffia, Due in una carne. Chiesa e sessualita’ nella storia, Laterza, Bari 2008, page
p.000012: 261 and following.
p.000012: 32 S. Cagliano, Dieci farmaci che sconvolsero il mondo, Laterza, Rome-Bari 1994, pages 43-68.
p.000012:
p.000013: 13
p.000013:
p.000013: women of childbearing age could participate to the studies in phases II and III only if sufficient
p.000013: information on the drug’s safety and efficacy, even in the studies on animals, had been collected, which excluded
p.000013: interferences with the reproductive functions. In 1982 the World Health Organisation promulgated the Proposed
p.000013: International Guidelines which affirmed the duty to exclude women from non-therapeutic experimentations on
p.000013: healthy volunteers33.
p.000013: In 1988 we register a radical change in the direction of the FDA that, with the publication of the document Guideline
p.000013: for the Format and Content of the Clinical and Statistical Sections of the New Drug Application, highlights the
p.000013: under-representation of women in pharmacological trial and recommends the analysis of sex-differentiated data in
p.000013: clinical trials34. In 1993 the FDA again issued the Guidelines for the Study and Evaluation of gender
...
p.000023: importance of a bioethical reflection on the question of the inclusion of women of childbearing
p.000023: age in pharmacological clinical trials. It is about – in this case – putting together important points
p.000023: for the progress of medical research and the marketing of new drugs, respecting the fundamental rights of the patients,
p.000023: if involved as trial subjects.
p.000023: On the one hand we must, in fact, consider the need to include women in clinical trials in order to properly evaluate –
p.000023: in relation to the particular differences of the female organism – the pharmacokinetics, the pharmacodynamics, the
p.000023: toxicity, the efficacy and the safety of the new pharmacological treatments. This represents an unavoidable medical
p.000023: need, with regards to the therapeutic advantage that results from the evaluation of the therapeutic
p.000023: efficacy and of the side effects. In addition, the possibility to have access to a
p.000023:
p.000023:
p.000024: 24
p.000024:
p.000024: clinical trial can constitute, especially for some situations of particular gravity (for example in the case
p.000024: of phatologies indifferent to standard treatments or of rare diseases) another opportunity of therapy – even if
p.000024: uncertain in outcome -, that can be a priori precluded to women because of their fertile condition. On
p.000024: the other hand, is equally important, for those who promote and conduct a clinical trial, to always
p.000024: consider the potential risk of teratogenicity in case of pregnancy, especially if there is already previous evidence
p.000024: from the studies on animals. From this, comes the absolute need, for potentially fertile subjects (even men carry
p.000024: such risk, when the drug can produce pathological changes of the spermatozoons), to avoid conception during the
p.000024: trial treatment and until the cessation of its effects.
p.000024: We believe that these aspects have been well identified in the document and we agree with the arguments put forward in
p.000024: it.
p.000024: We don’t think, however, that it is ethically acceptable or justifiable from a medical point of view,
p.000024: to force the inclusion of potentially fertile patients in pharmacological clinical trials to use
p.000024: contraceptive methods chosen and imposed by the sponsor and supported by binding clauses from insurance companies, in
p.000024: order to give the necessary economical guarantees to cover possible damages. This request, independently from ethical
p.000024: and religious positions, is not in fact in keeping with the responsible freedom of choice that – within completely
p.000024: personal choices like those regarding married life and the responsibility to procreate – the patient applying to enlist
p.000024: in clinical trials must take on in a personal and independent way, after an exhaustive conversation with the doctor
p.000024: experimentator.
p.000024: In addition, we highlight that contractual imposition from the sponsor of the trials to use contraceptive
p.000024: methods, gives ethical committees, which operate in health institutions regulated by particular
p.000024: rules, some evident difficulties in evaluating and accepting the protocols.
p.000024:
p.000024:
p.000024:
p.000024:
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p.000024:
p.000025: 25
p.000025:
p.000025: Redazi.one Comitato Nazionale per la
p.000025: Bioetica
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
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p.000025:
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p.000025:
p.000025:
p.000025:
...
Social / Access to Social Goods
Searching for indicator access:
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p.000014: specific theme of trials on women of childbearing age.
p.000014: Within the European biolegislation we highlight the focus on female specificity within the general area of
p.000014: health35, but lacking specific provisions of policies of non- exclusion or inclusion of women in clinical
p.000014: studies (simply highlighting the lack of data in such field)36. There are however some initiatives of awareness. In
p.000014: 1998, the EMEA
p.000014:
p.000014: 35 M.T. Ruiz Cantero, M.A. Pardo, European Medicines Agency Policies for Clinical Trials Leave Women Unprotected,
p.000014: “Journal Epidemiol. Community Health”, 2006, 60, pages 911-913.
p.000014: 36 The World Health Organization, Regional Office for Europe, specifically focused on the issue of the
p.000014: difference between sexes within Health System in general, without explicit reference to the issue of trial. Starting
p.000014: with highlighting the differences in social roles and in male and female behaviours, the WHO states that
p.000014: the health risk factors are inevitably different. For this reason it promoted the program “Gender and Health Program”
p.000014: with the aim of identifying the inequalities (the disadvantages of women in comparison to men) and of
p.000014: elaborating active responses to promote equality in the Health System with regards to the policies, the
p.000014: organisation of the services and the access to cures, adequate to the different needs determined by sexual difference.
p.000014: In 1999, in the document Highlights on Women’s Health in Europe, the WHO lists Italy amongst the European countries
p.000014: lacking in the supplying specific data on female health in comparison to data on the population in general. Due to the
p.000014: position of the Committee of Ministers of the Council of Europe, in 1998 the Report Mainstreaming:
p.000014: Conceptual Framework Methodology and Presentation of Good Practice was elaborated by the Comité Directeur pour
p.000014: l'égalitée de gendre (CDEG),
p.000014:
p.000015: 15
p.000015:
p.000015: (European Agency for the Evaluation of Pharmaceutical Products) issued the Note for Guidance on General
p.000015: Considerations for Clinical Trials allowing women of childbearing age to be part of clinical studies only if they were
p.000015: using contraceptives. Again the EMEA in 2003, after the contribution of a working group that included female
p.000015: researchers and representatives of the pharmaceutical industries from the whole of Europe (XX group), published the
p.000015: Note for Guidance on the Clinical Development of HIV-Medical Products recommending the elaboratation of study protocols
p.000015: which would promote the comparison between sexes, with the guarantee of a statistically significant participation of
p.000015: women and adequate medical training. In the document Gender Considerations in the Conduct of Clinical Trials
...
p.000015: i.), without distinction between men and women. We speak of protection of the trials’ subjects, with particular
p.000015: reference to adults unable to give their informed consent and to minors, but no explicit reference to women.
p.000015: The new regulation on Minimum requiremenst for the creation, the organisation and the functioning of ethical Committees
p.000015: for the trials of drugs (ministerial decree of the 12th of May 2006) does not specify that there must be a balanced
p.000015: representation of both sexes.
p.000015:
p.000015:
p.000015:
p.000015: intergovernamental body responsible for the definition and the implementation of the actions of the Council of Europe
p.000015: that aim to promote equality between men and women. The Report was supposed to provide the conceptual basis, where
p.000015: the need to take into consideration sexual differences in the context of their differing social roles was
p.000015: highlighted, for any future action that would be recommended to all the States members of the Council of Europe. The
p.000015: European Health Committee (CDSP-European Council), starting with a careful evaluation of the current situation with
p.000015: regards to the theme “women and health" and with an insufficient analysis in the European countries, highlights the
p.000015: lack of detailed information about the access to cures by men and women, the necessity to pre-empt discriminations in
p.000015: order to also improve the efficacy of health policies from an economic point of view. In particular the Committee
p.000015: highlights the lack of sex- disaggregated data and of indicators to define the effects of the difference
p.000015: between men and women in health research; the need to implement health policies in the consideration of
p.000015: sexual differences. In conclusion the document refers to existing distorsions in biomedical research, with
p.000015: specific reference to pharmacological tests conducted exclusively on male subjects.
p.000015:
p.000016: 16
p.000016:
p.000016:
p.000016: 11. Bioethical recommendations
p.000016:
p.000016: 1. The NBC intends to highlight some elements of bioethical relevance for the promotion of
p.000016: women’s health in those sectors of clinical experimentation that appear to suffer most from a kind of
p.000016: “neutralistic” ideology of medicine. In particular the NBC intends to underline the fundamental ethical
p.000016: principle of the fairness of a pharmacological trial on both men and women, in real conditions of equality,
p.000016: without exclusions or undue marginalisations, deeming necessary the identification and the removal of the
p.000016: causes of this unfairness. Just as a pharmacological trial that takes into account the conditions of fragility due to
p.000016: the patient’s age (for example periatric and geriatric trials) must be deemed fair and right, in the same
...
p.000023:
p.000023:
p.000023:
p.000023: Personal remark by Prof. Adriano Bompiani, Bruno Dallapiccola, Maria Luisa Di Pietro, Rodolfo Proietti
p.000023:
p.000023: The “abstension” vote – and not a “contrary vote” – on the document “Pharmacological trials on
p.000023: women”, approved by the National Bioethics Committee on the 28th of November 2008, is dictated by the awareness of the
p.000023: importance of a bioethical reflection on the question of the inclusion of women of childbearing
p.000023: age in pharmacological clinical trials. It is about – in this case – putting together important points
p.000023: for the progress of medical research and the marketing of new drugs, respecting the fundamental rights of the patients,
p.000023: if involved as trial subjects.
p.000023: On the one hand we must, in fact, consider the need to include women in clinical trials in order to properly evaluate –
p.000023: in relation to the particular differences of the female organism – the pharmacokinetics, the pharmacodynamics, the
p.000023: toxicity, the efficacy and the safety of the new pharmacological treatments. This represents an unavoidable medical
p.000023: need, with regards to the therapeutic advantage that results from the evaluation of the therapeutic
p.000023: efficacy and of the side effects. In addition, the possibility to have access to a
p.000023:
p.000023:
p.000024: 24
p.000024:
p.000024: clinical trial can constitute, especially for some situations of particular gravity (for example in the case
p.000024: of phatologies indifferent to standard treatments or of rare diseases) another opportunity of therapy – even if
p.000024: uncertain in outcome -, that can be a priori precluded to women because of their fertile condition. On
p.000024: the other hand, is equally important, for those who promote and conduct a clinical trial, to always
p.000024: consider the potential risk of teratogenicity in case of pregnancy, especially if there is already previous evidence
p.000024: from the studies on animals. From this, comes the absolute need, for potentially fertile subjects (even men carry
p.000024: such risk, when the drug can produce pathological changes of the spermatozoons), to avoid conception during the
p.000024: trial treatment and until the cessation of its effects.
p.000024: We believe that these aspects have been well identified in the document and we agree with the arguments put forward in
p.000024: it.
p.000024: We don’t think, however, that it is ethically acceptable or justifiable from a medical point of view,
p.000024: to force the inclusion of potentially fertile patients in pharmacological clinical trials to use
p.000024: contraceptive methods chosen and imposed by the sponsor and supported by binding clauses from insurance companies, in
...
Social / Age
Searching for indicator age:
(return to top)
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045: PI1àIJHàC0L0GIC࣠HIàLS
p.000045:
p.000045: 28ih Noember 2008
p.000045:
p.000045:
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p.000045:
p.000045:
p.000045: DEPARTMENT OF INROMATION AND PUBLISHING
p.000045:
p.000045: TABLE OF CONTENTS
p.000045:
p.000045:
p.000045: l'rosentntion
p.000045: 45
p.000045: 1. Introduction
p.000047: 47
p.000047: 2. Clinieal experimentation 50
p.000047: 3. Clinical experimentation on women: under-representation in the enlistment
p.000047: and shortcomings in the differentiated analysis of the data 51
p.000047: 4. New needs of experimentation differentiated by sex:
p.000047: the changes of health/illness in women 53
p.000047: 5. Women as drug users and the problem
p.000047: of the side-effects 55
p.000047: 6. Female vulnerability in clinical trails: women
p.000047: as “weak subjects” 56
p.000047: 7. The exclusion/inclusion of women of childbearing
p.000047: age in trials protocols 58
p.000047: 8. Female presence in medical teams and in ethical committees 60
p.000047: 9. International bioethical guidelines 60
p.000047: 10. National legislation 64
p.000047: 11. Bioethical recommendations 65
p.000047: Bibliography
p.000069: 69
p.000069: l‘ei•s‹i›snl remark
p.000076: 76
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p.000076:
p.000076:
p.000076: ITALIAN NATIONAL BIOETHICS COMMITTEE
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: PHARMACOLOGICAL TRIALS ON WOMEN
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: 28th November 2008
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
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p.000001: 1
p.000001:
p.000001:
p.000001: PRESENTATION
p.000001:
p.000001:
p.000001: The National Bioethics Committee (NBC) in the plenary meeting of the 28th of November 2008 approved the Opinion
p.000001: “Pharmacological Experimentation on Women”.
p.000001: This document, starting with the analysis of the data on clinical experimentation on women, highlights their
...
p.000003: the biological dimension, the psychic as well as symbolic component and the historical- social-cultural
p.000003: influences. The changes that women have lived through and are still living through are profound, especially in
p.000003: western civilizations, with consequent changes regarding the relationship between health and illness.
p.000003: Some illnesses traditionally considered typical of the male population are now statistically more
p.000003: widespread in women, but medicine – in some of the specializations in which it is developed – does not seem to take
p.000003: into adequate account such changes in their policies of prevention, diagnosis and cure.
p.000003: Biomedical research – in general and in past decades – tended to reflect predominantly a male
p.000003: perspective, according to some, assimilating women to men (except in some particular specializations): many
p.000003: researchers and doctors in some fields of human pathology have not adequately taken into account sexual
p.000003: differences with regards to the study of the symptoms, the assessment of the diagnosis and the efficacy of the
p.000003: treatments. The lack of consideration of sexual differences is part of a research that tends to the generalisation of
p.000003: any organic phenomenon (although this is necessary), not always paying enough attention to differences due to
p.000003: sex, as well as those due to age (taking into account under-age patients2 and the elderly), disability and
p.000003: ethnicity.
p.000003: However it is fair to indicate that not only a more “mature” clinic, but also a more careful research, have in recent
p.000003: time offered, and continue to offer more and more today, examples of greater balance in the formulation of protocols
p.000003: and the relative “enlistments” of the subjects.
p.000003: Medicine’s “neutral” approach, “in-different” to sex differences, has come to light for a long time in the
p.000003: experimentation of medicines, for reasons that will be subsequently clarified. As a consequence, although on one
p.000003: hand we highlight an increase in the consumption of medicines by women in comparison to men3, on the other hand
p.000003: it appears
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003: 1 This is true in almost all Countries although there are great differences in the life expectancy of men and women.
p.000003: A. Barford, D. Dorling, G Davey Smith, M. Shaw, Life Expectancy: Women Now on Top Everywhere, “British
p.000003: Medical Journal”, 2006, 332, p. 808.
p.000003: 2 On this topic cf Regulation (CE) number 190/2006 of the European Parliament and of the Council of
p.000003: Europe regarding drugs for paediatric use, which ends the marketing of drugs tested almost exclusively on adult
p.000003: subjects.
p.000003: 3 In Italy the greater consumption of drugs by women is per-capita data, therefore normalised. Cf.
p.000003: paragraph 5.
...
p.000008: the inclination to take care of others and the selflessness). The change of women’s conditions from
p.000008: a historical, cultural and psychological point of view has relevant implications on their conditions of illness
p.000008: and health, on the way women perceive them and live through them. We highlight how, many pathologies traditionally
p.000008: attributed to the male gender because of their physical structure or their behavioural habits on an individual and
p.000008: social basis, are also widespread – and at times more greatly – in the female sex, due to the change in lifestyles and
p.000008: risk factors and/or to a lack of an adequate prevention, diagnosis and cure.
p.000008: The research on women’s health, elaborated by NOWH (National Observatory on Women’s Health) in collaboration with
p.000008: the National Observatory of Health in Italian Regions, part of the Catholic University of the Sacred Heart19,
p.000008: highlights (in the second part: “Health needs and health assistance”) the condition of women’s health and
p.000008: the quality of health assistance. In the pathologies most common in women – where the frequency of the
p.000008: pathologies is linked to age and social condition – we can find some relevant elements: an increase in
p.000008: cardiac pathologies (arterial hypertension, coronary cardiomyopathy, peripheral arteriopathy and cardiac
p.000008: imbalance, thromboembolic pathologies); an increment in the oncological field, as well as “female cancers” (breast
p.000008: cancer, carcinoma of the uterine cervix, endometrial tumours, ovarian neoplasia), also of trachea-bronchi-lungs
p.000008: tumours, due to the spread of nicotine addition even during adolescence; an increase in psychological
p.000008: pathologies (anxiety and depressive syndromes, eating disorders, psychotic syndromes); a tendency to an increase
p.000008: in obesity, due to the lack of physical activity and sedentary life, with an increase in the risk of
p.000008: cardiovascular illnesses and diabetes; an increase in alcohol abuse (with nutritional imbalances and
p.000008: dependency); an increase in neurodegenerative illnesses (Alzheimer’s illness, Parkinson disease, multiple
p.000008: sclerosis, senile dementia); an increase in problems linked to infertility, caused by the postponement of the decision
p.000008: to have children or by the protracted use of contraceptives; problems and pathologies linked with the
p.000008: non- acceptance of aging also emerge20.
p.000008: These changes in the conditions of women’s health and illness emphasise even more the lack of an
p.000008: adequately differentiated trails for the care of women’s health, beyond traditional areas.
p.000008:
p.000008:
p.000008:
p.000008: 19 La salute della donna. Stato di salute a assistenza nelle regioni italiane. Libro bianco, Franco Angeli, Milano
p.000008: 2007.
p.000008: 20 Different the causes: the problems of the substitutive hormonal therapy; the possibility to postpone for decades
p.000008: physical aging, extending the menstrual cycle for years as well as intervening with plastic surgery, with possible
p.000008: dangers for women’s health, and not only because of the bad quality of the treatments – as in the case of deaths
p.000008: due to routing operations, like liposuction – but also because of extended negative effects, injected
p.000008: liquids and stress, due to the effort of not showing their real age.
p.000008:
p.000009: 9
p.000009:
p.000009: 5. Women as drug users and the problem of the side-effects
p.000009:
p.000009: The fact that women are not adequately taken into consideration within clinical trails is penalising, given the
p.000009: increase in the consumption of drugs on their part.
p.000009: As we can see from the data on territorial assistance in relation to the consumption and the
p.000009: gross public expense per capita for reimbursed drugs (class A) of the Italian National Health Service21, women
p.000009: appear to be the greatest consumers of drugs, in particular within the ages of 15 and 54 (cf. tab. 5). The
p.000009: reasons of the difference in the consumption of drugs, with regard to gender, would require
p.000009: complex pharmacoepidemiological analysis: some hypothesis have been formulated, according to which women take better
p.000009: care of themselves in comparison to men, they have better awareness of their pathological condition,
p.000009: but also undergo a greater number of treatments due to their reproductive state and to the fact that they
p.000009: are more easily affected by chronic but non-lethal pathologies22.
p.000009: But if women, in greater quantities, use drugs that have not been adequately tested on them, the result is inevitably a
p.000009: higher frequency and seriousness of adverse reactions, often due to overdosing or polytherapies23. In
...
p.000010: c) Economic reasons. The pharmaceutical industry prefers not to invest in the experimentation on women
p.000010: due to the inevitable rise in costs. The enlistment should necessarily be multiplied: to stratify the data
p.000010: according to gender, men and women should be recruited, doubling or quadrupling the amount of enlistments, increasing
p.000010: time and cost, trails costs and insurance costs to cover eventual negative effects. Even the use of
p.000010: female and male animals in the pre-clinical phase increases the time and the cost of the research. As the
p.000010: authorisation for the introduction of the drug on the market does not require it, the pharmaceutical
p.000010: industry is not motivated to undertake such studies, as they are seen as economically
p.000010: disadvantageous. On the other hand public funding chooses typically female pathologies (like osteoporosis
p.000010: during the menopause), to be able to better tackle the health policies of a country where women live
p.000010: longer, overlooking those pathologies traditionally considered not typical of the female population.
p.000010: d) Biological reasons. Women have always been considered “difficult” subjects for trials, due to their biological and
p.000010: physiological differences, but especially for their enzymatic and hormonal differences, due to the variations
p.000010: during childbearing and non-childbearing age (menstrual cycle, pregnancy, breast feeding,
p.000010: menopause) and to the possible consumption of contraceptives for contraceptive or therapeutic reasons (estrogens and
p.000010: progestin modify women’s metabolism; the estrogens also affect the way genes work). This kind of variability does not
p.000010: allow the collection of “clean data” in mixed sex trials and lowers the statistical relevance of the
p.000010: experimentation. Even when there are women involved in the trial, it is not certain that the enlisted
p.000010: number can allow us to see significant events.
p.000010:
p.000010:
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: e) Possible pregnancy during childbearing age27. One of the reasons that have led the pharmaceutical
p.000011: industry to exclude women from trials is connected to the possibility that the trial of a new drug
p.000011: could damage the foetus28 in case of pregnancy. There is also the possibility that the studied drug could have
p.000011: negative effects even after the end of the trial, months later. This explains why in general the pharmaceutical
p.000011: industry imposes the use of specific hormonal contraceptives29 as condition for the participation in a research
p.000011: that can be considered “without risk” for the foetus.
p.000011:
p.000011: 7. The exclusion/inclusion of women of childbearing age in trials protocols
p.000011:
p.000011: Regarding the problem of pharmacological experimentation on women of childbearing age, the literature
p.000011: presents a variety of positions: within those, we report the most spread ones.
p.000011: Some affirm that the inclusion of women of childbearing age in the trails is ethically of the outmost
p.000011: importance, when balancing the possible damage to the foetus (considered not yet to have dignity in a strong sense)
p.000011: with the predictable direct benefits to women and in general to society30. From this point of view, the a priori
p.000011: exclusion of women of childbearing age from trails (to protect the possible foetus) results in injustice in the
p.000011: biomedical research, as women do not have the same opportunities as men with regards to the cure of certain
p.000011: illnesses. The particular physio-psychological and social conditions of women should not justify their exclusion,
p.000011: but, on the contrary, motivate a differentiated study in comparison to men. The expectation of the
p.000011: pharmaceutical industry that women should use hormonal contraceptives is also criticised as restrictive of women’s
p.000011: freedom intended as self-determination.
p.000011: Others maintain that where clinical trials, even only hypothetically and probably, poses a danger to the foetus’ life
p.000011: and health (here the foetus is recognised as a subject
p.000011:
...
p.000012: experimentation of women of childbearing age, especially in phases I and II, as the data on teratogenicity was not
p.000012: known, with the exception of women with deadly pathologies;
p.000012:
p.000012: 31 This is the position that refers to the inseparability of the uniting and the procreating dimension of the marital
p.000012: act. Cf. R. Minacori, D. Sacchini, A.G. Spagnolo, Women of Childbearing Potential as Research Subjects in Clinical
p.000012: Trials: Ethical Issues, in A.G. Spagnolo, G. Gambino (edited by), Women’s Health Issues, Societa’ Editrice
p.000012: Universo, Roma 2003, pages 123-129; A.G. Spagnolo, M. Cicerone, Sperimantazione farmacologica e donne
p.000012: in eta’ fertile, “Medicina e Morale”, from international literature, 2005, 3, pages 667-670; Catholic University
p.000012: of the Sacred Heart, ethical Committee, Raccomandazioni riguardo alla inclusione di donne in eta’ fertile
p.000012: nei protocolli di sperimentazione clinica, “Medicina e Morale”, 1996, 46, pages 141-143. Cf. for a historical
p.000012: reconstruction M. Pelaja, L. Scaraffia, Due in una carne. Chiesa e sessualita’ nella storia, Laterza, Bari 2008, page
p.000012: 261 and following.
p.000012: 32 S. Cagliano, Dieci farmaci che sconvolsero il mondo, Laterza, Rome-Bari 1994, pages 43-68.
p.000012:
p.000013: 13
p.000013:
p.000013: women of childbearing age could participate to the studies in phases II and III only if sufficient
p.000013: information on the drug’s safety and efficacy, even in the studies on animals, had been collected, which excluded
p.000013: interferences with the reproductive functions. In 1982 the World Health Organisation promulgated the Proposed
p.000013: International Guidelines which affirmed the duty to exclude women from non-therapeutic experimentations on
p.000013: healthy volunteers33.
p.000013: In 1988 we register a radical change in the direction of the FDA that, with the publication of the document Guideline
p.000013: for the Format and Content of the Clinical and Statistical Sections of the New Drug Application, highlights the
p.000013: under-representation of women in pharmacological trial and recommends the analysis of sex-differentiated data in
p.000013: clinical trials34. In 1993 the FDA again issued the Guidelines for the Study and Evaluation of gender
p.000013: Differences in the Clinical Evaluation of Drugs, recognising that the percentage of the participation of women to
p.000013: clinical experimentations in pathologies not typically female is inferior to that of men and hoping for the inclusion
p.000013: of women in the trials protocols with the aim to guarantee equal representation. The FDA accepts that such exclusion
p.000013: could have, in subtle ways, caused the impression that men are the “primary focus” of medicine and of
p.000013: pharmacological development, with women being of secondary consideration; it therefore recommends the removal of the
p.000013: prohibition of the participation of women of childbearing age to the first phases of trial, with the aim
p.000013: to prevent forms of discrimination, avoiding a paternalistic attitude. The FDA believes that it is not necessary to
p.000013: exclude women because of the potential risks to the foetus, as the risks can be minimised with an explicit commitment
p.000013: of the woman to avoid pregnancy, as well as through the use of laboratory tests which can ascertain such behaviours.
p.000013: The FDA does not impose any obligations on the pharmaceutical industry and to IRBs (Institutional Review Boards,
p.000013: equivalent to independent ethical Committees), to include women in experimentation, but it aims to remove the
p.000013: “not necessary impediment”, in order to boost a higher participation of women in trials, leaving “flexibility”
p.000013: to the IRBs, to the researchers, to the sponsors and also, all considered, to the patients who have
p.000013: been correctly informed with regards to determining the safest measures to protect their health and individual
p.000013: rights, recognising the responsible autonomy of women as research subjects.
p.000013: At an international level these issues are included in an indicative document within the medical field.
p.000013: Also in 1993 the Council for International Organizations of Medical Sciences (CIOMS) promulgates the
p.000013: International Ethical Guidelines for Biomedical Research Involving Human Subjects (revised in 2002),
p.000013: recommending the researchers, the sponsors and the ethical committees to avoid excluding women of
p.000013: childbearing age from trials, as they do not believe the possibility of a pregnancy is sufficient reason
p.000013: to preclude or limit their participation and recognising that women have the ability to take a “rational decision” in
p.000013: participating in research (guideline number 16). In the case of risk to the foetus’ health, women have to accept to
p.000013: undertake a pregnancy
p.000013:
p.000013:
p.000013: 33 K.L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice,
p.000013: “Journal of Health Politics, Politics and Law”, 1999, 24 (3), pages 531-566.
p.000013: 34 R.B. Merkatz, Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, “Acad
p.000013: Med”, 1994, 69, pages 703-707; R.B. Merkatz, R. Temple, S. Sobel, Women in Clinical Trials of new Drugs. A Change in
p.000013: Food and Drug Administration Policy, “The New England Journal of Medicine”, 1993, 329 (4), pages 292-296.
p.000013:
p.000014: 14
p.000014:
p.000014: test and to use an “effective contraceptive method”, allowing, with such procedures, their enlistment also in the first
p.000014: phases of the trials with controlled doses of the new substance; we highlight that the informed consent must be
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p.000014: recommends that even pregnant women are acceptable (guideline number 17) as trials subjects, provided that the risks
p.000014: (for the woman and for the foetus) are minimised, leaving the decision to the individual woman, even in the
p.000014: case of uncertainty and ambiguity about the definition of risk; the research can be promoted only if it is relevant
p.000014: to the health of the woman who is subjected to the trials and to other women in the same condition; it is believed that
p.000014: women can be recruited into the research only in case there are pre-clinical studies which state the drug’s
p.000014: teratogenity.
p.000014: In 1994 in the United States, a dedicated office called “Office of Women’s Health” was created as part of
p.000014: the FDA, with the objective of boosting the inclusion of women in clinical studies, evaluating the different
p.000014: responses for the safety and the efficacy of drugs. In 1995 the previous instructions were strengthened
p.000014: further in the document Investigational New Drug Applications, which explicitly demands an end to any
p.000014: discrimination due to sexual difference, as well as age and race, in trials. In 1998 the FDA promulgates the Final Rule
p.000014: on the Investigational Drug Applications with the aim of actively intervening with sponsors who do not respect
p.000014: the instructions of fairness within sexual difference. In 1999 the working group “FDA-MA Women and Minorities
p.000014: Working Group” was created, with the aim of drawing up specific guidelines to boost the correct inclusion of women and
p.000014: of weak subjects in clinical trials. In 2001 the National Institute of Health in the USA issued the document
p.000014: Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research to promote a policy
p.000014: of women’s inclusion in the enlistment for pharmacological trials. It is important to highlight that the
p.000014: Department of Health and Human Services in issuing the Regulations for the Protection of Human Subjects in 2001,
p.000014: does not take explicitely into account tendencies and directives for the researchers, the doctors and IRBs on the
p.000014: specific theme of trials on women of childbearing age.
p.000014: Within the European biolegislation we highlight the focus on female specificity within the general area of
...
p.000014: Conceptual Framework Methodology and Presentation of Good Practice was elaborated by the Comité Directeur pour
p.000014: l'égalitée de gendre (CDEG),
p.000014:
p.000015: 15
p.000015:
p.000015: (European Agency for the Evaluation of Pharmaceutical Products) issued the Note for Guidance on General
p.000015: Considerations for Clinical Trials allowing women of childbearing age to be part of clinical studies only if they were
p.000015: using contraceptives. Again the EMEA in 2003, after the contribution of a working group that included female
p.000015: researchers and representatives of the pharmaceutical industries from the whole of Europe (XX group), published the
p.000015: Note for Guidance on the Clinical Development of HIV-Medical Products recommending the elaboratation of study protocols
p.000015: which would promote the comparison between sexes, with the guarantee of a statistically significant participation of
p.000015: women and adequate medical training. In the document Gender Considerations in the Conduct of Clinical Trials
p.000015: issued by the Committee for Medical Products for Human Use (CHMP) of the European Drugs’ Agency (EMEA) in January
p.000015: 2005, the lack of need for the elaboration of specific European guidelines on pharmacological trials on
p.000015: women is explicitely stated (differently to what occurred in reference to age difference, with regards to
p.000015: underage and elderly patients) considering as sufficient the international guidelines on the issue.
p.000015:
p.000015: 10. National legislation
p.000015:
p.000015: In the Italian legal system there is no explicit reference to the female condition within clinical trials. In the
p.000015: legislative decree of the 24th of June 2003 number 211 Carrying out of the directive 2001/20/CE in relation to
p.000015: the application of good clinical practice in the execution of clinical trials of drugs for clinical use to the article
p.000015: 1 c. 2 “The respect of good practice guarantees the protection of the rights, safety and wellbeing of the subjects and
p.000015: ensures the credibility of the data regarding the same clinical trials”, we refer to the “subject” intended as “person
p.000015: who participates to the clinical trials, both as the target for the experimented drug as well as its test” (art. 2.
p.000015: i.), without distinction between men and women. We speak of protection of the trials’ subjects, with particular
p.000015: reference to adults unable to give their informed consent and to minors, but no explicit reference to women.
p.000015: The new regulation on Minimum requiremenst for the creation, the organisation and the functioning of ethical Committees
p.000015: for the trials of drugs (ministerial decree of the 12th of May 2006) does not specify that there must be a balanced
p.000015: representation of both sexes.
p.000015:
p.000015:
p.000015:
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p.000015: lack of detailed information about the access to cures by men and women, the necessity to pre-empt discriminations in
p.000015: order to also improve the efficacy of health policies from an economic point of view. In particular the Committee
p.000015: highlights the lack of sex- disaggregated data and of indicators to define the effects of the difference
p.000015: between men and women in health research; the need to implement health policies in the consideration of
p.000015: sexual differences. In conclusion the document refers to existing distorsions in biomedical research, with
p.000015: specific reference to pharmacological tests conducted exclusively on male subjects.
p.000015:
p.000016: 16
p.000016:
p.000016:
p.000016: 11. Bioethical recommendations
p.000016:
p.000016: 1. The NBC intends to highlight some elements of bioethical relevance for the promotion of
p.000016: women’s health in those sectors of clinical experimentation that appear to suffer most from a kind of
p.000016: “neutralistic” ideology of medicine. In particular the NBC intends to underline the fundamental ethical
p.000016: principle of the fairness of a pharmacological trial on both men and women, in real conditions of equality,
p.000016: without exclusions or undue marginalisations, deeming necessary the identification and the removal of the
p.000016: causes of this unfairness. Just as a pharmacological trial that takes into account the conditions of fragility due to
p.000016: the patient’s age (for example periatric and geriatric trials) must be deemed fair and right, in the same
p.000016: way a trial that takes adequately into consideration sexual differences must be deemed proper.
p.000016: 2. The NBC hopes for a boost, already at the level of biomedical research, of studies specifically
p.000016: directed at the analysis of the condition of women’s health (diffused illnesses, risk factors, incidence,
p.000016: etc.), also and especially in the light of recent changes in their psychological-social and cultural condition,
p.000016: in order to identify the areas of deficiency of the health system in response to new and variable female needs. The
p.000016: study of physiological and psychological aspects should be implemented in this direction, as well as the analysis
p.000016: of social and cultural factors and their interaction with female health.
p.000016: 3. The NBC deems the increase of bioethically relevant clinical trials on women, as an important step towards
p.000016: guaranteeing the effective conditions of equality of care in comparison to men: the scarse
p.000016: representativeness of women and the lack of sex- differentiatied data constitute a discriminatory element
p.000016: for women’s health. The increase in clinical trials must be promoted not just with regard to traditionally female
p.000016: pathologies but also for new pathologies, hoping for a link between the results of sex differentiated medical
...
p.000016:
p.000016:
p.000017: 17
p.000017:
p.000017: accessXtoXhealthcare; b) promote the participation of women to clinical trials, giving adequate information (even
p.000017: through the media) on the negative consequences of the lack of differentiated trials and on the social importance of
p.000017: female trials, guaranteeing support and specific attention to women’s psychological and practical needs; c)
p.000017: ensure a greater presence of women as experimenters and as members of ethical committees in order to
p.000017: achieve an active participation of women (not only as researchers, but also as representatives of patients’
p.000017: associations) to the elaboration of the procedures for the protocols and for the relevant informed consent;
p.000017: to promote greater attention from ethical committees to sexual difference in research protocols;
p.000017: d) boost health training which focuses on the female dimension within pharmacological
p.000017: trials, as well as within research and cure; e) increase international cooperation, as well as national and
p.000017: local, with the focus on the female condition within clinical trials, involving health authorities and the
p.000017: pharmaceutical industry.
p.000017: 6. The NBC believes that even the participation of women of childbearing age in pharmacological trials is
p.000017: ethically and socially important, provided that an adequate protection of the future child can be guaranteed. The NBC
p.000017: highlights the importance of a preliminary consultation about the intended trials, including adequate
p.000017: information, clear and in full, according to an objective, technical-scientific classification of the
p.000017: risks and benefits that the study involves for the patient, but that also taking into account the risks for the foetus
p.000017: in case of pregnancy37. We must also take into account that the exclusion of women of childbearing age from trials does
p.000017: not allow, in practice, to protect the foetus, as women could take the experimented drug (but not tested on them) on
p.000017: the market with similar risks in case of pregnancy and, to make it worse, without adequate protection. The NBC believes
p.000017: that the inclusion of women of childbearing age in pharmacological trials that poses risks to the foetus
p.000017: needs, unavoidably, the woman’s clear statement of a conscious and responsible commitment to avoid
p.000017: intercourse that could lead to pregnancy. If it is not possible to exclude a risk to the foetus’ life and
p.000017: health within the trials, but there are possible benefits to women in general and in particular in the
p.000017: cure of illnesses, the NBC believes that requesting the commitment to take contraceptives as a safety measure
p.000017: believed necessary by the study’s sponsor – to avoid pregnancy, as the trials could be damaging to the foetus – can be
p.000017: included in the criteria to participate in the study.
p.000017: In addition, the NBC believes that it is important that the woman’s husband or partner is also involved in the
p.000017: informative counselling, as the choices being made involve them as a couple.
p.000017: The trial of drugs that can make hormonal contraceptives ineffective is an open problem, so it is the fact
p.000017: that there might be interactions between the treatments being studied and the contraceptive methods being used: in this
p.000017: case the experimenters have to adequately inform the woman (and also her husband or partner) and recruit only on
p.000017: condition of a commitment, clearly expressed in the informed consent (given a fair
p.000017:
p.000017:
...
p.000019: Administration’s Perspective, “International Journal of Toxicology”, 2001, 20 (3), pp. 149-152
p.000019:
p.000019: Ministero della salute, Lo stato di salute delle donne in Italia, Primo rapporto sui lavori della Commissione “Salute
p.000019: delle donne”, Roma, marzo 2008 (www.ministerosalute.it): F. Franconi in collaborazione con S. Canu, I. Campasi (a
p.000019: cura di), Approccio di genere nella ricerca, nelle sperimentazioni e nei trattamenti farmacologici, pp. 39-53
p.000019:
p.000019: Mordacci R., Bioetica della sperimentazione. Fondamenti e linee guida, Franco Angeli, Milano 1997, pp. 208-214
p.000019:
p.000019: Osservatorio Nazionale sull’impiego dei medicinali, Istituto Superiore di Sanità, Agenzia Italiana del
p.000019: Farmaco, L’uso dei farmaci in Italia. Rapporto nazionale anno 2006, Il Pensiero Scientifico, Roma 2006
p.000019:
p.000019: Prout M.N., Fish S.S., Participation of Women in Clinical Trials of Drug Therapies: a Context for the
p.000019: Controversies, “Medscape Women’s Health Journal”, 2001, 6 (5)
p.000019:
p.000019: Rosser S.V., Re-visioning Clinical Research: Gender and the Ethics of Experiment Design, “Hypatia”, 1989, 4
p.000019: (2)
p.000019:
p.000019: Schonfeld T.L., Gordon B.G., Contraception in Research: a Policy Suggestion, IRB Ethics & Human Research,
p.000019: 2005, 27 (2), pp. 15-20
p.000019:
p.000019: Schwartz J.B., The Current State of Knowledge on Age, Sex, and the Interactions on Clinical
p.000019: Pharmacology, “Clinical Parmacol. Ter.”, 2007, 82, pp. 87-96
p.000019:
p.000019: Uhl K., Parekh A., Kweder S., Females in Clinical Studies: Where are we Going?, “Clin. Pharmacol.
p.000019: Ther.”, 2007, 81, pp. 600-602
p.000019:
p.000019: United States General Accounting Office, Women’s Health: FDA Needs to Censure More Study of Gender Differences in
p.000019: Prescription Drug Testing, Washington D.C. 1992
p.000019:
p.000019:
p.000019:
p.000019:
p.000020: 20
p.000020:
p.000020: US National Institute of Health, NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in
p.000020: Clinical Research, October, 2001
p.000020:
p.000020: Wizemann T.M., Pardue M.L., Exploring the Biological Contributions to Human Health: Does Sex Matter?,
p.000020: Committee on Understanding the biology of sex and gender differences, National Academy Press, Washington D.C. 2001
p.000020:
p.000020:
p.000020: Table 1
p.000020:
p.000020:
p.000020: Year Clinical Trials
p.000020: 2000 55
p.000020: 2001 45
p.000020: 2002 62
p.000020: 2003 57
p.000020: 2004 51
p.000020: 2005 66
p.000020: 2006 76
p.000020: Total 412
p.000020: Clinical trials on women within all clinical trials – Observatory for clinical trials (data AIFA 01/01/2000 -
p.000020: 31/12/2006)
p.000020: Table 2
p.000020:
p.000020: Year Number of Clinical
p.000020: Trials
p.000020: % Phase II
...
p.000021: 279.179 24.1
p.000021: Antithrombotics 103 167.878 27.0
p.000021: Antiarrhythmics 80 45.430 22.6
p.000021: Beta blockers 70 56.517 20.6
p.000021: Antiaggregants 69 91.172 24.0
p.000021:
p.000021: Data on the participation of women to clinical trial in the principal therapeutic classas (80% of trials). The table is
p.000021: part of a more extensive table: not all therapeutic classes have been referred to (the others cover 20% of the trials).
p.000021: In the original version RCT stands for ‘Randomized Controlled Trials’. Data taken by
p.000021: P.Y. Lee, K.P. Alexander, B.G. Hammill et al., Representation of Elderly Persons and Women in Published Randomized
p.000021: Trials of Acute Coronary Syndromes, JAMA, 2001, 286(6), pages 708-713
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000022: 22
p.000022:
p.000022:
p.000022:
p.000022: Table 5
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022: Drug consumption by age and sex (DDD – Defined Daily Dose per day per 1000 inhabitants)- AIFA (National Drug Agency)
p.000022: data regarding 2006.
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000023: 23
p.000023:
p.000023:
p.000023: Table 6
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023: Reported cases of adverse reactions to drugs (Adrs – Adverse Drug ReactionS) by sex and age – AIFA data regarding 2007.
p.000023:
p.000023:
p.000023:
p.000023: Personal remark by Prof. Adriano Bompiani, Bruno Dallapiccola, Maria Luisa Di Pietro, Rodolfo Proietti
p.000023:
p.000023: The “abstension” vote – and not a “contrary vote” – on the document “Pharmacological trials on
p.000023: women”, approved by the National Bioethics Committee on the 28th of November 2008, is dictated by the awareness of the
p.000023: importance of a bioethical reflection on the question of the inclusion of women of childbearing
p.000023: age in pharmacological clinical trials. It is about – in this case – putting together important points
p.000023: for the progress of medical research and the marketing of new drugs, respecting the fundamental rights of the patients,
p.000023: if involved as trial subjects.
p.000023: On the one hand we must, in fact, consider the need to include women in clinical trials in order to properly evaluate –
p.000023: in relation to the particular differences of the female organism – the pharmacokinetics, the pharmacodynamics, the
p.000023: toxicity, the efficacy and the safety of the new pharmacological treatments. This represents an unavoidable medical
p.000023: need, with regards to the therapeutic advantage that results from the evaluation of the therapeutic
p.000023: efficacy and of the side effects. In addition, the possibility to have access to a
p.000023:
p.000023:
p.000024: 24
p.000024:
p.000024: clinical trial can constitute, especially for some situations of particular gravity (for example in the case
p.000024: of phatologies indifferent to standard treatments or of rare diseases) another opportunity of therapy – even if
p.000024: uncertain in outcome -, that can be a priori precluded to women because of their fertile condition. On
p.000024: the other hand, is equally important, for those who promote and conduct a clinical trial, to always
p.000024: consider the potential risk of teratogenicity in case of pregnancy, especially if there is already previous evidence
...
Social / Child
Searching for indicator child:
(return to top)
p.000005: Clinical experimentation in order to develop new drugs in Italy, as in the rest of Europe, takes place with common
p.000005: methods, through various experimental phases, in accordance with the norms of “Good Clinical Practices”10.
p.000005: This allows homogeneity from a scientific point of view as well as from an ethical point of view, with regards to the
p.000005: respect due to the rights of the patients involved. The regulations make provisions for the verification of the safety
p.000005: and the efficacy of the new drugs before their introduction on the market. This verification applies the methods of
p.000005: evidence based medicine (EBM), which at the moment is considered the most adequate model to guarantee that
p.000005: the introduction of new drugs will benefit the greatest amount of patients. We must remember that this
p.000005: is not the only possible model, but it is the one that is generally considered the most suitable because
p.000005: of the needs of modern medicine and because of its impact on the population’s health.
p.000005: Drugs’ experimentation, before the authorisation to market them, makes provisions, after the pre-clinical phase, for
p.000005: phase I, essentially about safety, and phases II and III, in which
p.000005:
p.000005: 9 With regards to experimentation which is not directly therapeutic in the interest of the pregnant woman or of the
p.000005: breast feeder, aiming to achieve effective protection of the health of the woman, of the embryo and of the foetus, and
p.000005: of the child after birth, the additional conditions anticipated in ch. VI of article 18 of the additional Protocol to
p.000005: the Convention of human rights and biomedicine are applied, relative to biomedical research, approved in Strasbourgh on
p.000005: the 25th of January 2005, which indicate particular precautions.
p.000005: 10 The “Good Clinical Practices” constitute an international standard of ethics and quality of planning,
p.000005: managing and recording clinical studies. In Italy they were first adopted as part of the national legislation with the
p.000005: ministerial decree of the 15th of July 1997.
p.000005:
p.000006: 6
p.000006:
p.000006: the efficacy of the drug on a growing number of patients is established. Subsequently the drug is authorised by the
p.000006: health authorities and becomes part of the clinical practice. Other phase IV studies can take place,
p.000006: always with experimental characteristics and therefore with the enlistment of a certain number of patients, aimed
p.000006: at better establishing the efficacy of a new drug with regards to the safety of use, even for longer periods of time.
p.000006: The whole process is under the control of health authorities, primarily of the Italian Drug Agency (IDA), which is
p.000006: called to supervise and if necessary direct, through its funding, drug research11.
p.000006:
p.000006: 3. Clinical experimentation on women: under-representation in the enlistment and shortcomings in the
...
p.000012: trials (that is as individuals enlisted in the trials), but also as trials’ “subject”, in the sense of active subjects,
p.000012: present in the medical teams that plan and define the trials’ development and present in the ethical
p.000012: committees that evaluate the trials protocols. The presence of women could contribute to a greater focus on the
p.000012: relevance of women’s participation to the trials and could allow greater sensitivity with regards to female needs, from
p.000012: a psychological and social point of view.
p.000012: There is no data regarding the presence of women in medical teams, however, it is possible to verify the presence of
p.000012: women in ethical Committees through an analysis of the committees’ composition, as reported by the data of the
p.000012: Observatory on trials. Generally women’s presence, although often linked to the nursing sector and to
p.000012: the representative of patients, is consistent, even if almost always inferior to that of men, and is strongly dependent
p.000012: on local circumstances.
p.000012:
p.000012: 9. International bioethical guidelines
p.000012:
p.000012: In the ‘70s explicit instructions emerged, that made rules for the exclusion of women from clinical studies
p.000012: with the aim of protecting the health of the future child, as dramatic cases of foetal death and severe damage
p.000012: to the infants had occurred, due to indiscriminate trials32. In 1977 the Food and Drug Administration (FDA) in
p.000012: the General Considerations for the Clinical Evaluation of Drugs recommended the exclusion from
p.000012: experimentation of women of childbearing age, especially in phases I and II, as the data on teratogenicity was not
p.000012: known, with the exception of women with deadly pathologies;
p.000012:
p.000012: 31 This is the position that refers to the inseparability of the uniting and the procreating dimension of the marital
p.000012: act. Cf. R. Minacori, D. Sacchini, A.G. Spagnolo, Women of Childbearing Potential as Research Subjects in Clinical
p.000012: Trials: Ethical Issues, in A.G. Spagnolo, G. Gambino (edited by), Women’s Health Issues, Societa’ Editrice
p.000012: Universo, Roma 2003, pages 123-129; A.G. Spagnolo, M. Cicerone, Sperimantazione farmacologica e donne
p.000012: in eta’ fertile, “Medicina e Morale”, from international literature, 2005, 3, pages 667-670; Catholic University
p.000012: of the Sacred Heart, ethical Committee, Raccomandazioni riguardo alla inclusione di donne in eta’ fertile
p.000012: nei protocolli di sperimentazione clinica, “Medicina e Morale”, 1996, 46, pages 141-143. Cf. for a historical
...
p.000017: through the media) on the negative consequences of the lack of differentiated trials and on the social importance of
p.000017: female trials, guaranteeing support and specific attention to women’s psychological and practical needs; c)
p.000017: ensure a greater presence of women as experimenters and as members of ethical committees in order to
p.000017: achieve an active participation of women (not only as researchers, but also as representatives of patients’
p.000017: associations) to the elaboration of the procedures for the protocols and for the relevant informed consent;
p.000017: to promote greater attention from ethical committees to sexual difference in research protocols;
p.000017: d) boost health training which focuses on the female dimension within pharmacological
p.000017: trials, as well as within research and cure; e) increase international cooperation, as well as national and
p.000017: local, with the focus on the female condition within clinical trials, involving health authorities and the
p.000017: pharmaceutical industry.
p.000017: 6. The NBC believes that even the participation of women of childbearing age in pharmacological trials is
p.000017: ethically and socially important, provided that an adequate protection of the future child can be guaranteed. The NBC
p.000017: highlights the importance of a preliminary consultation about the intended trials, including adequate
p.000017: information, clear and in full, according to an objective, technical-scientific classification of the
p.000017: risks and benefits that the study involves for the patient, but that also taking into account the risks for the foetus
p.000017: in case of pregnancy37. We must also take into account that the exclusion of women of childbearing age from trials does
p.000017: not allow, in practice, to protect the foetus, as women could take the experimented drug (but not tested on them) on
p.000017: the market with similar risks in case of pregnancy and, to make it worse, without adequate protection. The NBC believes
p.000017: that the inclusion of women of childbearing age in pharmacological trials that poses risks to the foetus
p.000017: needs, unavoidably, the woman’s clear statement of a conscious and responsible commitment to avoid
p.000017: intercourse that could lead to pregnancy. If it is not possible to exclude a risk to the foetus’ life and
...
p.000017: cure of illnesses, the NBC believes that requesting the commitment to take contraceptives as a safety measure
p.000017: believed necessary by the study’s sponsor – to avoid pregnancy, as the trials could be damaging to the foetus – can be
p.000017: included in the criteria to participate in the study.
p.000017: In addition, the NBC believes that it is important that the woman’s husband or partner is also involved in the
p.000017: informative counselling, as the choices being made involve them as a couple.
p.000017: The trial of drugs that can make hormonal contraceptives ineffective is an open problem, so it is the fact
p.000017: that there might be interactions between the treatments being studied and the contraceptive methods being used: in this
p.000017: case the experimenters have to adequately inform the woman (and also her husband or partner) and recruit only on
p.000017: condition of a commitment, clearly expressed in the informed consent (given a fair
p.000017:
p.000017:
p.000017: 37 The risks for the foetus and the benefits for the woman must be put in the balance, according to a gradation of
p.000017: ethical justification: the experimentation of drugs that do not present any risks to the foetus is
p.000017: considered as devoid of problems (for any purpose, both for therapeutic and non-therapeutic purposes, e.g. esthetic
p.000017: purposes); the experimentation that present a certain or uncertain risk to the life or health of the future child is
p.000017: considered ethically unacceptable, with the exception of drugs that can cure serious illnesses for the woman who
p.000017: undergoes the trial
p.000017:
p.000018: 18
p.000018:
p.000018: amount of time for reflection), to avoid starting a pregnancy during the time of the trials and, in some cases,
p.000018: also for a certain time afterwards, a time to be defined according to the typology of the trials. The woman,
p.000018: on her part, must be available to carry out checks (pregnancy tests) that allow the experimenters to verify
p.000018: the conditions of safety to proceed. The informed consent and the committment to avoid procreation applies also to men
p.000018: who enter a trial protocol which presents the risk of damage to the foetus through their gametes.
p.000018:
p.000018:
p.000018: Bibliography38
p.000018:
p.000018: Bennett J.C., Inclusion of Women in Clinical Trials. Policies for Population Subgroups, “New England
p.000018: Journal of Medicine”, 1993, 329 (4), pp. 288-292
p.000018:
p.000018: Borgia L.M. (a cura di), Manuale di bioetica per la sperimentazione clinica e i comitati etici,
p.000018: Edizioni Medico Scientifiche, Torino 2008 (cfr. pp. 36-45)
p.000018:
p.000018: Buffoni F., Donne nella ricerca farmacologica italiana, Quaderni della SIF, marzo 2006, 5, pp. 6-7
p.000018:
p.000018: Ceci A., Legislazione e criticità nella sperimentazione dei farmaci, Agenzia Sanitaria Servizi Sanitari
p.000018: Monitor ASSR, 2005, 12, pp. 67-71
p.000018:
p.000018: Commissione Nazionale per la parità e le pari opportunità tra uomo e donna, Presidenza del Consiglio dei Ministri,
...
Searching for indicator children:
(return to top)
p.000008: the quality of health assistance. In the pathologies most common in women – where the frequency of the
p.000008: pathologies is linked to age and social condition – we can find some relevant elements: an increase in
p.000008: cardiac pathologies (arterial hypertension, coronary cardiomyopathy, peripheral arteriopathy and cardiac
p.000008: imbalance, thromboembolic pathologies); an increment in the oncological field, as well as “female cancers” (breast
p.000008: cancer, carcinoma of the uterine cervix, endometrial tumours, ovarian neoplasia), also of trachea-bronchi-lungs
p.000008: tumours, due to the spread of nicotine addition even during adolescence; an increase in psychological
p.000008: pathologies (anxiety and depressive syndromes, eating disorders, psychotic syndromes); a tendency to an increase
p.000008: in obesity, due to the lack of physical activity and sedentary life, with an increase in the risk of
p.000008: cardiovascular illnesses and diabetes; an increase in alcohol abuse (with nutritional imbalances and
p.000008: dependency); an increase in neurodegenerative illnesses (Alzheimer’s illness, Parkinson disease, multiple
p.000008: sclerosis, senile dementia); an increase in problems linked to infertility, caused by the postponement of the decision
p.000008: to have children or by the protracted use of contraceptives; problems and pathologies linked with the
p.000008: non- acceptance of aging also emerge20.
p.000008: These changes in the conditions of women’s health and illness emphasise even more the lack of an
p.000008: adequately differentiated trails for the care of women’s health, beyond traditional areas.
p.000008:
p.000008:
p.000008:
p.000008: 19 La salute della donna. Stato di salute a assistenza nelle regioni italiane. Libro bianco, Franco Angeli, Milano
p.000008: 2007.
p.000008: 20 Different the causes: the problems of the substitutive hormonal therapy; the possibility to postpone for decades
p.000008: physical aging, extending the menstrual cycle for years as well as intervening with plastic surgery, with possible
p.000008: dangers for women’s health, and not only because of the bad quality of the treatments – as in the case of deaths
p.000008: due to routing operations, like liposuction – but also because of extended negative effects, injected
p.000008: liquids and stress, due to the effort of not showing their real age.
p.000008:
p.000009: 9
p.000009:
p.000009: 5. Women as drug users and the problem of the side-effects
p.000009:
p.000009: The fact that women are not adequately taken into consideration within clinical trails is penalising, given the
p.000009: increase in the consumption of drugs on their part.
...
Social / Elderly
Searching for indicator elderly:
(return to top)
p.000003: influences. The changes that women have lived through and are still living through are profound, especially in
p.000003: western civilizations, with consequent changes regarding the relationship between health and illness.
p.000003: Some illnesses traditionally considered typical of the male population are now statistically more
p.000003: widespread in women, but medicine – in some of the specializations in which it is developed – does not seem to take
p.000003: into adequate account such changes in their policies of prevention, diagnosis and cure.
p.000003: Biomedical research – in general and in past decades – tended to reflect predominantly a male
p.000003: perspective, according to some, assimilating women to men (except in some particular specializations): many
p.000003: researchers and doctors in some fields of human pathology have not adequately taken into account sexual
p.000003: differences with regards to the study of the symptoms, the assessment of the diagnosis and the efficacy of the
p.000003: treatments. The lack of consideration of sexual differences is part of a research that tends to the generalisation of
p.000003: any organic phenomenon (although this is necessary), not always paying enough attention to differences due to
p.000003: sex, as well as those due to age (taking into account under-age patients2 and the elderly), disability and
p.000003: ethnicity.
p.000003: However it is fair to indicate that not only a more “mature” clinic, but also a more careful research, have in recent
p.000003: time offered, and continue to offer more and more today, examples of greater balance in the formulation of protocols
p.000003: and the relative “enlistments” of the subjects.
p.000003: Medicine’s “neutral” approach, “in-different” to sex differences, has come to light for a long time in the
p.000003: experimentation of medicines, for reasons that will be subsequently clarified. As a consequence, although on one
p.000003: hand we highlight an increase in the consumption of medicines by women in comparison to men3, on the other hand
p.000003: it appears
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003: 1 This is true in almost all Countries although there are great differences in the life expectancy of men and women.
p.000003: A. Barford, D. Dorling, G Davey Smith, M. Shaw, Life Expectancy: Women Now on Top Everywhere, “British
p.000003: Medical Journal”, 2006, 332, p. 808.
p.000003: 2 On this topic cf Regulation (CE) number 190/2006 of the European Parliament and of the Council of
p.000003: Europe regarding drugs for paediatric use, which ends the marketing of drugs tested almost exclusively on adult
p.000003: subjects.
p.000003: 3 In Italy the greater consumption of drugs by women is per-capita data, therefore normalised. Cf.
p.000003: paragraph 5.
p.000003:
p.000004: 4
p.000004:
...
p.000014: Conceptual Framework Methodology and Presentation of Good Practice was elaborated by the Comité Directeur pour
p.000014: l'égalitée de gendre (CDEG),
p.000014:
p.000015: 15
p.000015:
p.000015: (European Agency for the Evaluation of Pharmaceutical Products) issued the Note for Guidance on General
p.000015: Considerations for Clinical Trials allowing women of childbearing age to be part of clinical studies only if they were
p.000015: using contraceptives. Again the EMEA in 2003, after the contribution of a working group that included female
p.000015: researchers and representatives of the pharmaceutical industries from the whole of Europe (XX group), published the
p.000015: Note for Guidance on the Clinical Development of HIV-Medical Products recommending the elaboratation of study protocols
p.000015: which would promote the comparison between sexes, with the guarantee of a statistically significant participation of
p.000015: women and adequate medical training. In the document Gender Considerations in the Conduct of Clinical Trials
p.000015: issued by the Committee for Medical Products for Human Use (CHMP) of the European Drugs’ Agency (EMEA) in January
p.000015: 2005, the lack of need for the elaboration of specific European guidelines on pharmacological trials on
p.000015: women is explicitely stated (differently to what occurred in reference to age difference, with regards to
p.000015: underage and elderly patients) considering as sufficient the international guidelines on the issue.
p.000015:
p.000015: 10. National legislation
p.000015:
p.000015: In the Italian legal system there is no explicit reference to the female condition within clinical trials. In the
p.000015: legislative decree of the 24th of June 2003 number 211 Carrying out of the directive 2001/20/CE in relation to
p.000015: the application of good clinical practice in the execution of clinical trials of drugs for clinical use to the article
p.000015: 1 c. 2 “The respect of good practice guarantees the protection of the rights, safety and wellbeing of the subjects and
p.000015: ensures the credibility of the data regarding the same clinical trials”, we refer to the “subject” intended as “person
p.000015: who participates to the clinical trials, both as the target for the experimented drug as well as its test” (art. 2.
p.000015: i.), without distinction between men and women. We speak of protection of the trials’ subjects, with particular
p.000015: reference to adults unable to give their informed consent and to minors, but no explicit reference to women.
p.000015: The new regulation on Minimum requiremenst for the creation, the organisation and the functioning of ethical Committees
p.000015: for the trials of drugs (ministerial decree of the 12th of May 2006) does not specify that there must be a balanced
p.000015: representation of both sexes.
p.000015:
p.000015:
p.000015:
p.000015: intergovernamental body responsible for the definition and the implementation of the actions of the Council of Europe
...
p.000021: Dermatology/Plastic surgery 4 1,0 2,2
p.000021: Cardiology/Vascular illnesses 1 0,0 11,1
p.000021: Gastroenterology 1 0,0 7,0
p.000021: Psychiatry/Psychology 1 0,0 2,8
p.000021: Pharmacology/Toxicology 1 0,0 0,8
p.000021: Total 412 100,0 100,0
p.000021:
p.000021: Clinical trials on women for therapeutic field (AIFA data 01/01/2000 - 31/12/2006)
p.000021:
p.000021:
p.000021: Table 4
p.000021: Therapeutic class Controlled clinical trials N. subjects Women (%) Thrombolytics 176
p.000021: 279.179 24.1
p.000021: Antithrombotics 103 167.878 27.0
p.000021: Antiarrhythmics 80 45.430 22.6
p.000021: Beta blockers 70 56.517 20.6
p.000021: Antiaggregants 69 91.172 24.0
p.000021:
p.000021: Data on the participation of women to clinical trial in the principal therapeutic classas (80% of trials). The table is
p.000021: part of a more extensive table: not all therapeutic classes have been referred to (the others cover 20% of the trials).
p.000021: In the original version RCT stands for ‘Randomized Controlled Trials’. Data taken by
p.000021: P.Y. Lee, K.P. Alexander, B.G. Hammill et al., Representation of Elderly Persons and Women in Published Randomized
p.000021: Trials of Acute Coronary Syndromes, JAMA, 2001, 286(6), pages 708-713
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000022: 22
p.000022:
p.000022:
p.000022:
p.000022: Table 5
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022: Drug consumption by age and sex (DDD – Defined Daily Dose per day per 1000 inhabitants)- AIFA (National Drug Agency)
p.000022: data regarding 2006.
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000023: 23
p.000023:
p.000023:
p.000023: Table 6
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023: Reported cases of adverse reactions to drugs (Adrs – Adverse Drug ReactionS) by sex and age – AIFA data regarding 2007.
p.000023:
p.000023:
p.000023:
...
Social / Ethnicity
Searching for indicator ethnicity:
(return to top)
p.000003: western civilizations, with consequent changes regarding the relationship between health and illness.
p.000003: Some illnesses traditionally considered typical of the male population are now statistically more
p.000003: widespread in women, but medicine – in some of the specializations in which it is developed – does not seem to take
p.000003: into adequate account such changes in their policies of prevention, diagnosis and cure.
p.000003: Biomedical research – in general and in past decades – tended to reflect predominantly a male
p.000003: perspective, according to some, assimilating women to men (except in some particular specializations): many
p.000003: researchers and doctors in some fields of human pathology have not adequately taken into account sexual
p.000003: differences with regards to the study of the symptoms, the assessment of the diagnosis and the efficacy of the
p.000003: treatments. The lack of consideration of sexual differences is part of a research that tends to the generalisation of
p.000003: any organic phenomenon (although this is necessary), not always paying enough attention to differences due to
p.000003: sex, as well as those due to age (taking into account under-age patients2 and the elderly), disability and
p.000003: ethnicity.
p.000003: However it is fair to indicate that not only a more “mature” clinic, but also a more careful research, have in recent
p.000003: time offered, and continue to offer more and more today, examples of greater balance in the formulation of protocols
p.000003: and the relative “enlistments” of the subjects.
p.000003: Medicine’s “neutral” approach, “in-different” to sex differences, has come to light for a long time in the
p.000003: experimentation of medicines, for reasons that will be subsequently clarified. As a consequence, although on one
p.000003: hand we highlight an increase in the consumption of medicines by women in comparison to men3, on the other hand
p.000003: it appears
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003: 1 This is true in almost all Countries although there are great differences in the life expectancy of men and women.
p.000003: A. Barford, D. Dorling, G Davey Smith, M. Shaw, Life Expectancy: Women Now on Top Everywhere, “British
p.000003: Medical Journal”, 2006, 332, p. 808.
p.000003: 2 On this topic cf Regulation (CE) number 190/2006 of the European Parliament and of the Council of
p.000003: Europe regarding drugs for paediatric use, which ends the marketing of drugs tested almost exclusively on adult
p.000003: subjects.
p.000003: 3 In Italy the greater consumption of drugs by women is per-capita data, therefore normalised. Cf.
p.000003: paragraph 5.
p.000003:
p.000004: 4
p.000004:
...
Social / Fetus/Neonate
Searching for indicator foetus:
(return to top)
p.000005: especially with regard to the protection of the patients.
p.000005: Clinical experimentation in order to develop new drugs in Italy, as in the rest of Europe, takes place with common
p.000005: methods, through various experimental phases, in accordance with the norms of “Good Clinical Practices”10.
p.000005: This allows homogeneity from a scientific point of view as well as from an ethical point of view, with regards to the
p.000005: respect due to the rights of the patients involved. The regulations make provisions for the verification of the safety
p.000005: and the efficacy of the new drugs before their introduction on the market. This verification applies the methods of
p.000005: evidence based medicine (EBM), which at the moment is considered the most adequate model to guarantee that
p.000005: the introduction of new drugs will benefit the greatest amount of patients. We must remember that this
p.000005: is not the only possible model, but it is the one that is generally considered the most suitable because
p.000005: of the needs of modern medicine and because of its impact on the population’s health.
p.000005: Drugs’ experimentation, before the authorisation to market them, makes provisions, after the pre-clinical phase, for
p.000005: phase I, essentially about safety, and phases II and III, in which
p.000005:
p.000005: 9 With regards to experimentation which is not directly therapeutic in the interest of the pregnant woman or of the
p.000005: breast feeder, aiming to achieve effective protection of the health of the woman, of the embryo and of the foetus, and
p.000005: of the child after birth, the additional conditions anticipated in ch. VI of article 18 of the additional Protocol to
p.000005: the Convention of human rights and biomedicine are applied, relative to biomedical research, approved in Strasbourgh on
p.000005: the 25th of January 2005, which indicate particular precautions.
p.000005: 10 The “Good Clinical Practices” constitute an international standard of ethics and quality of planning,
p.000005: managing and recording clinical studies. In Italy they were first adopted as part of the national legislation with the
p.000005: ministerial decree of the 15th of July 1997.
p.000005:
p.000006: 6
p.000006:
p.000006: the efficacy of the drug on a growing number of patients is established. Subsequently the drug is authorised by the
p.000006: health authorities and becomes part of the clinical practice. Other phase IV studies can take place,
p.000006: always with experimental characteristics and therefore with the enlistment of a certain number of patients, aimed
p.000006: at better establishing the efficacy of a new drug with regards to the safety of use, even for longer periods of time.
p.000006: The whole process is under the control of health authorities, primarily of the Italian Drug Agency (IDA), which is
p.000006: called to supervise and if necessary direct, through its funding, drug research11.
p.000006:
...
p.000010: during childbearing and non-childbearing age (menstrual cycle, pregnancy, breast feeding,
p.000010: menopause) and to the possible consumption of contraceptives for contraceptive or therapeutic reasons (estrogens and
p.000010: progestin modify women’s metabolism; the estrogens also affect the way genes work). This kind of variability does not
p.000010: allow the collection of “clean data” in mixed sex trials and lowers the statistical relevance of the
p.000010: experimentation. Even when there are women involved in the trial, it is not certain that the enlisted
p.000010: number can allow us to see significant events.
p.000010:
p.000010:
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: e) Possible pregnancy during childbearing age27. One of the reasons that have led the pharmaceutical
p.000011: industry to exclude women from trials is connected to the possibility that the trial of a new drug
p.000011: could damage the foetus28 in case of pregnancy. There is also the possibility that the studied drug could have
p.000011: negative effects even after the end of the trial, months later. This explains why in general the pharmaceutical
p.000011: industry imposes the use of specific hormonal contraceptives29 as condition for the participation in a research
p.000011: that can be considered “without risk” for the foetus.
p.000011:
p.000011: 7. The exclusion/inclusion of women of childbearing age in trials protocols
p.000011:
p.000011: Regarding the problem of pharmacological experimentation on women of childbearing age, the literature
p.000011: presents a variety of positions: within those, we report the most spread ones.
p.000011: Some affirm that the inclusion of women of childbearing age in the trails is ethically of the outmost
p.000011: importance, when balancing the possible damage to the foetus (considered not yet to have dignity in a strong sense)
p.000011: with the predictable direct benefits to women and in general to society30. From this point of view, the a priori
p.000011: exclusion of women of childbearing age from trails (to protect the possible foetus) results in injustice in the
p.000011: biomedical research, as women do not have the same opportunities as men with regards to the cure of certain
p.000011: illnesses. The particular physio-psychological and social conditions of women should not justify their exclusion,
p.000011: but, on the contrary, motivate a differentiated study in comparison to men. The expectation of the
p.000011: pharmaceutical industry that women should use hormonal contraceptives is also criticised as restrictive of women’s
p.000011: freedom intended as self-determination.
p.000011: Others maintain that where clinical trials, even only hypothetically and probably, poses a danger to the foetus’ life
p.000011: and health (here the foetus is recognised as a subject
p.000011:
p.000011: 27 U. Halbreich, S.W. Carson, Drug Studies in Women of Childbearing Age: Ethical and Methodological Considerations, “J.
p.000011: Clin. Pharmacol.”, 1989, 9, pages 328-333.
p.000011: 28 The risks of teratogenicity for the foetus are classified as follows by the Food and Drug Administration:
p.000011: “controlled study without risk” when the safety of the drug in all stages of pregnancy has been
p.000011: demonstrated; “remote but possible risk” when in the studies on animals an increase in foetal anomalies has not been
p.000011: demonstrated but the risk is possible; “no chance to exclude risk” when the risks have been demonstrated
p.000011: by teratogen effects in the studies on animals and there are few studies on humans; “positive evidence of risk” when
p.000011: the teratogen effect has been demonstrated; “contraindicated during pregnancy” when there is positive
p.000011: evidence, in both studies on animals and humans, of the risk for the foetus. Even the potential benefits for women are
p.000011: variable and oscillate from the therapy for deadly illnesses that cannot be cured in any other way (for instance,
p.000011: cancer cures) to the cure of non-deadly pathologies (take into account the cure of acne).
p.000011: 29 We refer to the use of hormonal contraceptives, as with the use of barrier contraceptives (e.g.
p.000011: preservatives), even if they do not interact with the drugs, there is a percentage of risk of pregnancy. The need for
p.000011: the use of contraceptives is functional to the experimentation to protect the foetus as well as to guarantee the
p.000011: conditions of homogeneity.
p.000011: 30 This is also the theory supported by the feminist circle. Cf. D.A. DeBruin, Justice and the Inclusion of Women in
p.000011: Clinical Studies: an Argument for Further Reform, “Kennedy of Institute of Ethics Journal”, 1994, 3,
p.000011: pages 533-538; Id., No Longer Patient. Feminist Ethics and Health Care, Temple University Press,
p.000011: Philadelphia 1992, pages 158-175; V. Merton, Ethical Obstacles to the Participation of Women in Biomedical Research,
p.000011: in Wolf S.M. (ed.), Feminism and Bioethics. Beyond Reproduction, Oxford University Press, Oxford-New York
p.000011: 1996.
p.000011:
p.000012: 12
p.000012:
p.000012: having dignity in the strong sense), it is ethically advisable to women of childbearing age to avoid participating in
p.000012: clinical studies, as the risk to the new life overrides the potential benefits to women. However, it is accepted that
p.000012: women could decide to be part of the trials for social reasons or for personal health needs. In such cases,
p.000012: however, the imposition by the pharmaceutical industry to use hormonal contraceptives is not
p.000012: considered morally acceptable as, even for those who support this point of view this imposition is seen
...
p.000013: for the Format and Content of the Clinical and Statistical Sections of the New Drug Application, highlights the
p.000013: under-representation of women in pharmacological trial and recommends the analysis of sex-differentiated data in
p.000013: clinical trials34. In 1993 the FDA again issued the Guidelines for the Study and Evaluation of gender
p.000013: Differences in the Clinical Evaluation of Drugs, recognising that the percentage of the participation of women to
p.000013: clinical experimentations in pathologies not typically female is inferior to that of men and hoping for the inclusion
p.000013: of women in the trials protocols with the aim to guarantee equal representation. The FDA accepts that such exclusion
p.000013: could have, in subtle ways, caused the impression that men are the “primary focus” of medicine and of
p.000013: pharmacological development, with women being of secondary consideration; it therefore recommends the removal of the
p.000013: prohibition of the participation of women of childbearing age to the first phases of trial, with the aim
p.000013: to prevent forms of discrimination, avoiding a paternalistic attitude. The FDA believes that it is not necessary to
p.000013: exclude women because of the potential risks to the foetus, as the risks can be minimised with an explicit commitment
p.000013: of the woman to avoid pregnancy, as well as through the use of laboratory tests which can ascertain such behaviours.
p.000013: The FDA does not impose any obligations on the pharmaceutical industry and to IRBs (Institutional Review Boards,
p.000013: equivalent to independent ethical Committees), to include women in experimentation, but it aims to remove the
p.000013: “not necessary impediment”, in order to boost a higher participation of women in trials, leaving “flexibility”
p.000013: to the IRBs, to the researchers, to the sponsors and also, all considered, to the patients who have
p.000013: been correctly informed with regards to determining the safest measures to protect their health and individual
p.000013: rights, recognising the responsible autonomy of women as research subjects.
p.000013: At an international level these issues are included in an indicative document within the medical field.
p.000013: Also in 1993 the Council for International Organizations of Medical Sciences (CIOMS) promulgates the
p.000013: International Ethical Guidelines for Biomedical Research Involving Human Subjects (revised in 2002),
p.000013: recommending the researchers, the sponsors and the ethical committees to avoid excluding women of
p.000013: childbearing age from trials, as they do not believe the possibility of a pregnancy is sufficient reason
p.000013: to preclude or limit their participation and recognising that women have the ability to take a “rational decision” in
p.000013: participating in research (guideline number 16). In the case of risk to the foetus’ health, women have to accept to
p.000013: undertake a pregnancy
p.000013:
p.000013:
p.000013: 33 K.L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice,
p.000013: “Journal of Health Politics, Politics and Law”, 1999, 24 (3), pages 531-566.
p.000013: 34 R.B. Merkatz, Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, “Acad
p.000013: Med”, 1994, 69, pages 703-707; R.B. Merkatz, R. Temple, S. Sobel, Women in Clinical Trials of new Drugs. A Change in
p.000013: Food and Drug Administration Policy, “The New England Journal of Medicine”, 1993, 329 (4), pages 292-296.
p.000013:
p.000014: 14
p.000014:
p.000014: test and to use an “effective contraceptive method”, allowing, with such procedures, their enlistment also in the first
p.000014: phases of the trials with controlled doses of the new substance; we highlight that the informed consent must be
p.000014: guaranteed offering women a fair amount of time and adequate environmental conditions to decide, believing
p.000014: that an individual consent is a must, and that it cannot be substituted by the partner’s consent. In addition, CIOMS
p.000014: recommends that even pregnant women are acceptable (guideline number 17) as trials subjects, provided that the risks
p.000014: (for the woman and for the foetus) are minimised, leaving the decision to the individual woman, even in the
p.000014: case of uncertainty and ambiguity about the definition of risk; the research can be promoted only if it is relevant
p.000014: to the health of the woman who is subjected to the trials and to other women in the same condition; it is believed that
p.000014: women can be recruited into the research only in case there are pre-clinical studies which state the drug’s
p.000014: teratogenity.
p.000014: In 1994 in the United States, a dedicated office called “Office of Women’s Health” was created as part of
p.000014: the FDA, with the objective of boosting the inclusion of women in clinical studies, evaluating the different
p.000014: responses for the safety and the efficacy of drugs. In 1995 the previous instructions were strengthened
p.000014: further in the document Investigational New Drug Applications, which explicitly demands an end to any
p.000014: discrimination due to sexual difference, as well as age and race, in trials. In 1998 the FDA promulgates the Final Rule
p.000014: on the Investigational Drug Applications with the aim of actively intervening with sponsors who do not respect
...
p.000017: achieve an active participation of women (not only as researchers, but also as representatives of patients’
p.000017: associations) to the elaboration of the procedures for the protocols and for the relevant informed consent;
p.000017: to promote greater attention from ethical committees to sexual difference in research protocols;
p.000017: d) boost health training which focuses on the female dimension within pharmacological
p.000017: trials, as well as within research and cure; e) increase international cooperation, as well as national and
p.000017: local, with the focus on the female condition within clinical trials, involving health authorities and the
p.000017: pharmaceutical industry.
p.000017: 6. The NBC believes that even the participation of women of childbearing age in pharmacological trials is
p.000017: ethically and socially important, provided that an adequate protection of the future child can be guaranteed. The NBC
p.000017: highlights the importance of a preliminary consultation about the intended trials, including adequate
p.000017: information, clear and in full, according to an objective, technical-scientific classification of the
p.000017: risks and benefits that the study involves for the patient, but that also taking into account the risks for the foetus
p.000017: in case of pregnancy37. We must also take into account that the exclusion of women of childbearing age from trials does
p.000017: not allow, in practice, to protect the foetus, as women could take the experimented drug (but not tested on them) on
p.000017: the market with similar risks in case of pregnancy and, to make it worse, without adequate protection. The NBC believes
p.000017: that the inclusion of women of childbearing age in pharmacological trials that poses risks to the foetus
p.000017: needs, unavoidably, the woman’s clear statement of a conscious and responsible commitment to avoid
p.000017: intercourse that could lead to pregnancy. If it is not possible to exclude a risk to the foetus’ life and
p.000017: health within the trials, but there are possible benefits to women in general and in particular in the
p.000017: cure of illnesses, the NBC believes that requesting the commitment to take contraceptives as a safety measure
p.000017: believed necessary by the study’s sponsor – to avoid pregnancy, as the trials could be damaging to the foetus – can be
p.000017: included in the criteria to participate in the study.
p.000017: In addition, the NBC believes that it is important that the woman’s husband or partner is also involved in the
p.000017: informative counselling, as the choices being made involve them as a couple.
p.000017: The trial of drugs that can make hormonal contraceptives ineffective is an open problem, so it is the fact
p.000017: that there might be interactions between the treatments being studied and the contraceptive methods being used: in this
p.000017: case the experimenters have to adequately inform the woman (and also her husband or partner) and recruit only on
p.000017: condition of a commitment, clearly expressed in the informed consent (given a fair
p.000017:
p.000017:
p.000017: 37 The risks for the foetus and the benefits for the woman must be put in the balance, according to a gradation of
p.000017: ethical justification: the experimentation of drugs that do not present any risks to the foetus is
p.000017: considered as devoid of problems (for any purpose, both for therapeutic and non-therapeutic purposes, e.g. esthetic
p.000017: purposes); the experimentation that present a certain or uncertain risk to the life or health of the future child is
p.000017: considered ethically unacceptable, with the exception of drugs that can cure serious illnesses for the woman who
p.000017: undergoes the trial
p.000017:
p.000018: 18
p.000018:
p.000018: amount of time for reflection), to avoid starting a pregnancy during the time of the trials and, in some cases,
p.000018: also for a certain time afterwards, a time to be defined according to the typology of the trials. The woman,
p.000018: on her part, must be available to carry out checks (pregnancy tests) that allow the experimenters to verify
p.000018: the conditions of safety to proceed. The informed consent and the committment to avoid procreation applies also to men
p.000018: who enter a trial protocol which presents the risk of damage to the foetus through their gametes.
p.000018:
p.000018:
p.000018: Bibliography38
p.000018:
p.000018: Bennett J.C., Inclusion of Women in Clinical Trials. Policies for Population Subgroups, “New England
p.000018: Journal of Medicine”, 1993, 329 (4), pp. 288-292
p.000018:
p.000018: Borgia L.M. (a cura di), Manuale di bioetica per la sperimentazione clinica e i comitati etici,
p.000018: Edizioni Medico Scientifiche, Torino 2008 (cfr. pp. 36-45)
p.000018:
p.000018: Buffoni F., Donne nella ricerca farmacologica italiana, Quaderni della SIF, marzo 2006, 5, pp. 6-7
p.000018:
p.000018: Ceci A., Legislazione e criticità nella sperimentazione dei farmaci, Agenzia Sanitaria Servizi Sanitari
p.000018: Monitor ASSR, 2005, 12, pp. 67-71
p.000018:
p.000018: Commissione Nazionale per la parità e le pari opportunità tra uomo e donna, Presidenza del Consiglio dei Ministri,
p.000018: Guida alla salute delle donne, a cura di E. Reale, Dipartimento per l’Informazione e l’Editoria, 2003
p.000018:
p.000018: Fleisch J., Fleisch M.C., Thurmann P.A., Women in Early-Phase Clinical Drugs Trials: Have Things Changed
p.000018: over the Past 20 Years?, “Clinical Pharmacology and Therapeutics”, 2005, 78 (5), pp. 445-452
p.000018:
p.000018: Food and Drug Administration, Department of Health and Human Services, FDA Scholarship in Women’s Health Program,
p.000018: Participation of Females in Clinical Trials and Gender Analysis of Data in Biologic Product Application,
p.002001: 2001
p.002001:
...
Social / Marital Status
Searching for indicator married:
(return to top)
p.000024: the other hand, is equally important, for those who promote and conduct a clinical trial, to always
p.000024: consider the potential risk of teratogenicity in case of pregnancy, especially if there is already previous evidence
p.000024: from the studies on animals. From this, comes the absolute need, for potentially fertile subjects (even men carry
p.000024: such risk, when the drug can produce pathological changes of the spermatozoons), to avoid conception during the
p.000024: trial treatment and until the cessation of its effects.
p.000024: We believe that these aspects have been well identified in the document and we agree with the arguments put forward in
p.000024: it.
p.000024: We don’t think, however, that it is ethically acceptable or justifiable from a medical point of view,
p.000024: to force the inclusion of potentially fertile patients in pharmacological clinical trials to use
p.000024: contraceptive methods chosen and imposed by the sponsor and supported by binding clauses from insurance companies, in
p.000024: order to give the necessary economical guarantees to cover possible damages. This request, independently from ethical
p.000024: and religious positions, is not in fact in keeping with the responsible freedom of choice that – within completely
p.000024: personal choices like those regarding married life and the responsibility to procreate – the patient applying to enlist
p.000024: in clinical trials must take on in a personal and independent way, after an exhaustive conversation with the doctor
p.000024: experimentator.
p.000024: In addition, we highlight that contractual imposition from the sponsor of the trials to use contraceptive
p.000024: methods, gives ethical committees, which operate in health institutions regulated by particular
p.000024: rules, some evident difficulties in evaluating and accepting the protocols.
p.000024:
p.000024:
p.000024:
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p.000024:
p.000024:
p.000024:
p.000025: 25
p.000025:
p.000025: Redazi.one Comitato Nazionale per la
p.000025: Bioetica
p.000025:
p.000025:
p.000025:
p.000025:
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p.000025:
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p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025: Pubblicazione edito d,olla Presidenza del Consiglio dei Ministri Diyarlime ritr• y er l’lrtformayione e
p.000025: l’Editoria
p.000025:
p.000025: Capo del Dipartimento Elisa Grande
p.000025:
...
Social / Property Ownership
Searching for indicator home:
(return to top)
p.000009: “British Medical Journal”, 2007, 334, p. 551; S. Saif Rathore, M.P.H. Yongfei Wang, H.M. Krumholtz, Sex-Based
p.000009: Differences in the Effect of Diagoxin for the Treatment of Heart Failure, “NEJM”, 2002, 347, pages. 1403-1411.
p.000009: 25 Cf. Withdrawn Drugs Posed Greater Health Risk for Women then Man, GAO says, “American Journal of Health-System
p.000009: Pharmacy”, March 15, 2001, 58 (6), pages 458-462; United States General Accounting Office, Drug Safety:
p.000009: Most Drugs Withdrawn in Recent Years had Greater Health Risk for Women, Washington D.C. 2001.
p.000009: 26 D. Wrigt, N.J. Chew, Women as Subjects in Clinical Research, “Applied Clinical Trials”, 1996, 5 (9), pages 44-54; E.
p.000009: Shuster, For her Own Good: Protecting (and Neglecting) Women in Research, “Cambridge Quarterly of Healthcare Ethics”,
p.000009: 1996, 5, pages 346-361.
p.000009:
p.000010: 10
p.000010:
p.000010: a) Social reasons. Some sociological studies highlight women’s difficulties in becoming part of clinical
p.000010: studies due to the lack of time (mainly because of their role of carers within the family or, in the case of
p.000010: working women, due to their double obligation at home and at work) or due to their low income (because of the not
p.000010: yet adequate participation of women in the work-market and because of their lower wages). In part the reticence to
p.000010: participate is also due to the recruiters’ lack of attention to the practical and psychological needs of women.
p.000010: b) External environmental reasons. There are also other factors linked with lifestyle or exposure to substances
p.000010: that can interact with the experimental drugs. In external working environments, generally any substances
p.000010: present should be known; in less controlled working environments however, risky conditions can occur. Even
p.000010: lifestyle, which includes dietary habits or the use of natural remedies, exposes the patients to substances that can
p.000010: influence the clinical response to the pharmacological experimentation. Women are generally more inclined to
p.000010: use natural substances or home remedies consolidated in the cultural tradition of the family. Even if in
p.000010: clinical experimentation the treatment in the various experimental branches is the same, it is not always
p.000010: possible to keep under control lifestyle differences and external factors that can affect the experimentation in a
p.000010: different way for men and women.
p.000010: c) Economic reasons. The pharmaceutical industry prefers not to invest in the experimentation on women
p.000010: due to the inevitable rise in costs. The enlistment should necessarily be multiplied: to stratify the data
p.000010: according to gender, men and women should be recruited, doubling or quadrupling the amount of enlistments, increasing
p.000010: time and cost, trails costs and insurance costs to cover eventual negative effects. Even the use of
p.000010: female and male animals in the pre-clinical phase increases the time and the cost of the research. As the
p.000010: authorisation for the introduction of the drug on the market does not require it, the pharmaceutical
p.000010: industry is not motivated to undertake such studies, as they are seen as economically
p.000010: disadvantageous. On the other hand public funding chooses typically female pathologies (like osteoporosis
p.000010: during the menopause), to be able to better tackle the health policies of a country where women live
...
Social / Racial Minority
Searching for indicator race:
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p.000014: recommends that even pregnant women are acceptable (guideline number 17) as trials subjects, provided that the risks
p.000014: (for the woman and for the foetus) are minimised, leaving the decision to the individual woman, even in the
p.000014: case of uncertainty and ambiguity about the definition of risk; the research can be promoted only if it is relevant
p.000014: to the health of the woman who is subjected to the trials and to other women in the same condition; it is believed that
p.000014: women can be recruited into the research only in case there are pre-clinical studies which state the drug’s
p.000014: teratogenity.
p.000014: In 1994 in the United States, a dedicated office called “Office of Women’s Health” was created as part of
p.000014: the FDA, with the objective of boosting the inclusion of women in clinical studies, evaluating the different
p.000014: responses for the safety and the efficacy of drugs. In 1995 the previous instructions were strengthened
p.000014: further in the document Investigational New Drug Applications, which explicitly demands an end to any
p.000014: discrimination due to sexual difference, as well as age and race, in trials. In 1998 the FDA promulgates the Final Rule
p.000014: on the Investigational Drug Applications with the aim of actively intervening with sponsors who do not respect
p.000014: the instructions of fairness within sexual difference. In 1999 the working group “FDA-MA Women and Minorities
p.000014: Working Group” was created, with the aim of drawing up specific guidelines to boost the correct inclusion of women and
p.000014: of weak subjects in clinical trials. In 2001 the National Institute of Health in the USA issued the document
p.000014: Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research to promote a policy
p.000014: of women’s inclusion in the enlistment for pharmacological trials. It is important to highlight that the
p.000014: Department of Health and Human Services in issuing the Regulations for the Protection of Human Subjects in 2001,
p.000014: does not take explicitely into account tendencies and directives for the researchers, the doctors and IRBs on the
p.000014: specific theme of trials on women of childbearing age.
p.000014: Within the European biolegislation we highlight the focus on female specificity within the general area of
p.000014: health35, but lacking specific provisions of policies of non- exclusion or inclusion of women in clinical
...
Social / Religion
Searching for indicator religious:
(return to top)
p.000024: of phatologies indifferent to standard treatments or of rare diseases) another opportunity of therapy – even if
p.000024: uncertain in outcome -, that can be a priori precluded to women because of their fertile condition. On
p.000024: the other hand, is equally important, for those who promote and conduct a clinical trial, to always
p.000024: consider the potential risk of teratogenicity in case of pregnancy, especially if there is already previous evidence
p.000024: from the studies on animals. From this, comes the absolute need, for potentially fertile subjects (even men carry
p.000024: such risk, when the drug can produce pathological changes of the spermatozoons), to avoid conception during the
p.000024: trial treatment and until the cessation of its effects.
p.000024: We believe that these aspects have been well identified in the document and we agree with the arguments put forward in
p.000024: it.
p.000024: We don’t think, however, that it is ethically acceptable or justifiable from a medical point of view,
p.000024: to force the inclusion of potentially fertile patients in pharmacological clinical trials to use
p.000024: contraceptive methods chosen and imposed by the sponsor and supported by binding clauses from insurance companies, in
p.000024: order to give the necessary economical guarantees to cover possible damages. This request, independently from ethical
p.000024: and religious positions, is not in fact in keeping with the responsible freedom of choice that – within completely
p.000024: personal choices like those regarding married life and the responsibility to procreate – the patient applying to enlist
p.000024: in clinical trials must take on in a personal and independent way, after an exhaustive conversation with the doctor
p.000024: experimentator.
p.000024: In addition, we highlight that contractual imposition from the sponsor of the trials to use contraceptive
p.000024: methods, gives ethical committees, which operate in health institutions regulated by particular
p.000024: rules, some evident difficulties in evaluating and accepting the protocols.
p.000024:
p.000024:
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p.000025: 25
p.000025:
p.000025: Redazi.one Comitato Nazionale per la
p.000025: Bioetica
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p.000025:
p.000025: Pubblicazione edito d,olla Presidenza del Consiglio dei Ministri Diyarlime ritr• y er l’lrtformayione e
p.000025: l’Editoria
p.000025:
p.000025: Capo del Dipartimento Elisa Grande
p.000025:
...
Social / Unemployment
Searching for indicator unemployment:
(return to top)
p.000007: 17 M. Anthony, M.J. Berg, Biological and Molecular Mechanism for Sex Differences in Pharmacokinetics, Pharmacodynamics,
p.000007: and Pharmacogenetics: part I, “Journal of Women’s Health and Gender-Based Medicine”, 2002, 11 (7), pages
p.000007: 601-615; M. Gandhi, F. Aweeka, R.M. Greenblatt, T. Blaschke, Sex Differences in Pharmacokinetics and
p.000007: Pharmacodynamics, “Ann. Rev. Pharmacol. Toxicol.”, 2004, 44, pages 499-523, A.D.M. Kashuba, A.N. Nafzinger
p.000007: Physiological Changes during the Menstrual Cycle and their Effects on the Pharmacokinetics and Pharmacodynamics
p.000007: of Drugs, “Clinical Pharmacokinetics”, 1998, 34 (3), pages 203-218; P.A. Thuermann, B.C. Hompesch,
p.000007: Influence on Gender on the Pharmacokinetics and Pharmacodynamics of Drugs,“International Journal of Clinical
p.000007: Pharmacology and Therapeutics”, 1998, 36 (11), pages 586-590.
p.000007: 18 Cf. A. Holdcroft, Gender Bias in Research: How does it affect Evidence Based Medicine?, editorial “J. Royal Soc.
p.000007: Med.”, p. 100.
p.000007:
p.000008: 8
p.000008:
p.000008: qualified workers); the change in the participation in the work-market (many traditionally male jobs are open to
p.000008: women), the strong female push towards a career, but the persistent difficulties in the work-market (the participation
p.000008: of women is nevertheless inferior to that of men, with greater unemployment problems or relinquishment of work
p.000008: places due to maternity and lack of working facilitations and social aids); the increase of the public
p.000008: participation on a social, political, economic basis, but the persistent marginalisation (there are still few
p.000008: women in positions of power and responsibility); the behavioural traits generally more frequent in women (e.g.
p.000008: the inclination to take care of others and the selflessness). The change of women’s conditions from
p.000008: a historical, cultural and psychological point of view has relevant implications on their conditions of illness
p.000008: and health, on the way women perceive them and live through them. We highlight how, many pathologies traditionally
p.000008: attributed to the male gender because of their physical structure or their behavioural habits on an individual and
p.000008: social basis, are also widespread – and at times more greatly – in the female sex, due to the change in lifestyles and
p.000008: risk factors and/or to a lack of an adequate prevention, diagnosis and cure.
p.000008: The research on women’s health, elaborated by NOWH (National Observatory on Women’s Health) in collaboration with
...
Social / Victim of Abuse
Searching for indicator abuse:
(return to top)
p.000008: The research on women’s health, elaborated by NOWH (National Observatory on Women’s Health) in collaboration with
p.000008: the National Observatory of Health in Italian Regions, part of the Catholic University of the Sacred Heart19,
p.000008: highlights (in the second part: “Health needs and health assistance”) the condition of women’s health and
p.000008: the quality of health assistance. In the pathologies most common in women – where the frequency of the
p.000008: pathologies is linked to age and social condition – we can find some relevant elements: an increase in
p.000008: cardiac pathologies (arterial hypertension, coronary cardiomyopathy, peripheral arteriopathy and cardiac
p.000008: imbalance, thromboembolic pathologies); an increment in the oncological field, as well as “female cancers” (breast
p.000008: cancer, carcinoma of the uterine cervix, endometrial tumours, ovarian neoplasia), also of trachea-bronchi-lungs
p.000008: tumours, due to the spread of nicotine addition even during adolescence; an increase in psychological
p.000008: pathologies (anxiety and depressive syndromes, eating disorders, psychotic syndromes); a tendency to an increase
p.000008: in obesity, due to the lack of physical activity and sedentary life, with an increase in the risk of
p.000008: cardiovascular illnesses and diabetes; an increase in alcohol abuse (with nutritional imbalances and
p.000008: dependency); an increase in neurodegenerative illnesses (Alzheimer’s illness, Parkinson disease, multiple
p.000008: sclerosis, senile dementia); an increase in problems linked to infertility, caused by the postponement of the decision
p.000008: to have children or by the protracted use of contraceptives; problems and pathologies linked with the
p.000008: non- acceptance of aging also emerge20.
p.000008: These changes in the conditions of women’s health and illness emphasise even more the lack of an
p.000008: adequately differentiated trails for the care of women’s health, beyond traditional areas.
p.000008:
p.000008:
p.000008:
p.000008: 19 La salute della donna. Stato di salute a assistenza nelle regioni italiane. Libro bianco, Franco Angeli, Milano
p.000008: 2007.
p.000008: 20 Different the causes: the problems of the substitutive hormonal therapy; the possibility to postpone for decades
p.000008: physical aging, extending the menstrual cycle for years as well as intervening with plastic surgery, with possible
p.000008: dangers for women’s health, and not only because of the bad quality of the treatments – as in the case of deaths
p.000008: due to routing operations, like liposuction – but also because of extended negative effects, injected
p.000008: liquids and stress, due to the effort of not showing their real age.
p.000008:
p.000009: 9
p.000009:
...
Social / Women
Searching for indicator women:
(return to top)
p.000045:
p.000045: N. 4
p.000045:
p.000045:
p.000045:
p.000045:
p.000045: Comitato Nazionale per la Bioetica
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
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p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045: La sperimentazione farmacologica
p.000045: sulle donne
p.000045: (26 nove »bt e 2008)
p.000045: VEBStONElTALlAM& E )NG6ESE
p.000045:
p.000045: NATIONAL BIOETHICS COMMITTEE
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045: PI1àIJHàC0L0GIC࣠HIàLS
p.000045:
p.000045: 28ih Noember 2008
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
p.000045:
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p.000045:
p.000045:
p.000045:
p.000045:
p.000045: DEPARTMENT OF INROMATION AND PUBLISHING
p.000045:
p.000045: TABLE OF CONTENTS
p.000045:
p.000045:
p.000045: l'rosentntion
p.000045: 45
p.000045: 1. Introduction
p.000047: 47
p.000047: 2. Clinieal experimentation 50
p.000047: 3. Clinical experimentation on women: under-representation in the enlistment
p.000047: and shortcomings in the differentiated analysis of the data 51
p.000047: 4. New needs of experimentation differentiated by sex:
p.000047: the changes of health/illness in women 53
p.000047: 5. Women as drug users and the problem
p.000047: of the side-effects 55
p.000047: 6. Female vulnerability in clinical trails: women
p.000047: as “weak subjects” 56
p.000047: 7. The exclusion/inclusion of women of childbearing
p.000047: age in trials protocols 58
p.000047: 8. Female presence in medical teams and in ethical committees 60
p.000047: 9. International bioethical guidelines 60
p.000047: 10. National legislation 64
p.000047: 11. Bioethical recommendations 65
p.000047: Bibliography
p.000069: 69
p.000069: l‘ei•s‹i›snl remark
p.000076: 76
p.000076:
p.000076:
p.000076:
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p.000076: ITALIAN NATIONAL BIOETHICS COMMITTEE
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: PHARMACOLOGICAL TRIALS ON WOMEN
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: 28th November 2008
p.000076:
p.000076:
p.000076:
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p.000001: 1
p.000001:
p.000001:
p.000001: PRESENTATION
p.000001:
p.000001:
p.000001: The National Bioethics Committee (NBC) in the plenary meeting of the 28th of November 2008 approved the Opinion
p.000001: “Pharmacological Experimentation on Women”.
p.000001: This document, starting with the analysis of the data on clinical experimentation on women, highlights their
p.000001: under-representation in enlistment and the poorly differentiated processing of the results, with particular
p.000001: reference to pathologies that are not specifically female. It is highlighted that, although women are the largest
p.000001: consumers of medicines, the experimentation tends not to sufficiently consider their specific nature and the change in
p.000001: the conditions of women’s health, with a consequent increase in side- effects when taking medicines. The document
p.000001: analyses the main reasons for this shortcoming, it discusses the ethical problems arising from it
p.000001: and analyses the international and national rules on the issue.
p.000001: The NBC proposes bioethical guidelines for an equal consideration of women in experimentation, highlighting the need
p.000001: for a differentiation, showing the dangers of a “neutral” pharmacology with regards to sexual differences.
p.000001: Women cannot be assimilated to men, like a mere variable, but have a specificity that experimentation must take into
p.000001: consideration in order to promote a medicine that adequately recognises equal opportunities
p.000001: between men and women. In order to increase pharmacological experimentation that is differentiated by
p.000001: sex, the NBC suggests to raise awareness within health authorities and to motivate pharmaceutical companies to support
p.000001: experimentation that is differentiated by sex, even though it might not be very profitable, encouraging
p.000001: research programs on the subject; to promote the participation of women in clinical trials with adequate information on
p.000001: the social importance of the experimentation on women; to guarantee a greater number of women as experimenters
p.000001: and as members of ethical Committees; to urge healthcare training that pays greater attention to the
p.000001: female dimension in pharmacological experimentation, as well as in research and treatment; to increase international
p.000001: cooperation, as well as national and local cooperation, focusing on the female condition in clinical experimentation.
p.000001: This text has been drafted by Prof. Laura Palazzani, coordinator of the working group, with the contributions of Prof.
p.000001: Silvio Garattini and of Dr. Laura Guidoni. Within the working group, Prof. Salvatore Amato, Prof. Luisella
p.000001: Battaglia, Prof. Adriano Bompiani, Prof. Cinzia Caporale, Prof. Francesco D’Agostino, Prof. Lorenzo d’Avack, Prof.
p.000001: Marianna Gensabella, Prof. Maria Luisa Di Pietro, Prof. Emma Fattorini, Prof. Carlo Flamigni, Prof.
p.000001: Assunta Morresi, Prof. Demetrio Neri, Prof. Andrea Nicolussi, Prof. Lucetta Scaraffia, Prof. Monica Toraldo di
p.000001: Francia, Prof. Giancarlo Umani Ronchi, Prof. Grazia Zuffa and Dr. Riccardo Di Segni participated to the discussion.
p.000001: During the meetings of the working group, the Presentations of Prof. Flavia Franconi, Prof Matilde Leonardi and Prof
p.000001: Carlo Tomino, offered important contributions.
p.000001: In the plenary meeting of the 28th of November 2008, the Opinion received the consensus of those present (Prof.
p.000001: Salvatore Amato, Prof. Stefano Canestrari, Prof. Antonio Da Re, Prof. Lorenzo d’Avack, Prof. Carlo Flamigni, Prof.
p.000001: Silvio Garattini, Prof. Marianna Gensabella Furnari, Prof. Laura Guidoni, Prof. Assunta Morresi,
p.000001: Prof.
p.000001:
p.000001:
p.000002: 2
p.000002:
p.000002: Demetrio Neri, Prof. Andrea Nicolussi, Prof. Laura Palazzani, Prof. Alberto Piazza, Prof. Lucetta Scaraffia, Prof.
p.000002: Monica Toraldo di Francia, Prof. Giancarlo Umani Ronchi and Dr. Riccardo Di Segni), with the abstention of
p.000002: Prof. Adriano Bompiani, Prof. Roberto Colombo, Prof. Francesco D’Agostino, Prof. Bruno Dallapiccola, Prof. Maria
p.000002: Luisa Di Pietro, Prof. Emma Fattorini.
p.000002: Prof. Adriano Bompiani, Prof. Bruno Dallapiccola, Prof. Maria Luisa Di Pietro, Prof. Rodolfo Proietti
p.000002: clarified their abstention with additional note, cited at the end of the text. Prof. Luisella Battaglia, Prof.
p.000002: Romano Forleo, Prof. Claudia Mancina, Prof. Vittorio Possenti and Prof. Grazia Zuffa, absent from the meeting,
p.000002: expressed their agreement.
p.000002: Rome, 28th November 2008 The President
p.000002: Prof. Francesco Paolo Casavola
p.000002:
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p.000003: 3
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003: 1.Introduction
p.000003:
p.000003: Recent studies highlight how women, in today’s society, have a longer life expectancy in
p.000003: comparison to men in the same socio-economic circumstances, but their life seems to have “less health”1.
p.000003: An apparent paradox – women live longer, but with more health problems in comparison to men – it can be
p.000003: explained also on the basis that the conditions of health and illness depend on complex relationships between
p.000003: the biological dimension, the psychic as well as symbolic component and the historical- social-cultural
p.000003: influences. The changes that women have lived through and are still living through are profound, especially in
p.000003: western civilizations, with consequent changes regarding the relationship between health and illness.
p.000003: Some illnesses traditionally considered typical of the male population are now statistically more
p.000003: widespread in women, but medicine – in some of the specializations in which it is developed – does not seem to take
p.000003: into adequate account such changes in their policies of prevention, diagnosis and cure.
p.000003: Biomedical research – in general and in past decades – tended to reflect predominantly a male
p.000003: perspective, according to some, assimilating women to men (except in some particular specializations): many
p.000003: researchers and doctors in some fields of human pathology have not adequately taken into account sexual
p.000003: differences with regards to the study of the symptoms, the assessment of the diagnosis and the efficacy of the
p.000003: treatments. The lack of consideration of sexual differences is part of a research that tends to the generalisation of
p.000003: any organic phenomenon (although this is necessary), not always paying enough attention to differences due to
p.000003: sex, as well as those due to age (taking into account under-age patients2 and the elderly), disability and
p.000003: ethnicity.
p.000003: However it is fair to indicate that not only a more “mature” clinic, but also a more careful research, have in recent
p.000003: time offered, and continue to offer more and more today, examples of greater balance in the formulation of protocols
p.000003: and the relative “enlistments” of the subjects.
p.000003: Medicine’s “neutral” approach, “in-different” to sex differences, has come to light for a long time in the
p.000003: experimentation of medicines, for reasons that will be subsequently clarified. As a consequence, although on one
p.000003: hand we highlight an increase in the consumption of medicines by women in comparison to men3, on the other hand
p.000003: it appears
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003: 1 This is true in almost all Countries although there are great differences in the life expectancy of men and women.
p.000003: A. Barford, D. Dorling, G Davey Smith, M. Shaw, Life Expectancy: Women Now on Top Everywhere, “British
p.000003: Medical Journal”, 2006, 332, p. 808.
p.000003: 2 On this topic cf Regulation (CE) number 190/2006 of the European Parliament and of the Council of
p.000003: Europe regarding drugs for paediatric use, which ends the marketing of drugs tested almost exclusively on adult
p.000003: subjects.
p.000003: 3 In Italy the greater consumption of drugs by women is per-capita data, therefore normalised. Cf.
p.000003: paragraph 5.
p.000003:
p.000004: 4
p.000004:
p.000004: that the effects of drugs on women are less studied or not adequately studied with regard to female specificity4. Women
p.000004: are more exposed to possible side-effects when
p.000004: they take drugs after their introduction on the market and we highlight less efficacy in the use of the drugs, with
p.000004: more frequent unwanted side-effects, which are also more serious compared to those experienced by men5.
p.000004: It is a bioethical problem that has emerged in international literature, in particular in the United States. It must be
p.000004: taken into account that the Food and Drug Administration (FDA) currently has an office that takes care specifically of
p.000004: women’s health and of their participation in clinical trials6 (the CDs “clinical trials gender oriented”)7. The
p.000004: European debate generally refers to the guidelines set by the United States; in Europe, until today, no National
p.000004: Bioethics Committee has chosen this theme as an object for reflection8. In Italy, studies regarding this field are
p.000004: still few, even if we can report recent initiatives in the direction of a greater consideration of the female
p.000004: specificity in pharmacological experimentation. In 2005 the Ministry of Health created the workbench on
p.000004: “Women’s health and drugs for women” (with the participation of the Superior Institute for Health, of the Italian
p.000004: Drug Agency, of the Regional Health Service Agency and of the Italian Society of Pharmacology). In 2007
p.000004: a working group was created “Gender approach to health” within the Women’s Health Commission, part of the
p.000004: Ministry of Health, with the primary objective of implementing the gathering of statistical data about female health,
p.000004: of promoting research and training in this field. In 2008, the Report on the “State of women’s health
p.000004: in Italy” was published, which, in the context of the general consideration of female health, also
p.000004: touches on the problem of drugs. Also in 2008, the Italian Drug Agency (IDA) introduced the equality between men and
p.000004: women as one of the criteria of the Evaluation of the Agreements’ Plan Commission to assign funds to
p.000004: industries which invest in Italy in pharmacological research. The Italian Society of Pharmacology (ISP) has
p.000004: in recent years started a working group that has the objective of motivating pharmacological research on sexual
p.000004: differences, through a campaign of information aimed at health workers, with the purpose of boosting the
p.000004: formation of experts in this sector and to raise awareness in health authorities.
p.000004: Awareness is growing – at a time in which we are trying to achieve the individualization of the cure,
p.000004: working on the genetic or immunity component – that the analysis of the data stratified by sex can give indications on
p.000004: the best therapy to follow and supply useful information for deeper studies with a scientific basis on the illnesses
p.000004: that
p.000004:
p.000004: 4 E. Annandale, K. Hunt, Gender Inequalities in Health, Open University Press, Buckingham 2000; F.
p.000004: Franconi, S. Canu, I. Campasi, working group “Approccio di genere alla salute”, Approccio di genere nella ricerca,
p.000004: nelle sperimentazioni e nei trattamenti farmacologici, in Lo Stato di Salute delle donne in Italia. Primo rapporto sui
p.000004: lavori della Commissione Salute delle Donne, Rome 2008, pages 39-53.
p.000004: 5 Cf. paragraph 5.
p.000004: 6 Cf. http://www.fda.gov/womens/trials.html. In some North American Universities, like the Columbia
p.000004: University in New York, there are activities entirely dedicated to these problems. In the last few years the
p.000004: publication “Gender Medicine” has published research aimed at highlighting the differences in the
p.000004: physiology, in the physiopathology or in the way the drugs respond. Even congresses on the topic are
p.000004: growing (htpp://www.gendercongress.com/).
p.000004: 7 We clarify that in this document the use of the expression “gender” refers to the sexual difference between men and
p.000004: women. This is not the place to tackle the problem of the identity of gender and of other meanings of the expression,
p.000004: on which the NBC intends to return in another document.
p.000004: 8 In the same month and year, the Austrian Committee for Bioethics issued “Recommendations with Gender
p.000004: Reference for Ethics Committees and Clinical Studies (15th November 2009),
p.000004:
p.000005: 5
p.000005:
p.000005: affect both men and women. Adequate participation of women in experimentation, would allow us to understand if in
p.000005: therapies there are significant differences that can be attributed to sex, even to be able to consider
p.000005: the different incidence or relapse of the pathology.
p.000005: The NBC has already looked at the general problem in pharmacological experimentation (The experimentation of drugs,
p.000005: 17th November 1992), but has not specifically analysed this problem in reference to women. The objective of this
p.000005: document is to reflect on the current state of pharmacological experimentation within sexual difference
p.000005: and on emerging bioethical problems, aiming to avoid any form of discrimination and to promote sexual
p.000005: equality in healthcare.
p.000005: In here, the document does not intend to look at the problem of the pharmacological
p.000005: experimentation on pregnant women, reserving the right to discuss the topic in a future document9.
p.000005:
p.000005: 2. Clinical experimentation
p.000005:
p.000005: When we speak of clinical trial, we generally refer to the process of verification of the safety and efficacy of a
p.000005: medicine in relation to therapeutic properties after a phase of laboratory research and pre-clinical experimentation on
p.000005: appropriate subjects. Clinical trial can in reality involve other therapeutic instruments, different from
p.000005: drugs, like medical devices, or diagnostic instruments, including genetic tests. However, as both the regulations and
p.000005: the ethical approach have essentially been developed for drugs, generally we refer to this sector of biomedical
p.000005: research, eventually transferring to the other sectors the models and the procedures that have been developed,
p.000005: especially with regard to the protection of the patients.
p.000005: Clinical experimentation in order to develop new drugs in Italy, as in the rest of Europe, takes place with common
p.000005: methods, through various experimental phases, in accordance with the norms of “Good Clinical Practices”10.
p.000005: This allows homogeneity from a scientific point of view as well as from an ethical point of view, with regards to the
p.000005: respect due to the rights of the patients involved. The regulations make provisions for the verification of the safety
p.000005: and the efficacy of the new drugs before their introduction on the market. This verification applies the methods of
p.000005: evidence based medicine (EBM), which at the moment is considered the most adequate model to guarantee that
p.000005: the introduction of new drugs will benefit the greatest amount of patients. We must remember that this
...
p.000005: of the child after birth, the additional conditions anticipated in ch. VI of article 18 of the additional Protocol to
p.000005: the Convention of human rights and biomedicine are applied, relative to biomedical research, approved in Strasbourgh on
p.000005: the 25th of January 2005, which indicate particular precautions.
p.000005: 10 The “Good Clinical Practices” constitute an international standard of ethics and quality of planning,
p.000005: managing and recording clinical studies. In Italy they were first adopted as part of the national legislation with the
p.000005: ministerial decree of the 15th of July 1997.
p.000005:
p.000006: 6
p.000006:
p.000006: the efficacy of the drug on a growing number of patients is established. Subsequently the drug is authorised by the
p.000006: health authorities and becomes part of the clinical practice. Other phase IV studies can take place,
p.000006: always with experimental characteristics and therefore with the enlistment of a certain number of patients, aimed
p.000006: at better establishing the efficacy of a new drug with regards to the safety of use, even for longer periods of time.
p.000006: The whole process is under the control of health authorities, primarily of the Italian Drug Agency (IDA), which is
p.000006: called to supervise and if necessary direct, through its funding, drug research11.
p.000006:
p.000006: 3. Clinical experimentation on women: under-representation in the enlistment and shortcomings in the
p.000006: differentiated analysis of the data
p.000006:
p.000006: Within clinical drugs experimentation, women appear to be “weak subjects”, or at least they appear to be not subjected
p.000006: to adequate consideration, which should take into account their specificity both from a quantitative point of
p.000006: view (number of enlisted women in comparison to the number of men) and a qualitative point of view (analysis of the
p.000006: data with regards to sexual difference).
p.000006: In Italy numerous studies are carried out on female pathologies: in this case the enlistment of the patients is
p.000006: determined by the pathology. Analysing the data reported by the IDA, we can see that on a total of 4,196
p.000006: experimentations from 2000 to 2006, there is a progressive increase of studies specifically carried out on women (cf.
p.000006: tab.1). Analysing the data of these trials, what emerges is a greater attention to phases II and III, an absence of
p.000006: phase I and a scarce emphasis on phase IV (cf. tab. 2). But what emerges the most is that such experimentations are
p.000006: mostly dedicated to therapeutic strategies for female pathologies, like the breast cancer and the control of the
p.000006: post-menopausal osteoporosis12. Studies are also carried out on the genitourinary field, the musculoskeletal
p.000006: system, connective tissue, the endocrinal system, in the context of the pregnancy, the labour and the time immediately
p.000006: after giving birth and in the context of the disorders of the nervous system. There are many studies on female
p.000006: fertilization with regards to ovarian stimulation as well as assisted fecundation; others are aimed at
p.000006: controlling incontinence in post- menopausal women (cf. tab. 3)13. We highlight that there are specific trials on
p.000006: women in the field of cardiovascular pathologies especially after the menopause, thanks to national studies on the
p.000006: incidence of these illnesses, in which the data is stratified by sex as well as age14. There are areas in which
p.000006: we notice a lack of pharmacological trials on female pathologies as well: in particular with regards to the
p.000006: substitutive hormonal treatment in post-menopausal women, where there are many risks of heart attack or breast cancer
p.000006: or cardiovascular toxicity of the chemotherapy drugs used to treat breast cancer.
p.000006:
p.000006:
p.000006: 11 Part of the IDA is the Observatory on drug experimentation, which collects the data of all the
p.000006: experimentation conducted in Italy, periodically published in their bulletins. The data of the Observatory can be found
p.000006: on http://oss-sper-clin.agenziafarmaco.it.
p.000006: 12 J.E. Rossouw, G.L. Anderson, R.L. Prentice, A.Z. LaCroix, et al. (Group for the Women’s Health
p.000006: Initiative Investigators), Risks and Benefits of Estrogen plus Progestin in Healthy Postmenopausal Women, “JAMA”, 2002,
p.000006: 288, pages 321-332.
p.000006: 13 On the site of the Observatory we can search for current studies, using the key word “women”: the
p.000006: studies which specifically involve women, in relation to female pathologies, are almost 60.
p.000006: 14 An example of this is the “CUORE” (heart) project, coordinated by the Higher Institute of Health.
p.000006:
p.000007: 7
p.000007:
p.000007: The areas of criticality and disadvantage for women are highlighted, in particular, with regard to the experimentation
p.000007: of drugs on pathologies that are not specifically and traditionally female15 (even if few data is reported, as
p.000007: confirmation of such lack of interest). The majority of trials do not allow for a difference between men and women
p.000007: at the moment of enlistment and of the analysis of the data. The percentage of women (if compared to that of men)
p.000007: recruited in the experimentation is still low: it is referred to as “representative inappropriateness” or
p.000007: “under-representation” of women16. Drug dosage is generally measured on men (70 Kg. in weight) and women are considered
p.000007: a “variation” of the male model: but the weight difference between men and women, as well as the
p.000007: morphological and physiological difference, determines a considerable difference in the pharmacokinetics, that is
p.000007: the different way in which the drug is absorbed, distributed, metabolised and eliminated, and in the
p.000007: pharmacodynamics, that is in the response of the body to a certain concentration of drug in the blood or in the
p.000007: tissue17. Despite the fact that the knowledge of the specificity of the female body has matured,
p.000007: experimentation protocols have not been modified, therefore the enlistment without distinction between men
p.000007: and women persists and so does a consequent undifferentiated analysis of the data. Women are generally included (if
p.000007: they are) in phase III of the enlistment in the trails, but not in phases I and II of the trails (important phases, as
p.000007: already mentioned, to establish dosage, side-effects and safety in the drug’s use). The lack of specific studies on
p.000007: women, especially in the early phases of the research, does not make it possible to measure the real efficacy of the
p.000007: drugs on women, but could even have limited the identification of specifically female drugs (cf. tab. 4)18.
p.000007:
p.000007: 4. New needs of experimentation differentiated by sex: the changes of health/illness in women
p.000007:
p.000007: The fact that there’s a lack of studies which take into account the sex difference within pharmacological
p.000007: experimentation, is even more problematic, given the recent change in the conditions of women’s
p.000007: health/illness within the context of the general change in the female condition. Some of the illnesses considered
p.000007: “male”, today tend to be more frequent in women.
p.000007: There are many factors, as we know, that have contributed to a change in the conditions of women, at
p.000007: least with regard to western societies. We need to consider: the increase in education (in latest years women exceed
p.000007: men in the number of graduates and
p.000007:
p.000007: 15 That is male/female pathologies.
p.000007: 16 F. Franconi, S. Canu, I. Campasi, Working Group “Approccio di genere alla salute”. Approccio di
p.000007: genere nella ricerca, nelle sperimentazioni e nei trattamenti farmacologici, cited.
p.000007: 17 M. Anthony, M.J. Berg, Biological and Molecular Mechanism for Sex Differences in Pharmacokinetics, Pharmacodynamics,
p.000007: and Pharmacogenetics: part I, “Journal of Women’s Health and Gender-Based Medicine”, 2002, 11 (7), pages
p.000007: 601-615; M. Gandhi, F. Aweeka, R.M. Greenblatt, T. Blaschke, Sex Differences in Pharmacokinetics and
p.000007: Pharmacodynamics, “Ann. Rev. Pharmacol. Toxicol.”, 2004, 44, pages 499-523, A.D.M. Kashuba, A.N. Nafzinger
p.000007: Physiological Changes during the Menstrual Cycle and their Effects on the Pharmacokinetics and Pharmacodynamics
p.000007: of Drugs, “Clinical Pharmacokinetics”, 1998, 34 (3), pages 203-218; P.A. Thuermann, B.C. Hompesch,
p.000007: Influence on Gender on the Pharmacokinetics and Pharmacodynamics of Drugs,“International Journal of Clinical
p.000007: Pharmacology and Therapeutics”, 1998, 36 (11), pages 586-590.
p.000007: 18 Cf. A. Holdcroft, Gender Bias in Research: How does it affect Evidence Based Medicine?, editorial “J. Royal Soc.
p.000007: Med.”, p. 100.
p.000007:
p.000008: 8
p.000008:
p.000008: qualified workers); the change in the participation in the work-market (many traditionally male jobs are open to
p.000008: women), the strong female push towards a career, but the persistent difficulties in the work-market (the participation
p.000008: of women is nevertheless inferior to that of men, with greater unemployment problems or relinquishment of work
p.000008: places due to maternity and lack of working facilitations and social aids); the increase of the public
p.000008: participation on a social, political, economic basis, but the persistent marginalisation (there are still few
p.000008: women in positions of power and responsibility); the behavioural traits generally more frequent in women (e.g.
p.000008: the inclination to take care of others and the selflessness). The change of women’s conditions from
p.000008: a historical, cultural and psychological point of view has relevant implications on their conditions of illness
p.000008: and health, on the way women perceive them and live through them. We highlight how, many pathologies traditionally
p.000008: attributed to the male gender because of their physical structure or their behavioural habits on an individual and
p.000008: social basis, are also widespread – and at times more greatly – in the female sex, due to the change in lifestyles and
p.000008: risk factors and/or to a lack of an adequate prevention, diagnosis and cure.
p.000008: The research on women’s health, elaborated by NOWH (National Observatory on Women’s Health) in collaboration with
p.000008: the National Observatory of Health in Italian Regions, part of the Catholic University of the Sacred Heart19,
p.000008: highlights (in the second part: “Health needs and health assistance”) the condition of women’s health and
p.000008: the quality of health assistance. In the pathologies most common in women – where the frequency of the
p.000008: pathologies is linked to age and social condition – we can find some relevant elements: an increase in
p.000008: cardiac pathologies (arterial hypertension, coronary cardiomyopathy, peripheral arteriopathy and cardiac
p.000008: imbalance, thromboembolic pathologies); an increment in the oncological field, as well as “female cancers” (breast
p.000008: cancer, carcinoma of the uterine cervix, endometrial tumours, ovarian neoplasia), also of trachea-bronchi-lungs
p.000008: tumours, due to the spread of nicotine addition even during adolescence; an increase in psychological
p.000008: pathologies (anxiety and depressive syndromes, eating disorders, psychotic syndromes); a tendency to an increase
p.000008: in obesity, due to the lack of physical activity and sedentary life, with an increase in the risk of
p.000008: cardiovascular illnesses and diabetes; an increase in alcohol abuse (with nutritional imbalances and
p.000008: dependency); an increase in neurodegenerative illnesses (Alzheimer’s illness, Parkinson disease, multiple
p.000008: sclerosis, senile dementia); an increase in problems linked to infertility, caused by the postponement of the decision
p.000008: to have children or by the protracted use of contraceptives; problems and pathologies linked with the
p.000008: non- acceptance of aging also emerge20.
p.000008: These changes in the conditions of women’s health and illness emphasise even more the lack of an
p.000008: adequately differentiated trails for the care of women’s health, beyond traditional areas.
p.000008:
p.000008:
p.000008:
p.000008: 19 La salute della donna. Stato di salute a assistenza nelle regioni italiane. Libro bianco, Franco Angeli, Milano
p.000008: 2007.
p.000008: 20 Different the causes: the problems of the substitutive hormonal therapy; the possibility to postpone for decades
p.000008: physical aging, extending the menstrual cycle for years as well as intervening with plastic surgery, with possible
p.000008: dangers for women’s health, and not only because of the bad quality of the treatments – as in the case of deaths
p.000008: due to routing operations, like liposuction – but also because of extended negative effects, injected
p.000008: liquids and stress, due to the effort of not showing their real age.
p.000008:
p.000009: 9
p.000009:
p.000009: 5. Women as drug users and the problem of the side-effects
p.000009:
p.000009: The fact that women are not adequately taken into consideration within clinical trails is penalising, given the
p.000009: increase in the consumption of drugs on their part.
p.000009: As we can see from the data on territorial assistance in relation to the consumption and the
p.000009: gross public expense per capita for reimbursed drugs (class A) of the Italian National Health Service21, women
p.000009: appear to be the greatest consumers of drugs, in particular within the ages of 15 and 54 (cf. tab. 5). The
p.000009: reasons of the difference in the consumption of drugs, with regard to gender, would require
p.000009: complex pharmacoepidemiological analysis: some hypothesis have been formulated, according to which women take better
p.000009: care of themselves in comparison to men, they have better awareness of their pathological condition,
p.000009: but also undergo a greater number of treatments due to their reproductive state and to the fact that they
p.000009: are more easily affected by chronic but non-lethal pathologies22.
p.000009: But if women, in greater quantities, use drugs that have not been adequately tested on them, the result is inevitably a
p.000009: higher frequency and seriousness of adverse reactions, often due to overdosing or polytherapies23. In
p.000009: 2007 the national Net of pharmacovigilance highlighted that spontaneous reports of adverse
p.000009: reactions in women constitute 57% of the total (cf. tab. 6). Examples of adverse reactions in women
p.000009: are: serious arrhythmia, cardiac imbalances and breaking of limbs due to drugs, even when commonly consumed24. In the
p.000009: United States some drugs have been withdrawn from the market because of the high number of side effects reported in
p.000009: women25.
p.000009:
p.000009: 6. Female vulnerability in clinical trails: women as “weak subjects”
p.000009:
p.000009: The lower number of women participating in experimental studies is due to a variety of reasons26.
p.000009:
p.000009: 21 Cf. National Observatory on the use of drugs, L’uso dei farmaci in Italia, 2006.
p.000009: 22 Arno Project, Donne e farmaci. Rapporto 2003, vol. VII, Ed. Centauro, Bologna 2004.
p.000009: 23 International analysis report a frequency 1,7 times higher and they highlight the gravity, including even hospital
p.000009: admissions, of 59% of women. Cf. M. Pirmohamed, S. Meakin, C. Green, et. Al., Adverse Drug Reactions as cause of
p.000009: Admission to Hospital: Prospective Analysis of 18.820 Patients, “British Medical Journal”, 2004, 329, pages
p.000009: 15-19.
p.000009: 24 An example of this is aspirin, which is used by both men and women as prevention for cardiovascular pathologies. It
p.000009: induces adverse reactions in higher percentage in women, due to a difference in blood coagulation. Cf.
p.000009: The Puzzle of Aspirin and Sex, “New England Journal of Medicine”, 2005, 352, pages 1366-1368. A case that
p.000009: caused the interest of public opinion is represented by the events linked to Digoxin; the analysis, mentioned in a
p.000009: prestigious, international journal, highlighted that the drug, when given to men, protected them from the risk of
p.000009: death, however it did not protect female patients. Cf. R. Short, Fracture Risk is a Class Effect of Glitazones,
p.000009: “British Medical Journal”, 2007, 334, p. 551; S. Saif Rathore, M.P.H. Yongfei Wang, H.M. Krumholtz, Sex-Based
p.000009: Differences in the Effect of Diagoxin for the Treatment of Heart Failure, “NEJM”, 2002, 347, pages. 1403-1411.
p.000009: 25 Cf. Withdrawn Drugs Posed Greater Health Risk for Women then Man, GAO says, “American Journal of Health-System
p.000009: Pharmacy”, March 15, 2001, 58 (6), pages 458-462; United States General Accounting Office, Drug Safety:
p.000009: Most Drugs Withdrawn in Recent Years had Greater Health Risk for Women, Washington D.C. 2001.
p.000009: 26 D. Wrigt, N.J. Chew, Women as Subjects in Clinical Research, “Applied Clinical Trials”, 1996, 5 (9), pages 44-54; E.
p.000009: Shuster, For her Own Good: Protecting (and Neglecting) Women in Research, “Cambridge Quarterly of Healthcare Ethics”,
p.000009: 1996, 5, pages 346-361.
p.000009:
p.000010: 10
p.000010:
p.000010: a) Social reasons. Some sociological studies highlight women’s difficulties in becoming part of clinical
p.000010: studies due to the lack of time (mainly because of their role of carers within the family or, in the case of
p.000010: working women, due to their double obligation at home and at work) or due to their low income (because of the not
p.000010: yet adequate participation of women in the work-market and because of their lower wages). In part the reticence to
p.000010: participate is also due to the recruiters’ lack of attention to the practical and psychological needs of women.
p.000010: b) External environmental reasons. There are also other factors linked with lifestyle or exposure to substances
p.000010: that can interact with the experimental drugs. In external working environments, generally any substances
p.000010: present should be known; in less controlled working environments however, risky conditions can occur. Even
p.000010: lifestyle, which includes dietary habits or the use of natural remedies, exposes the patients to substances that can
p.000010: influence the clinical response to the pharmacological experimentation. Women are generally more inclined to
p.000010: use natural substances or home remedies consolidated in the cultural tradition of the family. Even if in
p.000010: clinical experimentation the treatment in the various experimental branches is the same, it is not always
p.000010: possible to keep under control lifestyle differences and external factors that can affect the experimentation in a
p.000010: different way for men and women.
p.000010: c) Economic reasons. The pharmaceutical industry prefers not to invest in the experimentation on women
p.000010: due to the inevitable rise in costs. The enlistment should necessarily be multiplied: to stratify the data
p.000010: according to gender, men and women should be recruited, doubling or quadrupling the amount of enlistments, increasing
p.000010: time and cost, trails costs and insurance costs to cover eventual negative effects. Even the use of
p.000010: female and male animals in the pre-clinical phase increases the time and the cost of the research. As the
p.000010: authorisation for the introduction of the drug on the market does not require it, the pharmaceutical
p.000010: industry is not motivated to undertake such studies, as they are seen as economically
p.000010: disadvantageous. On the other hand public funding chooses typically female pathologies (like osteoporosis
p.000010: during the menopause), to be able to better tackle the health policies of a country where women live
p.000010: longer, overlooking those pathologies traditionally considered not typical of the female population.
p.000010: d) Biological reasons. Women have always been considered “difficult” subjects for trials, due to their biological and
p.000010: physiological differences, but especially for their enzymatic and hormonal differences, due to the variations
p.000010: during childbearing and non-childbearing age (menstrual cycle, pregnancy, breast feeding,
p.000010: menopause) and to the possible consumption of contraceptives for contraceptive or therapeutic reasons (estrogens and
p.000010: progestin modify women’s metabolism; the estrogens also affect the way genes work). This kind of variability does not
p.000010: allow the collection of “clean data” in mixed sex trials and lowers the statistical relevance of the
p.000010: experimentation. Even when there are women involved in the trial, it is not certain that the enlisted
p.000010: number can allow us to see significant events.
p.000010:
p.000010:
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: e) Possible pregnancy during childbearing age27. One of the reasons that have led the pharmaceutical
p.000011: industry to exclude women from trials is connected to the possibility that the trial of a new drug
p.000011: could damage the foetus28 in case of pregnancy. There is also the possibility that the studied drug could have
p.000011: negative effects even after the end of the trial, months later. This explains why in general the pharmaceutical
p.000011: industry imposes the use of specific hormonal contraceptives29 as condition for the participation in a research
p.000011: that can be considered “without risk” for the foetus.
p.000011:
p.000011: 7. The exclusion/inclusion of women of childbearing age in trials protocols
p.000011:
p.000011: Regarding the problem of pharmacological experimentation on women of childbearing age, the literature
p.000011: presents a variety of positions: within those, we report the most spread ones.
p.000011: Some affirm that the inclusion of women of childbearing age in the trails is ethically of the outmost
p.000011: importance, when balancing the possible damage to the foetus (considered not yet to have dignity in a strong sense)
p.000011: with the predictable direct benefits to women and in general to society30. From this point of view, the a priori
p.000011: exclusion of women of childbearing age from trails (to protect the possible foetus) results in injustice in the
p.000011: biomedical research, as women do not have the same opportunities as men with regards to the cure of certain
p.000011: illnesses. The particular physio-psychological and social conditions of women should not justify their exclusion,
p.000011: but, on the contrary, motivate a differentiated study in comparison to men. The expectation of the
p.000011: pharmaceutical industry that women should use hormonal contraceptives is also criticised as restrictive of women’s
p.000011: freedom intended as self-determination.
p.000011: Others maintain that where clinical trials, even only hypothetically and probably, poses a danger to the foetus’ life
p.000011: and health (here the foetus is recognised as a subject
p.000011:
p.000011: 27 U. Halbreich, S.W. Carson, Drug Studies in Women of Childbearing Age: Ethical and Methodological Considerations, “J.
p.000011: Clin. Pharmacol.”, 1989, 9, pages 328-333.
p.000011: 28 The risks of teratogenicity for the foetus are classified as follows by the Food and Drug Administration:
p.000011: “controlled study without risk” when the safety of the drug in all stages of pregnancy has been
p.000011: demonstrated; “remote but possible risk” when in the studies on animals an increase in foetal anomalies has not been
p.000011: demonstrated but the risk is possible; “no chance to exclude risk” when the risks have been demonstrated
p.000011: by teratogen effects in the studies on animals and there are few studies on humans; “positive evidence of risk” when
p.000011: the teratogen effect has been demonstrated; “contraindicated during pregnancy” when there is positive
p.000011: evidence, in both studies on animals and humans, of the risk for the foetus. Even the potential benefits for women are
p.000011: variable and oscillate from the therapy for deadly illnesses that cannot be cured in any other way (for instance,
p.000011: cancer cures) to the cure of non-deadly pathologies (take into account the cure of acne).
p.000011: 29 We refer to the use of hormonal contraceptives, as with the use of barrier contraceptives (e.g.
p.000011: preservatives), even if they do not interact with the drugs, there is a percentage of risk of pregnancy. The need for
p.000011: the use of contraceptives is functional to the experimentation to protect the foetus as well as to guarantee the
p.000011: conditions of homogeneity.
p.000011: 30 This is also the theory supported by the feminist circle. Cf. D.A. DeBruin, Justice and the Inclusion of Women in
p.000011: Clinical Studies: an Argument for Further Reform, “Kennedy of Institute of Ethics Journal”, 1994, 3,
p.000011: pages 533-538; Id., No Longer Patient. Feminist Ethics and Health Care, Temple University Press,
p.000011: Philadelphia 1992, pages 158-175; V. Merton, Ethical Obstacles to the Participation of Women in Biomedical Research,
p.000011: in Wolf S.M. (ed.), Feminism and Bioethics. Beyond Reproduction, Oxford University Press, Oxford-New York
p.000011: 1996.
p.000011:
p.000012: 12
p.000012:
p.000012: having dignity in the strong sense), it is ethically advisable to women of childbearing age to avoid participating in
p.000012: clinical studies, as the risk to the new life overrides the potential benefits to women. However, it is accepted that
p.000012: women could decide to be part of the trials for social reasons or for personal health needs. In such cases,
p.000012: however, the imposition by the pharmaceutical industry to use hormonal contraceptives is not
p.000012: considered morally acceptable as, even for those who support this point of view this imposition is seen
p.000012: as detrimental to the freedom and the responsibility of those who choose to be subjected to the trials.
p.000012: It is felt that the woman’s explicit commitment to avoid pregnancy is sufficient, and that it is up
p.000012: to her to choose the methods of birth control which coincide with her lifestyle and values, including
p.000012: abstaining from sexual intercourse31.
p.000012:
p.000012: 8. Female presence in medical teams and in ethical committees
p.000012:
p.000012: An important aspect of protecting women during the trials is the participation of women not only as “object” of the
p.000012: trials (that is as individuals enlisted in the trials), but also as trials’ “subject”, in the sense of active subjects,
p.000012: present in the medical teams that plan and define the trials’ development and present in the ethical
p.000012: committees that evaluate the trials protocols. The presence of women could contribute to a greater focus on the
p.000012: relevance of women’s participation to the trials and could allow greater sensitivity with regards to female needs, from
p.000012: a psychological and social point of view.
p.000012: There is no data regarding the presence of women in medical teams, however, it is possible to verify the presence of
p.000012: women in ethical Committees through an analysis of the committees’ composition, as reported by the data of the
p.000012: Observatory on trials. Generally women’s presence, although often linked to the nursing sector and to
p.000012: the representative of patients, is consistent, even if almost always inferior to that of men, and is strongly dependent
p.000012: on local circumstances.
p.000012:
p.000012: 9. International bioethical guidelines
p.000012:
p.000012: In the ‘70s explicit instructions emerged, that made rules for the exclusion of women from clinical studies
p.000012: with the aim of protecting the health of the future child, as dramatic cases of foetal death and severe damage
p.000012: to the infants had occurred, due to indiscriminate trials32. In 1977 the Food and Drug Administration (FDA) in
p.000012: the General Considerations for the Clinical Evaluation of Drugs recommended the exclusion from
p.000012: experimentation of women of childbearing age, especially in phases I and II, as the data on teratogenicity was not
p.000012: known, with the exception of women with deadly pathologies;
p.000012:
p.000012: 31 This is the position that refers to the inseparability of the uniting and the procreating dimension of the marital
p.000012: act. Cf. R. Minacori, D. Sacchini, A.G. Spagnolo, Women of Childbearing Potential as Research Subjects in Clinical
p.000012: Trials: Ethical Issues, in A.G. Spagnolo, G. Gambino (edited by), Women’s Health Issues, Societa’ Editrice
p.000012: Universo, Roma 2003, pages 123-129; A.G. Spagnolo, M. Cicerone, Sperimantazione farmacologica e donne
p.000012: in eta’ fertile, “Medicina e Morale”, from international literature, 2005, 3, pages 667-670; Catholic University
p.000012: of the Sacred Heart, ethical Committee, Raccomandazioni riguardo alla inclusione di donne in eta’ fertile
p.000012: nei protocolli di sperimentazione clinica, “Medicina e Morale”, 1996, 46, pages 141-143. Cf. for a historical
p.000012: reconstruction M. Pelaja, L. Scaraffia, Due in una carne. Chiesa e sessualita’ nella storia, Laterza, Bari 2008, page
p.000012: 261 and following.
p.000012: 32 S. Cagliano, Dieci farmaci che sconvolsero il mondo, Laterza, Rome-Bari 1994, pages 43-68.
p.000012:
p.000013: 13
p.000013:
p.000013: women of childbearing age could participate to the studies in phases II and III only if sufficient
p.000013: information on the drug’s safety and efficacy, even in the studies on animals, had been collected, which excluded
p.000013: interferences with the reproductive functions. In 1982 the World Health Organisation promulgated the Proposed
p.000013: International Guidelines which affirmed the duty to exclude women from non-therapeutic experimentations on
p.000013: healthy volunteers33.
p.000013: In 1988 we register a radical change in the direction of the FDA that, with the publication of the document Guideline
p.000013: for the Format and Content of the Clinical and Statistical Sections of the New Drug Application, highlights the
p.000013: under-representation of women in pharmacological trial and recommends the analysis of sex-differentiated data in
p.000013: clinical trials34. In 1993 the FDA again issued the Guidelines for the Study and Evaluation of gender
p.000013: Differences in the Clinical Evaluation of Drugs, recognising that the percentage of the participation of women to
p.000013: clinical experimentations in pathologies not typically female is inferior to that of men and hoping for the inclusion
p.000013: of women in the trials protocols with the aim to guarantee equal representation. The FDA accepts that such exclusion
p.000013: could have, in subtle ways, caused the impression that men are the “primary focus” of medicine and of
p.000013: pharmacological development, with women being of secondary consideration; it therefore recommends the removal of the
p.000013: prohibition of the participation of women of childbearing age to the first phases of trial, with the aim
p.000013: to prevent forms of discrimination, avoiding a paternalistic attitude. The FDA believes that it is not necessary to
p.000013: exclude women because of the potential risks to the foetus, as the risks can be minimised with an explicit commitment
p.000013: of the woman to avoid pregnancy, as well as through the use of laboratory tests which can ascertain such behaviours.
p.000013: The FDA does not impose any obligations on the pharmaceutical industry and to IRBs (Institutional Review Boards,
p.000013: equivalent to independent ethical Committees), to include women in experimentation, but it aims to remove the
p.000013: “not necessary impediment”, in order to boost a higher participation of women in trials, leaving “flexibility”
p.000013: to the IRBs, to the researchers, to the sponsors and also, all considered, to the patients who have
p.000013: been correctly informed with regards to determining the safest measures to protect their health and individual
p.000013: rights, recognising the responsible autonomy of women as research subjects.
p.000013: At an international level these issues are included in an indicative document within the medical field.
p.000013: Also in 1993 the Council for International Organizations of Medical Sciences (CIOMS) promulgates the
p.000013: International Ethical Guidelines for Biomedical Research Involving Human Subjects (revised in 2002),
p.000013: recommending the researchers, the sponsors and the ethical committees to avoid excluding women of
p.000013: childbearing age from trials, as they do not believe the possibility of a pregnancy is sufficient reason
p.000013: to preclude or limit their participation and recognising that women have the ability to take a “rational decision” in
p.000013: participating in research (guideline number 16). In the case of risk to the foetus’ health, women have to accept to
p.000013: undertake a pregnancy
p.000013:
p.000013:
p.000013: 33 K.L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice,
p.000013: “Journal of Health Politics, Politics and Law”, 1999, 24 (3), pages 531-566.
p.000013: 34 R.B. Merkatz, Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, “Acad
p.000013: Med”, 1994, 69, pages 703-707; R.B. Merkatz, R. Temple, S. Sobel, Women in Clinical Trials of new Drugs. A Change in
p.000013: Food and Drug Administration Policy, “The New England Journal of Medicine”, 1993, 329 (4), pages 292-296.
p.000013:
p.000014: 14
p.000014:
p.000014: test and to use an “effective contraceptive method”, allowing, with such procedures, their enlistment also in the first
p.000014: phases of the trials with controlled doses of the new substance; we highlight that the informed consent must be
p.000014: guaranteed offering women a fair amount of time and adequate environmental conditions to decide, believing
p.000014: that an individual consent is a must, and that it cannot be substituted by the partner’s consent. In addition, CIOMS
p.000014: recommends that even pregnant women are acceptable (guideline number 17) as trials subjects, provided that the risks
p.000014: (for the woman and for the foetus) are minimised, leaving the decision to the individual woman, even in the
p.000014: case of uncertainty and ambiguity about the definition of risk; the research can be promoted only if it is relevant
p.000014: to the health of the woman who is subjected to the trials and to other women in the same condition; it is believed that
p.000014: women can be recruited into the research only in case there are pre-clinical studies which state the drug’s
p.000014: teratogenity.
p.000014: In 1994 in the United States, a dedicated office called “Office of Women’s Health” was created as part of
p.000014: the FDA, with the objective of boosting the inclusion of women in clinical studies, evaluating the different
p.000014: responses for the safety and the efficacy of drugs. In 1995 the previous instructions were strengthened
p.000014: further in the document Investigational New Drug Applications, which explicitly demands an end to any
p.000014: discrimination due to sexual difference, as well as age and race, in trials. In 1998 the FDA promulgates the Final Rule
p.000014: on the Investigational Drug Applications with the aim of actively intervening with sponsors who do not respect
p.000014: the instructions of fairness within sexual difference. In 1999 the working group “FDA-MA Women and Minorities
p.000014: Working Group” was created, with the aim of drawing up specific guidelines to boost the correct inclusion of women and
p.000014: of weak subjects in clinical trials. In 2001 the National Institute of Health in the USA issued the document
p.000014: Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research to promote a policy
p.000014: of women’s inclusion in the enlistment for pharmacological trials. It is important to highlight that the
p.000014: Department of Health and Human Services in issuing the Regulations for the Protection of Human Subjects in 2001,
p.000014: does not take explicitely into account tendencies and directives for the researchers, the doctors and IRBs on the
p.000014: specific theme of trials on women of childbearing age.
p.000014: Within the European biolegislation we highlight the focus on female specificity within the general area of
p.000014: health35, but lacking specific provisions of policies of non- exclusion or inclusion of women in clinical
p.000014: studies (simply highlighting the lack of data in such field)36. There are however some initiatives of awareness. In
p.000014: 1998, the EMEA
p.000014:
p.000014: 35 M.T. Ruiz Cantero, M.A. Pardo, European Medicines Agency Policies for Clinical Trials Leave Women Unprotected,
p.000014: “Journal Epidemiol. Community Health”, 2006, 60, pages 911-913.
p.000014: 36 The World Health Organization, Regional Office for Europe, specifically focused on the issue of the
p.000014: difference between sexes within Health System in general, without explicit reference to the issue of trial. Starting
p.000014: with highlighting the differences in social roles and in male and female behaviours, the WHO states that
p.000014: the health risk factors are inevitably different. For this reason it promoted the program “Gender and Health Program”
p.000014: with the aim of identifying the inequalities (the disadvantages of women in comparison to men) and of
p.000014: elaborating active responses to promote equality in the Health System with regards to the policies, the
p.000014: organisation of the services and the access to cures, adequate to the different needs determined by sexual difference.
p.000014: In 1999, in the document Highlights on Women’s Health in Europe, the WHO lists Italy amongst the European countries
p.000014: lacking in the supplying specific data on female health in comparison to data on the population in general. Due to the
p.000014: position of the Committee of Ministers of the Council of Europe, in 1998 the Report Mainstreaming:
p.000014: Conceptual Framework Methodology and Presentation of Good Practice was elaborated by the Comité Directeur pour
p.000014: l'égalitée de gendre (CDEG),
p.000014:
p.000015: 15
p.000015:
p.000015: (European Agency for the Evaluation of Pharmaceutical Products) issued the Note for Guidance on General
p.000015: Considerations for Clinical Trials allowing women of childbearing age to be part of clinical studies only if they were
p.000015: using contraceptives. Again the EMEA in 2003, after the contribution of a working group that included female
p.000015: researchers and representatives of the pharmaceutical industries from the whole of Europe (XX group), published the
p.000015: Note for Guidance on the Clinical Development of HIV-Medical Products recommending the elaboratation of study protocols
p.000015: which would promote the comparison between sexes, with the guarantee of a statistically significant participation of
p.000015: women and adequate medical training. In the document Gender Considerations in the Conduct of Clinical Trials
p.000015: issued by the Committee for Medical Products for Human Use (CHMP) of the European Drugs’ Agency (EMEA) in January
p.000015: 2005, the lack of need for the elaboration of specific European guidelines on pharmacological trials on
p.000015: women is explicitely stated (differently to what occurred in reference to age difference, with regards to
p.000015: underage and elderly patients) considering as sufficient the international guidelines on the issue.
p.000015:
p.000015: 10. National legislation
p.000015:
p.000015: In the Italian legal system there is no explicit reference to the female condition within clinical trials. In the
p.000015: legislative decree of the 24th of June 2003 number 211 Carrying out of the directive 2001/20/CE in relation to
p.000015: the application of good clinical practice in the execution of clinical trials of drugs for clinical use to the article
p.000015: 1 c. 2 “The respect of good practice guarantees the protection of the rights, safety and wellbeing of the subjects and
p.000015: ensures the credibility of the data regarding the same clinical trials”, we refer to the “subject” intended as “person
p.000015: who participates to the clinical trials, both as the target for the experimented drug as well as its test” (art. 2.
p.000015: i.), without distinction between men and women. We speak of protection of the trials’ subjects, with particular
p.000015: reference to adults unable to give their informed consent and to minors, but no explicit reference to women.
p.000015: The new regulation on Minimum requiremenst for the creation, the organisation and the functioning of ethical Committees
p.000015: for the trials of drugs (ministerial decree of the 12th of May 2006) does not specify that there must be a balanced
p.000015: representation of both sexes.
p.000015:
p.000015:
p.000015:
p.000015: intergovernamental body responsible for the definition and the implementation of the actions of the Council of Europe
p.000015: that aim to promote equality between men and women. The Report was supposed to provide the conceptual basis, where
p.000015: the need to take into consideration sexual differences in the context of their differing social roles was
p.000015: highlighted, for any future action that would be recommended to all the States members of the Council of Europe. The
p.000015: European Health Committee (CDSP-European Council), starting with a careful evaluation of the current situation with
p.000015: regards to the theme “women and health" and with an insufficient analysis in the European countries, highlights the
p.000015: lack of detailed information about the access to cures by men and women, the necessity to pre-empt discriminations in
p.000015: order to also improve the efficacy of health policies from an economic point of view. In particular the Committee
p.000015: highlights the lack of sex- disaggregated data and of indicators to define the effects of the difference
p.000015: between men and women in health research; the need to implement health policies in the consideration of
p.000015: sexual differences. In conclusion the document refers to existing distorsions in biomedical research, with
p.000015: specific reference to pharmacological tests conducted exclusively on male subjects.
p.000015:
p.000016: 16
p.000016:
p.000016:
p.000016: 11. Bioethical recommendations
p.000016:
p.000016: 1. The NBC intends to highlight some elements of bioethical relevance for the promotion of
p.000016: women’s health in those sectors of clinical experimentation that appear to suffer most from a kind of
p.000016: “neutralistic” ideology of medicine. In particular the NBC intends to underline the fundamental ethical
p.000016: principle of the fairness of a pharmacological trial on both men and women, in real conditions of equality,
p.000016: without exclusions or undue marginalisations, deeming necessary the identification and the removal of the
p.000016: causes of this unfairness. Just as a pharmacological trial that takes into account the conditions of fragility due to
p.000016: the patient’s age (for example periatric and geriatric trials) must be deemed fair and right, in the same
p.000016: way a trial that takes adequately into consideration sexual differences must be deemed proper.
p.000016: 2. The NBC hopes for a boost, already at the level of biomedical research, of studies specifically
p.000016: directed at the analysis of the condition of women’s health (diffused illnesses, risk factors, incidence,
p.000016: etc.), also and especially in the light of recent changes in their psychological-social and cultural condition,
p.000016: in order to identify the areas of deficiency of the health system in response to new and variable female needs. The
p.000016: study of physiological and psychological aspects should be implemented in this direction, as well as the analysis
p.000016: of social and cultural factors and their interaction with female health.
p.000016: 3. The NBC deems the increase of bioethically relevant clinical trials on women, as an important step towards
p.000016: guaranteeing the effective conditions of equality of care in comparison to men: the scarse
p.000016: representativeness of women and the lack of sex- differentiatied data constitute a discriminatory element
p.000016: for women’s health. The increase in clinical trials must be promoted not just with regard to traditionally female
p.000016: pathologies but also for new pathologies, hoping for a link between the results of sex differentiated medical
p.000016: research and pharmacological trials. To this end, we recommend an increase of women’s enlistment in
p.000016: clinical trials at every phase, even when studying the drugs’ efficacy and their effect, promoting a sex
p.000016: differentiated analysis of the data. Trials should take into account sexual differences even at the pre- clinical
p.000016: level, in order to evaluate the toxicity of drugs in animal experimentation, but also in the research of alternative
p.000016: methodologies. The stratification of data according to sexual difference should also be boosted after the authorisation
p.000016: to market has been granted, in order to highlight the negative effects on women, which can contribute to an improvement
p.000016: in the planning of the course of the trials.
p.000016: 4. The NBC believes that drug’s labels should indicate whether the drug has been specifically tested on
p.000016: women or not and that they should clarify and highlight any element that could generate a different response
p.000016: in men and women. The lack of such references presumes an improper assimilation of women to men, with
p.000016: possible negative effects on women but also on men.
p.000016: 5. The NBC believes that the way to increase sex differentiated pharmacological trials can be indicated as follows:
p.000016: a) raise awareness in the local health authorities and motivate the pharmaceutical industry to support sex
p.000016: differentiated trials, even if not very lucrative, promoting research projects on the issue, showing
p.000016: its social importance in the achievement of a real equality between men and women in their
p.000016:
p.000016:
p.000017: 17
p.000017:
p.000017: accessXtoXhealthcare; b) promote the participation of women to clinical trials, giving adequate information (even
p.000017: through the media) on the negative consequences of the lack of differentiated trials and on the social importance of
p.000017: female trials, guaranteeing support and specific attention to women’s psychological and practical needs; c)
p.000017: ensure a greater presence of women as experimenters and as members of ethical committees in order to
p.000017: achieve an active participation of women (not only as researchers, but also as representatives of patients’
p.000017: associations) to the elaboration of the procedures for the protocols and for the relevant informed consent;
p.000017: to promote greater attention from ethical committees to sexual difference in research protocols;
p.000017: d) boost health training which focuses on the female dimension within pharmacological
p.000017: trials, as well as within research and cure; e) increase international cooperation, as well as national and
p.000017: local, with the focus on the female condition within clinical trials, involving health authorities and the
p.000017: pharmaceutical industry.
p.000017: 6. The NBC believes that even the participation of women of childbearing age in pharmacological trials is
p.000017: ethically and socially important, provided that an adequate protection of the future child can be guaranteed. The NBC
p.000017: highlights the importance of a preliminary consultation about the intended trials, including adequate
p.000017: information, clear and in full, according to an objective, technical-scientific classification of the
p.000017: risks and benefits that the study involves for the patient, but that also taking into account the risks for the foetus
p.000017: in case of pregnancy37. We must also take into account that the exclusion of women of childbearing age from trials does
p.000017: not allow, in practice, to protect the foetus, as women could take the experimented drug (but not tested on them) on
p.000017: the market with similar risks in case of pregnancy and, to make it worse, without adequate protection. The NBC believes
p.000017: that the inclusion of women of childbearing age in pharmacological trials that poses risks to the foetus
p.000017: needs, unavoidably, the woman’s clear statement of a conscious and responsible commitment to avoid
p.000017: intercourse that could lead to pregnancy. If it is not possible to exclude a risk to the foetus’ life and
p.000017: health within the trials, but there are possible benefits to women in general and in particular in the
p.000017: cure of illnesses, the NBC believes that requesting the commitment to take contraceptives as a safety measure
p.000017: believed necessary by the study’s sponsor – to avoid pregnancy, as the trials could be damaging to the foetus – can be
p.000017: included in the criteria to participate in the study.
p.000017: In addition, the NBC believes that it is important that the woman’s husband or partner is also involved in the
p.000017: informative counselling, as the choices being made involve them as a couple.
p.000017: The trial of drugs that can make hormonal contraceptives ineffective is an open problem, so it is the fact
p.000017: that there might be interactions between the treatments being studied and the contraceptive methods being used: in this
p.000017: case the experimenters have to adequately inform the woman (and also her husband or partner) and recruit only on
p.000017: condition of a commitment, clearly expressed in the informed consent (given a fair
p.000017:
p.000017:
p.000017: 37 The risks for the foetus and the benefits for the woman must be put in the balance, according to a gradation of
p.000017: ethical justification: the experimentation of drugs that do not present any risks to the foetus is
p.000017: considered as devoid of problems (for any purpose, both for therapeutic and non-therapeutic purposes, e.g. esthetic
p.000017: purposes); the experimentation that present a certain or uncertain risk to the life or health of the future child is
p.000017: considered ethically unacceptable, with the exception of drugs that can cure serious illnesses for the woman who
p.000017: undergoes the trial
p.000017:
p.000018: 18
p.000018:
p.000018: amount of time for reflection), to avoid starting a pregnancy during the time of the trials and, in some cases,
p.000018: also for a certain time afterwards, a time to be defined according to the typology of the trials. The woman,
p.000018: on her part, must be available to carry out checks (pregnancy tests) that allow the experimenters to verify
p.000018: the conditions of safety to proceed. The informed consent and the committment to avoid procreation applies also to men
p.000018: who enter a trial protocol which presents the risk of damage to the foetus through their gametes.
p.000018:
p.000018:
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p.000019:
p.000020: 20
p.000020:
p.000020: US National Institute of Health, NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in
p.000020: Clinical Research, October, 2001
p.000020:
p.000020: Wizemann T.M., Pardue M.L., Exploring the Biological Contributions to Human Health: Does Sex Matter?,
p.000020: Committee on Understanding the biology of sex and gender differences, National Academy Press, Washington D.C. 2001
p.000020:
p.000020:
p.000020: Table 1
p.000020:
p.000020:
p.000020: Year Clinical Trials
p.000020: 2000 55
p.000020: 2001 45
p.000020: 2002 62
p.000020: 2003 57
p.000020: 2004 51
p.000020: 2005 66
p.000020: 2006 76
p.000020: Total 412
p.000020: Clinical trials on women within all clinical trials – Observatory for clinical trials (data AIFA 01/01/2000 -
p.000020: 31/12/2006)
p.000020: Table 2
p.000020:
p.000020: Year Number of Clinical
p.000020: Trials
p.000020: % Phase II
p.000020: %
p.000020: Phase III
p.000020: %
p.000020: Phase IV
p.000020: % Bioeq
p.000020: / Biod
p.000020: %
p.000020: Tot.
p.000020: 2000 55 45,5 47,3 5,5 1,8
p.000020: 100,0
p.000020: 2001 45 42,2 55,6 2,2 0,0
p.000020: 100,0
p.000020: 2002 62 48,4 50,0 1,6 0,0
p.000020: 100,0
p.000020:
p.000020: 2003 57 45,6 52,6 1,8 0,0
p.000020: 100,0
p.000020: 2004 51 49,0 41,2 9,8 0,0
p.000020: 100,0
p.000020: 2005 66 50,0 42,4 6,1 1,5
p.000020: 100,0
p.000020: 2006 76 47,4 43,4 7,9 1,3
p.000020: 100,0
p.000020: Total 412 47,1 47,1 5,1 0,0
p.000020: 100,0
p.000020:
p.000020: In clinical trials on women, phase I trials are not present (dati AIFA 01/01/2000 - 31/12/2006)
p.000020:
p.000020:
p.000020:
p.000020:
p.000020:
p.000020:
p.000020:
p.000021: 21
p.000021:
p.000021:
p.000021:
p.000021: Table 3
p.000021:
p.000021: Therapeutic Area CE women % % Italy
p.000021: Oncology 258 62,6 28,1
p.000021: Gynecology and obstetrics 73 17,7 1,7
p.000021: Illnesses of the muscle-skeletal system 33 8,0 2,7
p.000021: Endocrinology 11 2,7 5,8
p.000021: Neurology 7 1,7 8,2
p.000021: Genito-urinary system 6 1,5 1,6
p.000021: Anaesthesiology 6 1,5 1,4
p.000021: Immunology and infectious diseases 5 1,2 9,4
p.000021: Nephrology/Urology 5 1,2 3,4
p.000021: Dermatology/Plastic surgery 4 1,0 2,2
p.000021: Cardiology/Vascular illnesses 1 0,0 11,1
p.000021: Gastroenterology 1 0,0 7,0
p.000021: Psychiatry/Psychology 1 0,0 2,8
p.000021: Pharmacology/Toxicology 1 0,0 0,8
p.000021: Total 412 100,0 100,0
p.000021:
p.000021: Clinical trials on women for therapeutic field (AIFA data 01/01/2000 - 31/12/2006)
p.000021:
p.000021:
p.000021: Table 4
p.000021: Therapeutic class Controlled clinical trials N. subjects Women (%) Thrombolytics 176
p.000021: 279.179 24.1
p.000021: Antithrombotics 103 167.878 27.0
p.000021: Antiarrhythmics 80 45.430 22.6
p.000021: Beta blockers 70 56.517 20.6
p.000021: Antiaggregants 69 91.172 24.0
p.000021:
p.000021: Data on the participation of women to clinical trial in the principal therapeutic classas (80% of trials). The table is
p.000021: part of a more extensive table: not all therapeutic classes have been referred to (the others cover 20% of the trials).
p.000021: In the original version RCT stands for ‘Randomized Controlled Trials’. Data taken by
p.000021: P.Y. Lee, K.P. Alexander, B.G. Hammill et al., Representation of Elderly Persons and Women in Published Randomized
p.000021: Trials of Acute Coronary Syndromes, JAMA, 2001, 286(6), pages 708-713
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000022: 22
p.000022:
p.000022:
p.000022:
p.000022: Table 5
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022: Drug consumption by age and sex (DDD – Defined Daily Dose per day per 1000 inhabitants)- AIFA (National Drug Agency)
p.000022: data regarding 2006.
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000023: 23
p.000023:
p.000023:
p.000023: Table 6
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023:
p.000023: Reported cases of adverse reactions to drugs (Adrs – Adverse Drug ReactionS) by sex and age – AIFA data regarding 2007.
p.000023:
p.000023:
p.000023:
p.000023: Personal remark by Prof. Adriano Bompiani, Bruno Dallapiccola, Maria Luisa Di Pietro, Rodolfo Proietti
p.000023:
p.000023: The “abstension” vote – and not a “contrary vote” – on the document “Pharmacological trials on
p.000023: women”, approved by the National Bioethics Committee on the 28th of November 2008, is dictated by the awareness of the
p.000023: importance of a bioethical reflection on the question of the inclusion of women of childbearing
p.000023: age in pharmacological clinical trials. It is about – in this case – putting together important points
p.000023: for the progress of medical research and the marketing of new drugs, respecting the fundamental rights of the patients,
p.000023: if involved as trial subjects.
p.000023: On the one hand we must, in fact, consider the need to include women in clinical trials in order to properly evaluate –
p.000023: in relation to the particular differences of the female organism – the pharmacokinetics, the pharmacodynamics, the
p.000023: toxicity, the efficacy and the safety of the new pharmacological treatments. This represents an unavoidable medical
p.000023: need, with regards to the therapeutic advantage that results from the evaluation of the therapeutic
p.000023: efficacy and of the side effects. In addition, the possibility to have access to a
p.000023:
p.000023:
p.000024: 24
p.000024:
p.000024: clinical trial can constitute, especially for some situations of particular gravity (for example in the case
p.000024: of phatologies indifferent to standard treatments or of rare diseases) another opportunity of therapy – even if
p.000024: uncertain in outcome -, that can be a priori precluded to women because of their fertile condition. On
p.000024: the other hand, is equally important, for those who promote and conduct a clinical trial, to always
p.000024: consider the potential risk of teratogenicity in case of pregnancy, especially if there is already previous evidence
p.000024: from the studies on animals. From this, comes the absolute need, for potentially fertile subjects (even men carry
p.000024: such risk, when the drug can produce pathological changes of the spermatozoons), to avoid conception during the
p.000024: trial treatment and until the cessation of its effects.
p.000024: We believe that these aspects have been well identified in the document and we agree with the arguments put forward in
p.000024: it.
p.000024: We don’t think, however, that it is ethically acceptable or justifiable from a medical point of view,
p.000024: to force the inclusion of potentially fertile patients in pharmacological clinical trials to use
p.000024: contraceptive methods chosen and imposed by the sponsor and supported by binding clauses from insurance companies, in
p.000024: order to give the necessary economical guarantees to cover possible damages. This request, independently from ethical
p.000024: and religious positions, is not in fact in keeping with the responsible freedom of choice that – within completely
...
Social / education
Searching for indicator education:
(return to top)
p.000007: they are) in phase III of the enlistment in the trails, but not in phases I and II of the trails (important phases, as
p.000007: already mentioned, to establish dosage, side-effects and safety in the drug’s use). The lack of specific studies on
p.000007: women, especially in the early phases of the research, does not make it possible to measure the real efficacy of the
p.000007: drugs on women, but could even have limited the identification of specifically female drugs (cf. tab. 4)18.
p.000007:
p.000007: 4. New needs of experimentation differentiated by sex: the changes of health/illness in women
p.000007:
p.000007: The fact that there’s a lack of studies which take into account the sex difference within pharmacological
p.000007: experimentation, is even more problematic, given the recent change in the conditions of women’s
p.000007: health/illness within the context of the general change in the female condition. Some of the illnesses considered
p.000007: “male”, today tend to be more frequent in women.
p.000007: There are many factors, as we know, that have contributed to a change in the conditions of women, at
p.000007: least with regard to western societies. We need to consider: the increase in education (in latest years women exceed
p.000007: men in the number of graduates and
p.000007:
p.000007: 15 That is male/female pathologies.
p.000007: 16 F. Franconi, S. Canu, I. Campasi, Working Group “Approccio di genere alla salute”. Approccio di
p.000007: genere nella ricerca, nelle sperimentazioni e nei trattamenti farmacologici, cited.
p.000007: 17 M. Anthony, M.J. Berg, Biological and Molecular Mechanism for Sex Differences in Pharmacokinetics, Pharmacodynamics,
p.000007: and Pharmacogenetics: part I, “Journal of Women’s Health and Gender-Based Medicine”, 2002, 11 (7), pages
p.000007: 601-615; M. Gandhi, F. Aweeka, R.M. Greenblatt, T. Blaschke, Sex Differences in Pharmacokinetics and
p.000007: Pharmacodynamics, “Ann. Rev. Pharmacol. Toxicol.”, 2004, 44, pages 499-523, A.D.M. Kashuba, A.N. Nafzinger
p.000007: Physiological Changes during the Menstrual Cycle and their Effects on the Pharmacokinetics and Pharmacodynamics
p.000007: of Drugs, “Clinical Pharmacokinetics”, 1998, 34 (3), pages 203-218; P.A. Thuermann, B.C. Hompesch,
p.000007: Influence on Gender on the Pharmacokinetics and Pharmacodynamics of Drugs,“International Journal of Clinical
p.000007: Pharmacology and Therapeutics”, 1998, 36 (11), pages 586-590.
p.000007: 18 Cf. A. Holdcroft, Gender Bias in Research: How does it affect Evidence Based Medicine?, editorial “J. Royal Soc.
p.000007: Med.”, p. 100.
p.000007:
p.000008: 8
p.000008:
...
Social / embryo
Searching for indicator embryo:
(return to top)
p.000005: especially with regard to the protection of the patients.
p.000005: Clinical experimentation in order to develop new drugs in Italy, as in the rest of Europe, takes place with common
p.000005: methods, through various experimental phases, in accordance with the norms of “Good Clinical Practices”10.
p.000005: This allows homogeneity from a scientific point of view as well as from an ethical point of view, with regards to the
p.000005: respect due to the rights of the patients involved. The regulations make provisions for the verification of the safety
p.000005: and the efficacy of the new drugs before their introduction on the market. This verification applies the methods of
p.000005: evidence based medicine (EBM), which at the moment is considered the most adequate model to guarantee that
p.000005: the introduction of new drugs will benefit the greatest amount of patients. We must remember that this
p.000005: is not the only possible model, but it is the one that is generally considered the most suitable because
p.000005: of the needs of modern medicine and because of its impact on the population’s health.
p.000005: Drugs’ experimentation, before the authorisation to market them, makes provisions, after the pre-clinical phase, for
p.000005: phase I, essentially about safety, and phases II and III, in which
p.000005:
p.000005: 9 With regards to experimentation which is not directly therapeutic in the interest of the pregnant woman or of the
p.000005: breast feeder, aiming to achieve effective protection of the health of the woman, of the embryo and of the foetus, and
p.000005: of the child after birth, the additional conditions anticipated in ch. VI of article 18 of the additional Protocol to
p.000005: the Convention of human rights and biomedicine are applied, relative to biomedical research, approved in Strasbourgh on
p.000005: the 25th of January 2005, which indicate particular precautions.
p.000005: 10 The “Good Clinical Practices” constitute an international standard of ethics and quality of planning,
p.000005: managing and recording clinical studies. In Italy they were first adopted as part of the national legislation with the
p.000005: ministerial decree of the 15th of July 1997.
p.000005:
p.000006: 6
p.000006:
p.000006: the efficacy of the drug on a growing number of patients is established. Subsequently the drug is authorised by the
p.000006: health authorities and becomes part of the clinical practice. Other phase IV studies can take place,
p.000006: always with experimental characteristics and therefore with the enlistment of a certain number of patients, aimed
p.000006: at better establishing the efficacy of a new drug with regards to the safety of use, even for longer periods of time.
p.000006: The whole process is under the control of health authorities, primarily of the Italian Drug Agency (IDA), which is
p.000006: called to supervise and if necessary direct, through its funding, drug research11.
p.000006:
...
Social / gender
Searching for indicator gender:
(return to top)
p.000003: A. Barford, D. Dorling, G Davey Smith, M. Shaw, Life Expectancy: Women Now on Top Everywhere, “British
p.000003: Medical Journal”, 2006, 332, p. 808.
p.000003: 2 On this topic cf Regulation (CE) number 190/2006 of the European Parliament and of the Council of
p.000003: Europe regarding drugs for paediatric use, which ends the marketing of drugs tested almost exclusively on adult
p.000003: subjects.
p.000003: 3 In Italy the greater consumption of drugs by women is per-capita data, therefore normalised. Cf.
p.000003: paragraph 5.
p.000003:
p.000004: 4
p.000004:
p.000004: that the effects of drugs on women are less studied or not adequately studied with regard to female specificity4. Women
p.000004: are more exposed to possible side-effects when
p.000004: they take drugs after their introduction on the market and we highlight less efficacy in the use of the drugs, with
p.000004: more frequent unwanted side-effects, which are also more serious compared to those experienced by men5.
p.000004: It is a bioethical problem that has emerged in international literature, in particular in the United States. It must be
p.000004: taken into account that the Food and Drug Administration (FDA) currently has an office that takes care specifically of
p.000004: women’s health and of their participation in clinical trials6 (the CDs “clinical trials gender oriented”)7. The
p.000004: European debate generally refers to the guidelines set by the United States; in Europe, until today, no National
p.000004: Bioethics Committee has chosen this theme as an object for reflection8. In Italy, studies regarding this field are
p.000004: still few, even if we can report recent initiatives in the direction of a greater consideration of the female
p.000004: specificity in pharmacological experimentation. In 2005 the Ministry of Health created the workbench on
p.000004: “Women’s health and drugs for women” (with the participation of the Superior Institute for Health, of the Italian
p.000004: Drug Agency, of the Regional Health Service Agency and of the Italian Society of Pharmacology). In 2007
p.000004: a working group was created “Gender approach to health” within the Women’s Health Commission, part of the
p.000004: Ministry of Health, with the primary objective of implementing the gathering of statistical data about female health,
p.000004: of promoting research and training in this field. In 2008, the Report on the “State of women’s health
p.000004: in Italy” was published, which, in the context of the general consideration of female health, also
p.000004: touches on the problem of drugs. Also in 2008, the Italian Drug Agency (IDA) introduced the equality between men and
p.000004: women as one of the criteria of the Evaluation of the Agreements’ Plan Commission to assign funds to
p.000004: industries which invest in Italy in pharmacological research. The Italian Society of Pharmacology (ISP) has
p.000004: in recent years started a working group that has the objective of motivating pharmacological research on sexual
p.000004: differences, through a campaign of information aimed at health workers, with the purpose of boosting the
p.000004: formation of experts in this sector and to raise awareness in health authorities.
p.000004: Awareness is growing – at a time in which we are trying to achieve the individualization of the cure,
p.000004: working on the genetic or immunity component – that the analysis of the data stratified by sex can give indications on
p.000004: the best therapy to follow and supply useful information for deeper studies with a scientific basis on the illnesses
p.000004: that
p.000004:
p.000004: 4 E. Annandale, K. Hunt, Gender Inequalities in Health, Open University Press, Buckingham 2000; F.
p.000004: Franconi, S. Canu, I. Campasi, working group “Approccio di genere alla salute”, Approccio di genere nella ricerca,
p.000004: nelle sperimentazioni e nei trattamenti farmacologici, in Lo Stato di Salute delle donne in Italia. Primo rapporto sui
p.000004: lavori della Commissione Salute delle Donne, Rome 2008, pages 39-53.
p.000004: 5 Cf. paragraph 5.
p.000004: 6 Cf. http://www.fda.gov/womens/trials.html. In some North American Universities, like the Columbia
p.000004: University in New York, there are activities entirely dedicated to these problems. In the last few years the
p.000004: publication “Gender Medicine” has published research aimed at highlighting the differences in the
p.000004: physiology, in the physiopathology or in the way the drugs respond. Even congresses on the topic are
p.000004: growing (htpp://www.gendercongress.com/).
p.000004: 7 We clarify that in this document the use of the expression “gender” refers to the sexual difference between men and
p.000004: women. This is not the place to tackle the problem of the identity of gender and of other meanings of the expression,
p.000004: on which the NBC intends to return in another document.
p.000004: 8 In the same month and year, the Austrian Committee for Bioethics issued “Recommendations with Gender
p.000004: Reference for Ethics Committees and Clinical Studies (15th November 2009),
p.000004:
p.000005: 5
p.000005:
p.000005: affect both men and women. Adequate participation of women in experimentation, would allow us to understand if in
p.000005: therapies there are significant differences that can be attributed to sex, even to be able to consider
p.000005: the different incidence or relapse of the pathology.
p.000005: The NBC has already looked at the general problem in pharmacological experimentation (The experimentation of drugs,
p.000005: 17th November 1992), but has not specifically analysed this problem in reference to women. The objective of this
p.000005: document is to reflect on the current state of pharmacological experimentation within sexual difference
p.000005: and on emerging bioethical problems, aiming to avoid any form of discrimination and to promote sexual
p.000005: equality in healthcare.
p.000005: In here, the document does not intend to look at the problem of the pharmacological
p.000005: experimentation on pregnant women, reserving the right to discuss the topic in a future document9.
p.000005:
p.000005: 2. Clinical experimentation
p.000005:
p.000005: When we speak of clinical trial, we generally refer to the process of verification of the safety and efficacy of a
p.000005: medicine in relation to therapeutic properties after a phase of laboratory research and pre-clinical experimentation on
...
p.000007:
p.000007: 4. New needs of experimentation differentiated by sex: the changes of health/illness in women
p.000007:
p.000007: The fact that there’s a lack of studies which take into account the sex difference within pharmacological
p.000007: experimentation, is even more problematic, given the recent change in the conditions of women’s
p.000007: health/illness within the context of the general change in the female condition. Some of the illnesses considered
p.000007: “male”, today tend to be more frequent in women.
p.000007: There are many factors, as we know, that have contributed to a change in the conditions of women, at
p.000007: least with regard to western societies. We need to consider: the increase in education (in latest years women exceed
p.000007: men in the number of graduates and
p.000007:
p.000007: 15 That is male/female pathologies.
p.000007: 16 F. Franconi, S. Canu, I. Campasi, Working Group “Approccio di genere alla salute”. Approccio di
p.000007: genere nella ricerca, nelle sperimentazioni e nei trattamenti farmacologici, cited.
p.000007: 17 M. Anthony, M.J. Berg, Biological and Molecular Mechanism for Sex Differences in Pharmacokinetics, Pharmacodynamics,
p.000007: and Pharmacogenetics: part I, “Journal of Women’s Health and Gender-Based Medicine”, 2002, 11 (7), pages
p.000007: 601-615; M. Gandhi, F. Aweeka, R.M. Greenblatt, T. Blaschke, Sex Differences in Pharmacokinetics and
p.000007: Pharmacodynamics, “Ann. Rev. Pharmacol. Toxicol.”, 2004, 44, pages 499-523, A.D.M. Kashuba, A.N. Nafzinger
p.000007: Physiological Changes during the Menstrual Cycle and their Effects on the Pharmacokinetics and Pharmacodynamics
p.000007: of Drugs, “Clinical Pharmacokinetics”, 1998, 34 (3), pages 203-218; P.A. Thuermann, B.C. Hompesch,
p.000007: Influence on Gender on the Pharmacokinetics and Pharmacodynamics of Drugs,“International Journal of Clinical
p.000007: Pharmacology and Therapeutics”, 1998, 36 (11), pages 586-590.
p.000007: 18 Cf. A. Holdcroft, Gender Bias in Research: How does it affect Evidence Based Medicine?, editorial “J. Royal Soc.
p.000007: Med.”, p. 100.
p.000007:
p.000008: 8
p.000008:
p.000008: qualified workers); the change in the participation in the work-market (many traditionally male jobs are open to
p.000008: women), the strong female push towards a career, but the persistent difficulties in the work-market (the participation
p.000008: of women is nevertheless inferior to that of men, with greater unemployment problems or relinquishment of work
p.000008: places due to maternity and lack of working facilitations and social aids); the increase of the public
p.000008: participation on a social, political, economic basis, but the persistent marginalisation (there are still few
p.000008: women in positions of power and responsibility); the behavioural traits generally more frequent in women (e.g.
p.000008: the inclination to take care of others and the selflessness). The change of women’s conditions from
p.000008: a historical, cultural and psychological point of view has relevant implications on their conditions of illness
p.000008: and health, on the way women perceive them and live through them. We highlight how, many pathologies traditionally
p.000008: attributed to the male gender because of their physical structure or their behavioural habits on an individual and
p.000008: social basis, are also widespread – and at times more greatly – in the female sex, due to the change in lifestyles and
p.000008: risk factors and/or to a lack of an adequate prevention, diagnosis and cure.
p.000008: The research on women’s health, elaborated by NOWH (National Observatory on Women’s Health) in collaboration with
p.000008: the National Observatory of Health in Italian Regions, part of the Catholic University of the Sacred Heart19,
p.000008: highlights (in the second part: “Health needs and health assistance”) the condition of women’s health and
p.000008: the quality of health assistance. In the pathologies most common in women – where the frequency of the
p.000008: pathologies is linked to age and social condition – we can find some relevant elements: an increase in
p.000008: cardiac pathologies (arterial hypertension, coronary cardiomyopathy, peripheral arteriopathy and cardiac
p.000008: imbalance, thromboembolic pathologies); an increment in the oncological field, as well as “female cancers” (breast
p.000008: cancer, carcinoma of the uterine cervix, endometrial tumours, ovarian neoplasia), also of trachea-bronchi-lungs
p.000008: tumours, due to the spread of nicotine addition even during adolescence; an increase in psychological
p.000008: pathologies (anxiety and depressive syndromes, eating disorders, psychotic syndromes); a tendency to an increase
...
p.000008:
p.000008:
p.000008:
p.000008: 19 La salute della donna. Stato di salute a assistenza nelle regioni italiane. Libro bianco, Franco Angeli, Milano
p.000008: 2007.
p.000008: 20 Different the causes: the problems of the substitutive hormonal therapy; the possibility to postpone for decades
p.000008: physical aging, extending the menstrual cycle for years as well as intervening with plastic surgery, with possible
p.000008: dangers for women’s health, and not only because of the bad quality of the treatments – as in the case of deaths
p.000008: due to routing operations, like liposuction – but also because of extended negative effects, injected
p.000008: liquids and stress, due to the effort of not showing their real age.
p.000008:
p.000009: 9
p.000009:
p.000009: 5. Women as drug users and the problem of the side-effects
p.000009:
p.000009: The fact that women are not adequately taken into consideration within clinical trails is penalising, given the
p.000009: increase in the consumption of drugs on their part.
p.000009: As we can see from the data on territorial assistance in relation to the consumption and the
p.000009: gross public expense per capita for reimbursed drugs (class A) of the Italian National Health Service21, women
p.000009: appear to be the greatest consumers of drugs, in particular within the ages of 15 and 54 (cf. tab. 5). The
p.000009: reasons of the difference in the consumption of drugs, with regard to gender, would require
p.000009: complex pharmacoepidemiological analysis: some hypothesis have been formulated, according to which women take better
p.000009: care of themselves in comparison to men, they have better awareness of their pathological condition,
p.000009: but also undergo a greater number of treatments due to their reproductive state and to the fact that they
p.000009: are more easily affected by chronic but non-lethal pathologies22.
p.000009: But if women, in greater quantities, use drugs that have not been adequately tested on them, the result is inevitably a
p.000009: higher frequency and seriousness of adverse reactions, often due to overdosing or polytherapies23. In
p.000009: 2007 the national Net of pharmacovigilance highlighted that spontaneous reports of adverse
p.000009: reactions in women constitute 57% of the total (cf. tab. 6). Examples of adverse reactions in women
p.000009: are: serious arrhythmia, cardiac imbalances and breaking of limbs due to drugs, even when commonly consumed24. In the
p.000009: United States some drugs have been withdrawn from the market because of the high number of side effects reported in
p.000009: women25.
p.000009:
p.000009: 6. Female vulnerability in clinical trails: women as “weak subjects”
p.000009:
p.000009: The lower number of women participating in experimental studies is due to a variety of reasons26.
p.000009:
...
p.000010: b) External environmental reasons. There are also other factors linked with lifestyle or exposure to substances
p.000010: that can interact with the experimental drugs. In external working environments, generally any substances
p.000010: present should be known; in less controlled working environments however, risky conditions can occur. Even
p.000010: lifestyle, which includes dietary habits or the use of natural remedies, exposes the patients to substances that can
p.000010: influence the clinical response to the pharmacological experimentation. Women are generally more inclined to
p.000010: use natural substances or home remedies consolidated in the cultural tradition of the family. Even if in
p.000010: clinical experimentation the treatment in the various experimental branches is the same, it is not always
p.000010: possible to keep under control lifestyle differences and external factors that can affect the experimentation in a
p.000010: different way for men and women.
p.000010: c) Economic reasons. The pharmaceutical industry prefers not to invest in the experimentation on women
p.000010: due to the inevitable rise in costs. The enlistment should necessarily be multiplied: to stratify the data
p.000010: according to gender, men and women should be recruited, doubling or quadrupling the amount of enlistments, increasing
p.000010: time and cost, trails costs and insurance costs to cover eventual negative effects. Even the use of
p.000010: female and male animals in the pre-clinical phase increases the time and the cost of the research. As the
p.000010: authorisation for the introduction of the drug on the market does not require it, the pharmaceutical
p.000010: industry is not motivated to undertake such studies, as they are seen as economically
p.000010: disadvantageous. On the other hand public funding chooses typically female pathologies (like osteoporosis
p.000010: during the menopause), to be able to better tackle the health policies of a country where women live
p.000010: longer, overlooking those pathologies traditionally considered not typical of the female population.
p.000010: d) Biological reasons. Women have always been considered “difficult” subjects for trials, due to their biological and
p.000010: physiological differences, but especially for their enzymatic and hormonal differences, due to the variations
p.000010: during childbearing and non-childbearing age (menstrual cycle, pregnancy, breast feeding,
p.000010: menopause) and to the possible consumption of contraceptives for contraceptive or therapeutic reasons (estrogens and
p.000010: progestin modify women’s metabolism; the estrogens also affect the way genes work). This kind of variability does not
...
p.000012: nei protocolli di sperimentazione clinica, “Medicina e Morale”, 1996, 46, pages 141-143. Cf. for a historical
p.000012: reconstruction M. Pelaja, L. Scaraffia, Due in una carne. Chiesa e sessualita’ nella storia, Laterza, Bari 2008, page
p.000012: 261 and following.
p.000012: 32 S. Cagliano, Dieci farmaci che sconvolsero il mondo, Laterza, Rome-Bari 1994, pages 43-68.
p.000012:
p.000013: 13
p.000013:
p.000013: women of childbearing age could participate to the studies in phases II and III only if sufficient
p.000013: information on the drug’s safety and efficacy, even in the studies on animals, had been collected, which excluded
p.000013: interferences with the reproductive functions. In 1982 the World Health Organisation promulgated the Proposed
p.000013: International Guidelines which affirmed the duty to exclude women from non-therapeutic experimentations on
p.000013: healthy volunteers33.
p.000013: In 1988 we register a radical change in the direction of the FDA that, with the publication of the document Guideline
p.000013: for the Format and Content of the Clinical and Statistical Sections of the New Drug Application, highlights the
p.000013: under-representation of women in pharmacological trial and recommends the analysis of sex-differentiated data in
p.000013: clinical trials34. In 1993 the FDA again issued the Guidelines for the Study and Evaluation of gender
p.000013: Differences in the Clinical Evaluation of Drugs, recognising that the percentage of the participation of women to
p.000013: clinical experimentations in pathologies not typically female is inferior to that of men and hoping for the inclusion
p.000013: of women in the trials protocols with the aim to guarantee equal representation. The FDA accepts that such exclusion
p.000013: could have, in subtle ways, caused the impression that men are the “primary focus” of medicine and of
p.000013: pharmacological development, with women being of secondary consideration; it therefore recommends the removal of the
p.000013: prohibition of the participation of women of childbearing age to the first phases of trial, with the aim
p.000013: to prevent forms of discrimination, avoiding a paternalistic attitude. The FDA believes that it is not necessary to
p.000013: exclude women because of the potential risks to the foetus, as the risks can be minimised with an explicit commitment
p.000013: of the woman to avoid pregnancy, as well as through the use of laboratory tests which can ascertain such behaviours.
p.000013: The FDA does not impose any obligations on the pharmaceutical industry and to IRBs (Institutional Review Boards,
p.000013: equivalent to independent ethical Committees), to include women in experimentation, but it aims to remove the
...
p.000013: been correctly informed with regards to determining the safest measures to protect their health and individual
p.000013: rights, recognising the responsible autonomy of women as research subjects.
p.000013: At an international level these issues are included in an indicative document within the medical field.
p.000013: Also in 1993 the Council for International Organizations of Medical Sciences (CIOMS) promulgates the
p.000013: International Ethical Guidelines for Biomedical Research Involving Human Subjects (revised in 2002),
p.000013: recommending the researchers, the sponsors and the ethical committees to avoid excluding women of
p.000013: childbearing age from trials, as they do not believe the possibility of a pregnancy is sufficient reason
p.000013: to preclude or limit their participation and recognising that women have the ability to take a “rational decision” in
p.000013: participating in research (guideline number 16). In the case of risk to the foetus’ health, women have to accept to
p.000013: undertake a pregnancy
p.000013:
p.000013:
p.000013: 33 K.L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice,
p.000013: “Journal of Health Politics, Politics and Law”, 1999, 24 (3), pages 531-566.
p.000013: 34 R.B. Merkatz, Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, “Acad
p.000013: Med”, 1994, 69, pages 703-707; R.B. Merkatz, R. Temple, S. Sobel, Women in Clinical Trials of new Drugs. A Change in
p.000013: Food and Drug Administration Policy, “The New England Journal of Medicine”, 1993, 329 (4), pages 292-296.
p.000013:
p.000014: 14
p.000014:
p.000014: test and to use an “effective contraceptive method”, allowing, with such procedures, their enlistment also in the first
p.000014: phases of the trials with controlled doses of the new substance; we highlight that the informed consent must be
p.000014: guaranteed offering women a fair amount of time and adequate environmental conditions to decide, believing
p.000014: that an individual consent is a must, and that it cannot be substituted by the partner’s consent. In addition, CIOMS
p.000014: recommends that even pregnant women are acceptable (guideline number 17) as trials subjects, provided that the risks
...
p.000014: Department of Health and Human Services in issuing the Regulations for the Protection of Human Subjects in 2001,
p.000014: does not take explicitely into account tendencies and directives for the researchers, the doctors and IRBs on the
p.000014: specific theme of trials on women of childbearing age.
p.000014: Within the European biolegislation we highlight the focus on female specificity within the general area of
p.000014: health35, but lacking specific provisions of policies of non- exclusion or inclusion of women in clinical
p.000014: studies (simply highlighting the lack of data in such field)36. There are however some initiatives of awareness. In
p.000014: 1998, the EMEA
p.000014:
p.000014: 35 M.T. Ruiz Cantero, M.A. Pardo, European Medicines Agency Policies for Clinical Trials Leave Women Unprotected,
p.000014: “Journal Epidemiol. Community Health”, 2006, 60, pages 911-913.
p.000014: 36 The World Health Organization, Regional Office for Europe, specifically focused on the issue of the
p.000014: difference between sexes within Health System in general, without explicit reference to the issue of trial. Starting
p.000014: with highlighting the differences in social roles and in male and female behaviours, the WHO states that
p.000014: the health risk factors are inevitably different. For this reason it promoted the program “Gender and Health Program”
p.000014: with the aim of identifying the inequalities (the disadvantages of women in comparison to men) and of
p.000014: elaborating active responses to promote equality in the Health System with regards to the policies, the
p.000014: organisation of the services and the access to cures, adequate to the different needs determined by sexual difference.
p.000014: In 1999, in the document Highlights on Women’s Health in Europe, the WHO lists Italy amongst the European countries
p.000014: lacking in the supplying specific data on female health in comparison to data on the population in general. Due to the
p.000014: position of the Committee of Ministers of the Council of Europe, in 1998 the Report Mainstreaming:
p.000014: Conceptual Framework Methodology and Presentation of Good Practice was elaborated by the Comité Directeur pour
p.000014: l'égalitée de gendre (CDEG),
p.000014:
p.000015: 15
p.000015:
p.000015: (European Agency for the Evaluation of Pharmaceutical Products) issued the Note for Guidance on General
p.000015: Considerations for Clinical Trials allowing women of childbearing age to be part of clinical studies only if they were
p.000015: using contraceptives. Again the EMEA in 2003, after the contribution of a working group that included female
p.000015: researchers and representatives of the pharmaceutical industries from the whole of Europe (XX group), published the
p.000015: Note for Guidance on the Clinical Development of HIV-Medical Products recommending the elaboratation of study protocols
p.000015: which would promote the comparison between sexes, with the guarantee of a statistically significant participation of
p.000015: women and adequate medical training. In the document Gender Considerations in the Conduct of Clinical Trials
p.000015: issued by the Committee for Medical Products for Human Use (CHMP) of the European Drugs’ Agency (EMEA) in January
p.000015: 2005, the lack of need for the elaboration of specific European guidelines on pharmacological trials on
p.000015: women is explicitely stated (differently to what occurred in reference to age difference, with regards to
p.000015: underage and elderly patients) considering as sufficient the international guidelines on the issue.
p.000015:
p.000015: 10. National legislation
p.000015:
p.000015: In the Italian legal system there is no explicit reference to the female condition within clinical trials. In the
p.000015: legislative decree of the 24th of June 2003 number 211 Carrying out of the directive 2001/20/CE in relation to
p.000015: the application of good clinical practice in the execution of clinical trials of drugs for clinical use to the article
p.000015: 1 c. 2 “The respect of good practice guarantees the protection of the rights, safety and wellbeing of the subjects and
p.000015: ensures the credibility of the data regarding the same clinical trials”, we refer to the “subject” intended as “person
p.000015: who participates to the clinical trials, both as the target for the experimented drug as well as its test” (art. 2.
p.000015: i.), without distinction between men and women. We speak of protection of the trials’ subjects, with particular
...
p.000018: who enter a trial protocol which presents the risk of damage to the foetus through their gametes.
p.000018:
p.000018:
p.000018: Bibliography38
p.000018:
p.000018: Bennett J.C., Inclusion of Women in Clinical Trials. Policies for Population Subgroups, “New England
p.000018: Journal of Medicine”, 1993, 329 (4), pp. 288-292
p.000018:
p.000018: Borgia L.M. (a cura di), Manuale di bioetica per la sperimentazione clinica e i comitati etici,
p.000018: Edizioni Medico Scientifiche, Torino 2008 (cfr. pp. 36-45)
p.000018:
p.000018: Buffoni F., Donne nella ricerca farmacologica italiana, Quaderni della SIF, marzo 2006, 5, pp. 6-7
p.000018:
p.000018: Ceci A., Legislazione e criticità nella sperimentazione dei farmaci, Agenzia Sanitaria Servizi Sanitari
p.000018: Monitor ASSR, 2005, 12, pp. 67-71
p.000018:
p.000018: Commissione Nazionale per la parità e le pari opportunità tra uomo e donna, Presidenza del Consiglio dei Ministri,
p.000018: Guida alla salute delle donne, a cura di E. Reale, Dipartimento per l’Informazione e l’Editoria, 2003
p.000018:
p.000018: Fleisch J., Fleisch M.C., Thurmann P.A., Women in Early-Phase Clinical Drugs Trials: Have Things Changed
p.000018: over the Past 20 Years?, “Clinical Pharmacology and Therapeutics”, 2005, 78 (5), pp. 445-452
p.000018:
p.000018: Food and Drug Administration, Department of Health and Human Services, FDA Scholarship in Women’s Health Program,
p.000018: Participation of Females in Clinical Trials and Gender Analysis of Data in Biologic Product Application,
p.002001: 2001
p.002001:
p.002001: Franconi F., Brunelleschi S., Steardo L., Cuomo G., Gender Differences in Drug Responses,
p.002001: “Pharmacological Research”, 2007, 55 (2), pp. 81-97
p.002001:
p.002001: Healy B., The Yentl Sindrome, “The New England Journal of Medicine”, 1991, 25, pp. 274-276 Holden C., Women Abound in
p.002001: NIH Trials, “Science”, 2008, 322, p. 219
p.002001: Kaiser J., Gender in the Pharmacy: Does it Matter?, “Science”, 2005, 308, pp. 1572-1574
p.002001:
p.002001: Keitt S.K., Wagner C.R., Marts S.A., Understanding the Biology of Sex and Gender Differences: Using Subgroup Analysis
p.002001: and Statistical Design to Detect Sex Differences in Clinical Trials, “Medscape General Medicine”, 2003, 5 (2)
p.002001:
p.002001: Louis M., J. Sieczkiewicz, Law, Ethics, and Gender Impact of the US Patent System on the Promise of
p.002001: Personalized Medicine, “Gender Medicine”, 2007; 4, 187–192; 1550-8579
p.002001:
p.002001:
p.002001: 38 For the bibliographical research we thank Dr. Vanna Pistotti and Dr. Cinzia Colombo of the Mario Negri Institute.
p.002001:
p.000019: 19
p.000019:
p.000019: Mastroianni A.C., Faden R., Federman D. (eds.), Women and Health Research: Ethical and Legal Issues of Including Women
p.000019: in Clinical Studies, vol. I e vol. II, National Academy Press, Washington D.C. 1994
p.000019:
p.000019: Mattison D.R., Sex Matters in Pharmacology: Principles of Pharmacology for Women, in Leppert P.C., Peipert
p.000019: J.F. (eds.), Primary Care for Women, Lippincot Williams and Wilkins, Philadelphia 2004, pp. 112- 117
p.000019:
p.000019: McCarthy C.R., Historical Background of Clinical Trials Involving Women and Minorities, “Academic Medicine”,
p.000019: 1994, 69 (9), pp. 695-698
p.000019:
p.000019: McCullough L., Coverdale J.H., Chervenak F.A., Preventive Ethics for Including Women of Childbearing Potential in
p.000019: Clinical Trials, “Americal Journal of Obstetrics & Gynecology”, 2006, 194, pp. 1221-1227
p.000019:
p.000019: McCullough L., Coverdale J.H., Chervenak F.A, A Comprehensive Ethical Framework for Responsibly Designing
p.000019: and Conducting Pharmacologic Research Involving Pregnant Women, “Americal Journal of Obstetrics & Gynecology”,
p.000019: 2005, 193, pp. 901-907
p.000019:
p.000019: Meinert C.L., Gilpin A.K., Unalp A., Dawson C., Gender Representation in Trials, “Controlled Clinical Trials”, 2000,
p.000019: 21, pp. 462-475
p.000019:
p.000019: Merton V., The Exclusion of Pregnant, Pregnable, and Once-Pregnable People (a.k.a. Women) from Biomedical
p.000019: Research, “Am. J. Law Med.”, 1993, 19, pp. 369-451
p.000019:
p.000019: Miller M.A., Gender-Based Differences in the Toxicity of Pharmaceutical, the Food and Drug
p.000019: Administration’s Perspective, “International Journal of Toxicology”, 2001, 20 (3), pp. 149-152
p.000019:
p.000019: Ministero della salute, Lo stato di salute delle donne in Italia, Primo rapporto sui lavori della Commissione “Salute
p.000019: delle donne”, Roma, marzo 2008 (www.ministerosalute.it): F. Franconi in collaborazione con S. Canu, I. Campasi (a
p.000019: cura di), Approccio di genere nella ricerca, nelle sperimentazioni e nei trattamenti farmacologici, pp. 39-53
p.000019:
p.000019: Mordacci R., Bioetica della sperimentazione. Fondamenti e linee guida, Franco Angeli, Milano 1997, pp. 208-214
p.000019:
p.000019: Osservatorio Nazionale sull’impiego dei medicinali, Istituto Superiore di Sanità, Agenzia Italiana del
p.000019: Farmaco, L’uso dei farmaci in Italia. Rapporto nazionale anno 2006, Il Pensiero Scientifico, Roma 2006
p.000019:
p.000019: Prout M.N., Fish S.S., Participation of Women in Clinical Trials of Drug Therapies: a Context for the
p.000019: Controversies, “Medscape Women’s Health Journal”, 2001, 6 (5)
p.000019:
p.000019: Rosser S.V., Re-visioning Clinical Research: Gender and the Ethics of Experiment Design, “Hypatia”, 1989, 4
p.000019: (2)
p.000019:
p.000019: Schonfeld T.L., Gordon B.G., Contraception in Research: a Policy Suggestion, IRB Ethics & Human Research,
p.000019: 2005, 27 (2), pp. 15-20
p.000019:
p.000019: Schwartz J.B., The Current State of Knowledge on Age, Sex, and the Interactions on Clinical
p.000019: Pharmacology, “Clinical Parmacol. Ter.”, 2007, 82, pp. 87-96
p.000019:
p.000019: Uhl K., Parekh A., Kweder S., Females in Clinical Studies: Where are we Going?, “Clin. Pharmacol.
p.000019: Ther.”, 2007, 81, pp. 600-602
p.000019:
p.000019: United States General Accounting Office, Women’s Health: FDA Needs to Censure More Study of Gender Differences in
p.000019: Prescription Drug Testing, Washington D.C. 1992
p.000019:
p.000019:
p.000019:
p.000019:
p.000020: 20
p.000020:
p.000020: US National Institute of Health, NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in
p.000020: Clinical Research, October, 2001
p.000020:
p.000020: Wizemann T.M., Pardue M.L., Exploring the Biological Contributions to Human Health: Does Sex Matter?,
p.000020: Committee on Understanding the biology of sex and gender differences, National Academy Press, Washington D.C. 2001
p.000020:
p.000020:
p.000020: Table 1
p.000020:
p.000020:
p.000020: Year Clinical Trials
p.000020: 2000 55
p.000020: 2001 45
p.000020: 2002 62
p.000020: 2003 57
p.000020: 2004 51
p.000020: 2005 66
p.000020: 2006 76
p.000020: Total 412
p.000020: Clinical trials on women within all clinical trials – Observatory for clinical trials (data AIFA 01/01/2000 -
p.000020: 31/12/2006)
p.000020: Table 2
p.000020:
p.000020: Year Number of Clinical
p.000020: Trials
p.000020: % Phase II
p.000020: %
p.000020: Phase III
p.000020: %
p.000020: Phase IV
p.000020: % Bioeq
p.000020: / Biod
p.000020: %
p.000020: Tot.
p.000020: 2000 55 45,5 47,3 5,5 1,8
p.000020: 100,0
p.000020: 2001 45 42,2 55,6 2,2 0,0
p.000020: 100,0
p.000020: 2002 62 48,4 50,0 1,6 0,0
p.000020: 100,0
p.000020:
p.000020: 2003 57 45,6 52,6 1,8 0,0
p.000020: 100,0
p.000020: 2004 51 49,0 41,2 9,8 0,0
p.000020: 100,0
p.000020: 2005 66 50,0 42,4 6,1 1,5
p.000020: 100,0
p.000020: 2006 76 47,4 43,4 7,9 1,3
p.000020: 100,0
p.000020: Total 412 47,1 47,1 5,1 0,0
p.000020: 100,0
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
(return to top)
p.000047: as “weak subjects” 56
p.000047: 7. The exclusion/inclusion of women of childbearing
p.000047: age in trials protocols 58
p.000047: 8. Female presence in medical teams and in ethical committees 60
p.000047: 9. International bioethical guidelines 60
p.000047: 10. National legislation 64
p.000047: 11. Bioethical recommendations 65
p.000047: Bibliography
p.000069: 69
p.000069: l‘ei•s‹i›snl remark
p.000076: 76
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p.000076: ITALIAN NATIONAL BIOETHICS COMMITTEE
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: PHARMACOLOGICAL TRIALS ON WOMEN
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: 28th November 2008
p.000076:
p.000076:
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p.000001:
p.000001: PRESENTATION
p.000001:
p.000001:
p.000001: The National Bioethics Committee (NBC) in the plenary meeting of the 28th of November 2008 approved the Opinion
p.000001: “Pharmacological Experimentation on Women”.
p.000001: This document, starting with the analysis of the data on clinical experimentation on women, highlights their
p.000001: under-representation in enlistment and the poorly differentiated processing of the results, with particular
p.000001: reference to pathologies that are not specifically female. It is highlighted that, although women are the largest
p.000001: consumers of medicines, the experimentation tends not to sufficiently consider their specific nature and the change in
p.000001: the conditions of women’s health, with a consequent increase in side- effects when taking medicines. The document
p.000001: analyses the main reasons for this shortcoming, it discusses the ethical problems arising from it
p.000001: and analyses the international and national rules on the issue.
p.000001: The NBC proposes bioethical guidelines for an equal consideration of women in experimentation, highlighting the need
p.000001: for a differentiation, showing the dangers of a “neutral” pharmacology with regards to sexual differences.
p.000001: Women cannot be assimilated to men, like a mere variable, but have a specificity that experimentation must take into
p.000001: consideration in order to promote a medicine that adequately recognises equal opportunities
p.000001: between men and women. In order to increase pharmacological experimentation that is differentiated by
...
p.000001: research programs on the subject; to promote the participation of women in clinical trials with adequate information on
p.000001: the social importance of the experimentation on women; to guarantee a greater number of women as experimenters
p.000001: and as members of ethical Committees; to urge healthcare training that pays greater attention to the
p.000001: female dimension in pharmacological experimentation, as well as in research and treatment; to increase international
p.000001: cooperation, as well as national and local cooperation, focusing on the female condition in clinical experimentation.
p.000001: This text has been drafted by Prof. Laura Palazzani, coordinator of the working group, with the contributions of Prof.
p.000001: Silvio Garattini and of Dr. Laura Guidoni. Within the working group, Prof. Salvatore Amato, Prof. Luisella
p.000001: Battaglia, Prof. Adriano Bompiani, Prof. Cinzia Caporale, Prof. Francesco D’Agostino, Prof. Lorenzo d’Avack, Prof.
p.000001: Marianna Gensabella, Prof. Maria Luisa Di Pietro, Prof. Emma Fattorini, Prof. Carlo Flamigni, Prof.
p.000001: Assunta Morresi, Prof. Demetrio Neri, Prof. Andrea Nicolussi, Prof. Lucetta Scaraffia, Prof. Monica Toraldo di
p.000001: Francia, Prof. Giancarlo Umani Ronchi, Prof. Grazia Zuffa and Dr. Riccardo Di Segni participated to the discussion.
p.000001: During the meetings of the working group, the Presentations of Prof. Flavia Franconi, Prof Matilde Leonardi and Prof
p.000001: Carlo Tomino, offered important contributions.
p.000001: In the plenary meeting of the 28th of November 2008, the Opinion received the consensus of those present (Prof.
p.000001: Salvatore Amato, Prof. Stefano Canestrari, Prof. Antonio Da Re, Prof. Lorenzo d’Avack, Prof. Carlo Flamigni, Prof.
p.000001: Silvio Garattini, Prof. Marianna Gensabella Furnari, Prof. Laura Guidoni, Prof. Assunta Morresi,
p.000001: Prof.
p.000001:
p.000001:
p.000002: 2
p.000002:
p.000002: Demetrio Neri, Prof. Andrea Nicolussi, Prof. Laura Palazzani, Prof. Alberto Piazza, Prof. Lucetta Scaraffia, Prof.
p.000002: Monica Toraldo di Francia, Prof. Giancarlo Umani Ronchi and Dr. Riccardo Di Segni), with the abstention of
p.000002: Prof. Adriano Bompiani, Prof. Roberto Colombo, Prof. Francesco D’Agostino, Prof. Bruno Dallapiccola, Prof. Maria
p.000002: Luisa Di Pietro, Prof. Emma Fattorini.
p.000002: Prof. Adriano Bompiani, Prof. Bruno Dallapiccola, Prof. Maria Luisa Di Pietro, Prof. Rodolfo Proietti
p.000002: clarified their abstention with additional note, cited at the end of the text. Prof. Luisella Battaglia, Prof.
p.000002: Romano Forleo, Prof. Claudia Mancina, Prof. Vittorio Possenti and Prof. Grazia Zuffa, absent from the meeting,
p.000002: expressed their agreement.
p.000002: Rome, 28th November 2008 The President
p.000002: Prof. Francesco Paolo Casavola
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p.000003: 3
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p.000003:
p.000003: 1.Introduction
p.000003:
...
p.000009: United States some drugs have been withdrawn from the market because of the high number of side effects reported in
p.000009: women25.
p.000009:
p.000009: 6. Female vulnerability in clinical trails: women as “weak subjects”
p.000009:
p.000009: The lower number of women participating in experimental studies is due to a variety of reasons26.
p.000009:
p.000009: 21 Cf. National Observatory on the use of drugs, L’uso dei farmaci in Italia, 2006.
p.000009: 22 Arno Project, Donne e farmaci. Rapporto 2003, vol. VII, Ed. Centauro, Bologna 2004.
p.000009: 23 International analysis report a frequency 1,7 times higher and they highlight the gravity, including even hospital
p.000009: admissions, of 59% of women. Cf. M. Pirmohamed, S. Meakin, C. Green, et. Al., Adverse Drug Reactions as cause of
p.000009: Admission to Hospital: Prospective Analysis of 18.820 Patients, “British Medical Journal”, 2004, 329, pages
p.000009: 15-19.
p.000009: 24 An example of this is aspirin, which is used by both men and women as prevention for cardiovascular pathologies. It
p.000009: induces adverse reactions in higher percentage in women, due to a difference in blood coagulation. Cf.
p.000009: The Puzzle of Aspirin and Sex, “New England Journal of Medicine”, 2005, 352, pages 1366-1368. A case that
p.000009: caused the interest of public opinion is represented by the events linked to Digoxin; the analysis, mentioned in a
p.000009: prestigious, international journal, highlighted that the drug, when given to men, protected them from the risk of
p.000009: death, however it did not protect female patients. Cf. R. Short, Fracture Risk is a Class Effect of Glitazones,
p.000009: “British Medical Journal”, 2007, 334, p. 551; S. Saif Rathore, M.P.H. Yongfei Wang, H.M. Krumholtz, Sex-Based
p.000009: Differences in the Effect of Diagoxin for the Treatment of Heart Failure, “NEJM”, 2002, 347, pages. 1403-1411.
p.000009: 25 Cf. Withdrawn Drugs Posed Greater Health Risk for Women then Man, GAO says, “American Journal of Health-System
p.000009: Pharmacy”, March 15, 2001, 58 (6), pages 458-462; United States General Accounting Office, Drug Safety:
p.000009: Most Drugs Withdrawn in Recent Years had Greater Health Risk for Women, Washington D.C. 2001.
p.000009: 26 D. Wrigt, N.J. Chew, Women as Subjects in Clinical Research, “Applied Clinical Trials”, 1996, 5 (9), pages 44-54; E.
p.000009: Shuster, For her Own Good: Protecting (and Neglecting) Women in Research, “Cambridge Quarterly of Healthcare Ethics”,
p.000009: 1996, 5, pages 346-361.
p.000009:
p.000010: 10
p.000010:
...
General/Other / Dependent
Searching for indicator dependent:
(return to top)
p.000012: to her to choose the methods of birth control which coincide with her lifestyle and values, including
p.000012: abstaining from sexual intercourse31.
p.000012:
p.000012: 8. Female presence in medical teams and in ethical committees
p.000012:
p.000012: An important aspect of protecting women during the trials is the participation of women not only as “object” of the
p.000012: trials (that is as individuals enlisted in the trials), but also as trials’ “subject”, in the sense of active subjects,
p.000012: present in the medical teams that plan and define the trials’ development and present in the ethical
p.000012: committees that evaluate the trials protocols. The presence of women could contribute to a greater focus on the
p.000012: relevance of women’s participation to the trials and could allow greater sensitivity with regards to female needs, from
p.000012: a psychological and social point of view.
p.000012: There is no data regarding the presence of women in medical teams, however, it is possible to verify the presence of
p.000012: women in ethical Committees through an analysis of the committees’ composition, as reported by the data of the
p.000012: Observatory on trials. Generally women’s presence, although often linked to the nursing sector and to
p.000012: the representative of patients, is consistent, even if almost always inferior to that of men, and is strongly dependent
p.000012: on local circumstances.
p.000012:
p.000012: 9. International bioethical guidelines
p.000012:
p.000012: In the ‘70s explicit instructions emerged, that made rules for the exclusion of women from clinical studies
p.000012: with the aim of protecting the health of the future child, as dramatic cases of foetal death and severe damage
p.000012: to the infants had occurred, due to indiscriminate trials32. In 1977 the Food and Drug Administration (FDA) in
p.000012: the General Considerations for the Clinical Evaluation of Drugs recommended the exclusion from
p.000012: experimentation of women of childbearing age, especially in phases I and II, as the data on teratogenicity was not
p.000012: known, with the exception of women with deadly pathologies;
p.000012:
p.000012: 31 This is the position that refers to the inseparability of the uniting and the procreating dimension of the marital
p.000012: act. Cf. R. Minacori, D. Sacchini, A.G. Spagnolo, Women of Childbearing Potential as Research Subjects in Clinical
p.000012: Trials: Ethical Issues, in A.G. Spagnolo, G. Gambino (edited by), Women’s Health Issues, Societa’ Editrice
p.000012: Universo, Roma 2003, pages 123-129; A.G. Spagnolo, M. Cicerone, Sperimantazione farmacologica e donne
...
General/Other / Impaired Autonomy
Searching for indicator autonomy:
(return to top)
p.000013: could have, in subtle ways, caused the impression that men are the “primary focus” of medicine and of
p.000013: pharmacological development, with women being of secondary consideration; it therefore recommends the removal of the
p.000013: prohibition of the participation of women of childbearing age to the first phases of trial, with the aim
p.000013: to prevent forms of discrimination, avoiding a paternalistic attitude. The FDA believes that it is not necessary to
p.000013: exclude women because of the potential risks to the foetus, as the risks can be minimised with an explicit commitment
p.000013: of the woman to avoid pregnancy, as well as through the use of laboratory tests which can ascertain such behaviours.
p.000013: The FDA does not impose any obligations on the pharmaceutical industry and to IRBs (Institutional Review Boards,
p.000013: equivalent to independent ethical Committees), to include women in experimentation, but it aims to remove the
p.000013: “not necessary impediment”, in order to boost a higher participation of women in trials, leaving “flexibility”
p.000013: to the IRBs, to the researchers, to the sponsors and also, all considered, to the patients who have
p.000013: been correctly informed with regards to determining the safest measures to protect their health and individual
p.000013: rights, recognising the responsible autonomy of women as research subjects.
p.000013: At an international level these issues are included in an indicative document within the medical field.
p.000013: Also in 1993 the Council for International Organizations of Medical Sciences (CIOMS) promulgates the
p.000013: International Ethical Guidelines for Biomedical Research Involving Human Subjects (revised in 2002),
p.000013: recommending the researchers, the sponsors and the ethical committees to avoid excluding women of
p.000013: childbearing age from trials, as they do not believe the possibility of a pregnancy is sufficient reason
p.000013: to preclude or limit their participation and recognising that women have the ability to take a “rational decision” in
p.000013: participating in research (guideline number 16). In the case of risk to the foetus’ health, women have to accept to
p.000013: undertake a pregnancy
p.000013:
p.000013:
p.000013: 33 K.L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice,
p.000013: “Journal of Health Politics, Politics and Law”, 1999, 24 (3), pages 531-566.
p.000013: 34 R.B. Merkatz, Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, “Acad
...
General/Other / cioms guidelines
Searching for indicator cioms:
(return to top)
p.000013: to prevent forms of discrimination, avoiding a paternalistic attitude. The FDA believes that it is not necessary to
p.000013: exclude women because of the potential risks to the foetus, as the risks can be minimised with an explicit commitment
p.000013: of the woman to avoid pregnancy, as well as through the use of laboratory tests which can ascertain such behaviours.
p.000013: The FDA does not impose any obligations on the pharmaceutical industry and to IRBs (Institutional Review Boards,
p.000013: equivalent to independent ethical Committees), to include women in experimentation, but it aims to remove the
p.000013: “not necessary impediment”, in order to boost a higher participation of women in trials, leaving “flexibility”
p.000013: to the IRBs, to the researchers, to the sponsors and also, all considered, to the patients who have
p.000013: been correctly informed with regards to determining the safest measures to protect their health and individual
p.000013: rights, recognising the responsible autonomy of women as research subjects.
p.000013: At an international level these issues are included in an indicative document within the medical field.
p.000013: Also in 1993 the Council for International Organizations of Medical Sciences (CIOMS) promulgates the
p.000013: International Ethical Guidelines for Biomedical Research Involving Human Subjects (revised in 2002),
p.000013: recommending the researchers, the sponsors and the ethical committees to avoid excluding women of
p.000013: childbearing age from trials, as they do not believe the possibility of a pregnancy is sufficient reason
p.000013: to preclude or limit their participation and recognising that women have the ability to take a “rational decision” in
p.000013: participating in research (guideline number 16). In the case of risk to the foetus’ health, women have to accept to
p.000013: undertake a pregnancy
p.000013:
p.000013:
p.000013: 33 K.L. Baird, The New NIH and FDA Medical Research Policies: Targeting Gender, Promoting Justice,
p.000013: “Journal of Health Politics, Politics and Law”, 1999, 24 (3), pages 531-566.
p.000013: 34 R.B. Merkatz, Historical Background of Changes in FDA Policy on the Study and Evaluation of Drugs in Women, “Acad
p.000013: Med”, 1994, 69, pages 703-707; R.B. Merkatz, R. Temple, S. Sobel, Women in Clinical Trials of new Drugs. A Change in
p.000013: Food and Drug Administration Policy, “The New England Journal of Medicine”, 1993, 329 (4), pages 292-296.
p.000013:
p.000014: 14
p.000014:
p.000014: test and to use an “effective contraceptive method”, allowing, with such procedures, their enlistment also in the first
p.000014: phases of the trials with controlled doses of the new substance; we highlight that the informed consent must be
p.000014: guaranteed offering women a fair amount of time and adequate environmental conditions to decide, believing
p.000014: that an individual consent is a must, and that it cannot be substituted by the partner’s consent. In addition, CIOMS
p.000014: recommends that even pregnant women are acceptable (guideline number 17) as trials subjects, provided that the risks
p.000014: (for the woman and for the foetus) are minimised, leaving the decision to the individual woman, even in the
p.000014: case of uncertainty and ambiguity about the definition of risk; the research can be promoted only if it is relevant
p.000014: to the health of the woman who is subjected to the trials and to other women in the same condition; it is believed that
p.000014: women can be recruited into the research only in case there are pre-clinical studies which state the drug’s
p.000014: teratogenity.
p.000014: In 1994 in the United States, a dedicated office called “Office of Women’s Health” was created as part of
p.000014: the FDA, with the objective of boosting the inclusion of women in clinical studies, evaluating the different
p.000014: responses for the safety and the efficacy of drugs. In 1995 the previous instructions were strengthened
p.000014: further in the document Investigational New Drug Applications, which explicitly demands an end to any
...
Orphaned Trigger Words
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| HIV | HIV/AIDS |
| abuse | Victim of Abuse |
| access | Access to Social Goods |
| age | Age |
| autonomy | Impaired Autonomy |
| child | Child |
| childbearing age | of childbearing age/fertile |
| children | Child |
| cioms | cioms guidelines |
| dependency | Drug Dependence |
| dependent | Dependent |
| disability | Mentally Disabled |
| drug | Drug Usage |
| education | education |
| elderly | Elderly |
| embryo | embryo |
| ethnicity | Ethnicity |
| family | Motherhood/Family |
| fertile | of childbearing age/fertile |
| foetus | Fetus/Neonate |
| gender | gender |
| home | Property Ownership |
| illness | Physically Disabled |
| influence | Drug Usage |
| married | Marital Status |
| opinion | philosophical differences/differences of opinion |
| political | political affiliation |
| pregnant | Pregnant |
| race | Racial Minority |
| religious | Religion |
| substance | Drug Usage |
| unemployment | Unemployment |
| vulnerability | vulnerable |
| women | Women |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| child | ['children'] |
| childbearing age | ['fertile'] |
| children | ['child'] |
| drug | ['influence', 'substance'] |
| fertile | ['childbearingXage'] |
| influence | ['drug', 'substance'] |
| substance | ['drug', 'influence'] |
Trigger Words
consent
cultural
ethics
justice
protect
protection
risk
self-determination
Applicable Type / Vulnerability / Indicator Overlay for this Input