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External Guidance on the Implementation of the European Medicines Agency Policy on the Publication of Clinical Data for Medicinal Products for Human Use (2016)
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/external-guidance-implementation-european-medicines-agency-policy-publication-clinical-data_en-2.pdf
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p.000068: to publication of clinical reports only2. Phase 2, which will be implemented at a later stage, pertains to the
p.000068: publishing of individual patient data (IPD)3. Clinical reports and IPD are collectively referred to as “clinical data”.
p.000068: There is a need for further guidance in order to ensure that Policy 0070 meets its objectives. For this purpose EMA has
p.000068: prepared the following documents:
p.000068: • External guidance on the procedural aspects related to the submission of clinical reports for the purpose of
p.000068: publication in accordance with EMA Policy 0070 (see Chapter 2).
p.000068: • External guidance on the anonymisation of clinical reports for the purpose of publication in accordance with EMA
p.000068: Policy 0070 (see Chapter 3).
p.000068: • External guidance on the identification and redaction of commercially confidential information in clinical
p.000068: reports submitted to EMA for the purpose of publication in accordance with EMA Policy 0070 (see Chapter 4).
p.000068:
p.000068: 2. Scope
p.000068:
p.000068: The scope of this guidance document relates to phase 1 of Policy 0070.
p.000068:
p.000068: Clinical reports will be published, under Policy 0070, following conclusion of the regulatory decision- making process
p.000068: in the frame of centralised marketing authorisation procedures, as follows:
p.000068: • as part of a marketing authorisation application (MAA) with the exception of informed consent applications;
p.000068: effective date 1 January 2015, or
p.000068: • as part of a procedure under Article 58 of Regulation (EC) No 726/2004; effective date 1 January 2015, or
p.000068: • submitted by a third party in the context of a MAA: effective date 1 January 2015, or
p.000068: • as part of extension of indication – understood as variations related to the “addition of a new therapeutic
p.000068: indication or modification of an approved one” as per the Guidelines4 on the details of the various categories of
p.000068: variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC)
p.000068: No 1234/2008 of 24 November 20085 - and line extension applications relating to existing centrally authorised
p.000068: medicinal products; effective date 1 July 2015, or
p.000068:
p.000068:
p.000068: 1 European Medicines Agency policy on publication of clinical data for medicinal products for human use
p.000068: (EMA/240810/2013)
p.000068: 2 For the definition of “clinical reports”, see section 3 - Definitions.
p.000068: 3 For the definition of “IPD”, see section 3 - Definitions.
p.000068: 4 https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/c_2013_2008/c_2013_2008_pdf/c_2013_2804_en.pdf
p.000068: 5 http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:334:0007:0024:EN:PDF
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
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p.000068:
p.000068: • requested by EMA/submitted by the applicant/Marketing Authorisation Holder (MAH) as additional clinical data in
p.000068: the context of the scientific assessment process for the aforementioned situations.
p.000068: Clinical reports contained in applications where the Applicant has notified EMA of the withdrawal of the MAA are also
p.000068: published under Policy 0070.
p.000068: The effective date of Policy 0070 for all other post-authorisation procedures will be decided on by EMA at a later
p.000068: date.
p.000068: Furthermore, EMA would like to clarify a number of specific situations:
p.000068: Clinical reports submitted as part of previous/other regulatory procedures
p.000068:
p.000068: The EMA’s view is that clinical reports submitted as part of, or cross-referred to within a regulatory application will
p.000068: be subject to publication following the redaction of CCI and anonymisation of the clinical data. This includes CSRs
p.000068: previously submitted in the context of earlier regulatory procedures which form the basis of the regulatory decision
p.000068: for those applications falling in the scope of the policy. This publication is independent of who the author or party
p.000068: holding any rights to the documents may be. Any such rights remain a contractual issue between the applicant/MAH and
p.000068: any third party(ies).
p.000068: For example, according to the submission requirements laid down in Article 46 of Regulation (EC) No 1901/2006, the
p.000068: results of studies involving the use of an authorised medicinal product in the paediatric population should be
p.000068: submitted to the competent authority within six months of completion of the clinical study. As a result, these same
p.000068: studies may not be resubmitted in a regulatory procedure to add or modify a paediatric indication, but instead be
p.000068: referenced to the data submitted in the context of an earlier Article 46 procedure. In such cases, the clinical data
p.000068: submitted in the context of Article 46 of Regulation (EC) No 1901/2006 to which reference is made in a regulatory
p.000068: procedure for the addition or modification of a paediatric indication is also subject to publication under Policy 0070.
p.000068: Informed consent applications
p.000068:
p.000068: For informed consent applications where only a complete module 1 is submitted, the applicant/MAH is not expected to
p.000068: submit any document as Policy 0070 does not apply.
p.000068: Duplicate marketing authorisations
p.000068:
p.000068: In order to avoid unnecessary work EMA will accept that, in the event of duplicate marketing authorisations, the
p.000068: clinical study report submitted by the applicant/MAH will be accompanied by a statement confirming that the same set of
p.000068: documents were filed for all duplicate marketing authorisations (bearing different invented names). Provided that there
p.000068: are no differences among the clinical study reports for all the concerned duplicate products, the submission of one
...
p.000068: • Aggregated data:
p.000068: Statistical data about several individuals that has been combined to show general trends or values without identifying
p.000068: individuals within the data.
p.000068:
p.000068: 6 It should be noted that some definitions are already included in the published Policy 0070. For the sake of
p.000068: completeness they have been incorporated as well in this guidance document.
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 7/99
p.000068:
p.000068: • Anonymisation:
p.000068: The process of rendering data into a form which does not identify individuals and where identification is not likely to
p.000068: take place.
p.000068: • Anonymised/de-identified data:
p.000068: Data in a form that does not identify individuals and where identification through its combination with other data is
p.000068: not likely to take place.
p.000068: • Applicant/MAH:
p.000068: Applicant/MAH shall mean the natural or legal person(s) or organisation(s) that submitted the clinical reports to EMA
p.000068: in the context of applications in support of centralised marketing authorisations (MAs)/post-authorisation submissions
p.000068: for existing centrally authorised medicinal products, or in support of an application for an opinion in accordance with
p.000068: Article 58 of Regulation (EC) No 726/2004, as well as any person(s) or organisation(s) who own(s) copyright or other
p.000068: intellectual property rights in the clinical reports.
p.000068: • Article 29 Data Protection Working Party (Art. 29 WP):
p.000068: The Art. 29 WP was set up under Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on
p.000068: the protection of individuals with regard to the processing of personal data and on the free movement of such data. It
p.000068: has advisory status and acts independently. It is composed of a representative of the supervisory authority(ies)
p.000068: designated by each EU country, a representative of the authority(ies) established for the EU institutions and bodies,
p.000068: and a representative of the European Commission.
p.000068: • Clinical reports:
p.000068: Clinical reports shall mean the clinical overviews (submitted in module 2.5), clinical summaries (submitted in module
p.000068: 2.7) and the clinical study reports (submitted in module 5, “CSR”) together with the following appendices to the CSRs:
p.000068: 16.1.1 (protocol and protocol amendments), 16.1.2 (sample case report form), and 16.1.9 (documentation of statistical
p.000068: methods).
p.000068: • Clinical data:
p.000068:
p.000068: Clinical data shall mean the clinical reports and IPD.
p.000068:
p.000068: • Clinical study:
p.000068:
p.000068: Clinical study shall mean any investigation in relation to humans intended to:
p.000068:
p.000068: - discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal
p.000068: products;
p.000068: - identify any adverse reactions to one or more medicinal products; or
p.000068: - study the absorption, distribution, metabolism and excretion of one or more medicinal products;
p.000068: with the objective of ascertaining the safety or efficacy of those medicinal products.
p.000068:
...
p.000070: data, is a field of active research and rapidly evolving. This guidance is not intended to provide an exhaustive list
p.000070: of the techniques available or to mandate a specific methodology but rather to highlight to MAHs/applicants the
p.000070: anonymisation process to be followed to ensure that clinical reports submitted to EMA for publication are rendered
p.000070: anonymous prior to publication. The guideline will be updated in light of new developments.
p.000070: This guidance document is without prejudice to the obligations of pharmaceutical companies as controllers of personal
p.000070: data under applicable national legislation on the protection of personal data.
p.000070:
p.000070: 2. Legal framework and available standards
p.000070: This guidance has been developed based on the current available legislation in the EU as well as guidance and standards
p.000070: on the anonymisation of personal data (see below).
p.000070: • Regulation (EC) No 45/2001 of the European Parliament and of the Council on the protection of individuals with
p.000070: regard to the processing of personal data by the Community institutions and bodies and on the free movement of such
p.000070: data, of 18 December 2000.
p.000070: • Directive 95/46/EC of the European Parliament and of the Council on the protection of individuals with regard to
p.000070: the processing of personal data and on the free movement of such data, of 24 October 1995.
p.000070: • Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070: • Opinion 06/2013 on open data and public sector information reuse of the Article 29 Data Protection Working
p.000070: Party.
p.000070: • Information Commissioner’s Office (ICO) Code of Practice. Anonymisation: managing data protection risk.
p.000070: • Sharing clinical trial data: Maximizing benefits, minimizing risk. Institute of Medicine (IOM). 2015.
p.000070: Washington, DC: The National Academies Press.
p.000070:
p.000070: 10 The term ‘trial participant’ in the current guidance relates to individuals on whom information has been collected
p.000070: related to the scientific objectives of the trial, e.g. patients and healthy volunteers.
p.000070:
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p.000070: medicinal products for human use
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p.000070:
p.000070: • Pharmaceutical Users Software Exchange (PhUSE) de-identification standards for CDISC SDTM 3.2.
p.000070:
p.000070: • Transcelerate BioPharma Inc.
p.000070:
p.000070: - Clinical Study Reports Approach to Protection of Personal Data.
p.000070: - Data De-identification and Anonymisation of Individual Patient Data in Clinical Studies– A Model Approach.
p.000070: • White Paper on Anonymisation of Clinical Trial Data Sets. International Pharmaceutical Privacy Consortium
p.000070: (IPPC).
p.000070: • Scientific literature (see References).
p.000070:
p.000070: 3. General considerations
p.000070: A number of general aspects need to be considered when providing recommendations on how best achieve anonymisation.
p.000070: These relate to:
p.000070:
p.000070: 3.1. Context of data disclosure
p.000070:
...
p.000070: adequately anonymised in different ways depending on the context of the data release. Therefore, it is necessary to
p.000070: take into consideration the context of the data release when deciding on the anonymisation process.
p.000070:
p.000070: 3.2. Concept of anonymisation
p.000070:
p.000070: According to Article 2(a) of Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December
p.000070: 2000 on the protection of individuals with regard to the processing of personal data by the Community institutions and
p.000070: bodies and on the free movement of such data: ‘Personal data’ shall mean any information relating to an identified or
p.000070: identifiable natural person (‘data subject’); an identifiable person is one who can be identified, directly or
p.000070: indirectly, in particular by reference to an identification number or to one or more factors specific to his/her
p.000070: physical, physiological, mental, economic, cultural or social identity.
p.000070: Directive 95/46/EC refers to anonymisation in recital 26 and excludes anonymised data from the scope of data protection
p.000070: legislation. Hence, data protection law does not apply to data rendered anonymous in such a way that the data subject
p.000070: is no longer identifiable11.
p.000070: Anonymisation is the process of turning data into a form that does not identify individuals and where identification is
p.000070: not likely to take place. It allows for a much wider use of the information.
p.000070: According to the Article 29 Data Protection Working Party (Art. 29 WP) data that have been altered using techniques to
p.000070: mitigate risks of re-identification of the individuals concerned, but have not attained the threshold required by
p.000070: Article 2(a) and recital 26 of Directive 95/46/EC are not considered anonymised data. Therefore, such approach is only
p.000070: appropriate for limited disclosure for re-use by screened parties but not for public disclosure and re-use under open
p.000070: licence. Recital 26 signifies that to
p.000070:
p.000070: 11 ICO (UK Data Protection Agency) Code of Practice entitled “Anonymisation: managing data protection risk”
p.000070: https://ico.org.uk/media/for-organisations/documents/1061/anonymisation-code.pdf
p.000070:
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p.000070: medicinal products for human use
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p.000070:
p.000070: anonymise any data, the data must be stripped of sufficient elements such that the data subject can no longer be
p.000070: identified. More precisely, the data must be processed in such a way that it can no longer be used to identify a
p.000070: natural person12 by using “all the means likely reasonably to be used” by either the controller or a third party. It
p.000070: must be emphasised that recital 26 of Directive 95/46/EC sets a high threshold, as described in the Opinion of Art. 29
p.000070: WP. Unless data can be anonymised to meet this threshold, data protection law continues to apply.13
p.000070: The irreversibility of the anonymisation methodologies or techniques is also an important element as it can be used in
p.000070: order to differentiate from “pseudonymisation”. Pseudonymisation consists of replacing one attribute (typically a
p.000070: unique attribute) in a record by another. When pseudonymisation is used alone, the natural person is still likely to be
p.000070: identified indirectly. Pseudonymisation reduces the linkability of a dataset with the original identity of a data
p.000070: subject but when used alone will not result in an anonymous dataset, therefore data protection rules still apply. It
p.000070: is, therefore, important to clarify that pseudonymisation is not an anonymisation method but a useful security measure.
p.000070: Consequently, additional measures should be considered in order to render the dataset anonymised, including removing
p.000070: and generalising attributes or deleting the original data or at least bringing them to a highly aggregated level.
p.000070:
p.000070: 3.2.1. Anonymisation criteria
p.000070:
p.000070: According to the Opinion 05/2014 on anonymisation techniques of the Art. 29 WP, two options are available to establish
p.000070: if the data is anonymised. Either through the demonstration of effective anonymisation based on three criteria:
p.000070: • Possibility to single out an individual.
p.000070:
p.000070: • Possibility to link records relating to an individual.
p.000070:
p.000070: • Whether information can be inferred concerning an individual.
p.000070: or, whenever a proposal does not meet one of these criteria, through an evaluation of the identification risks.
p.000070: An anonymisation solution preventing all three criteria is considered to be robust against identification performed by
p.000070: the most likely and reasonable means the data controller or any third party may employ, and will render the data
p.000070: anonymous.
p.000070:
p.000070: 3.2.2. Anonymisation techniques
p.000070:
p.000070: There are several techniques that can be used in order to achieve anonymisation. Opinion 05/2014 on anonymisation
p.000070: techniques of the Art. 29 WP analyses the effectiveness and limits of existing anonymisation techniques against the EU
p.000070: legal background of data protection, and provides recommendations to handle these techniques by taking account of the
p.000070: residual risk of identification inherent in each of them14.
p.000070:
p.000070:
p.000070: 12 The definition of personal data as described in Article 2(a) of Regulation (EC) No 45/2001 relates to a ‘natural
p.000070: person’. The Article 29 Working Party opinion 4/2007 on the concept of personal data further clarifies that information
p.000070: relating to dead individuals is therefore in principle not to be considered as personal data to the rules of the
p.000070: Directive, as dead are no longer natural persons in civil law. However, the opinion also points out that data on the
p.000070: deceased may still be personal information since it may refer to living persons, e.g. it may indicate family diseases
p.000070: relevant to living children or siblings. In addition, it might be difficult for the data controller to establish
p.000070: whether the person to whom the data relates is still alive.
p.000070: 13 Opinion 05/2014 on anonymisation techniques and Opinion 06/2013 on open data and public sector information reuse of
p.000070: the Article 29 Data Protection Working Party .
p.000070: 14 Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070:
p.000070:
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p.000070: medicinal products for human use
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p.000070: 3.3. Advances in technology
p.000070:
p.000070: It is also important to take note of advances in technology (e.g. data mining) together with greater availability of
p.000070: data and the possibility of database linkage with the increased risk of re-identification. MAHs/applicants need to take
p.000070: into account (realistic) future developments in terms of availability of data and technologies that would allow
p.000070: identification. The Art. 29 WP Opinion 05/2014 on anonymisation techniques emphasises that even where a data controller
p.000070: believes it has successfully anonymised personal data, the data controller must continuously follow the developments in
p.000070: re- identification techniques, and if necessary reassess the risk of re-identification.
p.000070:
p.000070: 4. Applying these general considerations in the context of clinical reports for publication in accordance with EMA
p.000070: policy
p.000070: 4.1. Context of data disclosure
p.000070:
p.000070: This guidance document comes within the context of public data release since EMA has defined a process for publication
p.000070: of clinical reports where clinical reports are available on-screen for any user, with a simple registration process,
p.000070: and are available for downloading to identified users. Both situations are governed by dedicated Terms of Use that
p.000070: clarify that users of the data shall not, in any case, attempt to re-identify trial participants or other individuals.
p.000070:
p.000070: 4.2. Concept of anonymisation
p.000070:
p.000070: Clinical reports submitted to EMA for applications for marketing authorisation or post authorisation procedures mostly
p.000070: consist of pseudonymised aggregated data. They may contain individual patient information within, e.g. case narratives
p.000070: or tables of patient characteristics. Therefore, the reports cannot be considered anonymised and cannot be published as
p.000070: such. Applicants/MAHs, as data controllers of the personal information that might be contained in these documents, are
p.000070: required to submit clinical reports that have been rendered anonymous for the purpose of publication under Policy 0070.
p.000070: The anonymised clinical reports should be a copy of the clinical reports submitted in the context of the scientific
p.000070: evaluation procedure, stripped of sufficient elements such that the participants can no longer be identified. The data
p.000070: in the clinical reports must be processed in such a way that it can no longer be used to identify a natural person by
p.000070: using “all the means likely reasonably to be used” by either the controller or a third party, as described in Directive
p.000070: 95/46/EC.
p.000070:
p.000070: 4.3. Data utility
p.000070:
p.000070: Different anonymisation techniques will lead to different levels of data utility in the anonymised reports.
p.000070: Applicants/MAHs should take into consideration the impact of the data transformations/redactions on the scientific
p.000070: usefulness of the data.
p.000070:
p.000070: 4.4. Advances in technology
p.000070:
p.000070: As mentioned above, the Art. 29 WP Opinion 05/2014 on anonymisation techniques emphasises that the data controller must
p.000070: continuously follow the developments in re-identification techniques, and if necessary reassess the risk of
p.000070: re-identification. Applicants/MAHs, in accordance with national legislation on data protection, will need to take this
p.000070: aspect into consideration and to monitor continuously the development of technologies in this area in order to assess
p.000070: novel risks of re- identification for any future clinical reports published.
p.000070:
p.000070:
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p.000070: 4.5. Rare diseases and small populations
p.000070:
p.000070: EMA understands the complexity involved in the anonymisation of clinical reports in the case of rare diseases and small
p.000070: populations, due to the very low number of trial participants and of overall population. Therefore, careful
p.000070: consideration should be taken in the anonymisation of the clinical reports in these instances.
p.000070:
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p.000070: Chapter 4
p.000070:
p.000070: External guidance on the identification and redaction of commercially confidential information in clinical reports
p.000070: submitted to EMA for the purpose of publication in accordance with EMA Policy 0070
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p.000070: 1. Introduction
p.000070: The guidance provided in this chapter has been developed as a working tool and a reference document for pharmaceutical
p.000070: companies preparing their justifications of CCI in documents that fall under the scope of Policy 0070.
p.000070: Generally, the majority of the clinical information contained in clinical reports which fall under the scope of Policy
p.000070: 0070 should not be considered CCI.
p.000070: However, EMA acknowledges that in limited circumstances clinical reports may contain CCI, and could, therefore, be
p.000070: subject to redaction prior to publication. Whenever redaction of CCI is proposed by the applicant/MAH, consultation
p.000070: with the party in question will be undertaken. The justification for the redaction of CCI will be scrutinised by EMA in
p.000070: order to assess whether the definition of CCI applies.
p.000070: Consequently, Annex 3 “Redaction principles” to Policy 0070 identifies certain types of information that
p.000070: potentially may be considered CCI.
p.000070:
p.000070: Please note that, as described in this document, the list of elements and pieces of information that would not be
p.000070: considered CCI by EMA is not exhaustive and provides only examples. Each individual redaction proposed by the
p.000070: applicant/MAH will be assessed by EMA on its own merit.
p.000070: It is anticipated that the preparation and publication of the documents covered by Policy 0070 will raise some
p.000070: practical questions, such as on how to apply the aforementioned redaction principles, and on the presentation and
p.000070: justification of the proposed redactions.
p.000070: This guidance will enable the public to obtain a better understanding of the level and nature of redactions that are
p.000070: typically accepted within the published documents as well as a comprehensive overview on how the redaction of CCI is
p.000070: handled within the context of Policy 0070. The guidance will focus on:
p.000070: • How to identify and flag/highlight in the clinical reports pieces of text (proposed redactions) that may
p.000070: potentially constitute CCI.
p.000070: • The minimum level of detail expected in the justification that will allow EMA to perform an adequate and
p.000070: informed evaluation of the proposed redactions.
p.000070: • Establishing a better defined approach of the identification of CCI when applying the redaction principles laid
p.000070: out in policy 0070.
p.000070: The ultimate goals of this guidance are:
p.000070:
...
p.000070: Whenever the justification provided by the applicant/MAH does not correspond to/match the (type of) information
p.000070: proposed for redaction, i.e. is not relevant to the information proposed to be redacted, the following rejection code
p.000070: will be used in the justification table:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
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p.000070: CCI - Rejection 05 – Irrelevant justification
p.000070:
p.000070: This code reads as follows:
p.000070:
p.000070: “EMA considers that the justification provided is not related to the information proposed to be redacted. Therefore, in
p.000070: the absence of an adequate justification EMA is unable to recognise how the disclosure of this particular information
p.000070: would undermine your economic interest or competitive position.
p.000070: EMA therefore adopts the position that the information proposed to be redacted does not constitute commercially
p.000070: confidential information and that is not accepted by EMA as a valid redaction proposal. “
p.000070: The following section of the guidance presents some examples of justifications that are considered by EMA to be
p.000070: insufficient.
p.000070: EXAMPLE 1
p.000070:
p.000070: “Unpublished data - These study results have not been published in any peered-reviewed [sic] publication.”
p.000070: EXAMPLE 2
p.000070:
p.000070: “Company confidential information - Disclosure of these elements will harm [the company]’s commercial interests because
p.000070: it may enable third party access to business-critical information.”
p.000070: EXAMPLE 3
p.000070:
p.000070: “This information can be interpreted out of context. Such interpretation could lead to a misleading image of the safety
p.000070: profile of the product.”
p.000070: EXAMPLE 4
p.000070:
p.000070: “Detailed Statistical/Analytical Method : See Article 4.2 1st indent of Regulation (EC) The institutions shall refuse
p.000070: access to a document where disclosure would undermine the protection of commercial interests of a natural or legal
p.000070: person, including intellectual property.”
p.000070: EXAMPLE 5
p.000070:
p.000070: “The deleted text is detailed information for the active substance which is considered as confidential information.”
p.000070: EXAMPLE 6
p.000070:
p.000070: “Regulatory interaction – approaches and interactions which could give competitors substantial advantages.”
p.000070: EXAMPLE 7
p.000070:
p.000070: “The analytical methods are [the company]’s intellectual property, which [the company] developed by expending a
p.000070: significant amount of time, and human, financial and commercial resources.”
p.000070: EXAMPLE 8
p.000070:
p.000070: “Information is commercially confidential, competitively sensitive information and includes intellectual property
p.000070: including trade secret information.”
p.000070: EXAMPLE 9
p.000070:
p.000070: “Information on the safety profile of the product not reflected in the SmPC.”
p.000070:
p.000070:
...
p.000070:
p.000070:
p.000070: SME Request for Redaction Tool License
p.000070:
p.000070: European Medicines Agency 30 Churchill Place
p.000070: Canary Wharf London
p.000070: E14 5EU
p.000070:
p.000070:
p.000070: Dear ,
p.000070:
p.000070: RE: EMEA/X/X/XXXXXX/XXXX
p.000070:
p.000070: [Product Invented Name; INN, Company Name, Company SME Registration number, EMA-SME number]
p.000070:
p.000070:
p.000070: Request for Redaction Tool License
p.000070:
p.000070:
p.000070: [Company name] is writing to request a redaction tool license for the purpose of creating the Redaction Proposal
p.000070: Version and Final Redacted Version of the clinical reports for the [withdrawn] initial marketing authorisation
p.000070: application/line extension application/extension of indication application (delete as appropriate) for [product INN].
p.000070:
p.000070:
p.000070: The Redaction Proposal version and Final Redacted Version of the clinical reports will be submitted in line with the
p.000070: European Medicines Agency’s policy on the publication of clinical data for medicinal products for human use, Policy
p.000070: 0070. [Company name] confirms eligibility for the redaction tool license, on the grounds of its awarded Small and
p.000070: Medium Sized Enterprise (SME) status. SME qualification by EMA () expires on XX XX XXXX. It is
p.000070: understood that SME status will be checked by EMA at time of issuing the licence, with disclaimers to access rights to
p.000070: be removed if the SME status has expired at that time or in cases of merger/out licensing.
p.000070: In addition, [Company name] undertakes not to transfer, redistribute, sublicense or otherwise make available the
p.000070: redaction tool license, as provided to [Company name] by EMA, to any third party, including to other EMA designated
p.000070: SMEs. [Company name] also confirms that by accepting a redaction tool license [company name] also accepts the licence
p.000070: terms of use related to the redaction tool and all related liability for noncompliance or breach thereof. [Company
p.000070: name] acknowledges and agrees that EMA will not be liable or responsible in any way for any non-compliance with or
p.000070: breaches of these terms on behalf of [Company name].
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 63/99
p.000070:
p.000070: Clinical Data Publication Policy:
p.000070:
p.000070: Redaction Tool Application – SME
p.000070:
p.000070: Please complete this form in capitals
p.000070:
p.000070: Company name:
p.000070: EMA-SME Number: Expiry: Product
p.000070: Invented Name: INN:
p.000070:
p.000070: EMA number: EMEA/H/C/
p.000070:
p.000070: Contact person for interaction purpose with EMA
p.000070: Name:
p.000070: Position within the SME:
p.000070: Address:
p.000070:
p.000070: Post Code:
p.000070: Country:
p.000070: Telephone
p.000070: Country Code: Area Code: Number:
p.000070:
p.000070: Email Address:
p.000070:
p.000070:
p.000070:
p.000070: Email address specifically for software licence purposes. This email address will be used for all subscription purposes
p.000070: with the supporting company. This email address will be your company’s identification reference with the supplier.
p.000070: Identification
p.000070:
p.000070: E-mail Address:
p.000070:
p.000070:
...
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 65/99
p.000070:
p.000070: possibility of personal data also being included in other sections or appendices of the clinical reports. Appendices of
p.000070: the clinical study report that are in scope of the Policy 0070 (protocol, protocol amendments, sample case report form,
p.000070: and documentation of statistical methods) generally do not contain personal data.
p.000070: • Describe direct and quasi identifiers in the clinical reports 26
p.000070: - Direct identifiers, e.g. patient ID
p.000070:
p.000070: - Indirect identifiers, e.g. age
p.000070:
p.000070: • De-identification
p.000070:
p.000070: Direct identifiers
p.000070:
p.000070: - Provide information on the redaction of direct identifiers, e.g. patient name, address if present in the reports
p.000070: - Regarding patient ID, provide information on whether it has been redacted or recoded and the resulting impact on
p.000070: the risk of re-identification
p.000070: Quasi (indirect) identifiers
p.000070:
p.000070: - For quasi-identifiers, provide information on the anonymisation techniques used and the rationale for using
p.000070: them.
p.000070:
p.000070: 1.2.2.1. Assessment of anonymisation
p.000070:
p.000070: As described in section 3 of the “External guidance on the anonymisation of clinical reports for the purpose of
p.000070: publication in accordance with EMA Policy 0070”, according to the Opinion 05/2014 on anonymisation techniques of the
p.000070: Article 29 Data Protection Working Party, two options are available to establish if the data is anonymised.
p.000070: One option relates to the anonymisation based on three criteria (see below Section 1.2.2.1.1); the second option refers
p.000070: to the anonymisation based on the evaluation of the re-identification risk (see below Section 1.2.2.1.2). Only one of
p.000070: the options should be followed for each clinical report, i.e. only section 1.2.2.1.1 or section 1.2.2.1.2 is to be
p.000070: completed.
p.000070:
p.000070: 1.2.2.1.1. Fulfilment of the criteria for anonymisation27
p.000070:
p.000070: The applicant/MAH confirms/demonstrates that after anonymisation of the clinical reports the three criteria described
p.000070: below have been fulfilled.
p.000070: a. No possibility to single out an individual
p.000070:
p.000070: Data presented in an aggregated manner does not usually lead to the possibility of singling out an individual. However,
p.000070: in the case of small studies with few patients it might be more likely to single out individuals and therefore this
p.000070: criterion may not be fulfilled. Individual patient data in the clinical reports can also allow singling out an
p.000070: individual, but if adequately anonymised it can be demonstrated that the possibility to single out an individual is
p.000070: remote.
p.000070:
p.000070:
p.000070: 26 PhUSE has listed direct and quasi identifiers that can be found in clinical data. This can facilitate the
p.000070: identification of variables in clinical reports (http://www.phuse.eu/Data_Transparency_download.aspx)
p.000070:
p.000070: 27 According to Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 66/99
p.000070:
p.000070:
p.000070: b. No possibility to link records relating to an individual
p.000070:
p.000070: If the patient ID is redacted from the clinical reports it is less likely to link information relating to an
p.000070: individual. A combination of quasi identifiers reported in several sections of the report could also lead to linking
p.000070: information relating to one individual.
p.000070: c. Information cannot be inferred concerning an individual
p.000070:
p.000070: The value of an additional variable concerning an individual can be inferred from a narrative that has not been
p.000070: suitably anonymised.
p.000070: [If this section has been completed and the three criteria have been met, there is no need to complete the next section
p.000070: on the risk assessment]
p.000070:
p.000070: 1.2.2.1.2. Risk assessment
p.000070:
p.000070: The aim of the risk assessment is to determine how much de-identification/anonymisation is required in order to reduce
p.000070: the risk of re-identification to an acceptable level.
p.000070: • Identification of possible adversaries and plausible attacks on the data - for public data release, adversaries
p.000070: are most likely interested in showing that an attack is possible (demonstration attack).
p.000070: • Evaluate the risk of re-identification
p.000070:
...
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 97/99
p.000070:
p.000070:
p.000070:
p.000070: Chapter 6 References
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 98/99
p.000070:
p.000070: 1. References
p.000070: European Medicines Agency policy on publication of clinical data for medicinal products for human use (EMA/240810/2013)
p.000070: Regulation (EC) No 45/2001 of the European Parliament and of the Council on the protection of individuals with regard
p.000070: to the processing of personal data by the Community institutions and bodies and on the free movement of such data, of
p.000070: 18 December 2000.
p.000070: Directive 95/46/EC of the European Parliament and of the Council on the protection of individuals with regard to the
p.000070: processing of personal data and on the free movement of such data, of 24 October 1995.Opinion 05/2014 on anonymisation
p.000070: techniques of the Article 29 Data Protection Working Party.
p.000070: Opinion 06/2013 on open data and public sector information reuse of the Article 29 Data Protection Working Party.
p.000070: Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070:
p.000070: ICO (UK Data Protection Agency) Code of Practice entitled “Anonymisation: managing data protection risk”.
p.000070: Institute of Medicine, Sharing clinical trial data: Maximizing benefits, minimizing risk. Washington, DC: The National
p.000070: Academies Press, 2015.
p.000070: ICH. The common technical document for the registration of pharmaceuticals for human use. Topic E3 Structure and
p.000070: Content of Clinical Study Reports.
p.000070: ICH. The common technical document for the registration of pharmaceuticals for human use. Efficacy – M4E (R1). Clinical
p.000070: overview and clinical summary of module 2, module 5: clinical study reports.
p.000070: K. El Emam, Kald Abdallah. “De-identifying Clinical Trials Data”. Applied Clinical Trials, Mar 20, 2015.
p.000070:
p.000070: Khaled El Emam, Sam Rodgers, Bradley Malin. Anonymising and sharing individual patient data. BMJ
p.000070: 2015; 350: h1139.
p.000070:
p.000070: PhUSE De-Identification Working Group, “De-Identification Standards for CDISC SDTM 3.2,” 2015.
p.000070:
p.000070: David Carrell, Bradley Malin, John Aberdeen, et al. “Hiding in plain sight: use of realistic surrogates to reduce
p.000070: exposure of protected health information in clinical text”. J Am Med Inform Assoc 2013;20:342–348.
p.000070: European Medicines Agency policy on access to documents (related to medicinal products for human and veterinary use)
p.000070: Output of the European Medicines Agency policy on access to documents related to medicinal products for human and
p.000070: veterinary use
...
Health / Drug Usage
Searching for indicator drug:
(return to top)
p.000070: • Standard Operating Procedure (SOP) numbers and titles.
p.000070:
p.000070: 3.2.3.2. Quality-related information
p.000070:
p.000070: • Structural formula of active metabolite(s) and metabolic pathway(s).
p.000070: • Lot/batch numbers of the investigational products understood as either test product, active comparator or
p.000070: placebo (excluding manufacturing site(s) IDs).
p.000070: • Excipient names which usually constitute publicly available information detailed in SmPCs.
p.000070:
p.000070: • Function of excipients as such information is widely available in the public domain.
p.000070:
p.000070: • Excipient batch numbers.
p.000070: • Even if a method of measurement is selected from several available methods, the name of the method or the
p.000070: combination of methods and their general description is not CCI.
p.000070: • High level safety-related information such as a virus inactivation process, ultrafiltration (removal of
p.000070: pyrogen), and the name of a purification process or the operation of a specific material.
p.000070: • The name of a cell line or strain with genetic recombination, when it is in commercial use or already published
p.000070: (e.g. CHO cell, E. Coli K-12).
p.000070: • Standard storage and shipping conditions of blood or tissue samples such as storage temperature or duration,
p.000070: which are described in related scientific guidelines (e.g. bioanalytical methods).
p.000070: • Temperature, humidity parameters, and storage duration as applied in stability tests.
p.000070:
p.000070: 3.2.3.3. Non-Clinical-related information
p.000070:
p.000070: • Information concerning a generally-used/well-known immunohistochemistry method (e.g. ELISA/LC-MS).
p.000070: • Drug concentration measurements including results.
p.000070: • The quantification range (lower and upper quantification limits) of pharmacokinetic and pharmacology
p.000070: tests/methods.
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 54/99
p.000070:
p.000070: • The name and high level description of test methods should not be redacted where a test is conducted based on a
p.000070: standard dissolution test/method referred to in scientific guidelines.
p.000070: • Information on radio-labelled molecules including information on the tagging site (unless it constitutes a
p.000070: novelty feature of the method developed by a company, as its disclosure would undermine the applicant’s/MAH’s
p.000070: legitimate economic interest).
p.000070: • Information on scientific advice received from any Regulatory Agency during the development of the product
p.000070: related to the approved indication. It includes but it is not limited to information on the design and conduct of
p.000070: completed studies for which the results were submitted within the marketing authorisation application, the timing of
p.000070: requesting/obtaining the scientific advice and the names of the Agencies that issued those scientific advice.
p.000070:
p.000070: 3.2.3.4. Clinical-related information
p.000070:
p.000070: • Primary and secondary endpoints (including biomarkers and exploratory endpoints).
p.000070:
p.000070: • The justification of planned sample size.
p.000070: • Protocol and protocol amendments (including and not limited to: treatment arms, inclusion/exclusion criteria,
p.000070: allowed concomitant medication(s), reasons for withdrawal and reasons for protocol amendments).
p.000070: • Statistical methods (including imputation methods used for missing data).
p.000070:
p.000070: • Information on clinical data management (such as query resolution).
p.000070: • Information on the purpose and outcome of audits and inspections carried out during the conduct of clinical
p.000070: trials, including the audit plans.
p.000070: • Literature reviews, meta-analyses and pooled data analyses supporting certain study design elements or certain
p.000070: safety and efficacy claims.
p.000070: • Bioanalytical methods: name of the methods and the general description together with the validation parameters.
p.000070: • The fact that the formulation was changed during the development programme including the description of any
p.000070: relationships between the different formulations used in the various development programme phases, as well as the
p.000070: timing of such changes and the results of equivalence tests.
p.000070: • Safety-related information such as adverse reactions (presented in various forms such as aggregated data or
p.000070: within case narratives) regardless of whether they are reflected in the approved product information or whether they
p.000070: were observed in clinical trials or reported after authorisation (unless certain elements/adverse reactions are deemed
p.000070: to constitute personal data – see the “External guidance on the anonymisation of clinical reports for the purpose of
p.000070: publication in accordance with EMA policy 0070”).
p.000070: • Safety-related information/case narratives, even where the described case is related to “off label use” or
p.000070: reported from clinical studies conducted in other indications not yet applied for or approved.
p.000070: • Plasma drug concentration values and pharmacokinetic and pharmacodynamic parameters.
p.000070:
p.000070: • General information on PK/PD models, parameters and the results of the PK/PD model simulations.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 55/99
p.000070:
p.000070: • Information on scientific advice received from any Regulatory Agency during the development of the product
p.000070: related to the approved indication. It includes but it is not limited to information on the design and conduct of
p.000070: completed studies for which the results were submitted within the marketing authorisation application, timing of
p.000070: requesting/obtaining the scientific advice and the names of the Agencies that issued those scientific advices.
p.000070: Should EMA deem that any of the proposed redactions fall under the scope of the information described above the
p.000070: following rejection code would be used in the justification table:
p.000070: CCI - Rejection 03 – Disclosure due to public interest
p.000070:
p.000070: This code reads as follows:
p.000070:
p.000070: “The information proposed to be redacted is relevant for the understanding of:
p.000070:
p.000070: • the conduct of the clinical studies;
p.000070:
p.000070: • the reliability and validity of the data/research findings (data submitted for evaluation;)
p.000070:
p.000070: • the safety and efficacy profile of the product;
p.000070: • the reasoning underpinning the company claims and the opinion adopted by the CHMP and the subsequent decision of
p.000070: the European Commission, if applicable.
...
p.000070: purpose of publication in accordance with EMA Policy 0070.
p.000070:
p.000070: 1.2.1. Anonymisation methodology
p.000070:
p.000070: Applicants/MAHs should provide information on the approach chosen to protect personal information:
p.000070:
p.000070: • Non-analytical
p.000070: • Analytics – these methods analyse the data itself to measure the risk and to how best de-identify the data. Some
p.000070: of the open source software tools available are listed below.
p.000070: - Tools available for unstructured text data http://idash-nlp.ucsd.edu/nlp-tools-new.php
p.000070: - Tools for structured microdata http://arx.deidentifier.org/
p.000070: http://arx.deidentifier.org/overview/related-software/
p.000070: 1.2.2. Identification of data variables (direct and quasi identifiers)
p.000070:
p.000070: There are several sections with data results in clinical reports that may contain personal data of trial participants:
p.000070: these include disposition of trial participants, protocol deviations, demographics, other baseline characteristics,
p.000070: treatment compliance, pharmacodynamics, pharmacokinetics, efficacy and safety (adverse events, laboratory findings, and
p.000070: vital signs).
p.000070: In general, clinical overviews and clinical summaries do not contain personal data related to trial participants. An
p.000070: exception is section 2.7.4.2.2 (Narratives) of the Summary of Clinical Safety as described in ICH M4E (R1) which states
p.000070: that “Narratives should not be included here, unless an abbreviated narrative of particular events is considered
p.000070: critical to the summary assessment of the drug.” In addition, some of the tables included in the clinical overviews and
p.000070: clinical summaries may also contain personal data. Following the structure of the CSR as described in ICH Topic E3,
p.000070: sections 2 (synopsis) and sections 10 to 14 (study patients, efficacy, safety, conclusions, tables-figures-graphs) of
p.000070: the CSRs are likely to contain personal data of trial participants. However, it does not exclude the
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 65/99
p.000070:
p.000070: possibility of personal data also being included in other sections or appendices of the clinical reports. Appendices of
p.000070: the clinical study report that are in scope of the Policy 0070 (protocol, protocol amendments, sample case report form,
p.000070: and documentation of statistical methods) generally do not contain personal data.
p.000070: • Describe direct and quasi identifiers in the clinical reports 26
p.000070: - Direct identifiers, e.g. patient ID
p.000070:
p.000070: - Indirect identifiers, e.g. age
p.000070:
p.000070: • De-identification
p.000070:
p.000070: Direct identifiers
p.000070:
p.000070: - Provide information on the redaction of direct identifiers, e.g. patient name, address if present in the reports
p.000070: - Regarding patient ID, provide information on whether it has been redacted or recoded and the resulting impact on
p.000070: the risk of re-identification
p.000070: Quasi (indirect) identifiers
p.000070:
p.000070: - For quasi-identifiers, provide information on the anonymisation techniques used and the rationale for using
p.000070: them.
p.000070:
...
p.000070:
p.000070: 2, statement that it is per patient per visit data removed as out of scope of policy 0070, reading:
p.000070: “Out of Scope of phase I of Policy 0070- Per patient/per visit line listings”.
p.000070:
p.000070: The Agency considers per patient per visit data as those listings including values of the measured parameters (eg. lab
p.000070: values) listed for all patients recruited and covering all study visits.
p.000070: Therefore, for example, tables listing values of the measured parameters (eg. HbA1C) or outcomes (protocol deviation,
p.000070: death, SAE, overall survival) at a certain single time point will not be considered per patient per visit line listing.
p.000070: Also, the Agency does not consider per patient per visit line listings those tables where parameter or outcome values
p.000070: for selected patients and selected visits are presented.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 87/99
p.000070:
p.000070:
p.000070: 2.7.4 Summary of Clinical Safety
p.000070:
p.000070:
p.000070: 2.7.4
p.000070:
p.000070: 2.7.4.1
p.000070:
p.000070: 2.7.4.2
p.000070:
p.000070: 2.7.4.3
p.000070:
p.000070:
p.000070: 2.7.4.4
p.000070:
p.000070:
p.000070: 2.7.4.5
p.000070:
p.000070: 2.7.4.6
p.000070:
p.000070: 2.7.4.7
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: 2.7.4
p.000070: Summary of Clinical Safety In
p.000070:
p.000070: Exposure to the Drug In
p.000070:
p.000070: Adverse Events In
p.000070:
p.000070: Clinical Laboratory Evaluations In
p.000070:
p.000070: Vital Signs, Physical Findings, and Other Observations
p.000070: In
p.000070: Related to Safety
p.000070:
p.000070: Safety in Special Groups and Situations In
p.000070:
p.000070: Post-marketing Data In
p.000070:
p.000070: Appendix In
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: Any other documents (not explicitly mentioned in ICH M4) In
p.000070:
p.000070: All sections of the “Summary of Clinical Safety” regardless whether they are submitted as separate standalone documents
p.000070: or all together in a single document are subject to publication.
p.000070:
p.000070:
p.000070: All additional documents included in CTD section 2.7.4 such as “Clinical summary supplement/amendment/appendix” or
p.000070: “Integrated Summary of Safety (ISS)” which were submitted during the evaluation procedure are subject to publication.
p.000070:
p.000070:
p.000070: However, EMA notes that, the appendixes to clinical overviews(Module 2.5), appendixes to clinical summaries (Modules
p.000070: 2.7.1 to 2.7.4) and CSR bodies may contain individual patient data listings (referred to further below as “per
p.000070: patient/per visit line listings”). For example, these per patient/per visit line listings may be contained in CSR
p.000070: section 14.3.4 Abnormal Laboratory Value Listing (Per Patient/per Visit). EMA considers that such per patient/per visit
...
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: 5.3.1.3
p.000070:
p.000070:
p.000070: (All) In vitro - In vivo Correlation Study Reports
p.000070:
p.000070:
p.000070: Out
p.000070: These study reports contain information on predictive mathematical models describing the relationship between an in
p.000070: vitro property and a relevant in vivo response. These reports are not expected to contain safety and efficacy results.
p.000070: Therefore, EMA considers that these study reports are not subject to publication.
p.000070: 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: 5.3.1.4
p.000070:
p.000070: (All) Reports of Bioanalytical and Analytical Methods for Human Studies
p.000070:
p.000070:
p.000070: Out
p.000070: These study reports contain information on the assays validation and analytical methods employed during the conduct of
p.000070: the clinical trials. These reports are not expected to contain safety and efficacy results. Therefore, EMA considers
p.000070: that these study reports are not subject to publication.
p.000070: 5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials
p.000070:
p.000070: 5.3.2.1 Plasma Protein Binding Study Reports
p.000070:
p.000070: 5.3.2.1 (All) Plasma Protein Binding Study Reports In
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 90/99
p.000070:
p.000070:
p.000070: 5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
p.000070:
p.000070:
p.000070: 5.3.2.2
p.000070: (All) Reports of Hepatic Metabolism and Drug Interaction
p.000070: In
p.000070: Studies
p.000070:
p.000070: 5.3.2.3 Reports of Studies Using Other Human Biomaterials
p.000070:
p.000070: 5.3.2.3 (All) Reports of Studies Using Other Human Biomaterials In
p.000070:
p.000070: 5.3.3 Reports of Human Pharmacokinetic (PK) Studies
p.000070:
p.000070: 5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports
p.000070:
p.000070:
p.000070: 5.3.3.1
p.000070: (All) Healthy Subject PK and Initial Tolerability Study
p.000070: In
p.000070: Reports
p.000070:
p.000070: 5.3.3.2 Patient PK and Initial Tolerability Study Reports
p.000070:
p.000070: 5.3.3.2 (All) Patient PK and Initial Tolerability Study Reports In
p.000070:
p.000070: 5.3.3.3 Intrinsic Factor PK Study Reports
p.000070:
p.000070: 5.3.3.3 (All) Intrinsic Factor PK Study Reports In
p.000070:
p.000070: 5.3.3.4 Extrinsic Factor PK Study Reports
p.000070:
p.000070: 5.3.3.4 (All) Extrinsic Factor PK Study Reports In
p.000070:
p.000070: 5.3.3.5 Population PK Study Reports
p.000070:
p.000070: 5.3.3.5 (All) Population PK Study Reports In
p.000070:
p.000070: 5.3.4 Reports of Human Pharmacodynamic (PD) Studies
p.000070:
p.000070: 5.3.4.1 Healthy Subject PD and PK/PD Study Reports
p.000070:
p.000070: 5.3.4.1 (All) Healthy Subject PD and PK/PD Study Reports In
p.000070:
p.000070: 5.3.4.2 Patient PD and PK/PD Study Reports
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 91/99
p.000070:
p.000070:
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p.000070: amendments
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 95/99
p.000070:
p.000070:
p.000070:
p.000070: Clinical Study Report (CSR) components
p.000070:
p.000070: Clinical Study Report (CSR) sections
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070: 16.1.2 Sample case report form (unique pages only)
p.000070:
p.000070: 16.1.9 Documentation of statistical methods
p.000070:
p.000070: If for a particular CSR the ICH E3 format is not followed, the corresponding information/sections (1-15) and annexes
p.000070: (16.1.1, 16.1.2, 16.1.9) will be subject to publication.
p.000070:
p.000070: 16.1.3 List of IECs or IRBs (plus the name of the committee Chair if required by the regulatory authority) -
p.000070: Representative written information for patient and sample consent forms
p.000070:
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.4 List and description of investigators and other important participants in the study, including brief (1 page)
p.000070: CVs or equivalent summaries of training and experience relevant to the performance of the clinical study
p.000070:
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.5 Signatures of principal or coordinating investigator(s) or sponsor’s responsible medical officer, depending on
p.000070: the regulatory authority's requirement
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.6 Listing of patients receiving test drug(s)/investigational product(s) from specific batches, where more than one
p.000070: batch was used
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.7 Randomisation scheme and codes (patient identification and treatment assigned)
p.000070:
p.000070: Out
p.000070: 16.1.8 Audit certificates (if available) (see Annex IVa and IVb of the guideline) Out
p.000070:
p.000070: 16.1.9 Documentation of statistical methods In
p.000070:
p.000070:
p.000070: 16.1.10 Documentation of inter-laboratory standardisation methods and quality assurance procedures if used
p.000070:
p.000070: Out
p.000070: 16.1.11 Publications based on the study Out
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 96/99
p.000070:
p.000070:
p.000070:
p.000070: Clinical Study Report (CSR) components
p.000070:
p.000070: Clinical Study Report (CSR) sections
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070: 16.1.12 Important publications referenced in the report Out
p.000070:
p.000070: 16.2. PATIENT DATA LISTINGS
p.000070:
p.000070: All appendices located under 16.2. PATIENT DATA LISTINGS Out
p.000070:
p.000070: 16.3 CASE REPORT FORMS
p.000070:
p.000070: All appendices located under 16.3 CASE REPORT FORMS Out
p.000070:
p.000070: 16.4. INDIVIDUAL PATIENT DATA LISTINGS (US ARCHIVAL LISTINGS)
p.000070:
p.000070:
p.000070: All appendices located under 16.4. INDIVIDUAL PATIENT DATA LISTINGS (US ARCHIVAL LISTINGS)
p.000070:
p.000070: Out
p.000070:
p.000070:
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p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 16/99
p.000068:
p.000068: 3.3.1.4. Anonymisation Report
p.000068:
p.000068: One overall anonymisation report has to be submitted describing the methodology of the anonymisation applied in the
p.000068: submitted clinical reports. The report should also describe how the risk of re-identification has been measured and
p.000068: managed, or if the three criteria for anonymisation have been fulfilled. A template anonymisation report can be found
p.000068: at Annex 1.2 setting out its content and structure requirements.
p.000068:
p.000068: 3.3.1.5. Issues with hyperlinks, bookmarks or external links
p.000068:
p.000068: The applicant/MAH is not expected to provide/ensure that hyperlinks between and within documents are functional. This
p.000068: also applies to bookmarks.
p.000068:
p.000068: 3.3.1.6. Leaf title naming in index XML of eCTD submission
p.000068:
p.000068: For submission of the Redaction Proposal version and the Final Redacted version of the clinical reports, EMA requires
p.000068: the applicant/MAH to follow a predefined naming convention. During the submission the documents will have an XML leaf
p.000068: title as well as a filename (pdf). The naming convention applies to both the XML leaf title as well as the filename.
p.000068: Publishing the submission with recommended leaf titles and filenames as below will generate Best practice warnings
p.000068: (15.BP3, 15.BP5) during the eCTD technical validation, however this will not lead to validation failure or influence
p.000068: the acceptance of submission from a technical perspective.
p.000068: The construction of the above naming conventions is based on the use of the following elements:
p.000068:
p.000068: EMA requires the applicant/MAH to apply the following naming convention for the leaf titles in the index.xml:
p.000068:
p.000068: Module 2 documents
p.000068:
p.000068: TradeName7H/C/xxxxxx/xx/xxxx m25-clinical-overview-var TradeName7 H/C/xxxxxx/xx/xxxx m271-summary-biopharm-var
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m272-summary-clin-pharm-var TradeName7 H/C/xxxxxx/xx/xxxx m273-summary-clin-efficacy-var
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m274-summary-clin-safety-var Module 5 documents
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m53xx-StudyReportNumber8 P (for PIVOTAL) or S (for SUPPORTIVE) CSR body
p.000068:
p.000068:
p.000068: 7 The trade name will be looked into on a case by case basis in case of a very long string of characters.
p.000068: 8 For reports which present analysis of data collected from multiple studies, the applicant/MAH should include the
p.000068: report identification number (one identification number), instead of the study report numbers of each study from which
p.000068: the data was analysed (clinical trial or clinical study numbers). This information has to be included in the leaf
p.000068: titles and in the file names.
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 17/99
p.000068:
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m53xx-StudyReportNumber8 P (for PIVOTAL) or S (for SUPPORTIVE) app1611 protocol
p.000068:
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m53xx-StudyReportNumber8 P (for PIVOTAL) or S (for SUPPORTIVE) app1612 crf
p.000068:
...
p.000068: document package. An automated Gateway MDN (Message Delivery Notification) message will be sent to the applicant/MAH
p.000068: acknowledging receipt of the transmission. The MDN is equal to the signature upon delivery by the courier and only
p.000068: confirms that the package has been received by EMA. It does not confirm that a submission (eCTD) is technically valid,
p.000068: but only submission receipt. Users sending eCTD sequences containing the Redaction Proposal document package will also
p.000068: receive an acknowledgement confirming the receipt and pass/fail of the technical compliance check as per the current
p.000068: eCTD validation criteria for all submissions (the second automated reply). For failed submissions the error description
p.000068: can be found in the ‘failure’ acknowledgement (xml) and the submission has to be sent again.
p.000068:
p.000068: 3.3.1.13. Technical validation
p.000068:
p.000068: Technical validation refers to the automated tool validation carried out on an eCTD submission by checking the document
p.000068: type definition (DTD) and technical components of the submission. Upon receiving the eCTD sequence EMA performs
p.000068: technical validation on the submitted eCTD sequence. On successful completion of this validation step, the
p.000068: applicant/MAH is informed.
p.000068: Where an error is found during technical validation, the submission will not be loaded into the review system and a
p.000068: replacement sequence (sequence as appropriate) should be sent by the applicant/MAH by EMA.
p.000068: For all submissions it is expected that following the recommended file naming conventions (in Sections
p.000068: 3.3.1.6 and 3.3.1.7) eCTD technical validation report will contain certain ’Best practice’ warnings (15.BP3, 15.BP5),
p.000068: however this will not lead to rejection or influence the acceptance of submission from a technical perspective.
p.000068:
p.000068: 3.3.2. Consultation process
p.000068:
p.000068: 3.3.2.1. Redaction consultation process
p.000068:
p.000068: On receipt of the Redaction Proposal document package, EMA initiates a redaction consultation process. A flowchart of
p.000068: the process is at Annex 1.11. This consultation process will allow EMA to thoroughly assess the validity of the
p.000068: proposed CCI redactions, and will enable the applicant/MAH to communicate clearly why, in their view, the information
p.000068: proposed for redaction is considered CCI. Following the assessment EMA will communicate its final conclusion to the
p.000068: company.
p.000068: The redaction consultation consists of three different stages that are:
p.000068:
p.000068: 1. Internal receipt and distribution.
p.000068:
p.000068: 2. Validation.
p.000068:
p.000068: 3. Assessment of CCI.
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 27/99
p.000068:
p.000068: 3.3.2.1.1. Internal receipt and distribution stage
p.000068:
p.000068: Upon receipt of the Redaction Proposal version of the clinical reports, together with the completed justification
p.000068: tables, a dedicated team in EMA will be assigned to coordinate the redaction consultation process. For each submitted
p.000068: package a contact person will be nominated.
p.000068:
p.000068: 3.3.2.1.2. Validation stage
p.000068:
p.000068: Following internal receipt and distribution, EMA will first assess the validity of the justification comments. This
p.000068: stage will ensure that clear and valid justifications are assessed in the next stage of the consultation process. If
...
p.000068: confirms that the package has been received by EMA. It does not confirm that a submission (eCTD) is technically valid,
p.000068: but only submission receipt. Users submitting eCTD sequences containing the Final Redacted document package will also
p.000068: receive an acknowledgement confirming the receipt and pass/fail of the technical compliance check as per the current
p.000068: eCTD validation criteria for all submissions (the second automated reply). For failed
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 32/99
p.000068:
p.000068: submissions the error description can be found in the ‘failure’ acknowledgement (xml) and the submission has to be sent
p.000068: again.
p.000068:
p.000068: 3.3.3.9. Technical validation
p.000068:
p.000068: Technical validation refers to the automated tool validation carried out on an eCTD submission by checking the document
p.000068: type definition (DTD) and technical components of the submission. If the technical validation is successful, the
p.000068: applicant/MAH is informed through an acknowledgement of receipt. Where an error is found during technical validation,
p.000068: the submission will not be loaded into the review system and a replacement sequence 0000 (or sequence as appropriate)
p.000068: should be requested from the applicant/MAH by EMA.
p.000068: For all submissions it is expected that following the recommended file naming conventions (in Section
p.000068: 3.3.1.6 & 3.3.1.7) eCTD technical validation report will contain certain ’Best practice’ warnings (15.BP3, 15.BP5),
p.000068: however this will not lead to rejection or influence the acceptance of submission from a technical perspective.
p.000068:
p.000068: 3.3.4. Publication process
p.000068:
p.000068: Redacted/anonymised clinical reports will be published by EMA on its corporate website. Prior to publication EMA will
p.000068: watermark each page9 of the clinical reports in the Final Redacted version submitted by the applicant/MAH. The
p.000068: timelines for the publication of redacted/anonymised clinical reports will vary depending on the regulatory procedure.
p.000068: For initial MAAs, line extension applications and extension of indication applications EMA will publish the
p.000068: redacted/anonymised clinical reports within 60 days of the issuance of the Commission decision. For withdrawn
p.000068: applications the publication of the redacted/anonymised clinical reports will take place within 150 days after the
p.000068: receipt of the withdrawal letter. The applicant/MAH will receive an automated confirmation from EMA once publication
p.000068: has taken place.
p.000068: A situation may arise where an agreement between the applicant/MAH and EMA was not reached on the proposed redaction,
p.000068: and the applicant/MAH decided to apply for interim relief against an EMA decision to publish the documents without
p.000068: accepting the redactions which are still controversial. In this case, the applicant/MAH will submit a partial Final
p.000068: Redacted version package, whereby the clinical reports would be redacted according to the applicant/MAH’s views. The
p.000068: applicant/MAH will confirm, in the text of the cover letter, which controversial redactions (page, line) have been made
p.000068: in the documents. Please note that applications for annulment of EMA decisions and the related application for interim
...
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p.000070: which, in EMA’s view, is necessary for the understanding of the rest of the clinical report, and therefore its
p.000070: disclosure is in the public interest. EMA foresees the use of 5 rejection codes that would mirror the above
p.000070: considerations. At the end of the redaction consultation process, these codes will be included in the justification
p.000070: table, reflecting EMA’s final position.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 51/99
p.000070:
p.000070: 3.2.1. Information that is already in the public domain or publicly available
p.000070: – Rejection code 01
p.000070:
p.000070: EMA recommends that the applicant/MAH compiles a list of the most common websites/locations where information regarding
p.000070: their own medicinal product is usually made available. Applicants/MAHs should create and maintain their own specific
p.000070: list detailing the level of public information concerning their product(s). Based on EMA experience gained through
p.000070: handling Access to Documents Requests, EMA suggests that the following sources of information be included in the list
p.000070: (as a minimum):
p.000070: • Applicants’/MAHs’ own web-site(s).
p.000070:
p.000070: • EMA web-site (product EPAR, scientific guidelines).
p.000070:
p.000070: • Clinical trials registries (such as EU Clinical Trials Register, ClinicalTrials.gov).
p.000070: • Web-sites of other regulatory authorities within the EU and outside the EU (such as FDA, PMDA, TGA, Health
p.000070: Canada) especially when the product (or another product containing the same active substance) is approved in those
p.000070: specific jurisdictions.
p.000070: • Scientific literature and articles (such as Textbooks, PubMed, Medline).
p.000070: The information sources suggested above by EMA are not intended to constitute an exhaustive list, but rather to serve
p.000070: as a starting point for the applicant/MAH in the creation of their own (more exhaustive, customized) list. Should the
p.000070: company compile such list, the above mentioned examples should be considered as the minimum number of information
p.000070: sources to be scrutinized by the applicant/MAH in order to reach a basic level of awareness on publicly available
p.000070: information related to the product concerned. As this list is not required as per Policy 0070, EMA only recommends it
p.000070: to be prepared for the company’s internal use.
p.000070: Should EMA deem that any of the proposed redactions concern information which is already in the public domain the
p.000070: following rejection code will be used in the justification table:
p.000070: CCI - Rejection 01 – Information already available in the public domain or publicly available
p.000070:
p.000070: This code reads as follows:
p.000070:
p.000070: “The information proposed to be redacted is already available in the public domain.
p.000070:
p.000070: In addition, EMA considers that it has not been demonstrated how the disclosure of this publicly available information
p.000070: would undermine your economic interest or competitive position.
p.000070: EMA therefore adopts the position that the information proposed to be redacted does not constitute commercially
p.000070: confidential information and it is not accepted by EMA as a valid redaction proposal. “
p.000070: In addition, EMA will add the reference to the publicly available information source.
p.000070:
p.000070: 3.2.2. Information that does not bear any innovative features – Rejection code 02
p.000070:
...
p.000070: would undermine your economic interest or competitive position.
p.000070: EMA therefore adopts the position that the information proposed to be redacted does not constitute commercially
p.000070: confidential information and that is not accepted by EMA as a valid redaction proposal. “
p.000070: The following section of the guidance presents some examples of justifications that are considered by EMA to be
p.000070: insufficient.
p.000070: EXAMPLE 1
p.000070:
p.000070: “Unpublished data - These study results have not been published in any peered-reviewed [sic] publication.”
p.000070: EXAMPLE 2
p.000070:
p.000070: “Company confidential information - Disclosure of these elements will harm [the company]’s commercial interests because
p.000070: it may enable third party access to business-critical information.”
p.000070: EXAMPLE 3
p.000070:
p.000070: “This information can be interpreted out of context. Such interpretation could lead to a misleading image of the safety
p.000070: profile of the product.”
p.000070: EXAMPLE 4
p.000070:
p.000070: “Detailed Statistical/Analytical Method : See Article 4.2 1st indent of Regulation (EC) The institutions shall refuse
p.000070: access to a document where disclosure would undermine the protection of commercial interests of a natural or legal
p.000070: person, including intellectual property.”
p.000070: EXAMPLE 5
p.000070:
p.000070: “The deleted text is detailed information for the active substance which is considered as confidential information.”
p.000070: EXAMPLE 6
p.000070:
p.000070: “Regulatory interaction – approaches and interactions which could give competitors substantial advantages.”
p.000070: EXAMPLE 7
p.000070:
p.000070: “The analytical methods are [the company]’s intellectual property, which [the company] developed by expending a
p.000070: significant amount of time, and human, financial and commercial resources.”
p.000070: EXAMPLE 8
p.000070:
p.000070: “Information is commercially confidential, competitively sensitive information and includes intellectual property
p.000070: including trade secret information.”
p.000070: EXAMPLE 9
p.000070:
p.000070: “Information on the safety profile of the product not reflected in the SmPC.”
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 57/99
p.000070:
p.000070: EXAMPLE 10
p.000070:
p.000070: “Information is commercially confidential, competitively sensitive information and includes intellectual property
p.000070: including trade secret information.”
p.000070: EXAMPLE 11
p.000070:
p.000070: “The text proposed to be redacted reveals purpose and timing of discussions with health authorities, this is considered
p.000070: sensitive information that is not consolidated in this way within the public domain, and indeed we cannot find this
p.000070: information in public forum.
p.000070:
...
p.000070:
p.000070: Clinical Data Publication Policy:
p.000070:
p.000070: Redaction Tool Application – SME
p.000070:
p.000070: Please complete this form in capitals
p.000070:
p.000070: Company name:
p.000070: EMA-SME Number: Expiry: Product
p.000070: Invented Name: INN:
p.000070:
p.000070: EMA number: EMEA/H/C/
p.000070:
p.000070: Contact person for interaction purpose with EMA
p.000070: Name:
p.000070: Position within the SME:
p.000070: Address:
p.000070:
p.000070: Post Code:
p.000070: Country:
p.000070: Telephone
p.000070: Country Code: Area Code: Number:
p.000070:
p.000070: Email Address:
p.000070:
p.000070:
p.000070:
p.000070: Email address specifically for software licence purposes. This email address will be used for all subscription purposes
p.000070: with the supporting company. This email address will be your company’s identification reference with the supplier.
p.000070: Identification
p.000070:
p.000070: E-mail Address:
p.000070:
p.000070:
p.000070: Name (in Capitals):
p.000070:
p.000070:
p.000070: Signed Date:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 64/99
p.000070:
p.000070: 1.2. Anonymisation report - Template
p.000070:
p.000070: Product name:
p.000070:
p.000070: Active substance:
p.000070:
p.000070: Procedure number:
p.000070:
p.000070: Applicant/MAH:
p.000070:
p.000070: The aim of the anonymisation report is to provide an overview of the anonymisation process followed, the methodology
p.000070: used, the rationale for data transformations/redactions required for the adequate anonymisation of the data and the
p.000070: impact on data utility. The information presented in the anonymisation report should not in itself lead to an increased
p.000070: risk of re-identification. The report can be divided in subsections, one for each of the clinical study reports
p.000070: submitted for publication.
p.000070: This document is without prejudice to the obligations of pharmaceutical companies as controllers of personal data under
p.000070: applicable EU and national legislation on the protection of personal data.
p.000070: This template should be used in conjunction with the External guidance on the anonymisation of clinical reports for the
p.000070: purpose of publication in accordance with EMA Policy 0070.
p.000070:
p.000070: 1.2.1. Anonymisation methodology
p.000070:
p.000070: Applicants/MAHs should provide information on the approach chosen to protect personal information:
p.000070:
p.000070: • Non-analytical
p.000070: • Analytics – these methods analyse the data itself to measure the risk and to how best de-identify the data. Some
p.000070: of the open source software tools available are listed below.
p.000070: - Tools available for unstructured text data http://idash-nlp.ucsd.edu/nlp-tools-new.php
p.000070: - Tools for structured microdata http://arx.deidentifier.org/
p.000070: http://arx.deidentifier.org/overview/related-software/
...
Health / Healthy People
Searching for indicator healthy volunteers:
(return to top)
p.000070: regard to the processing of personal data by the Community institutions and bodies and on the free movement of such
p.000070: data, of 18 December 2000.
p.000070: • Directive 95/46/EC of the European Parliament and of the Council on the protection of individuals with regard to
p.000070: the processing of personal data and on the free movement of such data, of 24 October 1995.
p.000070: • Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070: • Opinion 06/2013 on open data and public sector information reuse of the Article 29 Data Protection Working
p.000070: Party.
p.000070: • Information Commissioner’s Office (ICO) Code of Practice. Anonymisation: managing data protection risk.
p.000070: • Sharing clinical trial data: Maximizing benefits, minimizing risk. Institute of Medicine (IOM). 2015.
p.000070: Washington, DC: The National Academies Press.
p.000070:
p.000070: 10 The term ‘trial participant’ in the current guidance relates to individuals on whom information has been collected
p.000070: related to the scientific objectives of the trial, e.g. patients and healthy volunteers.
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 36/99
p.000070:
p.000070: • Pharmaceutical Users Software Exchange (PhUSE) de-identification standards for CDISC SDTM 3.2.
p.000070:
p.000070: • Transcelerate BioPharma Inc.
p.000070:
p.000070: - Clinical Study Reports Approach to Protection of Personal Data.
p.000070: - Data De-identification and Anonymisation of Individual Patient Data in Clinical Studies– A Model Approach.
p.000070: • White Paper on Anonymisation of Clinical Trial Data Sets. International Pharmaceutical Privacy Consortium
p.000070: (IPPC).
p.000070: • Scientific literature (see References).
p.000070:
p.000070: 3. General considerations
p.000070: A number of general aspects need to be considered when providing recommendations on how best achieve anonymisation.
p.000070: These relate to:
p.000070:
p.000070: 3.1. Context of data disclosure
p.000070:
p.000070: The risk of re-identification can vary depending on the context of disclosure. In the case of public data release
p.000070: (publication to the world at large) the risk of re-identification needs to be very low since there are no controls that
p.000070: can be put in place. However, for non-public data-sharing a higher risk could be acceptable because robust governance
p.000070: arrangements (security, privacy, and contractual controls) can be established. It means that the same data can be
...
Health / Motherhood/Family
Searching for indicator family:
(return to top)
p.000070: An anonymisation solution preventing all three criteria is considered to be robust against identification performed by
p.000070: the most likely and reasonable means the data controller or any third party may employ, and will render the data
p.000070: anonymous.
p.000070:
p.000070: 3.2.2. Anonymisation techniques
p.000070:
p.000070: There are several techniques that can be used in order to achieve anonymisation. Opinion 05/2014 on anonymisation
p.000070: techniques of the Art. 29 WP analyses the effectiveness and limits of existing anonymisation techniques against the EU
p.000070: legal background of data protection, and provides recommendations to handle these techniques by taking account of the
p.000070: residual risk of identification inherent in each of them14.
p.000070:
p.000070:
p.000070: 12 The definition of personal data as described in Article 2(a) of Regulation (EC) No 45/2001 relates to a ‘natural
p.000070: person’. The Article 29 Working Party opinion 4/2007 on the concept of personal data further clarifies that information
p.000070: relating to dead individuals is therefore in principle not to be considered as personal data to the rules of the
p.000070: Directive, as dead are no longer natural persons in civil law. However, the opinion also points out that data on the
p.000070: deceased may still be personal information since it may refer to living persons, e.g. it may indicate family diseases
p.000070: relevant to living children or siblings. In addition, it might be difficult for the data controller to establish
p.000070: whether the person to whom the data relates is still alive.
p.000070: 13 Opinion 05/2014 on anonymisation techniques and Opinion 06/2013 on open data and public sector information reuse of
p.000070: the Article 29 Data Protection Working Party .
p.000070: 14 Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 38/99
p.000070:
p.000070: 3.3. Advances in technology
p.000070:
p.000070: It is also important to take note of advances in technology (e.g. data mining) together with greater availability of
p.000070: data and the possibility of database linkage with the increased risk of re-identification. MAHs/applicants need to take
p.000070: into account (realistic) future developments in terms of availability of data and technologies that would allow
p.000070: identification. The Art. 29 WP Opinion 05/2014 on anonymisation techniques emphasises that even where a data controller
...
p.000070:
p.000070: 5.3.2. Anonymisation techniques
p.000070:
p.000070: It should be noted that each anonymisation technique has its own strengths and weaknesses. The robustness of each
p.000070: anonymisation technique is based upon the aforementioned anonymisation criteria and will help identify the most
p.000070: suitable technique (or combination of different techniques) to establish an adequate anonymisation process for a given
p.000070: clinical report. Ultimately, the aim is to preserve data utility as much as possible whilst ensuring adequate
p.000070: anonymisation.
p.000070: Not all anonymisation techniques described in Opinion 05/2014 of the Art. 29 WP may be suitable to anonymise personal
p.000070: data in clinical reports. The specificities of the clinical data should therefore be taken into consideration when
p.000070: selecting the most appropriate technique(s).
p.000070: The simplest method of anonymisation is the removal of values for variables which allow direct or indirect
p.000070: identification of an individual from the data. This technique is sometimes called masking. Technically, it can be
p.000070: achieved by using a redaction tool which ensures that the redacted information is irreversibly blocked out. Masking of
p.000070: pre-specified variables can be done manually and/or may include the use of software that can help identifying
p.000070: pre-specified variables that need redaction. Masking of pre-specified variables is recommended. Removing entire
p.000070: sections of the report where masking is possible is not considered appropriate, and is, therefore, not recommended by
p.000070: EMA.
p.000070: Apart from masking, the main anonymisation techniques are randomisation and generalisation.
p.000070:
p.000070: Randomisation is a family of techniques that alters the veracity of the data in order to remove the strong link between
p.000070: the data and the individual. Recommended techniques include noise addition and permutation. Noise addition can consist
p.000070: of, for example, shifting dates randomly by a few days (forward or backwards), based on a uniform, or other type of,
p.000070: distribution. Permutation may have limitations as regards clinical utility as relationships between attributes can be
p.000070: destroyed. The differential privacy technique may not be applicable in the context of Policy 0070 since the same
p.000070: documents will be made available to all users.
p.000070: The other main family of anonymisation techniques consists of generalising, or diluting the attributes of the data by
p.000070: modifying the respective scale or order of magnitude. An example would be a trial participant who suffers from asthma,
p.000070: born on 19 August 1978. This date of birth would be generalised
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 41/99
p.000070:
p.000070: to 1978. Recommended generalisation techniques include aggregation and k-anonymity. L-diversity and t-closeness may not
p.000070: be recommended as they limit inferences significantly. Aggregation involves the replacement of a value by a range, e.g.
p.000070: a trial participant’s age is replaced with an age range (age of 56 replaced with range of 50 to 60). K-anonymity goes a
p.000070: step further by preventing a trial participant from being singled out since it is grouped with, at least, k other trial
p.000070: participants in that range.
p.000070: EMA follows closely the developments in techniques that can be used to anonymise clinical data through mathematical
p.000070: models together with metrics of re-identification. These techniques can be directly applied to the anonymisation of
p.000070: electronic datasets and allow the anonymisation of the copy of the CSR for publication using the underlying clinical
p.000070: data which has already been anonymised. This may facilitate the anonymisation process and maximise the information
p.000070: included in the copy of the CSR anonymised for publication. It does not mean that anonymisation will take place before
...
Social / Access to Social Goods
Searching for indicator access:
(return to top)
p.000070: • How to identify and flag/highlight in the clinical reports pieces of text (proposed redactions) that may
p.000070: potentially constitute CCI.
p.000070: • The minimum level of detail expected in the justification that will allow EMA to perform an adequate and
p.000070: informed evaluation of the proposed redactions.
p.000070: • Establishing a better defined approach of the identification of CCI when applying the redaction principles laid
p.000070: out in policy 0070.
p.000070: The ultimate goals of this guidance are:
p.000070:
p.000070: • To ensure a common understanding of what may potentially be or cannot be considered CCI within clinical reports.
p.000070: • To increase consistency in the proposed and accepted redactions across the range of clinical reports relating
p.000070: to various human medicinal products and regulatory procedures falling under Policy 0070.
p.000070: • To ensure a good quality of the justifications for the proposed redactions, hereby reducing the administrative
p.000070: burden for all parties involved in the preparation and publication of the documents falling under Policy 0070.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 49/99
p.000070:
p.000070: 2. Existing guidance documents
p.000070: While Policy 0070 applies without prejudice to EMA’s activities conducted in accordance with Regulation (EC) No
p.000070: 1049/2001, EMA strives to ensure consistency between the approach for the redaction of documents published in
p.000070: accordance with Policy 0070 and similar documents released in response to requests for access to documents in
p.000070: accordance with Regulation (EC) No 1049/2001. This document should therefore be read in conjunction with the following
p.000070: policies and guidance documents which have been released in the past and provide relevant background:
p.000070: • European Medicines Agency policy on publication of clinical data for medicinal products for human use (Policy
p.000070: 0070).
p.000070: • European Medicines Agency policy on access to documents (related to medicinal products for human and veterinary
p.000070: use)21 (Policy 0043) – adopted on 30 November 2010. Policy 0043 should be read in conjunction with the Output of the
p.000070: European Medicines Agency policy on access to documents related to medicinal products for human and veterinary use22 –
p.000070: adopted on 30 November 2010.
p.000070: Over the past few years, EMA has worked in partnership with National Competent Authorities in establishing guidance
p.000070: which has contributed to a harmonised approach for access to documents across EU Member States. As a result several
p.000070: documents were prepared, all finding their legal basis in the above-mentioned Regulation (EC) No 1049/2001. Released
p.000070: over time, they established sets of principles and recommendations covering both redactions of CCI and personal data
p.000070: regardless of the nature of the information (quality, non-clinical and clinical):
p.000070: • HMA/EMEA recommendations on transparency – recommendations on the handling of requests for access to Periodic
p.000070: Safety Update Reports (PSURs)23 – adopted on 23 November 2009.
p.000070: • HMA/EMA guidance document on the identification of commercially confidential information and personal data
p.000070: within the structure of the marketing authorisation (MA) application – release of information after the granting of a
p.000070: marketing authorisation24 – adopted on 09 March 2012.
p.000070: • Principles to be applied for the implementation of the HMA/EMA Guidance on the identification of CCI and PPD in
p.000070: MA Applications25 – adopted on 09 March 2012.
p.000070:
p.000070: 3. Points to be taken into account for the preparation of the redaction proposal version of a clinical report
p.000070: For the purpose of this guidance, CCI shall mean any information contained in the clinical reports submitted to EMA by
p.000070: the applicant/MAH which is not in the public domain or publicly available, and where disclosure may undermine the
p.000070: legitimate economic interest of the applicant/MAH.
p.000070: Prior to proposing any redactions, the applicant/MAH should be aware of the level of information already available in
p.000070: the public domain concerning their product’s development (e.g. study design and results), scientific knowledge and
p.000070: advancements within the relevant (for the particular product)
p.000070:
p.000070: 21 European Medicines Agency policy on access to documents (related to medicinal products for human and veterinary use)
p.000070: 22 Output of the European Medicines Agency policy on access to documents related to medicinal products for human and
p.000070: veterinary use
p.000070: 23 HMA/EMEA recommendations on transparency – recommendations on the handling of requests for access to Periodic Safety
p.000070: Update Reports (PSURs)
p.000070: 24 HMA/EMA guidance document on the identification of commercially confidential information and personal data within
p.000070: the structure of the marketing authorisation (MA) application – release of information after the granting of a
p.000070: marketing authorisation
p.000070: 25 Principles to be applied for the implementation of the HMA/EMA Guidance on the identification of CCI and PPD in MA
p.000070: Applications
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 50/99
p.000070:
p.000070: therapeutic area(s). Such preparatory work by the applicant/MAH is essential and will enable an expedited consultation
p.000070: process, thereby reducing the number of instances in which EMA will have to reject proposed redactions because the
p.000070: information is already in the public domain.
p.000070:
p.000070: 3.1. How to read and apply the redaction principles laid out in Policy 0070
p.000070:
p.000070: EMA has identified in Policy 0070 (Annex 3 – Redaction principles) certain types of information that may potentially be
p.000070: considered CCI. These principles should not be perceived by the applicant/MAH as an open and unconditional invitation
p.000070: to propose, on a regular basis, the redaction of information falling within the types of information described in the
p.000070: aforementioned Annex 3. In other words, the applicant/MAH should not consider by default such types of information as
p.000070: being CCI. The redaction proposals based on grounds of CCI must be backed up by the applicant/MAH with a specific and
p.000070: clear justification which is subject to EMA’s review.
...
p.000070: document.
p.000070: • DOES fall under the types of information that may potentially be considered CCI according to Policy 0070 Annex
p.000070: 3.
p.000070: Moreover, the applicant/MAH should ensure that a specific, pertinent, relevant, not overstated, and appropriate
p.000070: justification is included in the justification table corresponding to the piece of information that is proposed for
p.000070: redaction.
p.000070: The applicant/MAH is advised to limit the extent of the proposed redactions to the word(s), figure, and pieces of text
p.000070: that, in their view, can be considered CCI. The applicant/MAH is discouraged from proposing the redaction of entire
p.000070: pages, sub-sections of a report or full tables, especially when, in their view, only some sentences within the text or
p.000070: some specific figures within the tables fall under the types of information described in Annex 3 and are considered
p.000070: CCI.
p.000070:
p.000070: 3.2. Information that EMA does not consider CCI
p.000070:
p.000070: In order to achieve a high level of consistency in the redaction of CCI in the final redacted documents (and to
p.000070: decrease the administrative burden) EMA has grouped the types of information that EMA does not consider CCI. Should the
p.000070: information proposed to be redacted be in the public domain or bear no innovative features, EMA will not accept its
p.000070: redaction. In addition, if the applicant/MAH fails to provide sufficient and relevant justification, the proposed
p.000070: redactions will be rejected. Finally, section 3.2.3 describes some additional examples of types of information which
p.000070: will not be accepted to be redacted as CCI. These examples reflect the most common redactions proposed by
p.000070: applicants/MAHs which are usually rejected by EMA in the framework of Access to Documents in accordance with Regulation
p.000070: (EC) No 1049/2001. The information covered by the above examples pertains to quality, non-clinical and clinical data
p.000070: which, in EMA’s view, is necessary for the understanding of the rest of the clinical report, and therefore its
p.000070: disclosure is in the public interest. EMA foresees the use of 5 rejection codes that would mirror the above
p.000070: considerations. At the end of the redaction consultation process, these codes will be included in the justification
p.000070: table, reflecting EMA’s final position.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 51/99
p.000070:
p.000070: 3.2.1. Information that is already in the public domain or publicly available
p.000070: – Rejection code 01
p.000070:
p.000070: EMA recommends that the applicant/MAH compiles a list of the most common websites/locations where information regarding
p.000070: their own medicinal product is usually made available. Applicants/MAHs should create and maintain their own specific
p.000070: list detailing the level of public information concerning their product(s). Based on EMA experience gained through
p.000070: handling Access to Documents Requests, EMA suggests that the following sources of information be included in the list
p.000070: (as a minimum):
p.000070: • Applicants’/MAHs’ own web-site(s).
p.000070:
p.000070: • EMA web-site (product EPAR, scientific guidelines).
p.000070:
p.000070: • Clinical trials registries (such as EU Clinical Trials Register, ClinicalTrials.gov).
p.000070: • Web-sites of other regulatory authorities within the EU and outside the EU (such as FDA, PMDA, TGA, Health
p.000070: Canada) especially when the product (or another product containing the same active substance) is approved in those
p.000070: specific jurisdictions.
p.000070: • Scientific literature and articles (such as Textbooks, PubMed, Medline).
p.000070: The information sources suggested above by EMA are not intended to constitute an exhaustive list, but rather to serve
p.000070: as a starting point for the applicant/MAH in the creation of their own (more exhaustive, customized) list. Should the
p.000070: company compile such list, the above mentioned examples should be considered as the minimum number of information
p.000070: sources to be scrutinized by the applicant/MAH in order to reach a basic level of awareness on publicly available
p.000070: information related to the product concerned. As this list is not required as per Policy 0070, EMA only recommends it
p.000070: to be prepared for the company’s internal use.
p.000070: Should EMA deem that any of the proposed redactions concern information which is already in the public domain the
p.000070: following rejection code will be used in the justification table:
p.000070: CCI - Rejection 01 – Information already available in the public domain or publicly available
p.000070:
p.000070: This code reads as follows:
p.000070:
...
p.000070: • Scientific and regulatory guidelines and guidance documents.
p.000070:
p.000070: • Treatment/clinical practice/disease management guidelines.
p.000070: Should EMA deem that any of the proposed redactions fall within the scope of the information described above, the
p.000070: following rejection code will be used in the justification table:
p.000070: CCI - Rejection 02 – Common knowledge
p.000070:
p.000070: This code reads as follows:
p.000070:
p.000070: “The information proposed to be redacted reflects approaches or decisions that were/are based on widely known
p.000070: practices/regulatory and scientific information.
p.000070: In addition, EMA considers that its innovative features have not been pointed out and it has not been demonstrated how
p.000070: its disclosure would undermine your economic interest or competitive position.
p.000070: EMA therefore adopts the position that the information proposed to be redacted does not constitute commercially
p.000070: confidential information and it is not accepted by EMA as a valid redaction proposal. “
p.000070: In addition, EMA will add the reference to the publicly available source of information that would suggest that the
p.000070: information in question can be considered common knowledge.
p.000070:
p.000070: 3.2.3. Additional information the disclosure of which would be in the public interest – Rejection code 03
p.000070:
p.000070: It is EMA’s view that some data elements should not be redacted from clinical reports due to the fact that they are
p.000070: relevant for the understanding of the documents published in accordance with Policy 0070. Some of these elements are
p.000070: presented below in Sections 3.2.3.1 to 3.2.3.4. The list is not intended to be exhaustive but details the most frequent
p.000070: data elements, considered CCI by applicants/MAHs during the Access to Documents consultation process, and which are
p.000070: rejected by EMA.
p.000070: The vast majority of information contained in clinical reports is of a clinical nature. However, these clinical reports
p.000070: may also contain information of a quality, non-clinical and general or administrative nature, some of which may
p.000070: potentially be considered CCI. Therefore, EMA has grouped the elements which are not considered CCI into four
p.000070: categories as follows:
p.000070:
p.000070: 3.2.3.1. General or administrative information
p.000070:
p.000070: • Unit measurements, in such cases only the actual value may be considered CCI. [e.g.]2.5mL/kg ◇
p.000070: mL/kg.
p.000070:
p.000070: • Study identification number(s) (e.g. EudraCT, ClinicalTrials.gov Identifier (NCT…), sponsor’s internal study
p.000070: number).
p.000070: • Names and addresses of investigator sites and the names of the principal investigators at each study site
p.000070: (unless it is mentioned in the context of individual patient data/case narratives and is
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 53/99
p.000070:
p.000070: deemed to constitute personal data – see “External guidance on the anonymisation of clinical reports for the purpose of
p.000070: publication in accordance with EMA policy 0070”).
p.000070: • Names of the countries where the clinical study is/was conducted (unless it is mentioned in the context of
p.000070: individual patient data/case narratives and is deemed to constitute personal data – see “External guidance on the
p.000070: anonymisation of clinical reports for the purpose of publication in accordance with EMA policy 0070”).
...
p.000070: Whenever the justification provided by the applicant/MAH does not correspond to/match the (type of) information
p.000070: proposed for redaction, i.e. is not relevant to the information proposed to be redacted, the following rejection code
p.000070: will be used in the justification table:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 56/99
p.000070:
p.000070: CCI - Rejection 05 – Irrelevant justification
p.000070:
p.000070: This code reads as follows:
p.000070:
p.000070: “EMA considers that the justification provided is not related to the information proposed to be redacted. Therefore, in
p.000070: the absence of an adequate justification EMA is unable to recognise how the disclosure of this particular information
p.000070: would undermine your economic interest or competitive position.
p.000070: EMA therefore adopts the position that the information proposed to be redacted does not constitute commercially
p.000070: confidential information and that is not accepted by EMA as a valid redaction proposal. “
p.000070: The following section of the guidance presents some examples of justifications that are considered by EMA to be
p.000070: insufficient.
p.000070: EXAMPLE 1
p.000070:
p.000070: “Unpublished data - These study results have not been published in any peered-reviewed [sic] publication.”
p.000070: EXAMPLE 2
p.000070:
p.000070: “Company confidential information - Disclosure of these elements will harm [the company]’s commercial interests because
p.000070: it may enable third party access to business-critical information.”
p.000070: EXAMPLE 3
p.000070:
p.000070: “This information can be interpreted out of context. Such interpretation could lead to a misleading image of the safety
p.000070: profile of the product.”
p.000070: EXAMPLE 4
p.000070:
p.000070: “Detailed Statistical/Analytical Method : See Article 4.2 1st indent of Regulation (EC) The institutions shall refuse
p.000070: access to a document where disclosure would undermine the protection of commercial interests of a natural or legal
p.000070: person, including intellectual property.”
p.000070: EXAMPLE 5
p.000070:
p.000070: “The deleted text is detailed information for the active substance which is considered as confidential information.”
p.000070: EXAMPLE 6
p.000070:
p.000070: “Regulatory interaction – approaches and interactions which could give competitors substantial advantages.”
p.000070: EXAMPLE 7
p.000070:
p.000070: “The analytical methods are [the company]’s intellectual property, which [the company] developed by expending a
p.000070: significant amount of time, and human, financial and commercial resources.”
p.000070: EXAMPLE 8
p.000070:
p.000070: “Information is commercially confidential, competitively sensitive information and includes intellectual property
p.000070: including trade secret information.”
p.000070: EXAMPLE 9
p.000070:
p.000070: “Information on the safety profile of the product not reflected in the SmPC.”
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 57/99
p.000070:
p.000070: EXAMPLE 10
p.000070:
p.000070: “Information is commercially confidential, competitively sensitive information and includes intellectual property
p.000070: including trade secret information.”
...
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 62/99
p.000070:
p.000070: 1. Annexes
p.000070: 1.1. Redaction tool application letter for SMEs
p.000070:
p.000070:
p.000070: SME Request for Redaction Tool License
p.000070:
p.000070: European Medicines Agency 30 Churchill Place
p.000070: Canary Wharf London
p.000070: E14 5EU
p.000070:
p.000070:
p.000070: Dear ,
p.000070:
p.000070: RE: EMEA/X/X/XXXXXX/XXXX
p.000070:
p.000070: [Product Invented Name; INN, Company Name, Company SME Registration number, EMA-SME number]
p.000070:
p.000070:
p.000070: Request for Redaction Tool License
p.000070:
p.000070:
p.000070: [Company name] is writing to request a redaction tool license for the purpose of creating the Redaction Proposal
p.000070: Version and Final Redacted Version of the clinical reports for the [withdrawn] initial marketing authorisation
p.000070: application/line extension application/extension of indication application (delete as appropriate) for [product INN].
p.000070:
p.000070:
p.000070: The Redaction Proposal version and Final Redacted Version of the clinical reports will be submitted in line with the
p.000070: European Medicines Agency’s policy on the publication of clinical data for medicinal products for human use, Policy
p.000070: 0070. [Company name] confirms eligibility for the redaction tool license, on the grounds of its awarded Small and
p.000070: Medium Sized Enterprise (SME) status. SME qualification by EMA () expires on XX XX XXXX. It is
p.000070: understood that SME status will be checked by EMA at time of issuing the licence, with disclaimers to access rights to
p.000070: be removed if the SME status has expired at that time or in cases of merger/out licensing.
p.000070: In addition, [Company name] undertakes not to transfer, redistribute, sublicense or otherwise make available the
p.000070: redaction tool license, as provided to [Company name] by EMA, to any third party, including to other EMA designated
p.000070: SMEs. [Company name] also confirms that by accepting a redaction tool license [company name] also accepts the licence
p.000070: terms of use related to the redaction tool and all related liability for noncompliance or breach thereof. [Company
p.000070: name] acknowledges and agrees that EMA will not be liable or responsible in any way for any non-compliance with or
p.000070: breaches of these terms on behalf of [Company name].
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 63/99
p.000070:
p.000070: Clinical Data Publication Policy:
p.000070:
p.000070: Redaction Tool Application – SME
p.000070:
p.000070: Please complete this form in capitals
p.000070:
p.000070: Company name:
p.000070: EMA-SME Number: Expiry: Product
p.000070: Invented Name: INN:
p.000070:
p.000070: EMA number: EMEA/H/C/
p.000070:
p.000070: Contact person for interaction purpose with EMA
p.000070: Name:
p.000070: Position within the SME:
p.000070: Address:
p.000070:
p.000070: Post Code:
p.000070: Country:
p.000070: Telephone
p.000070: Country Code: Area Code: Number:
p.000070:
p.000070: Email Address:
...
p.000070: Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070:
p.000070: ICO (UK Data Protection Agency) Code of Practice entitled “Anonymisation: managing data protection risk”.
p.000070: Institute of Medicine, Sharing clinical trial data: Maximizing benefits, minimizing risk. Washington, DC: The National
p.000070: Academies Press, 2015.
p.000070: ICH. The common technical document for the registration of pharmaceuticals for human use. Topic E3 Structure and
p.000070: Content of Clinical Study Reports.
p.000070: ICH. The common technical document for the registration of pharmaceuticals for human use. Efficacy – M4E (R1). Clinical
p.000070: overview and clinical summary of module 2, module 5: clinical study reports.
p.000070: K. El Emam, Kald Abdallah. “De-identifying Clinical Trials Data”. Applied Clinical Trials, Mar 20, 2015.
p.000070:
p.000070: Khaled El Emam, Sam Rodgers, Bradley Malin. Anonymising and sharing individual patient data. BMJ
p.000070: 2015; 350: h1139.
p.000070:
p.000070: PhUSE De-Identification Working Group, “De-Identification Standards for CDISC SDTM 3.2,” 2015.
p.000070:
p.000070: David Carrell, Bradley Malin, John Aberdeen, et al. “Hiding in plain sight: use of realistic surrogates to reduce
p.000070: exposure of protected health information in clinical text”. J Am Med Inform Assoc 2013;20:342–348.
p.000070: European Medicines Agency policy on access to documents (related to medicinal products for human and veterinary use)
p.000070: Output of the European Medicines Agency policy on access to documents related to medicinal products for human and
p.000070: veterinary use
p.000070: HMA/EMEA recommendations on transparency – recommendations on the handling of requests for access to Periodic Safety
p.000070: Update Reports (PSURs);
p.000070: HMA/EMA guidance document on the identification of commercially confidential information and personal data within the
p.000070: structure of the marketing authorisation (MA) application – release of information after the granting of a marketing
p.000070: authorisation;
p.000070: Principles to be applied for the implementation of the HMA/EMA Guidance on the identification of CCI and PPD in MA
p.000070: Applications
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
...
Social / Age
Searching for indicator age:
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p.000070: EMA.
p.000070: Apart from masking, the main anonymisation techniques are randomisation and generalisation.
p.000070:
p.000070: Randomisation is a family of techniques that alters the veracity of the data in order to remove the strong link between
p.000070: the data and the individual. Recommended techniques include noise addition and permutation. Noise addition can consist
p.000070: of, for example, shifting dates randomly by a few days (forward or backwards), based on a uniform, or other type of,
p.000070: distribution. Permutation may have limitations as regards clinical utility as relationships between attributes can be
p.000070: destroyed. The differential privacy technique may not be applicable in the context of Policy 0070 since the same
p.000070: documents will be made available to all users.
p.000070: The other main family of anonymisation techniques consists of generalising, or diluting the attributes of the data by
p.000070: modifying the respective scale or order of magnitude. An example would be a trial participant who suffers from asthma,
p.000070: born on 19 August 1978. This date of birth would be generalised
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 41/99
p.000070:
p.000070: to 1978. Recommended generalisation techniques include aggregation and k-anonymity. L-diversity and t-closeness may not
p.000070: be recommended as they limit inferences significantly. Aggregation involves the replacement of a value by a range, e.g.
p.000070: a trial participant’s age is replaced with an age range (age of 56 replaced with range of 50 to 60). K-anonymity goes a
p.000070: step further by preventing a trial participant from being singled out since it is grouped with, at least, k other trial
p.000070: participants in that range.
p.000070: EMA follows closely the developments in techniques that can be used to anonymise clinical data through mathematical
p.000070: models together with metrics of re-identification. These techniques can be directly applied to the anonymisation of
p.000070: electronic datasets and allow the anonymisation of the copy of the CSR for publication using the underlying clinical
p.000070: data which has already been anonymised. This may facilitate the anonymisation process and maximise the information
p.000070: included in the copy of the CSR anonymised for publication. It does not mean that anonymisation will take place before
p.000070: the scientific review of the data for the purposes of the clinical trial and marketing authorisation assessment. None
p.000070: of these processes should undermine the submission of the full, pseudonymised clinical reports and underlying data.
p.000070: Most importantly, it needs to be demonstrated that these techniques can ensure that the risk of re-identification is
p.000070: acceptably low and in line with requirements for public disclosure and that the data transformation resulting from the
p.000070: applied anonymisation techniques will not lead to a different interpretation of the study results.
p.000070:
p.000070: 5.3.2.1. Anonymisation of Direct Identifiers
p.000070:
p.000070: Direct identifiers are elements that permit direct recognition or communication with the corresponding individuals.
p.000070: Direct identifiers generally do not have data utility, with the exception of the patient ID.
...
p.000070: on a case-by-case basis based on the impact on the risk. Moreover, it should also be considered that for any extension
p.000070: to the initial marketing authorisation application study, the same patients will be recoded differently from the
p.000070: initial marketing authorisation study. EMA recognises that in such situations data utility may be suboptimal since this
p.000070: creates a problem of linkability between the initial study and the extension study.
p.000070:
p.000070: 5.3.2.2. Anonymisation of Quasi Identifiers
p.000070:
p.000070: Quasi identifiers are variables representing an individual’s background information that can indirectly identify
p.000070: individuals. Unlike direct identifiers, information from quasi identifiers increases the scientific usefulness of the
p.000070: information published. Geographical location is an important variable since clinical practice can vary from country to
p.000070: country and this can impact on the outcome. Relative dates relating to individual patients are also important due to
p.000070: the potential impact on the outcome of the trial. Patient
p.000070:
p.000070:
p.000070: 16 David Carrell, Bradley Malin, John Aberdeen, et al. “Hiding in plain sight: use of realistic surrogates to reduce
p.000070: exposure of protected health information in clinical text”. J Am Med Inform Assoc 2013;20:342–348.
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 42/99
p.000070:
p.000070: level demographic information such as sex, age, race, ethnicity, height and weight can be confounders and therefore of
p.000070: critical scientific utility.
p.000070: In order to render the clinical reports anonymised it is not always necessary to redact all quasi identifiers. The need
p.000070: to redact quasi identifiers will depend on the following aspects:
p.000070: • Number of quasi identifiers per trial participant
p.000070: • Frequency of trial participants with same category/value on a set of the quasi identifiers (group size)
p.000070: • Size of population
p.000070: It is up to the applicant/MAH to decide which quasi identifiers need to be redacted and which could remain in the
p.000070: reports. The rationale for the decision should be included in the risk assessment section of the anonymisation report
p.000070: to be provided to EMA (see section 5.5).
p.000070: The factors having the most impact on data de-identification are geographical location and dates leading to a higher
p.000070: risk of re-identification. A feature of anonymisation is that it is only partially determined by the data to be
p.000070: protected. The ability to identify a trial participant depends on both these data and the state of knowledge of the
p.000070: observer concerning the trial participants in the data. For these reasons, location and dates are important. They may
p.000070: not be the most specific identifiers of a trial participant but they are often the most easily obtainable from other
p.000070: sources. Therefore, clinical data containing information on geographical location and dates should be carefully
p.000070: anonymised (see sections 5.3.2.2.1 and 5.3.2.2.2).
p.000070:
p.000070: 5.3.2.2.1. Dates
p.000070:
...
p.000070: treatment compliance, pharmacodynamics, pharmacokinetics, efficacy and safety (adverse events, laboratory findings, and
p.000070: vital signs).
p.000070: In general, clinical overviews and clinical summaries do not contain personal data related to trial participants. An
p.000070: exception is section 2.7.4.2.2 (Narratives) of the Summary of Clinical Safety as described in ICH M4E (R1) which states
p.000070: that “Narratives should not be included here, unless an abbreviated narrative of particular events is considered
p.000070: critical to the summary assessment of the drug.” In addition, some of the tables included in the clinical overviews and
p.000070: clinical summaries may also contain personal data. Following the structure of the CSR as described in ICH Topic E3,
p.000070: sections 2 (synopsis) and sections 10 to 14 (study patients, efficacy, safety, conclusions, tables-figures-graphs) of
p.000070: the CSRs are likely to contain personal data of trial participants. However, it does not exclude the
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 65/99
p.000070:
p.000070: possibility of personal data also being included in other sections or appendices of the clinical reports. Appendices of
p.000070: the clinical study report that are in scope of the Policy 0070 (protocol, protocol amendments, sample case report form,
p.000070: and documentation of statistical methods) generally do not contain personal data.
p.000070: • Describe direct and quasi identifiers in the clinical reports 26
p.000070: - Direct identifiers, e.g. patient ID
p.000070:
p.000070: - Indirect identifiers, e.g. age
p.000070:
p.000070: • De-identification
p.000070:
p.000070: Direct identifiers
p.000070:
p.000070: - Provide information on the redaction of direct identifiers, e.g. patient name, address if present in the reports
p.000070: - Regarding patient ID, provide information on whether it has been redacted or recoded and the resulting impact on
p.000070: the risk of re-identification
p.000070: Quasi (indirect) identifiers
p.000070:
p.000070: - For quasi-identifiers, provide information on the anonymisation techniques used and the rationale for using
p.000070: them.
p.000070:
p.000070: 1.2.2.1. Assessment of anonymisation
p.000070:
p.000070: As described in section 3 of the “External guidance on the anonymisation of clinical reports for the purpose of
p.000070: publication in accordance with EMA Policy 0070”, according to the Opinion 05/2014 on anonymisation techniques of the
p.000070: Article 29 Data Protection Working Party, two options are available to establish if the data is anonymised.
p.000070: One option relates to the anonymisation based on three criteria (see below Section 1.2.2.1.1); the second option refers
p.000070: to the anonymisation based on the evaluation of the re-identification risk (see below Section 1.2.2.1.2). Only one of
p.000070: the options should be followed for each clinical report, i.e. only section 1.2.2.1.1 or section 1.2.2.1.2 is to be
p.000070: completed.
p.000070:
p.000070: 1.2.2.1.1. Fulfilment of the criteria for anonymisation27
p.000070:
p.000070: The applicant/MAH confirms/demonstrates that after anonymisation of the clinical reports the three criteria described
...
Social / Child
Searching for indicator children:
(return to top)
p.000070: the most likely and reasonable means the data controller or any third party may employ, and will render the data
p.000070: anonymous.
p.000070:
p.000070: 3.2.2. Anonymisation techniques
p.000070:
p.000070: There are several techniques that can be used in order to achieve anonymisation. Opinion 05/2014 on anonymisation
p.000070: techniques of the Art. 29 WP analyses the effectiveness and limits of existing anonymisation techniques against the EU
p.000070: legal background of data protection, and provides recommendations to handle these techniques by taking account of the
p.000070: residual risk of identification inherent in each of them14.
p.000070:
p.000070:
p.000070: 12 The definition of personal data as described in Article 2(a) of Regulation (EC) No 45/2001 relates to a ‘natural
p.000070: person’. The Article 29 Working Party opinion 4/2007 on the concept of personal data further clarifies that information
p.000070: relating to dead individuals is therefore in principle not to be considered as personal data to the rules of the
p.000070: Directive, as dead are no longer natural persons in civil law. However, the opinion also points out that data on the
p.000070: deceased may still be personal information since it may refer to living persons, e.g. it may indicate family diseases
p.000070: relevant to living children or siblings. In addition, it might be difficult for the data controller to establish
p.000070: whether the person to whom the data relates is still alive.
p.000070: 13 Opinion 05/2014 on anonymisation techniques and Opinion 06/2013 on open data and public sector information reuse of
p.000070: the Article 29 Data Protection Working Party .
p.000070: 14 Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 38/99
p.000070:
p.000070: 3.3. Advances in technology
p.000070:
p.000070: It is also important to take note of advances in technology (e.g. data mining) together with greater availability of
p.000070: data and the possibility of database linkage with the increased risk of re-identification. MAHs/applicants need to take
p.000070: into account (realistic) future developments in terms of availability of data and technologies that would allow
p.000070: identification. The Art. 29 WP Opinion 05/2014 on anonymisation techniques emphasises that even where a data controller
p.000070: believes it has successfully anonymised personal data, the data controller must continuously follow the developments in
...
Social / Ethnicity
Searching for indicator ethnicity:
(return to top)
p.000070: on a case-by-case basis based on the impact on the risk. Moreover, it should also be considered that for any extension
p.000070: to the initial marketing authorisation application study, the same patients will be recoded differently from the
p.000070: initial marketing authorisation study. EMA recognises that in such situations data utility may be suboptimal since this
p.000070: creates a problem of linkability between the initial study and the extension study.
p.000070:
p.000070: 5.3.2.2. Anonymisation of Quasi Identifiers
p.000070:
p.000070: Quasi identifiers are variables representing an individual’s background information that can indirectly identify
p.000070: individuals. Unlike direct identifiers, information from quasi identifiers increases the scientific usefulness of the
p.000070: information published. Geographical location is an important variable since clinical practice can vary from country to
p.000070: country and this can impact on the outcome. Relative dates relating to individual patients are also important due to
p.000070: the potential impact on the outcome of the trial. Patient
p.000070:
p.000070:
p.000070: 16 David Carrell, Bradley Malin, John Aberdeen, et al. “Hiding in plain sight: use of realistic surrogates to reduce
p.000070: exposure of protected health information in clinical text”. J Am Med Inform Assoc 2013;20:342–348.
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 42/99
p.000070:
p.000070: level demographic information such as sex, age, race, ethnicity, height and weight can be confounders and therefore of
p.000070: critical scientific utility.
p.000070: In order to render the clinical reports anonymised it is not always necessary to redact all quasi identifiers. The need
p.000070: to redact quasi identifiers will depend on the following aspects:
p.000070: • Number of quasi identifiers per trial participant
p.000070: • Frequency of trial participants with same category/value on a set of the quasi identifiers (group size)
p.000070: • Size of population
p.000070: It is up to the applicant/MAH to decide which quasi identifiers need to be redacted and which could remain in the
p.000070: reports. The rationale for the decision should be included in the risk assessment section of the anonymisation report
p.000070: to be provided to EMA (see section 5.5).
p.000070: The factors having the most impact on data de-identification are geographical location and dates leading to a higher
p.000070: risk of re-identification. A feature of anonymisation is that it is only partially determined by the data to be
p.000070: protected. The ability to identify a trial participant depends on both these data and the state of knowledge of the
p.000070: observer concerning the trial participants in the data. For these reasons, location and dates are important. They may
p.000070: not be the most specific identifiers of a trial participant but they are often the most easily obtainable from other
p.000070: sources. Therefore, clinical data containing information on geographical location and dates should be carefully
p.000070: anonymised (see sections 5.3.2.2.1 and 5.3.2.2.2).
p.000070:
p.000070: 5.3.2.2.1. Dates
p.000070:
p.000070: There are various dates that can be included in clinical reports, e.g. date of birth of trial participants, date of
...
p.000070: relative.17
p.000070:
p.000070: 5.3.2.2.2. Geographical location
p.000070:
p.000070: The geographical location is an important element that can lead to re-identification of patients. It might be necessary
p.000070: to aggregate or generalise from country to region or continent unless this information is critical to the analysis. The
p.000070: need to aggregate or generalise should be considered when performing the risk assessment. The link between individual
p.000070: patient data and the identity of the site should be removed since a frequency analysis can most likely reveal the most
p.000070: recruiting site in a country, which will in turn include many of the trial participants. However, it may not be the
p.000070: case where the recruitment is uniform across all sites.
p.000070:
p.000070: 5.4. Anonymisation process
p.000070:
p.000070: In order to facilitate the applicant/MAH approach to anonymisation EMA recommends to follow the anonymisation process
p.000070: described below18:
p.000070: 1. Determination of direct identifiers and quasi-identifiers
p.000070:
p.000070: A person’s identity can be disclosed from either direct identifiers or indirect/quasi identifiers. Direct identifiers
p.000070: are elements that permit direct recognition or communication with the corresponding individuals, such as personal
p.000070: names, email addresses, telephone numbers, and national insurance numbers. Direct identifiers are not often useful for
p.000070: data analysis.
p.000070: Quasi identifiers are variables representing an individual’s background information that can indirectly identify
p.000070: individuals, such as their date of birth, death, or clinic visit, residence postal code, sex and ethnicity. Quasi
p.000070: identifiers also include demographics and socioeconomic information. Both types of variables must be addressed during
p.000070: anonymisation. In recent cases of re-identification, attackers used quasi identifiers to successfully determine the
p.000070: identity of individuals19. It is therefore important to protect the quasi identifiers as well as the direct
p.000070: identifiers.
p.000070: Classification of variables into categories of personal data
p.000070:
p.000070: There are three conditions for a variable to be considered an identifier (direct or quasi), i.e. replicability (the
p.000070: variable values must be sufficiently stable over time so that the values will occur consistently in relation to the
p.000070: data subject), distinguishability (the variable must have sufficient variability to distinguish among individuals in
p.000070: the data) and knowability (an adversary must know the identifiers about the data subject in order to re-identify them).
p.000070: If a variable is not knowable by an adversary, it cannot be used to launch a re-identification attack on the data (see
p.000070: below for further details on adversaries and attacks).
p.000070:
p.000070: 17 PhUSE De-Identification Working Group, “De-Identification Standards for CDISC SDTM 3.2,” 2015.
p.000070: 18 Institute of Medicine (IOM). 2015. Sharing clinical trial data: Maximizing benefits, minimizing risk. Washington,
p.000070: DC: The National Academies Press. Appendix B.
p.000070: 19 BMJ 2015; 350: h1139 Anonymising and sharing individual patient data.
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 44/99
p.000070:
...
Social / Marital Status
Searching for indicator single:
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p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 9/99
p.000068:
p.000068: • Residual risk:
p.000068:
p.000068: The risk that remains after controls are taken into account (the net risk or risk after controls).
p.000068:
p.000068: • Risk:
p.000068:
p.000068: The probability of re-identifying a trial participant.
p.000068:
p.000068: • Study subject:
p.000068: For the purpose of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on
p.000068: clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, a ‘subject’ is defined as ‘an
p.000068: individual who participates in a clinical trial, either as a recipient of an investigational medicinal product or as a
p.000068: control’.
p.000068: Use is made in the guidance of the term ‘research participant’ as an equivalent to ‘subject’, in order to avoid
p.000068: confusion with the aforementioned protected personal data (PPD) term ‘data subject’.
p.000068: • Redaction Proposal Version:
p.000068: This is the clinical report version containing the applicant’s/MAH’s proposed redactions on commercial confidential
p.000068: information (CCI) and personal data. These proposed redactions should be highlighted in a ‘read-through’ manner.
p.000068: • Redaction Proposal Document Package:
p.000068: The “Redaction Proposal Document” package shall contain the redaction proposal versions of all clinical reports related
p.000068: to one single finalised regulatory procedure that falls under the scope of Policy 0070, along with a number of
p.000068: additional documents listed in the “External guidance on the procedural aspects related to the submission of clinical
p.000068: reports for the purpose of publication in accordance with EMA Policy 0070”.
p.000068: • Final Redacted Version:
p.000068: This is the clinical report version, submitted by the applicant/MAH for publication, which should reflect the EMA
p.000068: review outcome (accepted/rejected redactions).
p.000068: • Final Redacted Document Package:
p.000068: A “Final Redacted Document” package shall contain the final redacted versions of all clinical reports related to one
p.000068: single finalised regulatory procedure that falls under the scope of Policy 0070.
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 10/99
p.000068:
p.000068: 4. Implementing Policy 0070
p.000068: The publication of clinical reports in accordance with Policy 0070 is a new undertaking for EMA. Several new
p.000068: arrangements had to be developed to fully meet the purpose of Policy 0070. Taking into account the availability of
p.000068: limited resources and the anticipated high volume of work, EMA has aimed for the most cost-efficient approach in
p.000068: implementing Policy 0070, whilst respecting the objectives of Policy 0070. In order to achieve such objectives
p.000068: particular consideration had to be given to protecting personal data and protecting CCI.
p.000068: In this guidance document detailed guidance is provided in the following fields:
p.000068:
p.000068: - Procedural aspects related to the submission of clinical reports.
p.000068:
p.000068: - Identification and redaction of CCI in clinical reports.
p.000068:
p.000068: - Anonymisation of clinical reports.
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
...
p.000068:
p.000068: Module 2 documents
p.000068:
p.000068: TradeName7H/C/xxxxxx/xx/xxxx m25-clinical-overview-var TradeName7 H/C/xxxxxx/xx/xxxx m271-summary-biopharm-var
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m272-summary-clin-pharm-var TradeName7 H/C/xxxxxx/xx/xxxx m273-summary-clin-efficacy-var
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m274-summary-clin-safety-var Module 5 documents
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m53xx-StudyReportNumber8 P (for PIVOTAL) or S (for SUPPORTIVE) CSR body
p.000068:
p.000068:
p.000068: 7 The trade name will be looked into on a case by case basis in case of a very long string of characters.
p.000068: 8 For reports which present analysis of data collected from multiple studies, the applicant/MAH should include the
p.000068: report identification number (one identification number), instead of the study report numbers of each study from which
p.000068: the data was analysed (clinical trial or clinical study numbers). This information has to be included in the leaf
p.000068: titles and in the file names.
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 17/99
p.000068:
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m53xx-StudyReportNumber8 P (for PIVOTAL) or S (for SUPPORTIVE) app1611 protocol
p.000068:
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m53xx-StudyReportNumber8 P (for PIVOTAL) or S (for SUPPORTIVE) app1612 crf
p.000068:
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m53xx-StudyReportNumber8 P (for PIVOTAL) or S (for SUPPORTIVE) app1619 sap
p.000068:
p.000068: Where the applicant/MAH submits the body of the CSR together with the 3 Annexes (16.1.1, 16.1.2 and 16.1.9) as a single
p.000068: file, the leaf titles should follow the below naming convention:
p.000068:
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m53xx-StudyReportNumber8 P CSR with app TradeName7 H/C/xxxxxx/xx/xxxx
p.000068: m53xx-StudyReportNumber8 S CSR with app
p.000068: In case the applicant/MAH has included US Integrated Summary of Safety (ISS) and US Integrated Summary of Efficacy
p.000068: (ISE), the leaf titles should follow the below naming convention:
p.000068:
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m274-ISS-var TradeName7 H/C/xxxxxx/xx/xxxx m273-ISE-var TradeName7 H/C/xxxxxx/xx/xxxx
p.000068: m53xx-ISS-var
p.000068: TradeName7 H/C/xxxxxx/xx/xxxx m53xx-ISE-var
p.000068:
p.000068: 3.3.1.7. Corresponding file names for the PDF documents
p.000068:
p.000068: EMA requires the applicant/MAH to apply the following naming convention for the filenames of the PDF documents:
p.000068:
p.000068: Module 2 documents
p.000068:
p.000068: m25-clinical-overview-var.pdf m271-summary-biopharm-var.pdf m272-summary-clin-pharm-var.pdf
p.000068: m273-summary-clin-efficacy-var.pdf m274-summary-clin-safety-var.pdf
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 18/99
p.000068:
p.000068: Module 5 documents
p.000068:
p.000068: m53xx-StudyReportNumber8-p-csr-body.pdf m53xx-StudyReportNumber8-s-csr-body.pdf
p.000068: m53xx-StudyReportNumber8-p-app1611-protocol.pdf m53xx-StudyReportNumber8-p-app1612-crf.pdf
p.000068: m53xx-StudyReportNumber8-p-app1619-sap.pdf
p.000068: Where the applicant/MAH submits the body of the CSR together with the 3 Annexes (16.1.1, 16.1.2 and 16.1.9) as a single
p.000068: file, the file names should follow the naming convention below:
p.000068:
p.000068: m53xx-StudyReportNumber8-p-csr-with-app.pdf m53xx-StudyReportNumber8-s-csr-with-app.pdf
p.000068: In case the applicant/MAH has included US Integrated Summary of Safety (ISS) and US Integrated Summary of Efficacy
p.000068: (ISE), the File/document names should naming convention below:
p.000068:
p.000068: m273-summary-clin-efficacy-ISE-var.pdf m274-summary-clin-safety-ISS-var.pdf m53xx-ISS-var
p.000068: m53xx-ISE-var
p.000068:
p.000068: In rare cases, or where more than one document is submitted in Module 2.5 or 2.7.1, 2.7.2, 2.7.3,
p.000068: 2.7.4 for the same indication/procedure, it should be indicated clearly in the var. part of the file name.
p.000068: m25-clinical-overview-var.pdf
p.000068: m271-summary-biopharm-var.pdf m272-summary-clin-pharm-var.pdf m273-summary-clin-efficacy-var.pdf
p.000068: m274-summary-clin-safety-var.pdf
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 19/99
p.000068:
p.000068: This var. part of the file name should only be inserted where more than one document is submitted for that particular
p.000068: indication/procedure. If for one submission there is only one 2.5, 2.7.1., 2.7.2, 2.7.3, and 2.7.4 var. should be
p.000068: excluded from the file name.
p.000068: Regarding the technical requirements, please note that the PDF file names should be written in lower case and should
p.000068: not contain any special characters.
p.000068: The construction of the above naming conventions is based on the use of the following elements:
p.000068:
p.000068: 1. Trade name: Product name
p.000068:
p.000068: 2. Procedure number: EMEA/H/C/xxxxxx/xx/xxxx
p.000068:
p.000068: 3. CTD Location
...
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 23/99
p.000068:
p.000068: further information on anonymisation please see Chapter 3 “External guidance on the anonymisation of clinical reports
p.000068: for the purpose of publication in accordance with EMA Policy 0070”.
p.000068: Please note that for sections where per patient per visit IPD are identified in the clinical reports and the Agency
p.000068: agrees that they are out of the scope, these sections can be removed from the documents.
p.000068: Where pages have been removed from the documents as out of scope the EMA requires the applicant/MAH to clearly indicate
p.000068: which pages and what information has been removed. The removed pages should be replaced by the following text in black
p.000068: contained on a white page:
p.000068: 1, removed page numbers (from-to) and the corresponding section title
p.000068: 2, statement to reflect the above (“Out of Scope of phase I of Policy 0070 – ”).
p.000068:
p.000068: For example in case there is per patient per visit data removed as out of scope of policy 0070, it should read:
p.000068:
p.000068: “Out of Scope of phase I of Policy 0070 - Per patient/per visit line listings”.
p.000068: The Agency considers per patient per visit data as those listings including values of the measured parameters (e.g. lab
p.000068: values) listed for all patients recruited and covering all study visits.
p.000068: Therefore, for example, tables listing values of the measured parameters (e.g. HbA1C) or outcomes (protocol deviation,
p.000068: death, SAE, overall survival) at a certain single time point will not be considered per patient per visit line listing.
p.000068: Also, the Agency does not consider per patient per visit line listings those tables where parameter or outcome values
p.000068: for selected patients and selected visits are presented.
p.000068:
p.000068: 3.3.1.9. Cover letter including declaration
p.000068:
p.000068: The applicant/MAH should use the template cover letter text provided in Annex 1.4 or 1.5 when preparing the submission.
p.000068: In addition, the applicant/MAH should populate the formatted table template as published on EMA’s website
p.000068: (http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2011/05/WC50010637 1.doc). The completed
p.000068: formatted table template, the link to which is provided, should be embedded in the completed cover letter (Annex 1.4 or
p.000068: 1.5), for the Redaction Proposal document package. Below is an example illustrating the approach when working with the
p.000068: formatted table template:
p.000068: The fields highlighted with yellow are specific for the sequences containing the documents submitted for the purpose of
p.000068: publication.
p.000068:
p.000068: 7 – Please select Clinical data for publication – Redaction Proposal
p.000068:
p.000068: 7.1 - Please select “initial”
p.000068:
p.000068: 7.2 – Please leave blank
p.000068:
p.000068: 7.3 – Please leave blank
p.000068:
p.000068: 10 – eCTD sequence: please insert the eCTD sequence of the procedure. For ‘related sequence’ field Same sequence number
p.000068: as stated in the EU Module 1 v3.0.1 specification. e.g. for Sequence 0010, related sequence field should be populated
p.000068: with value 0010.
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 24/99
p.000068:
...
p.000068: name matches the name of the corresponding clinical report. Please see the detailed guidance in Section 3.3.1.6 and
p.000068: 3.3.1.7 of this chapter on the naming conventions that must be followed for individual documents. As a general
p.000068: principle EMA expects that each of the justification tables corresponds to one submitted file. For example, if during
p.000068: the regulatory procedure a clinical overview addendum is submitted in addition to the initial clinical overview, EMA
p.000068: expects the applicant/MAH to prepare two separate justification tables since both documents are subject to publication.
p.000068: For CSRs in Module 5 the applicant/MAH should submit the justification tables taking into consideration the following
p.000068: principle:
p.000068: If the CSR and the appendices are submitted for publication purposes as one standalone file, then one justification
p.000068: table is expected to be prepared. This justification table will have separate subheadings for each of the parts of the
p.000068: document (body, 16.1.1, 16.1.2, 16.1.9). Such template is available for download from the following link
p.000068: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001743.js
p.000068: p&mid=WC0b01ac0580ae88cc.
p.000068: If the CSR and the appendices are submitted for publication purposes as separate files, then four justification tables
p.000068: are expected to be submitted: one for each of the files, e.g. body, 16.1.1, 16.1.2,
p.000068: 16.1.9. Such template is available for download from the following link
p.000068: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001743.js
p.000068: p&mid=WC0b01ac0580ae88cc.
p.000068: The justification tables should be submitted only to EMA with the Redaction Proposal document package, as part of a
p.000068: single ZIP package and outside the eCTD sequence structure in the separate folder named “Working Documents”. The
p.000068: Working Documents are submitted together with the eCTD sequence as part of one ZIP package through the Gateway. EMA
p.000068: requires that within the “Working Documents’’ folder the justification tables are placed in a separate folder entitled
p.000068: “Justification Tables”. Applicants/MAHs must ensure that the sequence number folder (e.g. 0000) is a root folder in the
p.000068: ZIP package within the same gateway transmission. This sequence number is required to ensure that the submission passes
p.000068: the technical validation.
p.000068:
p.000068: 3.3.1.11. Submitting the Redaction Proposal document package through the Gateway
p.000068:
p.000068: Table 1 is set out to demonstrate where each document of the Redaction Proposal document package should be uploaded.
p.000068: The applicant/MAH must create a separate eCTD sequence with the relevant submission type (please refer to new EU Module
p.000068: 1 specifications), which will contain redacted/anonymised clinical reports as a separate data set (using eCTD operator
p.000068: ‘new’). The related sequence field in the eCTD sequence and the formatted table (cover letter) should always be the
p.000068: same sequence number as stated in the EU Module 1 v3.0.1 specification. e.g. for Sequence 0010, related sequence field
p.000068: should be populated with value 0010.
p.000068: The clinical reports submitted in the Redaction Proposal document package must not be linked to any previously
p.000068: submitted documentation for the purpose of the scientific evaluation of a medicinal product. An applicant/MAH
p.000068: submitting multiple applications for the same medicinal product under different invented names is also required to
...
p.000068:
p.000068: 3.3.3.2. Timeline
p.000068:
p.000068: Within 7 calendar days following the issuance of the EMA redaction conclusion, applicants/MAHs must provide their
p.000068: written agreement to the redaction conclusion. The Final Redacted document package must then be provided ≤ 20 days
p.000068: following the receipt of this agreement. A workflow for the submission of the Final Redacted document package can be
p.000068: found at Annex 1.8 of this guidance document. If the applicant/MAH disagrees with the redaction conclusion, EMA will
p.000068: adopt a decision against which the applicant/MAH can file an application for annulment and related application for
p.000068: interim relief to the General Court of the European Union, in accordance with Article 263 of the Treaty of the European
p.000068: Union and the Rules of Procedure of the General Court. The related deadlines and time limits are set therein. Please
p.000068: see section 3.3.4 below for function details on this case.
p.000068:
p.000068: 3.3.3.3. Content of the Final Redacted document package
p.000068:
p.000068: The applicant/MAH is required to prepare a separate sequence in eCTD format to submit the Final Redacted Document
p.000068: package. The eCTD submission of the final redacted document package falls under the same eCTD life-cycle of the initial
p.000068: MAA, line extension application or extension of indication application, as applicable. An exhaustive list of the
p.000068: documents to be submitted within the final redacted document package is provided in Table 2 below, including the final
p.000068: redacted versions of all the listed clinical reports.
p.000068: The applicant/MAH is required to submit the package of documents listed in Table 2 as part of a single Final Redacted
p.000068: document package, all of which must be included in the same eCTD sequence. In respect of publication of multiple
p.000068: applications for the same medicinal product under different invented names where the clinical reports are identical
p.000068: (with the exception of references to the product names), EMA will provide a notice on its corporate website to cross
p.000068: reference the different invented names to the published final redacted version of the original medicinal product.
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 29/99
p.000068:
p.000068: Table 2: Content of the Final Redacted document package, corresponding eCTD locations and the publication status
p.000068:
p.000068: Final Redacted document package eCTD Module/Section
p.000068: within eCTD
p.000068: Document published
p.000068:
p.000068: Cover letter, see the template at Annex 1.6, together with a list of documents submitted annexed to this letter
p.000068: A list of documents submitted, annexed to the cover letter. A template for this list is at Annex 1.3
p.000068: clinical overview supplement/amendment/appendix
p.000068: clinical summary supplement/amendment/appendix
p.000068: Clinical study report - body Clinical study report – Appendices
p.000068: 16.1.1 (protocol and protocol amendments)
p.000068:
p.000068: 16.1.2 (sample case report form)
p.000068:
p.000068: 16.1.9 (documentation of statistical methods).
p.000068: Anonymisation report, the report template is at Annex 1.2
p.000068: 1.0
p.000068:
p.000068:
p.000068:
p.000068: 1.0
p.000068:
p.000068:
p.000068:
p.000068: 2.5
p.000068:
p.000068:
...
p.000070: must be emphasised that recital 26 of Directive 95/46/EC sets a high threshold, as described in the Opinion of Art. 29
p.000070: WP. Unless data can be anonymised to meet this threshold, data protection law continues to apply.13
p.000070: The irreversibility of the anonymisation methodologies or techniques is also an important element as it can be used in
p.000070: order to differentiate from “pseudonymisation”. Pseudonymisation consists of replacing one attribute (typically a
p.000070: unique attribute) in a record by another. When pseudonymisation is used alone, the natural person is still likely to be
p.000070: identified indirectly. Pseudonymisation reduces the linkability of a dataset with the original identity of a data
p.000070: subject but when used alone will not result in an anonymous dataset, therefore data protection rules still apply. It
p.000070: is, therefore, important to clarify that pseudonymisation is not an anonymisation method but a useful security measure.
p.000070: Consequently, additional measures should be considered in order to render the dataset anonymised, including removing
p.000070: and generalising attributes or deleting the original data or at least bringing them to a highly aggregated level.
p.000070:
p.000070: 3.2.1. Anonymisation criteria
p.000070:
p.000070: According to the Opinion 05/2014 on anonymisation techniques of the Art. 29 WP, two options are available to establish
p.000070: if the data is anonymised. Either through the demonstration of effective anonymisation based on three criteria:
p.000070: • Possibility to single out an individual.
p.000070:
p.000070: • Possibility to link records relating to an individual.
p.000070:
p.000070: • Whether information can be inferred concerning an individual.
p.000070: or, whenever a proposal does not meet one of these criteria, through an evaluation of the identification risks.
p.000070: An anonymisation solution preventing all three criteria is considered to be robust against identification performed by
p.000070: the most likely and reasonable means the data controller or any third party may employ, and will render the data
p.000070: anonymous.
p.000070:
p.000070: 3.2.2. Anonymisation techniques
p.000070:
p.000070: There are several techniques that can be used in order to achieve anonymisation. Opinion 05/2014 on anonymisation
p.000070: techniques of the Art. 29 WP analyses the effectiveness and limits of existing anonymisation techniques against the EU
p.000070: legal background of data protection, and provides recommendations to handle these techniques by taking account of the
p.000070: residual risk of identification inherent in each of them14.
p.000070:
p.000070:
p.000070: 12 The definition of personal data as described in Article 2(a) of Regulation (EC) No 45/2001 relates to a ‘natural
p.000070: person’. The Article 29 Working Party opinion 4/2007 on the concept of personal data further clarifies that information
p.000070: relating to dead individuals is therefore in principle not to be considered as personal data to the rules of the
...
p.000070: - Regarding patient ID, provide information on whether it has been redacted or recoded and the resulting impact on
p.000070: the risk of re-identification
p.000070: Quasi (indirect) identifiers
p.000070:
p.000070: - For quasi-identifiers, provide information on the anonymisation techniques used and the rationale for using
p.000070: them.
p.000070:
p.000070: 1.2.2.1. Assessment of anonymisation
p.000070:
p.000070: As described in section 3 of the “External guidance on the anonymisation of clinical reports for the purpose of
p.000070: publication in accordance with EMA Policy 0070”, according to the Opinion 05/2014 on anonymisation techniques of the
p.000070: Article 29 Data Protection Working Party, two options are available to establish if the data is anonymised.
p.000070: One option relates to the anonymisation based on three criteria (see below Section 1.2.2.1.1); the second option refers
p.000070: to the anonymisation based on the evaluation of the re-identification risk (see below Section 1.2.2.1.2). Only one of
p.000070: the options should be followed for each clinical report, i.e. only section 1.2.2.1.1 or section 1.2.2.1.2 is to be
p.000070: completed.
p.000070:
p.000070: 1.2.2.1.1. Fulfilment of the criteria for anonymisation27
p.000070:
p.000070: The applicant/MAH confirms/demonstrates that after anonymisation of the clinical reports the three criteria described
p.000070: below have been fulfilled.
p.000070: a. No possibility to single out an individual
p.000070:
p.000070: Data presented in an aggregated manner does not usually lead to the possibility of singling out an individual. However,
p.000070: in the case of small studies with few patients it might be more likely to single out individuals and therefore this
p.000070: criterion may not be fulfilled. Individual patient data in the clinical reports can also allow singling out an
p.000070: individual, but if adequately anonymised it can be demonstrated that the possibility to single out an individual is
p.000070: remote.
p.000070:
p.000070:
p.000070: 26 PhUSE has listed direct and quasi identifiers that can be found in clinical data. This can facilitate the
p.000070: identification of variables in clinical reports (http://www.phuse.eu/Data_Transparency_download.aspx)
p.000070:
p.000070: 27 According to Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 66/99
p.000070:
p.000070:
p.000070: b. No possibility to link records relating to an individual
p.000070:
p.000070: If the patient ID is redacted from the clinical reports it is less likely to link information relating to an
p.000070: individual. A combination of quasi identifiers reported in several sections of the report could also lead to linking
p.000070: information relating to one individual.
p.000070: c. Information cannot be inferred concerning an individual
p.000070:
p.000070: The value of an additional variable concerning an individual can be inferred from a narrative that has not been
p.000070: suitably anonymised.
p.000070: [If this section has been completed and the three criteria have been met, there is no need to complete the next section
p.000070: on the risk assessment]
p.000070:
p.000070: 1.2.2.1.2. Risk assessment
p.000070:
...
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
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p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: Annexes
p.000070: EMA/471266/2015
p.000070:
p.000070: Page 79/99
p.000070:
p.000070: 1.11. Redaction consultation process flowchart
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
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p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 80/99
p.000070:
p.000070:
p.000070: 1.12. In and Out of scope of phase 1 of Policy 0070
p.000070:
p.000070: • Common Technical Document (CTD) structure
p.000070:
p.000070:
p.000070: CTD
p.000070: Module/ Section
p.000070:
p.000070: Document
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070: 2.5 Clinical Overview
p.000070:
p.000070: 2.5 Clinical Overview In
p.000070: All sections of the “Clinical overview” regardless whether they are submitted as separate standalone documents or all
p.000070: together in a single document are subject to
p.000070: publication.
p.000070: 2.5.1 Product Development Rationale In
p.000070:
p.000070:
p.000070:
p.000070: 2.5.2
p.000070:
p.000070:
p.000070: 2.5.3
p.000070:
p.000070:
p.000070: 2.5.4
p.000070:
p.000070:
p.000070: 2.5.5
p.000070:
p.000070:
p.000070: 2.5.6
p.000070:
p.000070:
p.000070: 2.5.7
p.000070:
p.000070:
p.000070: 2.5
p.000070:
p.000070: Overview of Biopharmaceutics In
p.000070:
p.000070:
p.000070: Overview of Clinical Pharmacology In
p.000070:
p.000070:
p.000070: Overview of Efficacy In
p.000070:
p.000070:
p.000070: Overview of Safety In
p.000070:
p.000070:
p.000070: Benefits and Risks Conclusions In
p.000070:
p.000070:
p.000070: Literature References In
p.000070:
p.000070:
p.000070: Any other documents (not explicitly mentioned in ICH M4) In
p.000070: All documents included in CTD Module 2.5 such as “Clinical overview supplement/amendment/appendix” which were submitted
p.000070: during the evaluation procedure are subject to publication.
p.000070:
p.000070:
p.000070: However, EMA notes that, the appendixes to clinical overviews(Module 2.5), appendixes to clinical summaries (Modules
p.000070: 2.7.1 to 2.7.4) and CSR bodies may contain individual patient data listings (referred to further below as “per
p.000070: patient/per visit line listings”).
p.000070: For example, these per patient/per visit line listings may be contained in CSR section
p.000070: 14.3.4 Abnormal Laboratory Value Listing (Per Patient/per Visit). EMA considers that such per patient/per visit line
p.000070: listings fall outside the scope of phase 1 of the Policy and, therefore, it is acceptable to have them removed from the
p.000070: clinical reports prepared for publication at this stage of the implementation. All these per patient/per visit line
p.000070: listings will be falling in the scope of phase 2 of the Policy.
p.000070: Please note that for sections where per patient per visit IPD are identified in the clinical reports and the Agency
p.000070: agrees that they are out of the scope, these sections can be removed from the documents.
p.000070: However the pages/sections considered out of scope and therefore removed
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 81/99
p.000070:
p.000070:
p.000070:
p.000070: CTD
p.000070: Module/ Section
p.000070:
p.000070: Document
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070:
p.000070:
p.000070: have to be replaced by a blank page containing the following:
p.000070:
p.000070: 1, removed page numbers (from-to) and the corresponding section title
p.000070:
p.000070: 2, statement that it is per patient per visit data removed as out of scope of policy 0070, reading:
p.000070: “Out of Scope of phase I of Policy 0070- Per patient/per visit line listings”.
p.000070: The Agency considers per patient per visit data as those listings including values of the measured parameters (eg. lab
p.000070: values) listed for all patients recruited and covering all study visits.
p.000070: Therefore, for example, tables listing values of the measured parameters (eg. HbA1C) or outcomes (protocol deviation,
p.000070: death, SAE, overall survival) at a certain single time point will not be considered per patient per visit line listing.
p.000070: Also, the Agency does not consider per patient per visit line listings those tables where parameter or outcome values
p.000070: for selected patients and selected visits are presented.
p.000070: Please note that only the list of references is subject to publication. If actual scientific papers and articles are
p.000070: included in CTD section 2.5.7 these documents are NOT subject to publication.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
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p.000070:
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p.000070: 2.7 Clinical Summary
p.000070:
p.000070:
p.000070: 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods
p.000070:
p.000070: Summary of Biopharmaceutic Studies and Associated
p.000070:
p.000070:
p.000070: All sections of the “Summary of Biopharmaceutic Studies and Associated
p.000070:
p.000070: 2.7.1
p.000070: Analytical Methods
p.000070: In Analytical Methods” regardless whether they are submitted as separate single documents or all
p.000070: together in a standalone document are subject to publication.
p.000070: 2.7.1.1 Background and Overview In
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: 2.7.1.2
p.000070:
p.000070:
p.000070: 2.7.1.3
p.000070:
p.000070:
p.000070: 2.7.1.4
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: 2.7.1
p.000070:
p.000070:
p.000070: Summary of Results of Individual Studies In
p.000070:
p.000070:
p.000070: Comparison and Analyses of Results Across Studies In
p.000070:
p.000070:
p.000070: Appendix In
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: Any other documents (not explicitly mentioned in ICH M4) In
p.000070: All documents included in CTD section 2.7.1 such as “Clinical summary supplement/amendment/appendix”” which were
p.000070: submitted during the evaluation procedure are subject to publication.
p.000070:
p.000070:
p.000070: However, EMA notes that, the appendixes to clinical overviews (Module 2.5), appendixes to clinical summaries (Modules
p.000070: 2.7.1 to 2.7.4) and CSR bodies may contain individual patient data listings (referred to further below as “per
p.000070: patient/per visit line listings”). For example, these per patient/per visit line listings may be contained in CSR
p.000070: section 14.3.4 Abnormal Laboratory Value Listing (Per Patient/per Visit). EMA considers that such per patient/per visit
p.000070: line listings fall outside the scope of phase 1 of the Policy and, therefore, it is acceptable to have them removed
p.000070: from the clinical reports prepared for publication at this stage of the implementation. All these per patient/per visit
p.000070: line listings will be falling in the scope of phase 2 of the Policy.
p.000070: Please note that for sections where per patient per visit IPD are identified in the clinical reports and the Agency
p.000070: agrees that they are out of the scope, these sections can be removed from the documents.
p.000070: However the pages/sections considered out of scope and therefore removed have to be replaced by a blank page containing
p.000070: the following:
p.000070: 1, removed page numbers (from-to) and the corresponding section title
p.000070:
p.000070: 2, statement that it is per patient per visit data removed as out of scope of policy 0070,
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 83/99
p.000070:
p.000070:
p.000070: reading:
p.000070:
p.000070: “Out of Scope of phase I of Policy 0070- Per patient/per visit line listings”.
p.000070:
p.000070: The Agency considers per patient per visit data as those listings including values of the measured parameters (eg. lab
p.000070: values) listed for all patients recruited and covering all study visits.
p.000070: Therefore, for example, tables listing values of the measured parameters (eg. HbA1C) or outcomes (protocol deviation,
p.000070: death, SAE, overall survival) at a certain single time point will not be considered per patient per visit line listing.
p.000070: Also, the Agency does not consider per patient per visit line listings those tables where parameter or outcome values
p.000070: for selected patients and selected visits are presented.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 84/99
p.000070:
p.000070:
p.000070: 2.7.2 Summary of Clinical Pharmacology Studies
p.000070:
p.000070: 2.7.2 Summary of Clinical Pharmacology Studies In All
p.000070: sections of the “Summary of Clinical Pharmacology Studies” regardless
p.000070: whether they are submitted as separate standalone documents or all together in a
p.000070: single document are subject to publication.
p.000070: 2.7.2.1 Background and Overview In
p.000070:
p.000070:
p.000070:
p.000070: 2.7.2.2
p.000070:
p.000070:
p.000070: 2.7.2.3
p.000070:
p.000070:
p.000070: 2.7.2.4
p.000070:
p.000070:
p.000070: 2.7.2.5
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: 2.7.2
p.000070:
p.000070: Summary of Results of Individual Studies In
p.000070:
p.000070:
p.000070: Comparison and Analyses of Results Across Studies In
p.000070:
p.000070:
p.000070: Special Studies In
p.000070:
p.000070:
p.000070: Appendix In
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: Any other documents (not explicitly mentioned in ICH M4) In
p.000070: All documents included in CTD section 2.7.2 such as “Clinical summary supplement/amendment/appendix” which were
p.000070: submitted during the evaluation procedure are subject to publication.
p.000070:
p.000070:
p.000070: However, EMA notes that, the appendixes to clinical overviews(Module 2.5), appendixes to clinical summaries (Modules
p.000070: 2.7.1 to 2.7.4) and CSR bodies may contain individual patient data listings (referred to further below as “per
p.000070: patient/per visit line listings”). For example, these per patient/per visit line listings may be contained in CSR
p.000070: section 14.3.4 Abnormal Laboratory Value Listing (Per Patient/per Visit). EMA considers that such per patient/per visit
p.000070: line listings fall outside the scope of phase 1 of the Policy and, therefore, it is acceptable to have them removed
p.000070: from the clinical reports prepared for publication at this stage of the implementation. All these per patient/per visit
p.000070: line listings will be falling in the scope of phase 2 of the Policy.
p.000070: Please note that for sections where per patient per visit IPD are identified in the clinical reports and the Agency
p.000070: agrees that they are out of the scope, these sections can be removed from the documents.
p.000070: However the pages/sections considered out of scope and therefore removed have to be replaced by a blank page containing
p.000070: the following:
p.000070: 1, removed page numbers (from-to) and the corresponding section title
p.000070:
p.000070: 2, statement that it is per patient per visit data removed as out of scope of policy
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 85/99
p.000070:
p.000070:
p.000070: 0070, reading:
p.000070:
p.000070: “Out of Scope of phase I of Policy 0070- Per patient/per visit line listings”.
p.000070:
p.000070: The Agency considers per patient per visit data as those listings including values of the measured parameters (eg. lab
p.000070: values) listed for all patients recruited and covering all study visits.
p.000070: Therefore, for example, tables listing values of the measured parameters (eg. HbA1C) or outcomes (protocol deviation,
p.000070: death, SAE, overall survival) at a certain single time point will not be considered per patient per visit line listing.
p.000070: Also, the Agency does not consider per patient per visit line listings those tables where parameter or outcome values
p.000070: for selected patients and selected visits are presented.
p.000070: 2.7.3 Summary of Clinical Efficacy
p.000070:
p.000070:
p.000070: 2.7.3
p.000070:
p.000070:
p.000070: 2.7.3.1
p.000070:
p.000070:
p.000070: 2.7.3.2
p.000070:
p.000070:
p.000070: 2.7.3.3
p.000070:
p.000070:
p.000070: 2.7.3.4
p.000070:
p.000070:
p.000070: 2.7.3.5
p.000070:
p.000070:
p.000070: 2.7.3.6
p.000070: Summary of Clinical Efficacy In
p.000070:
p.000070:
p.000070: Background and Overview of Clinical Efficacy In
p.000070:
p.000070:
p.000070: Summary of Results of Individual Studies In
p.000070:
p.000070:
p.000070: Comparison and Analyses of Results Across Studies In
p.000070:
p.000070:
p.000070: Analysis of Clinical Information Relevant to Dosing
p.000070: In
p.000070: Recommendations
p.000070:
p.000070:
p.000070: Persistence of Efficacy and/or Tolerance Effects In
p.000070:
p.000070:
p.000070: Appendix In
p.000070:
p.000070:
p.000070: All sections of the “Summary of Clinical Efficacy” regardless whether they are submitted as separate standalone
p.000070: documents or all together in a single document are subject to publication.
p.000070:
p.000070:
p.000070: All documents included in CTD section 2.7.3 such as “Clinical summary supplement/amendment/appendix” or “Integrated
p.000070: Summary of Efficacy (ISE)” which were submitted during the evaluation procedure are subject to publication.
p.000070:
p.000070:
p.000070: However, EMA notes that, the appendixes to clinical overviews(Module 2.5), appendixes to clinical summaries (Modules
p.000070: 2.7.1 to 2.7.4) and CSR bodies may contain individual patient data listings (referred to further below as “per
p.000070: patient/per visit line listings”). For example, these per patient/per visit line listings may be
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 86/99
p.000070:
p.000070:
p.000070: contained in CSR section 14.3.4 Abnormal Laboratory Value Listing (Per Patient/per Visit). EMA considers that such per
p.000070: patient/per visit line listings fall outside the scope of phase 1 of the Policy and, therefore, it is acceptable to
p.000070: have them removed from the clinical reports prepared for publication at this stage of the implementation. All these per
p.000070: patient/per visit line listings will be falling in the scope of phase 2 of the Policy.
p.000070: Please note that for sections where per patient per visit IPD are identified in the clinical reports and the Agency
p.000070: agrees that they are out of the scope, these sections can be removed from the documents.
p.000070: However the pages/sections considered out of scope and therefore removed have to be replaced by a blank page containing
p.000070: the following:
p.000070:
p.000070:
p.000070: 2.7.3
p.000070:
p.000070: Any other documents (not explicitly mentioned in ICH M4) In
p.000070: 1, removed page numbers (from-to) and the corresponding section title
p.000070:
p.000070: 2, statement that it is per patient per visit data removed as out of scope of policy 0070, reading:
p.000070: “Out of Scope of phase I of Policy 0070- Per patient/per visit line listings”.
p.000070:
p.000070: The Agency considers per patient per visit data as those listings including values of the measured parameters (eg. lab
p.000070: values) listed for all patients recruited and covering all study visits.
p.000070: Therefore, for example, tables listing values of the measured parameters (eg. HbA1C) or outcomes (protocol deviation,
p.000070: death, SAE, overall survival) at a certain single time point will not be considered per patient per visit line listing.
p.000070: Also, the Agency does not consider per patient per visit line listings those tables where parameter or outcome values
p.000070: for selected patients and selected visits are presented.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 87/99
p.000070:
p.000070:
p.000070: 2.7.4 Summary of Clinical Safety
p.000070:
p.000070:
p.000070: 2.7.4
p.000070:
p.000070: 2.7.4.1
p.000070:
p.000070: 2.7.4.2
p.000070:
p.000070: 2.7.4.3
p.000070:
p.000070:
p.000070: 2.7.4.4
p.000070:
p.000070:
p.000070: 2.7.4.5
p.000070:
p.000070: 2.7.4.6
p.000070:
p.000070: 2.7.4.7
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: 2.7.4
p.000070: Summary of Clinical Safety In
p.000070:
p.000070: Exposure to the Drug In
p.000070:
p.000070: Adverse Events In
p.000070:
p.000070: Clinical Laboratory Evaluations In
p.000070:
p.000070: Vital Signs, Physical Findings, and Other Observations
p.000070: In
p.000070: Related to Safety
p.000070:
p.000070: Safety in Special Groups and Situations In
p.000070:
p.000070: Post-marketing Data In
p.000070:
p.000070: Appendix In
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: Any other documents (not explicitly mentioned in ICH M4) In
p.000070:
p.000070: All sections of the “Summary of Clinical Safety” regardless whether they are submitted as separate standalone documents
p.000070: or all together in a single document are subject to publication.
p.000070:
p.000070:
p.000070: All additional documents included in CTD section 2.7.4 such as “Clinical summary supplement/amendment/appendix” or
p.000070: “Integrated Summary of Safety (ISS)” which were submitted during the evaluation procedure are subject to publication.
p.000070:
p.000070:
p.000070: However, EMA notes that, the appendixes to clinical overviews(Module 2.5), appendixes to clinical summaries (Modules
p.000070: 2.7.1 to 2.7.4) and CSR bodies may contain individual patient data listings (referred to further below as “per
p.000070: patient/per visit line listings”). For example, these per patient/per visit line listings may be contained in CSR
p.000070: section 14.3.4 Abnormal Laboratory Value Listing (Per Patient/per Visit). EMA considers that such per patient/per visit
p.000070: line listings fall outside the scope of phase 1 of the Policy and, therefore, it is acceptable to have them removed
p.000070: from the clinical reports prepared for publication at this stage of the implementation. All these per patient/per visit
p.000070: line listings will be falling in the scope of phase 2 of the Policy.
p.000070: Please note that for sections where per patient per visit IPD are identified in the clinical reports and the Agency
p.000070: agrees that they are out of the scope, these sections can be removed from the documents.
p.000070: However the pages/sections considered out of scope and therefore removed have to be replaced by a blank page containing
p.000070: the following:
p.000070: 1, removed page numbers (from-to) and the corresponding section title
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 88/99
p.000070:
p.000070:
p.000070: 2, statement that it is per patient per visit data removed as out of scope of policy 0070, reading:
p.000070: “Out of Scope of phase I of Policy 0070- Per patient/per visit line listings”.
p.000070:
p.000070: The Agency considers per patient per visit data as those listings including values of the measured parameters (eg. lab
p.000070: values) listed for all patients recruited and covering all study visits.
p.000070: Therefore, for example, tables listing values of the measured parameters (eg. HbA1C) or outcomes (protocol deviation,
p.000070: death, SAE, overall survival) at a certain single time point will not be considered per patient per visit line listing.
p.000070: Also, the Agency does not consider per patient per visit line listings those tables where parameter or outcome values
p.000070: for selected patients and selected visits are presented.
p.000070: 2.7.5 References
p.000070:
p.000070:
p.000070:
p.000070: 2.7.5
p.000070:
p.000070: (All) References
p.000070:
p.000070: Out
p.000070: These documents (the list of references or the literature references themselves) are not clinical summaries therefore
p.000070: are not subject to publication
p.000070: 2.7.6 Synopsis of Individual Studies
p.000070:
p.000070:
p.000070: 2.7.6
p.000070: (All) Synopsis of Individual Studies
p.000070:
p.000070: Out
p.000070: These documents are not clinical summaries therefore are not subject to publication
p.000070: 5 Clinical Study Reports
p.000070:
p.000070: 5.1 Table of Contents of Module 5
p.000070:
p.000070:
p.000070:
p.000070: 5.1
p.000070:
p.000070: Table of Contents of Module 5
p.000070:
p.000070: Out
p.000070: This document is not a clinical study report (CSR) therefore is not subject to publication
p.000070: 5.2 Tabular Listing of All Clinical Studies
p.000070:
p.000070:
p.000070:
p.000070: 5.2
p.000070:
p.000070: Tabular Listing of All Clinical Studies
p.000070:
p.000070: Out
p.000070: This document is not a clinical study report (CSR) therefore is not subject to publication
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 89/99
p.000070:
p.000070:
p.000070: 5.3 Clinical Study Reports
p.000070:
p.000070: 5.3.1 Reports of Biopharmaceutic Studies
p.000070:
p.000070: 5.3.1.1 Bioavailability (BA) Study Reports
p.000070:
...
p.000070:
p.000070: - 14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events
p.000070: DO FALL in the scope of the policy and SHOULD NOT BE REMOVED from the CSRs that are prepared for publication.
p.000070: Please note that for sections where per patient per visit IPD are identified in the clinical reports and the Agency
p.000070: agrees that they are out of the scope, these sections can be removed from the documents.
p.000070: However the pages/sections considered out of scope and therefore removed
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 94/99
p.000070:
p.000070:
p.000070:
p.000070: Clinical Study Report (CSR) components
p.000070:
p.000070: Clinical Study Report (CSR) sections
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070:
p.000070:
p.000070: have to be replaced by a blank page containing the following:
p.000070:
p.000070: 1, removed page numbers (from-to) and the corresponding section title
p.000070:
p.000070: 2, statement that it is per patient per visit data removed as out of scope of policy 0070, reading:
p.000070: “Out of Scope of phase I of Policy 0070- Per patient/per visit line listings”.
p.000070: The Agency considers per patient per visit data as those listings including values of the measured parameters (eg. lab
p.000070: values) listed for all patients recruited and covering all study visits.
p.000070: Therefore, for example, tables listing values of the measured parameters (eg. HbA1C) or outcomes (protocol deviation,
p.000070: death, SAE, overall survival) at a certain single time point will not be considered per patient per visit line listing.
p.000070: Also, the Agency does not consider per patient per visit line listings those tables where parameter or outcome values
p.000070: for selected patients and selected visits are presented.
p.000070: To be noted that the same CCI, PPD and publication principles will apply to EU as well as non-EU studies in the context
p.000070: of Policy 0070.
p.000070: B. CSR Appendices
p.000070:
p.000070: 16.1 STUDY INFORMATION
p.000070:
p.000070:
p.000070: 16.1.1 Protocol and protocol amendments
p.000070:
p.000070: 16.1.2 Sample case report form (unique pages only)
p.000070: In The following CSR appendices ONLY are subject to publication: In 16.1.1 Protocol and protocol
p.000070: amendments
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 95/99
p.000070:
p.000070:
p.000070:
p.000070: Clinical Study Report (CSR) components
p.000070:
p.000070: Clinical Study Report (CSR) sections
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070: 16.1.2 Sample case report form (unique pages only)
p.000070:
p.000070: 16.1.9 Documentation of statistical methods
p.000070:
p.000070: If for a particular CSR the ICH E3 format is not followed, the corresponding information/sections (1-15) and annexes
p.000070: (16.1.1, 16.1.2, 16.1.9) will be subject to publication.
p.000070:
p.000070: 16.1.3 List of IECs or IRBs (plus the name of the committee Chair if required by the regulatory authority) -
p.000070: Representative written information for patient and sample consent forms
p.000070:
...
Social / Police Officer
Searching for indicator officer:
(return to top)
p.000070:
p.000070:
p.000070: 16.1.1 Protocol and protocol amendments
p.000070:
p.000070: 16.1.2 Sample case report form (unique pages only)
p.000070: In The following CSR appendices ONLY are subject to publication: In 16.1.1 Protocol and protocol
p.000070: amendments
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 95/99
p.000070:
p.000070:
p.000070:
p.000070: Clinical Study Report (CSR) components
p.000070:
p.000070: Clinical Study Report (CSR) sections
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070: 16.1.2 Sample case report form (unique pages only)
p.000070:
p.000070: 16.1.9 Documentation of statistical methods
p.000070:
p.000070: If for a particular CSR the ICH E3 format is not followed, the corresponding information/sections (1-15) and annexes
p.000070: (16.1.1, 16.1.2, 16.1.9) will be subject to publication.
p.000070:
p.000070: 16.1.3 List of IECs or IRBs (plus the name of the committee Chair if required by the regulatory authority) -
p.000070: Representative written information for patient and sample consent forms
p.000070:
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.4 List and description of investigators and other important participants in the study, including brief (1 page)
p.000070: CVs or equivalent summaries of training and experience relevant to the performance of the clinical study
p.000070:
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.5 Signatures of principal or coordinating investigator(s) or sponsor’s responsible medical officer, depending on
p.000070: the regulatory authority's requirement
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.6 Listing of patients receiving test drug(s)/investigational product(s) from specific batches, where more than one
p.000070: batch was used
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.7 Randomisation scheme and codes (patient identification and treatment assigned)
p.000070:
p.000070: Out
p.000070: 16.1.8 Audit certificates (if available) (see Annex IVa and IVb of the guideline) Out
p.000070:
p.000070: 16.1.9 Documentation of statistical methods In
p.000070:
p.000070:
p.000070: 16.1.10 Documentation of inter-laboratory standardisation methods and quality assurance procedures if used
p.000070:
p.000070: Out
p.000070: 16.1.11 Publications based on the study Out
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 96/99
p.000070:
p.000070:
p.000070:
p.000070: Clinical Study Report (CSR) components
p.000070:
p.000070: Clinical Study Report (CSR) sections
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070: 16.1.12 Important publications referenced in the report Out
p.000070:
p.000070: 16.2. PATIENT DATA LISTINGS
p.000070:
p.000070: All appendices located under 16.2. PATIENT DATA LISTINGS Out
p.000070:
p.000070: 16.3 CASE REPORT FORMS
p.000070:
...
Social / Property Ownership
Searching for indicator property:
(return to top)
p.000068:
p.000068: 3. Definitions
p.000068:
p.000068: For the purposes of the implementation of Policy 0070 the following definitions6 will apply:
p.000068: • Aggregated data:
p.000068: Statistical data about several individuals that has been combined to show general trends or values without identifying
p.000068: individuals within the data.
p.000068:
p.000068: 6 It should be noted that some definitions are already included in the published Policy 0070. For the sake of
p.000068: completeness they have been incorporated as well in this guidance document.
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 7/99
p.000068:
p.000068: • Anonymisation:
p.000068: The process of rendering data into a form which does not identify individuals and where identification is not likely to
p.000068: take place.
p.000068: • Anonymised/de-identified data:
p.000068: Data in a form that does not identify individuals and where identification through its combination with other data is
p.000068: not likely to take place.
p.000068: • Applicant/MAH:
p.000068: Applicant/MAH shall mean the natural or legal person(s) or organisation(s) that submitted the clinical reports to EMA
p.000068: in the context of applications in support of centralised marketing authorisations (MAs)/post-authorisation submissions
p.000068: for existing centrally authorised medicinal products, or in support of an application for an opinion in accordance with
p.000068: Article 58 of Regulation (EC) No 726/2004, as well as any person(s) or organisation(s) who own(s) copyright or other
p.000068: intellectual property rights in the clinical reports.
p.000068: • Article 29 Data Protection Working Party (Art. 29 WP):
p.000068: The Art. 29 WP was set up under Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on
p.000068: the protection of individuals with regard to the processing of personal data and on the free movement of such data. It
p.000068: has advisory status and acts independently. It is composed of a representative of the supervisory authority(ies)
p.000068: designated by each EU country, a representative of the authority(ies) established for the EU institutions and bodies,
p.000068: and a representative of the European Commission.
p.000068: • Clinical reports:
p.000068: Clinical reports shall mean the clinical overviews (submitted in module 2.5), clinical summaries (submitted in module
p.000068: 2.7) and the clinical study reports (submitted in module 5, “CSR”) together with the following appendices to the CSRs:
p.000068: 16.1.1 (protocol and protocol amendments), 16.1.2 (sample case report form), and 16.1.9 (documentation of statistical
p.000068: methods).
p.000068: • Clinical data:
p.000068:
p.000068: Clinical data shall mean the clinical reports and IPD.
p.000068:
p.000068: • Clinical study:
p.000068:
p.000068: Clinical study shall mean any investigation in relation to humans intended to:
p.000068:
p.000068: - discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal
p.000068: products;
p.000068: - identify any adverse reactions to one or more medicinal products; or
...
p.000070: the absence of an adequate justification EMA is unable to recognise how the disclosure of this particular information
p.000070: would undermine your economic interest or competitive position.
p.000070: EMA therefore adopts the position that the information proposed to be redacted does not constitute commercially
p.000070: confidential information and that is not accepted by EMA as a valid redaction proposal. “
p.000070: The following section of the guidance presents some examples of justifications that are considered by EMA to be
p.000070: insufficient.
p.000070: EXAMPLE 1
p.000070:
p.000070: “Unpublished data - These study results have not been published in any peered-reviewed [sic] publication.”
p.000070: EXAMPLE 2
p.000070:
p.000070: “Company confidential information - Disclosure of these elements will harm [the company]’s commercial interests because
p.000070: it may enable third party access to business-critical information.”
p.000070: EXAMPLE 3
p.000070:
p.000070: “This information can be interpreted out of context. Such interpretation could lead to a misleading image of the safety
p.000070: profile of the product.”
p.000070: EXAMPLE 4
p.000070:
p.000070: “Detailed Statistical/Analytical Method : See Article 4.2 1st indent of Regulation (EC) The institutions shall refuse
p.000070: access to a document where disclosure would undermine the protection of commercial interests of a natural or legal
p.000070: person, including intellectual property.”
p.000070: EXAMPLE 5
p.000070:
p.000070: “The deleted text is detailed information for the active substance which is considered as confidential information.”
p.000070: EXAMPLE 6
p.000070:
p.000070: “Regulatory interaction – approaches and interactions which could give competitors substantial advantages.”
p.000070: EXAMPLE 7
p.000070:
p.000070: “The analytical methods are [the company]’s intellectual property, which [the company] developed by expending a
p.000070: significant amount of time, and human, financial and commercial resources.”
p.000070: EXAMPLE 8
p.000070:
p.000070: “Information is commercially confidential, competitively sensitive information and includes intellectual property
p.000070: including trade secret information.”
p.000070: EXAMPLE 9
p.000070:
p.000070: “Information on the safety profile of the product not reflected in the SmPC.”
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 57/99
p.000070:
p.000070: EXAMPLE 10
p.000070:
p.000070: “Information is commercially confidential, competitively sensitive information and includes intellectual property
p.000070: including trade secret information.”
p.000070: EXAMPLE 11
p.000070:
p.000070: “The text proposed to be redacted reveals purpose and timing of discussions with health authorities, this is considered
p.000070: sensitive information that is not consolidated in this way within the public domain, and indeed we cannot find this
p.000070: information in public forum.
p.000070:
p.000070: 4. How to prepare justifications in support of proposed redactions
p.000070: 4.1. The content of the justification table and its use
p.000070:
p.000070: The purpose of the justification table is to enable targeted comments on the proposed CCI redactions for use by both
p.000070: EMA and the applicant/MAH. The justification table is essentially a living document and will be used as a communication
p.000070: tool throughout the redaction consultation process. It will contain the justifications from the applicant/MAH on the
p.000070: proposed CCI to redact and EMA’s assessment. At the end of the redaction consultation process this table will be sent
p.000070: to the applicant/MAH as part of EMA’s conclusion. The justification tables should contain justifications for all pieces
p.000070: of text considered CCI and proposed to be redacted. All the proposed redactions listed in the justification table
p.000070: should correspond to the text highlighted for redaction in the redaction proposal version of the corresponding clinical
p.000070: report. Should the company highlight a piece of text proposed for redaction in the document, but fails to explain its
p.000070: redaction in the justification table, the proposal will be considered invalid and will be sent back for clarification.
p.000070: For further details on the redaction consultation process see the “External guidance on the procedural aspects related
...
p.000070:
p.000070: Out
p.000070: These documents are not clinical summaries therefore are not subject to publication
p.000070: 5 Clinical Study Reports
p.000070:
p.000070: 5.1 Table of Contents of Module 5
p.000070:
p.000070:
p.000070:
p.000070: 5.1
p.000070:
p.000070: Table of Contents of Module 5
p.000070:
p.000070: Out
p.000070: This document is not a clinical study report (CSR) therefore is not subject to publication
p.000070: 5.2 Tabular Listing of All Clinical Studies
p.000070:
p.000070:
p.000070:
p.000070: 5.2
p.000070:
p.000070: Tabular Listing of All Clinical Studies
p.000070:
p.000070: Out
p.000070: This document is not a clinical study report (CSR) therefore is not subject to publication
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 89/99
p.000070:
p.000070:
p.000070: 5.3 Clinical Study Reports
p.000070:
p.000070: 5.3.1 Reports of Biopharmaceutic Studies
p.000070:
p.000070: 5.3.1.1 Bioavailability (BA) Study Reports
p.000070:
p.000070: 5.3.1.1 (All) Bioavailability (BA) Study Reports In
p.000070:
p.000070: 5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports
p.000070:
p.000070: 5.3.1.2 (All) Comparative BA and Bioequivalence (BE) Study Reports In
p.000070:
p.000070: 5.3.1.3 In vitro - In vivo Correlation Study Reports
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: 5.3.1.3
p.000070:
p.000070:
p.000070: (All) In vitro - In vivo Correlation Study Reports
p.000070:
p.000070:
p.000070: Out
p.000070: These study reports contain information on predictive mathematical models describing the relationship between an in
p.000070: vitro property and a relevant in vivo response. These reports are not expected to contain safety and efficacy results.
p.000070: Therefore, EMA considers that these study reports are not subject to publication.
p.000070: 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: 5.3.1.4
p.000070:
p.000070: (All) Reports of Bioanalytical and Analytical Methods for Human Studies
p.000070:
p.000070:
p.000070: Out
p.000070: These study reports contain information on the assays validation and analytical methods employed during the conduct of
p.000070: the clinical trials. These reports are not expected to contain safety and efficacy results. Therefore, EMA considers
p.000070: that these study reports are not subject to publication.
p.000070: 5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials
p.000070:
p.000070: 5.3.2.1 Plasma Protein Binding Study Reports
p.000070:
p.000070: 5.3.2.1 (All) Plasma Protein Binding Study Reports In
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 90/99
p.000070:
p.000070:
p.000070: 5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
p.000070:
p.000070:
p.000070: 5.3.2.2
p.000070: (All) Reports of Hepatic Metabolism and Drug Interaction
p.000070: In
p.000070: Studies
p.000070:
p.000070: 5.3.2.3 Reports of Studies Using Other Human Biomaterials
p.000070:
...
Social / Racial Minority
Searching for indicator race:
(return to top)
p.000070: on a case-by-case basis based on the impact on the risk. Moreover, it should also be considered that for any extension
p.000070: to the initial marketing authorisation application study, the same patients will be recoded differently from the
p.000070: initial marketing authorisation study. EMA recognises that in such situations data utility may be suboptimal since this
p.000070: creates a problem of linkability between the initial study and the extension study.
p.000070:
p.000070: 5.3.2.2. Anonymisation of Quasi Identifiers
p.000070:
p.000070: Quasi identifiers are variables representing an individual’s background information that can indirectly identify
p.000070: individuals. Unlike direct identifiers, information from quasi identifiers increases the scientific usefulness of the
p.000070: information published. Geographical location is an important variable since clinical practice can vary from country to
p.000070: country and this can impact on the outcome. Relative dates relating to individual patients are also important due to
p.000070: the potential impact on the outcome of the trial. Patient
p.000070:
p.000070:
p.000070: 16 David Carrell, Bradley Malin, John Aberdeen, et al. “Hiding in plain sight: use of realistic surrogates to reduce
p.000070: exposure of protected health information in clinical text”. J Am Med Inform Assoc 2013;20:342–348.
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 42/99
p.000070:
p.000070: level demographic information such as sex, age, race, ethnicity, height and weight can be confounders and therefore of
p.000070: critical scientific utility.
p.000070: In order to render the clinical reports anonymised it is not always necessary to redact all quasi identifiers. The need
p.000070: to redact quasi identifiers will depend on the following aspects:
p.000070: • Number of quasi identifiers per trial participant
p.000070: • Frequency of trial participants with same category/value on a set of the quasi identifiers (group size)
p.000070: • Size of population
p.000070: It is up to the applicant/MAH to decide which quasi identifiers need to be redacted and which could remain in the
p.000070: reports. The rationale for the decision should be included in the risk assessment section of the anonymisation report
p.000070: to be provided to EMA (see section 5.5).
p.000070: The factors having the most impact on data de-identification are geographical location and dates leading to a higher
p.000070: risk of re-identification. A feature of anonymisation is that it is only partially determined by the data to be
p.000070: protected. The ability to identify a trial participant depends on both these data and the state of knowledge of the
p.000070: observer concerning the trial participants in the data. For these reasons, location and dates are important. They may
p.000070: not be the most specific identifiers of a trial participant but they are often the most easily obtainable from other
p.000070: sources. Therefore, clinical data containing information on geographical location and dates should be carefully
p.000070: anonymised (see sections 5.3.2.2.1 and 5.3.2.2.2).
p.000070:
p.000070: 5.3.2.2.1. Dates
p.000070:
...
Social / Trade Union Membership
Searching for indicator union:
(return to top)
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013: 16 December 2016 EMA/90915/2016
p.000013: Version 1.1 published 19 December 2016
p.000013:
p.000013:
p.000013:
p.000013:
p.000013: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000013: medicinal products for human use
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013:
p.000013: 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20
p.000013: 3660 5505 Send a question via our website www.ema.europa.eu/contact
p.000013:
p.000013:
p.000013:
p.000013:
p.000013: An agency of the European Union
p.000013:
p.000013: © European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged.
p.000013:
p.000013:
p.000013: Table of contents
p.000013: Chapter 1
p.000013: General information
p.000013: 1. Introduction 6
p.000013: 2. Scope 6
p.000013: 3. Definitions 7
p.000013: 4. Implementing Policy 0070 11
p.000013: Chapter 2
p.000013: External guidance on the procedural aspects related to the submission of clinical reports for the purpose of
p.000013: publication in accordance with EMA Policy 0070
p.000013: 1. Introduction 13
p.000013: 2. Clinical report document types 13
p.000013: 2.1. Types of documents that fall within the scope of Policy 0070 13
p.000013: 2.2. Types of documents or sections of documents considered to be in or out of scope of phase 1 of Policy 0070
p.000013: 13
p.000013: 3. Process for the submission, review and publication of clinical reports 14
p.000013: 3.1. High level summary of the process 14
p.000013: 3.2. Notifications to Applicants
p.000014: 14
p.000014: 3.3. Detailed end-to end process 14
p.000014: 3.3.1. Submission of the Redaction Proposal document package 15
...
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 28/99
p.000068:
p.000068: 3.3.2.2. Review of the anonymisation report
p.000068:
p.000068: EMA will review the anonymisation report to check whether the applicant/MAH followed the anonymisation guidance and
p.000068: applied it consistently throughout the documents. EMA will transmit its comments, if any, to the applicant/MAH but does
p.000068: not formally adopt the anonymisation report. If required, the applicant/MAH will send a revised anonymisation report
p.000068: and the anonymised, Final Redacted version of the clinical reports which will subsequently be published by EMA.
p.000068:
p.000068: 3.3.3. Submission of the Final Redacted document package
p.000068:
p.000068: 3.3.3.1. Process to submit the Final redacted document package
p.000068:
p.000068: A workflow for the submission of the Final redacted document package can be found in Annex 1.8 of this guidance
p.000068: document. This process requires the applicant/MAH to submit to EMA a redaction proposal version of the clinical reports
p.000068: for publication.
p.000068:
p.000068: 3.3.3.2. Timeline
p.000068:
p.000068: Within 7 calendar days following the issuance of the EMA redaction conclusion, applicants/MAHs must provide their
p.000068: written agreement to the redaction conclusion. The Final Redacted document package must then be provided ≤ 20 days
p.000068: following the receipt of this agreement. A workflow for the submission of the Final Redacted document package can be
p.000068: found at Annex 1.8 of this guidance document. If the applicant/MAH disagrees with the redaction conclusion, EMA will
p.000068: adopt a decision against which the applicant/MAH can file an application for annulment and related application for
p.000068: interim relief to the General Court of the European Union, in accordance with Article 263 of the Treaty of the European
p.000068: Union and the Rules of Procedure of the General Court. The related deadlines and time limits are set therein. Please
p.000068: see section 3.3.4 below for function details on this case.
p.000068:
p.000068: 3.3.3.3. Content of the Final Redacted document package
p.000068:
p.000068: The applicant/MAH is required to prepare a separate sequence in eCTD format to submit the Final Redacted Document
p.000068: package. The eCTD submission of the final redacted document package falls under the same eCTD life-cycle of the initial
p.000068: MAA, line extension application or extension of indication application, as applicable. An exhaustive list of the
p.000068: documents to be submitted within the final redacted document package is provided in Table 2 below, including the final
p.000068: redacted versions of all the listed clinical reports.
p.000068: The applicant/MAH is required to submit the package of documents listed in Table 2 as part of a single Final Redacted
p.000068: document package, all of which must be included in the same eCTD sequence. In respect of publication of multiple
p.000068: applications for the same medicinal product under different invented names where the clinical reports are identical
p.000068: (with the exception of references to the product names), EMA will provide a notice on its corporate website to cross
p.000068: reference the different invented names to the published final redacted version of the original medicinal product.
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 29/99
p.000068:
...
p.000068:
p.000068: 3.3.4. Publication process
p.000068:
p.000068: Redacted/anonymised clinical reports will be published by EMA on its corporate website. Prior to publication EMA will
p.000068: watermark each page9 of the clinical reports in the Final Redacted version submitted by the applicant/MAH. The
p.000068: timelines for the publication of redacted/anonymised clinical reports will vary depending on the regulatory procedure.
p.000068: For initial MAAs, line extension applications and extension of indication applications EMA will publish the
p.000068: redacted/anonymised clinical reports within 60 days of the issuance of the Commission decision. For withdrawn
p.000068: applications the publication of the redacted/anonymised clinical reports will take place within 150 days after the
p.000068: receipt of the withdrawal letter. The applicant/MAH will receive an automated confirmation from EMA once publication
p.000068: has taken place.
p.000068: A situation may arise where an agreement between the applicant/MAH and EMA was not reached on the proposed redaction,
p.000068: and the applicant/MAH decided to apply for interim relief against an EMA decision to publish the documents without
p.000068: accepting the redactions which are still controversial. In this case, the applicant/MAH will submit a partial Final
p.000068: Redacted version package, whereby the clinical reports would be redacted according to the applicant/MAH’s views. The
p.000068: applicant/MAH will confirm, in the text of the cover letter, which controversial redactions (page, line) have been made
p.000068: in the documents. Please note that applications for annulment of EMA decisions and the related application for interim
p.000068: relief are filed with the General Court of the European Union in accordance with Article 263 of the Treaty of the
p.000068: European Union and the Rules of Procedure of the General Court. The related deadlines and time limits are set therein.
p.000068: In the event that interim relief is sought against the EMA decision, EMA will publish a partial Final Redacted Version
p.000068: of the clinical reports. When a final decision on the interim relief proceedings is issued, the applicant/MAH shall
p.000068: submit a Final Redacted Version in accordance with the indications from the Court of Justice of the European Union. EMA
p.000068: will withdraw from its corporate website the partial Final Redacted version previously published. EMA will then publish
p.000068: the Final Redacted version.
p.000068: In an exceptional situation where an applicant/MAH does not submit a complete Redaction Proposal Document package or a
p.000068: complete Final Redacted document package, EMA will publish a non- compliance notice.
p.000068:
p.000068: 9 The watermark text is:’www.ema.europa.eu
p.000068: This document cannot be used to support any marketing authorisation application and any extensions or variations
p.000068: thereof’
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 33/99
p.000068:
p.000068: 4. Marketing authorisation transfers
p.000068: In cases where a marketing authorisation holder (the Transferor) submits an application to transfer a marketing
p.000068: authorisation to another company (the Transferee), as of the date of notification of the amendment of the Commission
p.000068: decision in relation to the transfer of the marketing authorisation based on Regulation (EC) No 2141/96 (the transfer
p.000068: date), the Transferee becomes the new marketing authorisation holder and takes over all responsibilities pertaining to
p.000068: a marketing authorisation holder under EU pharmaceutical legislation.
p.000068: Responsibilities under Policy 0070 are also transferred to the Transferee, and include responsibility for clinical
p.000068: reports that were redacted by the Transferor and published by the EMA before the transfer date. Should an MA transfer
p.000068: application be sent to the EMA during the Policy 0070 process, the process will continue on the basis of the
p.000068: agreements, submissions and declarations made by the Transferor.
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Social / philosophical differences/differences of opinion
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p.000053: 53
p.000053: 3.2.4. Information lacking sufficient or relevant justification – Rejection code 04 and 05 56
p.000053: 4. How to prepare justifications in support of proposed redactions 58
p.000053: 4.1. The content of the justification table and its use 58
p.000053: 4.2. Completing the justification table 58
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p.000053:
p.000053: Chapter 5 Annexes
p.000053: 1. Annexes 63
p.000053: 1.1. Redaction tool application letter for SMEs 63
p.000053: 1.2. Anonymisation report - Template 65
p.000053: 1.2.1. Anonymisation methodology 65
p.000053: 1.2.2. Identification of data variables (direct and quasi identifiers) 65
p.000053: 1.2.3. Data utility considerations 67
p.000053: 1.2.4. Conclusion
p.000068: 68
p.000068: 1.3. Template for list of documents submitted 69
p.000068: 1.4. Template cover letter text: “Redaction Proposal Document” package 70
p.000068: For applications for which a CHMP opinion has been adopted 70
p.000068: 1.5. Template cover letter text: “Redaction Proposal Document” package 72
p.000068: In case of withdrawal of applications 72
p.000068: 1.6. Template cover letter text: “Final Redacted Document” package 74
p.000068: For all applications covered by the policy 74
p.000068: 1.7. “Redaction Proposal Version” process flowchart 76
p.000068: 1.8. “Final Redacted Version” process flowchart 77
p.000068: 1.9. Workflow for the submission of clinical reports for publication 78
p.000068: 1.10. Sample of Justification table for CCI redactions 79
p.000068: 1.11. Redaction consultation process flowchart 80
p.000068: 1.12. In and Out of scope of phase 1 of Policy 0070 81
p.000068: Chapter 6
p.000068: 1. References 99
p.000068:
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p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
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p.000068: redaction proposal for all such documents would suffice. Hence, the applicant/MAH will not have to replicate submission
p.000068: for the documents pertaining to the individual marketing authorisation concerned or to the second or the third etc.
p.000068:
p.000068: 3. Definitions
p.000068:
p.000068: For the purposes of the implementation of Policy 0070 the following definitions6 will apply:
p.000068: • Aggregated data:
p.000068: Statistical data about several individuals that has been combined to show general trends or values without identifying
p.000068: individuals within the data.
p.000068:
p.000068: 6 It should be noted that some definitions are already included in the published Policy 0070. For the sake of
p.000068: completeness they have been incorporated as well in this guidance document.
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
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p.000068:
p.000068: • Anonymisation:
p.000068: The process of rendering data into a form which does not identify individuals and where identification is not likely to
p.000068: take place.
p.000068: • Anonymised/de-identified data:
p.000068: Data in a form that does not identify individuals and where identification through its combination with other data is
p.000068: not likely to take place.
p.000068: • Applicant/MAH:
p.000068: Applicant/MAH shall mean the natural or legal person(s) or organisation(s) that submitted the clinical reports to EMA
p.000068: in the context of applications in support of centralised marketing authorisations (MAs)/post-authorisation submissions
p.000068: for existing centrally authorised medicinal products, or in support of an application for an opinion in accordance with
p.000068: Article 58 of Regulation (EC) No 726/2004, as well as any person(s) or organisation(s) who own(s) copyright or other
p.000068: intellectual property rights in the clinical reports.
p.000068: • Article 29 Data Protection Working Party (Art. 29 WP):
p.000068: The Art. 29 WP was set up under Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on
p.000068: the protection of individuals with regard to the processing of personal data and on the free movement of such data. It
p.000068: has advisory status and acts independently. It is composed of a representative of the supervisory authority(ies)
p.000068: designated by each EU country, a representative of the authority(ies) established for the EU institutions and bodies,
p.000068: and a representative of the European Commission.
p.000068: • Clinical reports:
p.000068: Clinical reports shall mean the clinical overviews (submitted in module 2.5), clinical summaries (submitted in module
p.000068: 2.7) and the clinical study reports (submitted in module 5, “CSR”) together with the following appendices to the CSRs:
p.000068: 16.1.1 (protocol and protocol amendments), 16.1.2 (sample case report form), and 16.1.9 (documentation of statistical
p.000068: methods).
p.000068: • Clinical data:
p.000068:
p.000068: Clinical data shall mean the clinical reports and IPD.
p.000068:
p.000068: • Clinical study:
p.000068:
p.000068: Clinical study shall mean any investigation in relation to humans intended to:
p.000068:
...
p.000068: (body of the report or listings). They should be, instead, anonymised. Regardless of the anonymisation technique used
p.000068: by the applicant/MAH, EMA cannot accept the redaction of the entire case narrative by default (as a rule). If,
p.000068: exceptionally, the entire case narrative needs to be redacted to ensure anonymisation, i.e. all identifiers (direct and
p.000068: indirect) need to be redacted, it has to be clearly justified in the anonymisation report.
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
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p.000068:
p.000068: • Likewise, patient level information referred to in the free-text should not be redacted in full but instead
p.000068: anonymised. Please refer to Chapter 3 “External guidance on the anonymisation of clinical reports for the purpose of
p.000068: publication in accordance with EMA Policy 0070”.
p.000068:
p.000068: 3. Process for the submission, review and publication of clinical reports
p.000068: 3.1. High level summary of the process
p.000068:
p.000068: A high level workflow outlines the key components of the process from the submission by an applicant/MAH to the
p.000068: publication (please see Annex 1.9 for more details).
p.000068:
p.000068: 3.2. Notifications to Applicants
p.000068:
p.000068: The applicant/MAH will receive notifications to submit a Redaction Proposal document package. In the case of initial
p.000068: marketing authorisation applications (initial MAAs), line extension applications and extension of indication
p.000068: applications, two notifications will be sent as follows: (i) the validation letter and (ii) the CHMP Opinion letter.
p.000068: The notification will be within the letter sent to the applicant/MAH for the relevant stage of the scientific review
p.000068: process. In the case of a withdrawal, the applicant/MAH will receive two notifications to submit a Redaction Proposal
p.000068: document package (i) in the validation letter (when the application was originally submitted) and (ii) in the
p.000068: acknowledgement letter of withdrawal to the applicant. A table outlining when each notification will be issued, for
p.000068: each application type, is provided below.
p.000068: Application Type First Notification Second Notification
p.000068:
p.000068: Initial MAA
p.000068: Line Extension
p.000068: Extension of Indication Application
p.000068:
p.000068:
p.000068: Validation letter
p.000068: CHMP Opinion letter or Acknowledgement letter of withdrawal
p.000068:
p.000068: 3.3. Detailed end-to end process
p.000068:
p.000068: There are de facto four sub processes:
p.000068:
p.000068: • Submission of Redaction Proposal document package.
p.000068:
p.000068: • Consultation process.
p.000068:
p.000068: • Submission of the Final Redacted document package.
p.000068:
p.000068: • Publication process
p.000068:
p.000068: The applicant/MAH is required to submit two packages to EMA:
p.000068:
p.000068: • Redaction Proposal document package.
p.000068:
p.000068: • Final Redacted document package.
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
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p.000068: medicinal products for human use
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p.000068:
p.000068: 3.3.1. Submission of the Redaction Proposal document package
p.000068:
p.000068: 3.3.1.1. Process to submit the Redaction Proposal document package
p.000068:
p.000068: A workflow for the submission of the Redaction Proposal document package can be found in Annex 1.7 of this guidance
p.000068: document. This process requires the applicant/MAH to submit to EMA a redaction proposal version of the clinical reports
p.000068: for publication, in which proposed redactions are marked, in line with the CTD format of Modules 1, 2, and 5 or
p.000068: equivalent sections if the submission structure does not follow the ICH M4 guideline.
p.000068:
p.000068: 3.3.1.2. Timeline
p.000068:
p.000068: The timeline for the submission of the Redaction Proposal document package by the applicant/MAH varies depending on the
p.000068: regulatory procedure.
p.000068: For the Initial MAAs, and line extension applications, applicants/MAHs must submit their Redaction Proposal document
p.000068: package between day 181 and day 220 of the procedure (≤ 30 days pre-opinion and ≤ 10 days post-opinion).
p.000068: For extension of indication applications, applicants/MAHs must submit their Redaction Proposal document package ≤ 30
p.000068: days pre-opinion and ≤ 10 days post-opinion.
p.000068: For withdrawn applications, applicants/MAHs must submit their Redaction Proposal document package
p.000068: ≤ 30 days post-receipt of the withdrawal letter by EMA. The notification to the applicant/MAH at CHMP opinion stage
p.000068: will state the specific deadline for the submission of the Redaction Proposal version for the medicinal product in
p.000068: question.
p.000068:
p.000068: 3.3.1.3. Content of the Redaction Proposal document package
p.000068:
p.000068: An exhaustive list of the documents to be submitted within the Redaction Proposal document package is provided in Table
p.000068: 1 below, including the redaction proposal versions of all the listed clinical reports.
p.000068: The required documents should be submitted within the relevant eCTD sections. For further reference please consult the
p.000068: eCTD Guidance Document (eSubmission) for the Centralized Procedure:
p.000068: User Guidance for submissions via eSubmission Gatway Harmonised Technical Guidance for eCTD Submissions in the EU
p.000068: All documents including the cover letter with the required declaration of the Redaction Proposal document package must
p.000068: be uploaded via the gateway at the same time. Both, the proposed and the final redaction document packages should
p.000068: contain the same number of clinical reports. Therefore, even clinical reports where no CCI and/or PPD redactions are
p.000068: proposed and no justification table is required have to be submitted as part of both packages. The eCTD submission of
p.000068: the Redaction Proposal document package falls under the same eCTD life cycle of the initial MAA, line extension
p.000068: application or extension of indication application as applicable.
p.000068:
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p.000068:
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p.000068: medicinal products for human use
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p.000068:
p.000068: • It should be possible to easily (with minimal intervention) render each of the proposed redactions permanent or
p.000068: to remove the proposed redaction.
p.000068: • It should be possible to select one or more marked proposed redactions for comment, redaction or deletion.
p.000068: Editing individual proposed redactions should be possible for all parties. In order to view the history of the changes
p.000068: made, each change has to be visible in a comment list or audit trail.
p.000068: Differences between format requirements for the preparation of the redaction proposal and final redacted version of the
p.000068: clinical reports are intentional as the Redaction Proposal version will not be watermarked and published. Some format
p.000068: limitations apply to the published documents only.
p.000068: Although the choice of the redaction tool is a decision to be taken by each applicant/MAH, EMA will make available to
p.000068: Micro, Small and Medium sized Enterprises (SMEs) a license for a redaction tool for a period of 12 months. SMEs are
p.000068: advised to write to EMA five months prior to the CHMP opinion to apply for the redaction tool licence. The template of
p.000068: the letter to send to EMA is at Annex 1.1. SMEs will need to hold their SME status at the time of issuing the license
p.000068: for the product in question to qualify for the redaction tool licence.
p.000068: EMA will assess the proposed CCI redactions. It is important that in the Redaction Proposal version of the submitted
p.000068: clinical reports the applicant/MAH clearly indicates each proposed CCI redaction.
p.000068: Therefore, all pieces of information proposed for CCI redaction should have a label, clearly indicating that the
p.000068: proposed redaction is requested on CCI grounds. Justification for each proposed CCI redaction should be included in the
p.000068: justification table. Please refer to Chapter 4 “External guidance on the identification and redaction of commercially
p.000068: confidential information in clinical reports submitted to EMA for the purpose of publication in accordance with EMA
p.000068: policy 0070” for further details.
p.000068: EMA will review the anonymisation report to the effect that the applicant/MAH has followed the guidance and applied the
p.000068: chosen approach for anonymisation consistently in all clinical reports. For
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
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p.000068:
p.000068: further information on anonymisation please see Chapter 3 “External guidance on the anonymisation of clinical reports
p.000068: for the purpose of publication in accordance with EMA Policy 0070”.
p.000068: Please note that for sections where per patient per visit IPD are identified in the clinical reports and the Agency
p.000068: agrees that they are out of the scope, these sections can be removed from the documents.
...
p.000070: MAHs/applicants. The field of anonymisation, i.e. the techniques used by controllers of personal data to anonymise
p.000070: data, is a field of active research and rapidly evolving. This guidance is not intended to provide an exhaustive list
p.000070: of the techniques available or to mandate a specific methodology but rather to highlight to MAHs/applicants the
p.000070: anonymisation process to be followed to ensure that clinical reports submitted to EMA for publication are rendered
p.000070: anonymous prior to publication. The guideline will be updated in light of new developments.
p.000070: This guidance document is without prejudice to the obligations of pharmaceutical companies as controllers of personal
p.000070: data under applicable national legislation on the protection of personal data.
p.000070:
p.000070: 2. Legal framework and available standards
p.000070: This guidance has been developed based on the current available legislation in the EU as well as guidance and standards
p.000070: on the anonymisation of personal data (see below).
p.000070: • Regulation (EC) No 45/2001 of the European Parliament and of the Council on the protection of individuals with
p.000070: regard to the processing of personal data by the Community institutions and bodies and on the free movement of such
p.000070: data, of 18 December 2000.
p.000070: • Directive 95/46/EC of the European Parliament and of the Council on the protection of individuals with regard to
p.000070: the processing of personal data and on the free movement of such data, of 24 October 1995.
p.000070: • Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070: • Opinion 06/2013 on open data and public sector information reuse of the Article 29 Data Protection Working
p.000070: Party.
p.000070: • Information Commissioner’s Office (ICO) Code of Practice. Anonymisation: managing data protection risk.
p.000070: • Sharing clinical trial data: Maximizing benefits, minimizing risk. Institute of Medicine (IOM). 2015.
p.000070: Washington, DC: The National Academies Press.
p.000070:
p.000070: 10 The term ‘trial participant’ in the current guidance relates to individuals on whom information has been collected
p.000070: related to the scientific objectives of the trial, e.g. patients and healthy volunteers.
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
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p.000070:
p.000070: • Pharmaceutical Users Software Exchange (PhUSE) de-identification standards for CDISC SDTM 3.2.
p.000070:
p.000070: • Transcelerate BioPharma Inc.
p.000070:
p.000070: - Clinical Study Reports Approach to Protection of Personal Data.
p.000070: - Data De-identification and Anonymisation of Individual Patient Data in Clinical Studies– A Model Approach.
p.000070: • White Paper on Anonymisation of Clinical Trial Data Sets. International Pharmaceutical Privacy Consortium
p.000070: (IPPC).
p.000070: • Scientific literature (see References).
p.000070:
p.000070: 3. General considerations
...
p.000070: According to the Article 29 Data Protection Working Party (Art. 29 WP) data that have been altered using techniques to
p.000070: mitigate risks of re-identification of the individuals concerned, but have not attained the threshold required by
p.000070: Article 2(a) and recital 26 of Directive 95/46/EC are not considered anonymised data. Therefore, such approach is only
p.000070: appropriate for limited disclosure for re-use by screened parties but not for public disclosure and re-use under open
p.000070: licence. Recital 26 signifies that to
p.000070:
p.000070: 11 ICO (UK Data Protection Agency) Code of Practice entitled “Anonymisation: managing data protection risk”
p.000070: https://ico.org.uk/media/for-organisations/documents/1061/anonymisation-code.pdf
p.000070:
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p.000070: medicinal products for human use
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p.000070:
p.000070: anonymise any data, the data must be stripped of sufficient elements such that the data subject can no longer be
p.000070: identified. More precisely, the data must be processed in such a way that it can no longer be used to identify a
p.000070: natural person12 by using “all the means likely reasonably to be used” by either the controller or a third party. It
p.000070: must be emphasised that recital 26 of Directive 95/46/EC sets a high threshold, as described in the Opinion of Art. 29
p.000070: WP. Unless data can be anonymised to meet this threshold, data protection law continues to apply.13
p.000070: The irreversibility of the anonymisation methodologies or techniques is also an important element as it can be used in
p.000070: order to differentiate from “pseudonymisation”. Pseudonymisation consists of replacing one attribute (typically a
p.000070: unique attribute) in a record by another. When pseudonymisation is used alone, the natural person is still likely to be
p.000070: identified indirectly. Pseudonymisation reduces the linkability of a dataset with the original identity of a data
p.000070: subject but when used alone will not result in an anonymous dataset, therefore data protection rules still apply. It
p.000070: is, therefore, important to clarify that pseudonymisation is not an anonymisation method but a useful security measure.
p.000070: Consequently, additional measures should be considered in order to render the dataset anonymised, including removing
p.000070: and generalising attributes or deleting the original data or at least bringing them to a highly aggregated level.
p.000070:
p.000070: 3.2.1. Anonymisation criteria
p.000070:
p.000070: According to the Opinion 05/2014 on anonymisation techniques of the Art. 29 WP, two options are available to establish
p.000070: if the data is anonymised. Either through the demonstration of effective anonymisation based on three criteria:
p.000070: • Possibility to single out an individual.
p.000070:
p.000070: • Possibility to link records relating to an individual.
p.000070:
p.000070: • Whether information can be inferred concerning an individual.
p.000070: or, whenever a proposal does not meet one of these criteria, through an evaluation of the identification risks.
p.000070: An anonymisation solution preventing all three criteria is considered to be robust against identification performed by
p.000070: the most likely and reasonable means the data controller or any third party may employ, and will render the data
p.000070: anonymous.
p.000070:
p.000070: 3.2.2. Anonymisation techniques
p.000070:
p.000070: There are several techniques that can be used in order to achieve anonymisation. Opinion 05/2014 on anonymisation
p.000070: techniques of the Art. 29 WP analyses the effectiveness and limits of existing anonymisation techniques against the EU
p.000070: legal background of data protection, and provides recommendations to handle these techniques by taking account of the
p.000070: residual risk of identification inherent in each of them14.
p.000070:
p.000070:
p.000070: 12 The definition of personal data as described in Article 2(a) of Regulation (EC) No 45/2001 relates to a ‘natural
p.000070: person’. The Article 29 Working Party opinion 4/2007 on the concept of personal data further clarifies that information
p.000070: relating to dead individuals is therefore in principle not to be considered as personal data to the rules of the
p.000070: Directive, as dead are no longer natural persons in civil law. However, the opinion also points out that data on the
p.000070: deceased may still be personal information since it may refer to living persons, e.g. it may indicate family diseases
p.000070: relevant to living children or siblings. In addition, it might be difficult for the data controller to establish
p.000070: whether the person to whom the data relates is still alive.
p.000070: 13 Opinion 05/2014 on anonymisation techniques and Opinion 06/2013 on open data and public sector information reuse of
p.000070: the Article 29 Data Protection Working Party .
p.000070: 14 Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070:
p.000070:
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p.000070: medicinal products for human use
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p.000070:
p.000070: 3.3. Advances in technology
p.000070:
p.000070: It is also important to take note of advances in technology (e.g. data mining) together with greater availability of
p.000070: data and the possibility of database linkage with the increased risk of re-identification. MAHs/applicants need to take
p.000070: into account (realistic) future developments in terms of availability of data and technologies that would allow
p.000070: identification. The Art. 29 WP Opinion 05/2014 on anonymisation techniques emphasises that even where a data controller
p.000070: believes it has successfully anonymised personal data, the data controller must continuously follow the developments in
p.000070: re- identification techniques, and if necessary reassess the risk of re-identification.
p.000070:
p.000070: 4. Applying these general considerations in the context of clinical reports for publication in accordance with EMA
p.000070: policy
p.000070: 4.1. Context of data disclosure
p.000070:
p.000070: This guidance document comes within the context of public data release since EMA has defined a process for publication
p.000070: of clinical reports where clinical reports are available on-screen for any user, with a simple registration process,
p.000070: and are available for downloading to identified users. Both situations are governed by dedicated Terms of Use that
p.000070: clarify that users of the data shall not, in any case, attempt to re-identify trial participants or other individuals.
p.000070:
p.000070: 4.2. Concept of anonymisation
p.000070:
p.000070: Clinical reports submitted to EMA for applications for marketing authorisation or post authorisation procedures mostly
p.000070: consist of pseudonymised aggregated data. They may contain individual patient information within, e.g. case narratives
p.000070: or tables of patient characteristics. Therefore, the reports cannot be considered anonymised and cannot be published as
p.000070: such. Applicants/MAHs, as data controllers of the personal information that might be contained in these documents, are
p.000070: required to submit clinical reports that have been rendered anonymous for the purpose of publication under Policy 0070.
p.000070: The anonymised clinical reports should be a copy of the clinical reports submitted in the context of the scientific
p.000070: evaluation procedure, stripped of sufficient elements such that the participants can no longer be identified. The data
p.000070: in the clinical reports must be processed in such a way that it can no longer be used to identify a natural person by
p.000070: using “all the means likely reasonably to be used” by either the controller or a third party, as described in Directive
p.000070: 95/46/EC.
p.000070:
p.000070: 4.3. Data utility
p.000070:
p.000070: Different anonymisation techniques will lead to different levels of data utility in the anonymised reports.
p.000070: Applicants/MAHs should take into consideration the impact of the data transformations/redactions on the scientific
p.000070: usefulness of the data.
p.000070:
p.000070: 4.4. Advances in technology
p.000070:
p.000070: As mentioned above, the Art. 29 WP Opinion 05/2014 on anonymisation techniques emphasises that the data controller must
p.000070: continuously follow the developments in re-identification techniques, and if necessary reassess the risk of
p.000070: re-identification. Applicants/MAHs, in accordance with national legislation on data protection, will need to take this
p.000070: aspect into consideration and to monitor continuously the development of technologies in this area in order to assess
p.000070: novel risks of re- identification for any future clinical reports published.
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 39/99
p.000070:
p.000070: 4.5. Rare diseases and small populations
p.000070:
p.000070: EMA understands the complexity involved in the anonymisation of clinical reports in the case of rare diseases and small
p.000070: populations, due to the very low number of trial participants and of overall population. Therefore, careful
p.000070: consideration should be taken in the anonymisation of the clinical reports in these instances.
p.000070:
p.000070: 5. EMA recommendations to MAHs/applicants on how best to achieve anonymisation
p.000070: 5.1. Data utility
p.000070:
p.000070: Taking into account the need to find the best balance between data utility and achieving an acceptably low risk of
p.000070: re-identification, what EMA ultimately would like to achieve is to retain a maximum of scientifically useful
p.000070: information on medicinal products for the benefit of the public while achieving adequate anonymisation. Therefore, the
...
p.000070:
p.000070: The anonymisation techniques described in this guidance are applicable only to trial participants15. Personal data in
p.000070: relation to investigators, sponsors and applicants/MAHs should be redacted as described in section 6.
p.000070:
p.000070: 5.3.1. Anonymisation criteria
p.000070:
p.000070: For clinical data, retaining the linkability of multiple records belonging to the same trial participant within the
p.000070: same document is important to understand the safety and efficacy profile of a medicinal product. In addition, inference
p.000070: is important in view of the scientific utility of the data, and emphasis should be made on the potential impact of
p.000070: inferred data on the trial participants. Therefore, since in order to achieve a maximum usefulness of the data
p.000070: published, it is unlikely that for clinical reports all three criteria can be fulfilled by any anonymisation solution,
p.000070: it is EMA’s view that a thorough evaluation of the risk of re-identification needs to be performed (see section 5.4).
p.000070:
p.000070: 5.3.2. Anonymisation techniques
p.000070:
p.000070: It should be noted that each anonymisation technique has its own strengths and weaknesses. The robustness of each
p.000070: anonymisation technique is based upon the aforementioned anonymisation criteria and will help identify the most
p.000070: suitable technique (or combination of different techniques) to establish an adequate anonymisation process for a given
p.000070: clinical report. Ultimately, the aim is to preserve data utility as much as possible whilst ensuring adequate
p.000070: anonymisation.
p.000070: Not all anonymisation techniques described in Opinion 05/2014 of the Art. 29 WP may be suitable to anonymise personal
p.000070: data in clinical reports. The specificities of the clinical data should therefore be taken into consideration when
p.000070: selecting the most appropriate technique(s).
p.000070: The simplest method of anonymisation is the removal of values for variables which allow direct or indirect
p.000070: identification of an individual from the data. This technique is sometimes called masking. Technically, it can be
p.000070: achieved by using a redaction tool which ensures that the redacted information is irreversibly blocked out. Masking of
p.000070: pre-specified variables can be done manually and/or may include the use of software that can help identifying
p.000070: pre-specified variables that need redaction. Masking of pre-specified variables is recommended. Removing entire
p.000070: sections of the report where masking is possible is not considered appropriate, and is, therefore, not recommended by
p.000070: EMA.
p.000070: Apart from masking, the main anonymisation techniques are randomisation and generalisation.
p.000070:
p.000070: Randomisation is a family of techniques that alters the veracity of the data in order to remove the strong link between
p.000070: the data and the individual. Recommended techniques include noise addition and permutation. Noise addition can consist
p.000070: of, for example, shifting dates randomly by a few days (forward or backwards), based on a uniform, or other type of,
p.000070: distribution. Permutation may have limitations as regards clinical utility as relationships between attributes can be
p.000070: destroyed. The differential privacy technique may not be applicable in the context of Policy 0070 since the same
p.000070: documents will be made available to all users.
...
p.000070: • Plasma drug concentration values and pharmacokinetic and pharmacodynamic parameters.
p.000070:
p.000070: • General information on PK/PD models, parameters and the results of the PK/PD model simulations.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 55/99
p.000070:
p.000070: • Information on scientific advice received from any Regulatory Agency during the development of the product
p.000070: related to the approved indication. It includes but it is not limited to information on the design and conduct of
p.000070: completed studies for which the results were submitted within the marketing authorisation application, timing of
p.000070: requesting/obtaining the scientific advice and the names of the Agencies that issued those scientific advices.
p.000070: Should EMA deem that any of the proposed redactions fall under the scope of the information described above the
p.000070: following rejection code would be used in the justification table:
p.000070: CCI - Rejection 03 – Disclosure due to public interest
p.000070:
p.000070: This code reads as follows:
p.000070:
p.000070: “The information proposed to be redacted is relevant for the understanding of:
p.000070:
p.000070: • the conduct of the clinical studies;
p.000070:
p.000070: • the reliability and validity of the data/research findings (data submitted for evaluation;)
p.000070:
p.000070: • the safety and efficacy profile of the product;
p.000070: • the reasoning underpinning the company claims and the opinion adopted by the CHMP and the subsequent decision of
p.000070: the European Commission, if applicable.
p.000070: EMA therefore adopts the position that there is a genuine public interest in the disclosure of this information and
p.000070: consequently it should be released.”
p.000070:
p.000070: 3.2.4. Information lacking sufficient or relevant justification – Rejection code 04 and 05
p.000070:
p.000070: The justification wording has to refer clearly to the information proposed to be redacted. It has to highlight the
p.000070: innovative features of the information in the context of the common knowledge within the specific scientific area. It
p.000070: has to indicate explicitly to which on-going development programme the proposed redaction relates. It also has to
p.000070: explain how the disclosure of the information concerned would undermine the applicant’s/MAH’s legitimate economic
p.000070: interest. If EMA considers that the level of justification is not sufficiently detailed, additional clarifications will
p.000070: be requested on an ad-hoc basis, whether formally or informally, e.g. via a telephone call. Failure to provide the
p.000070: requested clarifications within a reasonable time frame would render the available justification insufficient, as
p.000070: detailed below.
p.000070: Whenever EMA considers that the level of justification provided by the applicant/MAH is not sufficiently specific or
p.000070: too vague, the following rejection code will be used in the justification table:
p.000070: CCI – Rejection 04 – Insufficient justification
p.000070:
p.000070: This code reads as follows:
p.000070:
p.000070: “EMA has concluded that the justification is not satisfactory as it does not clearly demonstrate how the disclosure of
p.000070: this particular information would undermine the economic interest or competitive position of your company.”
...
p.000070: the CSRs are likely to contain personal data of trial participants. However, it does not exclude the
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 65/99
p.000070:
p.000070: possibility of personal data also being included in other sections or appendices of the clinical reports. Appendices of
p.000070: the clinical study report that are in scope of the Policy 0070 (protocol, protocol amendments, sample case report form,
p.000070: and documentation of statistical methods) generally do not contain personal data.
p.000070: • Describe direct and quasi identifiers in the clinical reports 26
p.000070: - Direct identifiers, e.g. patient ID
p.000070:
p.000070: - Indirect identifiers, e.g. age
p.000070:
p.000070: • De-identification
p.000070:
p.000070: Direct identifiers
p.000070:
p.000070: - Provide information on the redaction of direct identifiers, e.g. patient name, address if present in the reports
p.000070: - Regarding patient ID, provide information on whether it has been redacted or recoded and the resulting impact on
p.000070: the risk of re-identification
p.000070: Quasi (indirect) identifiers
p.000070:
p.000070: - For quasi-identifiers, provide information on the anonymisation techniques used and the rationale for using
p.000070: them.
p.000070:
p.000070: 1.2.2.1. Assessment of anonymisation
p.000070:
p.000070: As described in section 3 of the “External guidance on the anonymisation of clinical reports for the purpose of
p.000070: publication in accordance with EMA Policy 0070”, according to the Opinion 05/2014 on anonymisation techniques of the
p.000070: Article 29 Data Protection Working Party, two options are available to establish if the data is anonymised.
p.000070: One option relates to the anonymisation based on three criteria (see below Section 1.2.2.1.1); the second option refers
p.000070: to the anonymisation based on the evaluation of the re-identification risk (see below Section 1.2.2.1.2). Only one of
p.000070: the options should be followed for each clinical report, i.e. only section 1.2.2.1.1 or section 1.2.2.1.2 is to be
p.000070: completed.
p.000070:
p.000070: 1.2.2.1.1. Fulfilment of the criteria for anonymisation27
p.000070:
p.000070: The applicant/MAH confirms/demonstrates that after anonymisation of the clinical reports the three criteria described
p.000070: below have been fulfilled.
p.000070: a. No possibility to single out an individual
p.000070:
p.000070: Data presented in an aggregated manner does not usually lead to the possibility of singling out an individual. However,
p.000070: in the case of small studies with few patients it might be more likely to single out individuals and therefore this
p.000070: criterion may not be fulfilled. Individual patient data in the clinical reports can also allow singling out an
p.000070: individual, but if adequately anonymised it can be demonstrated that the possibility to single out an individual is
p.000070: remote.
p.000070:
p.000070:
p.000070: 26 PhUSE has listed direct and quasi identifiers that can be found in clinical data. This can facilitate the
p.000070: identification of variables in clinical reports (http://www.phuse.eu/Data_Transparency_download.aspx)
p.000070:
p.000070: 27 According to Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 66/99
p.000070:
p.000070:
p.000070: b. No possibility to link records relating to an individual
p.000070:
p.000070: If the patient ID is redacted from the clinical reports it is less likely to link information relating to an
p.000070: individual. A combination of quasi identifiers reported in several sections of the report could also lead to linking
p.000070: information relating to one individual.
p.000070: c. Information cannot be inferred concerning an individual
p.000070:
p.000070: The value of an additional variable concerning an individual can be inferred from a narrative that has not been
p.000070: suitably anonymised.
p.000070: [If this section has been completed and the three criteria have been met, there is no need to complete the next section
p.000070: on the risk assessment]
p.000070:
p.000070: 1.2.2.1.2. Risk assessment
p.000070:
p.000070: The aim of the risk assessment is to determine how much de-identification/anonymisation is required in order to reduce
p.000070: the risk of re-identification to an acceptable level.
p.000070: • Identification of possible adversaries and plausible attacks on the data - for public data release, adversaries
p.000070: are most likely interested in showing that an attack is possible (demonstration attack).
...
p.000070:
p.000070:
p.000070:
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p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 68/99
p.000070:
p.000070: 1.3. Template for list of documents submitted
p.000070:
p.000070: Module 2.5
p.000070:
p.000070: - document 1
p.000070:
p.000070: - doucment2
p.000070:
p.000070: Module 2.7
p.000070:
p.000070: - document 1
p.000070:
p.000070: - document 2
p.000070:
p.000070: Module 5
p.000070:
p.000070: - document 1 – [CSR1] body
p.000070:
p.000070: - document 2 – [CSR1] Appendix 16.1.1
p.000070:
p.000070: - document 3 – [CSR1] Appendix 16.1.2
p.000070:
p.000070: - document 4 – [CSR1] Appendix 16.1.9
p.000070:
p.000070: - document 5
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
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p.000070:
p.000070:
p.000070:
p.000070:
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p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 69/99
p.000070:
p.000070: 1.4. Template cover letter text: “Redaction Proposal Document” package
p.000070:
p.000070: For applications for which a CHMP opinion has been adopted
p.000070:
p.000070:
p.000070: European Medicines Agency 30 Churchill Place
p.000070: Canary Wharf London
p.000070: E14 5EU
p.000070:
p.000070:
p.000070: XX XXXX XXXX
p.000070:
p.000070:
p.000070: Dear ,
p.000070:
p.000070:
p.000070: RE: EMEA/X/X/XXXXXX/XXXX
p.000070:
p.000070: [Product INN, Company Name] Redaction Proposal Document package
p.000070: Please find enclosed the “Redaction Proposal Document” package submitted at procedural Day xxx of the initial marketing
p.000070: authorisation application/line extension application/extension of indication application (delete as appropriate) for
p.000070: [product INN]. The “Redaction Proposal Document” package is submitted in line with the European Medicines Agency policy
p.000070: on the publication of clinical data for medicinal products for human use, Policy 0070. Comprising the “Redaction
p.000070: Proposal Document” package submitted to EMA are the following, with their respective locations in the eCTD:
p.000070: • Cover letter [with annexed list of documents covering the entire Redaction Proposal sequence] (Module 1.0)
p.000070: • Clinical Overviews (Module 2.5)
p.000070:
p.000070: • Clinical Summaries (Module 2.7, Sections 2.7.1 – 2.7.4)
p.000070:
p.000070: • Clinical Study Reports – body and appendices 16.1.1, 16.1.2 and 16.1.9 (Module 5.0, Section 5.3)
p.000070:
p.000070: • Justification table for each document (uploaded as a ‘working document’)
p.000070:
p.000070: • Anonymisation Report (Module 1.9)
p.000070: <[NAME OF THE COMPANY] points out that no commercial confidential information has been identified in the entire
p.000070: “Redaction Proposal Document’’ package and, therefore, justification tables are not submitted.> [Optional text as
p.000070: applicable]
...
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 97/99
p.000070:
p.000070:
p.000070:
p.000070: Chapter 6 References
p.000070:
p.000070:
p.000070:
p.000070:
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p.000070:
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p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 98/99
p.000070:
p.000070: 1. References
p.000070: European Medicines Agency policy on publication of clinical data for medicinal products for human use (EMA/240810/2013)
p.000070: Regulation (EC) No 45/2001 of the European Parliament and of the Council on the protection of individuals with regard
p.000070: to the processing of personal data by the Community institutions and bodies and on the free movement of such data, of
p.000070: 18 December 2000.
p.000070: Directive 95/46/EC of the European Parliament and of the Council on the protection of individuals with regard to the
p.000070: processing of personal data and on the free movement of such data, of 24 October 1995.Opinion 05/2014 on anonymisation
p.000070: techniques of the Article 29 Data Protection Working Party.
p.000070: Opinion 06/2013 on open data and public sector information reuse of the Article 29 Data Protection Working Party.
p.000070: Opinion 05/2014 on anonymisation techniques of the Article 29 Data Protection Working Party.
p.000070:
p.000070: ICO (UK Data Protection Agency) Code of Practice entitled “Anonymisation: managing data protection risk”.
p.000070: Institute of Medicine, Sharing clinical trial data: Maximizing benefits, minimizing risk. Washington, DC: The National
p.000070: Academies Press, 2015.
p.000070: ICH. The common technical document for the registration of pharmaceuticals for human use. Topic E3 Structure and
p.000070: Content of Clinical Study Reports.
p.000070: ICH. The common technical document for the registration of pharmaceuticals for human use. Efficacy – M4E (R1). Clinical
p.000070: overview and clinical summary of module 2, module 5: clinical study reports.
p.000070: K. El Emam, Kald Abdallah. “De-identifying Clinical Trials Data”. Applied Clinical Trials, Mar 20, 2015.
p.000070:
p.000070: Khaled El Emam, Sam Rodgers, Bradley Malin. Anonymising and sharing individual patient data. BMJ
p.000070: 2015; 350: h1139.
p.000070:
p.000070: PhUSE De-Identification Working Group, “De-Identification Standards for CDISC SDTM 3.2,” 2015.
p.000070:
p.000070: David Carrell, Bradley Malin, John Aberdeen, et al. “Hiding in plain sight: use of realistic surrogates to reduce
p.000070: exposure of protected health information in clinical text”. J Am Med Inform Assoc 2013;20:342–348.
p.000070: European Medicines Agency policy on access to documents (related to medicinal products for human and veterinary use)
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General/Other / Relationship to Authority
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p.000068: medicinal products for human use
p.000068: EMA/90915/2016
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p.000068:
p.000068: • requested by EMA/submitted by the applicant/Marketing Authorisation Holder (MAH) as additional clinical data in
p.000068: the context of the scientific assessment process for the aforementioned situations.
p.000068: Clinical reports contained in applications where the Applicant has notified EMA of the withdrawal of the MAA are also
p.000068: published under Policy 0070.
p.000068: The effective date of Policy 0070 for all other post-authorisation procedures will be decided on by EMA at a later
p.000068: date.
p.000068: Furthermore, EMA would like to clarify a number of specific situations:
p.000068: Clinical reports submitted as part of previous/other regulatory procedures
p.000068:
p.000068: The EMA’s view is that clinical reports submitted as part of, or cross-referred to within a regulatory application will
p.000068: be subject to publication following the redaction of CCI and anonymisation of the clinical data. This includes CSRs
p.000068: previously submitted in the context of earlier regulatory procedures which form the basis of the regulatory decision
p.000068: for those applications falling in the scope of the policy. This publication is independent of who the author or party
p.000068: holding any rights to the documents may be. Any such rights remain a contractual issue between the applicant/MAH and
p.000068: any third party(ies).
p.000068: For example, according to the submission requirements laid down in Article 46 of Regulation (EC) No 1901/2006, the
p.000068: results of studies involving the use of an authorised medicinal product in the paediatric population should be
p.000068: submitted to the competent authority within six months of completion of the clinical study. As a result, these same
p.000068: studies may not be resubmitted in a regulatory procedure to add or modify a paediatric indication, but instead be
p.000068: referenced to the data submitted in the context of an earlier Article 46 procedure. In such cases, the clinical data
p.000068: submitted in the context of Article 46 of Regulation (EC) No 1901/2006 to which reference is made in a regulatory
p.000068: procedure for the addition or modification of a paediatric indication is also subject to publication under Policy 0070.
p.000068: Informed consent applications
p.000068:
p.000068: For informed consent applications where only a complete module 1 is submitted, the applicant/MAH is not expected to
p.000068: submit any document as Policy 0070 does not apply.
p.000068: Duplicate marketing authorisations
p.000068:
p.000068: In order to avoid unnecessary work EMA will accept that, in the event of duplicate marketing authorisations, the
p.000068: clinical study report submitted by the applicant/MAH will be accompanied by a statement confirming that the same set of
p.000068: documents were filed for all duplicate marketing authorisations (bearing different invented names). Provided that there
p.000068: are no differences among the clinical study reports for all the concerned duplicate products, the submission of one
p.000068: redaction proposal for all such documents would suffice. Hence, the applicant/MAH will not have to replicate submission
p.000068: for the documents pertaining to the individual marketing authorisation concerned or to the second or the third etc.
p.000068:
p.000068: 3. Definitions
p.000068:
p.000068: For the purposes of the implementation of Policy 0070 the following definitions6 will apply:
p.000068: • Aggregated data:
...
p.000068: medicinal products for human use
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p.000068:
p.000068: • Anonymisation:
p.000068: The process of rendering data into a form which does not identify individuals and where identification is not likely to
p.000068: take place.
p.000068: • Anonymised/de-identified data:
p.000068: Data in a form that does not identify individuals and where identification through its combination with other data is
p.000068: not likely to take place.
p.000068: • Applicant/MAH:
p.000068: Applicant/MAH shall mean the natural or legal person(s) or organisation(s) that submitted the clinical reports to EMA
p.000068: in the context of applications in support of centralised marketing authorisations (MAs)/post-authorisation submissions
p.000068: for existing centrally authorised medicinal products, or in support of an application for an opinion in accordance with
p.000068: Article 58 of Regulation (EC) No 726/2004, as well as any person(s) or organisation(s) who own(s) copyright or other
p.000068: intellectual property rights in the clinical reports.
p.000068: • Article 29 Data Protection Working Party (Art. 29 WP):
p.000068: The Art. 29 WP was set up under Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on
p.000068: the protection of individuals with regard to the processing of personal data and on the free movement of such data. It
p.000068: has advisory status and acts independently. It is composed of a representative of the supervisory authority(ies)
p.000068: designated by each EU country, a representative of the authority(ies) established for the EU institutions and bodies,
p.000068: and a representative of the European Commission.
p.000068: • Clinical reports:
p.000068: Clinical reports shall mean the clinical overviews (submitted in module 2.5), clinical summaries (submitted in module
p.000068: 2.7) and the clinical study reports (submitted in module 5, “CSR”) together with the following appendices to the CSRs:
p.000068: 16.1.1 (protocol and protocol amendments), 16.1.2 (sample case report form), and 16.1.9 (documentation of statistical
p.000068: methods).
p.000068: • Clinical data:
p.000068:
p.000068: Clinical data shall mean the clinical reports and IPD.
p.000068:
p.000068: • Clinical study:
p.000068:
p.000068: Clinical study shall mean any investigation in relation to humans intended to:
p.000068:
p.000068: - discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal
p.000068: products;
p.000068: - identify any adverse reactions to one or more medicinal products; or
p.000068: - study the absorption, distribution, metabolism and excretion of one or more medicinal products;
p.000068: with the objective of ascertaining the safety or efficacy of those medicinal products.
p.000068:
p.000068: • Commercially Confidential Information (CCI):
p.000068: CCI shall mean any information contained in the clinical reports submitted to EMA by the applicant/MAH which is not in
p.000068: the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the
p.000068: applicant/MAH.
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 8/99
p.000068:
p.000068: • Data:
...
p.000070: death, SAE, overall survival) at a certain single time point will not be considered per patient per visit line listing.
p.000070: Also, the Agency does not consider per patient per visit line listings those tables where parameter or outcome values
p.000070: for selected patients and selected visits are presented.
p.000070: To be noted that the same CCI, PPD and publication principles will apply to EU as well as non-EU studies in the context
p.000070: of Policy 0070.
p.000070: B. CSR Appendices
p.000070:
p.000070: 16.1 STUDY INFORMATION
p.000070:
p.000070:
p.000070: 16.1.1 Protocol and protocol amendments
p.000070:
p.000070: 16.1.2 Sample case report form (unique pages only)
p.000070: In The following CSR appendices ONLY are subject to publication: In 16.1.1 Protocol and protocol
p.000070: amendments
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 95/99
p.000070:
p.000070:
p.000070:
p.000070: Clinical Study Report (CSR) components
p.000070:
p.000070: Clinical Study Report (CSR) sections
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070: 16.1.2 Sample case report form (unique pages only)
p.000070:
p.000070: 16.1.9 Documentation of statistical methods
p.000070:
p.000070: If for a particular CSR the ICH E3 format is not followed, the corresponding information/sections (1-15) and annexes
p.000070: (16.1.1, 16.1.2, 16.1.9) will be subject to publication.
p.000070:
p.000070: 16.1.3 List of IECs or IRBs (plus the name of the committee Chair if required by the regulatory authority) -
p.000070: Representative written information for patient and sample consent forms
p.000070:
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.4 List and description of investigators and other important participants in the study, including brief (1 page)
p.000070: CVs or equivalent summaries of training and experience relevant to the performance of the clinical study
p.000070:
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.5 Signatures of principal or coordinating investigator(s) or sponsor’s responsible medical officer, depending on
p.000070: the regulatory authority's requirement
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.6 Listing of patients receiving test drug(s)/investigational product(s) from specific batches, where more than one
p.000070: batch was used
p.000070:
p.000070: Out
p.000070:
p.000070: 16.1.7 Randomisation scheme and codes (patient identification and treatment assigned)
p.000070:
p.000070: Out
p.000070: 16.1.8 Audit certificates (if available) (see Annex IVa and IVb of the guideline) Out
p.000070:
p.000070: 16.1.9 Documentation of statistical methods In
p.000070:
p.000070:
p.000070: 16.1.10 Documentation of inter-laboratory standardisation methods and quality assurance procedures if used
p.000070:
p.000070: Out
p.000070: 16.1.11 Publications based on the study Out
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070:
p.000070: Page 96/99
p.000070:
p.000070:
p.000070:
p.000070: Clinical Study Report (CSR) components
p.000070:
p.000070: Clinical Study Report (CSR) sections
p.000070:
p.000070: Scope
p.000070:
p.000070: Explanation/Clarification
p.000070: 16.1.12 Important publications referenced in the report Out
p.000070:
p.000070: 16.2. PATIENT DATA LISTINGS
p.000070:
p.000070: All appendices located under 16.2. PATIENT DATA LISTINGS Out
p.000070:
p.000070: 16.3 CASE REPORT FORMS
p.000070:
p.000070: All appendices located under 16.3 CASE REPORT FORMS Out
p.000070:
p.000070: 16.4. INDIVIDUAL PATIENT DATA LISTINGS (US ARCHIVAL LISTINGS)
...
General/Other / participants in a control group
Searching for indicator placebo:
(return to top)
p.000070: (unless it is mentioned in the context of individual patient data/case narratives and is
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 53/99
p.000070:
p.000070: deemed to constitute personal data – see “External guidance on the anonymisation of clinical reports for the purpose of
p.000070: publication in accordance with EMA policy 0070”).
p.000070: • Names of the countries where the clinical study is/was conducted (unless it is mentioned in the context of
p.000070: individual patient data/case narratives and is deemed to constitute personal data – see “External guidance on the
p.000070: anonymisation of clinical reports for the purpose of publication in accordance with EMA policy 0070”).
p.000070: • Number (how many) of study sites/research facilities were involved in the research.
p.000070: • Name of the applicant’s/MAH’s own research facility(ies) where clinical studies were conducted (e.g. phase I
p.000070: studies).
p.000070: • Name of the trial sponsor or the legal entity (CRO) that acted as the clinical trial (CT) applicant on behalf of
p.000070: the sponsor.
p.000070: • Names of all CROs and vendors involved in trial-related duties and functions (e.g. central laboratories, IVRS
p.000070: provider, image reading centres, conduct of assays).
p.000070: • Standard Operating Procedure (SOP) numbers and titles.
p.000070:
p.000070: 3.2.3.2. Quality-related information
p.000070:
p.000070: • Structural formula of active metabolite(s) and metabolic pathway(s).
p.000070: • Lot/batch numbers of the investigational products understood as either test product, active comparator or
p.000070: placebo (excluding manufacturing site(s) IDs).
p.000070: • Excipient names which usually constitute publicly available information detailed in SmPCs.
p.000070:
p.000070: • Function of excipients as such information is widely available in the public domain.
p.000070:
p.000070: • Excipient batch numbers.
p.000070: • Even if a method of measurement is selected from several available methods, the name of the method or the
p.000070: combination of methods and their general description is not CCI.
p.000070: • High level safety-related information such as a virus inactivation process, ultrafiltration (removal of
p.000070: pyrogen), and the name of a purification process or the operation of a specific material.
p.000070: • The name of a cell line or strain with genetic recombination, when it is in commercial use or already published
p.000070: (e.g. CHO cell, E. Coli K-12).
p.000070: • Standard storage and shipping conditions of blood or tissue samples such as storage temperature or duration,
p.000070: which are described in related scientific guidelines (e.g. bioanalytical methods).
p.000070: • Temperature, humidity parameters, and storage duration as applied in stability tests.
p.000070:
p.000070: 3.2.3.3. Non-Clinical-related information
p.000070:
p.000070: • Information concerning a generally-used/well-known immunohistochemistry method (e.g. ELISA/LC-MS).
p.000070: • Drug concentration measurements including results.
p.000070: • The quantification range (lower and upper quantification limits) of pharmacokinetic and pharmacology
p.000070: tests/methods.
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 54/99
p.000070:
...
Orphaned Trigger Words
p.000068:
p.000068: • Data:
p.000068: Data shall mean characteristics or information, usually numerical, that are collected through observation. The word can
p.000068: also be used to describe statistics (i.e. aggregations or transformations of raw data).
p.000068: • Data controller:
p.000068: A person who (either alone or jointly or in common with other persons) determines the purposes for which and the manner
p.000068: in which any personal data are, or are to be, processed.
p.000068: • Data linkage:
p.000068: A technique that involves bringing together and analysing data from a variety of sources, typically data that relates
p.000068: to the same individual.
p.000068: • Data mining:
p.000068:
p.000068: Activity of going through big data sets to look for relevant or pertinent information.
p.000068:
p.000068: • Data processor:
p.000068:
p.000068: An organisation that processes personal data on behalf of a data controller.
p.000068:
p.000068: • Data subject:
p.000068:
p.000068: An individual who is the subject of personal data.
p.000068:
p.000068: • Disclosure:
p.000068:
p.000068: The act of making data available to one or more third parties.
p.000068:
p.000068: • Individual patient data (IPD):
p.000068:
p.000068: IPD shall mean the individual data separately recorded for each participant in a clinical study.
p.000068:
p.000068: • Protected personal data (PPD):
p.000068: For the purpose of this guidance document the definition from Directive 95/46/EC applies: “Personal data” shall mean
p.000068: any information relating to an identified or identifiable natural person ('data subject'); an identifiable person is
p.000068: one who can be identified, directly or indirectly, in particular by reference to an identification number or to one or
p.000068: more factors specific to his physical, physiological, mental, economic, cultural or social identity.
p.000068: • Pseudonymisation:
p.000068: Consists of replacing one attribute (typically a unique attribute) in a record by another. The natural person is still
p.000068: likely to be identified indirectly. Pseudonymisation reduces the linkability of a dataset with the original identity of
p.000068: a data subject.
p.000068: • Publishing:
p.000068:
p.000068: The act of making data publicly available.
p.000068:
p.000068: • Re-identification:
p.000068: The process of analysing data or combining it with other data with the result that individuals become identifiable,
p.000068: sometimes also referred to as ‘de-anonymisation’.
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 9/99
p.000068:
p.000068: • Residual risk:
p.000068:
p.000068: The risk that remains after controls are taken into account (the net risk or risk after controls).
p.000068:
p.000068: • Risk:
p.000068:
p.000068: The probability of re-identifying a trial participant.
p.000068:
p.000068: • Study subject:
p.000068: For the purpose of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on
p.000068: clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, a ‘subject’ is defined as ‘an
p.000068: individual who participates in a clinical trial, either as a recipient of an investigational medicinal product or as a
p.000068: control’.
...
p.000068: A list of documents submitted, annexed to the cover letter. A template for this list is at Annex 1.3
p.000068: clinical overview supplement/amendment/appendix
p.000068: clinical summary supplement/amendment/appendix
p.000068: Clinical study report - body Clinical study report – Appendices
p.000068: 16.1.1 (protocol and protocol amendments)
p.000068:
p.000068: 16.1.2 (sample case report form)
p.000068:
p.000068: 16.1.9 (documentation of statistical methods).
p.000068: Anonymisation report, the report template is at Annex 1.2
p.000068: 1.0
p.000068:
p.000068:
p.000068:
p.000068: 1.0
p.000068:
p.000068:
p.000068:
p.000068: 2.5
p.000068:
p.000068:
p.000068: 2.7.1 - 2.7.4
p.000068:
p.000068:
p.000068: 5.3
p.000068:
p.000068:
p.000068: 5.3
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: 1.9
p.000068: Not published
p.000068:
p.000068:
p.000068:
p.000068: Not published
p.000068:
p.000068:
p.000068:
p.000068: Published
p.000068:
p.000068:
p.000068: Published
p.000068:
p.000068:
p.000068: Published Published
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: Published
p.000068:
p.000068: If any of the parts of the Final Redacted document package, set out Table 2 above, including the cover letter is not
p.000068: submitted, the whole package will be rejected. In that case, a corrected complete package must be submitted. Individual
p.000068: parts cannot be submitted separately to correct submission deficiencies.
p.000068:
p.000068: Anonymisation report
p.000068:
p.000068: The submitted anonymisation report has to describe the methodology of the anonymisation applied in each of the clinical
p.000068: reports in the Final Redacted version. The report should also describe how the risk of re-identification has been
p.000068: measured and managed, or if the three criteria for anonymisation have been fulfilled. A template anonymization report
p.000068: can be found at Annex 1.2 of this guidance, setting out the content and structure requirements.
p.000068: The anonymisation report must be uploaded by applicant/MAH in PDF format with the filename format of
p.000068: ‘clinicaltrials-anonymisation_report-TRADENAME.pdf’ where Trade Name is the name of the medicinal product.
p.000068:
p.000068: 3.3.3.4. Technical requirements for the preparation of the final redacted version of clinical reports
p.000068:
p.000068: The applicant/MAH must prepare a Final Redacted version of their clinical reports, as part of the Final Redacted
p.000068: document package, using a redaction tool. In order to support the watermarking and
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 30/99
p.000068:
p.000068: publication process, the Final Redacted Version of the documents must fulfil technical requirements compared to the
p.000068: Redaction Proposal version. The Final Redacted version of the clinical reports must adhere to the requirements outlined
p.000068: below:
p.000068: • With regards to PDF formats submitted within the eCTD, the current eCTD specification applies. PDF versions
p.000068: 1.4-1.7 are currently accepted.
p.000068: • The size of the PDF files should not exceed 200 Mbyte each as a best practice rule.
p.000068:
p.000068: • The PDF files must not be password protected, as EMA will add a watermark to every page.
p.000068: • The un-redacted text only must be text-searchable. Redacted text and the blackened redaction box (that covers
...
p.000068: encourages that the Transferor and Transferee exchange information on the agreements, submissions or declarations made
p.000068: between the Transferor and EMA under the scope of the Policy 0070 publication process.
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000068: medicinal products for human use
p.000068: EMA/90915/2016
p.000068: Page 34/99
p.000068:
p.000068: Chapter 3
p.000068:
p.000068: External guidance on the anonymisation of clinical reports for the purpose of publication in accordance with EMA Policy
p.000070: 0070
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 35/99
p.000070:
p.000070:
p.000070: 1. Introduction
p.000070: Policy 0070 states that adequate personal data protection needs to be ensured and that full compliance with applicable
p.000070: EU legislation needs to be achieved. Furthermore, the processing of personal data and its publication on the website
p.000070: by EMA is subject to the provisions of Regulation (EC) No 45/2001 and in particular is limited only to information that
p.000070: is adequate, relevant and not excessive for the purpose of transparency. It is important to recall that no personal
p.000070: data of trial participants10 should be published.
p.000070: The objective of this chapter is to provide information to the pharmaceutical industry on the anonymisation of clinical
p.000070: reports in the context of the implementation of phase 1 of EMA Policy 0070,
p.000070: i.e. publication of clinical reports on EMA’s website. The information contained in this guidance document should be
p.000070: considered as EMA recommendations to MAHs/applicants on how best achieve anonymisation.
p.000070: The current guidance provides information on some of the anonymisation techniques that are available to
p.000070: MAHs/applicants. The field of anonymisation, i.e. the techniques used by controllers of personal data to anonymise
p.000070: data, is a field of active research and rapidly evolving. This guidance is not intended to provide an exhaustive list
p.000070: of the techniques available or to mandate a specific methodology but rather to highlight to MAHs/applicants the
p.000070: anonymisation process to be followed to ensure that clinical reports submitted to EMA for publication are rendered
p.000070: anonymous prior to publication. The guideline will be updated in light of new developments.
p.000070: This guidance document is without prejudice to the obligations of pharmaceutical companies as controllers of personal
p.000070: data under applicable national legislation on the protection of personal data.
p.000070:
...
p.000070: populations, due to the very low number of trial participants and of overall population. Therefore, careful
p.000070: consideration should be taken in the anonymisation of the clinical reports in these instances.
p.000070:
p.000070: 5. EMA recommendations to MAHs/applicants on how best to achieve anonymisation
p.000070: 5.1. Data utility
p.000070:
p.000070: Taking into account the need to find the best balance between data utility and achieving an acceptably low risk of
p.000070: re-identification, what EMA ultimately would like to achieve is to retain a maximum of scientifically useful
p.000070: information on medicinal products for the benefit of the public while achieving adequate anonymisation. Therefore, the
p.000070: aim of this guidance is to assist pharmaceutical companies in achieving this objective by recommending methodologies
p.000070: and a process that could be applied to clinical reports.
p.000070: The guidance is not intended to mandate any specific methodology but to highlight to applicants/MAHs the available
p.000070: techniques and those that EMA considers most relevant in the context of the anonymisation, to ensure that clinical
p.000070: reports submitted to EMA for publication are rendered anonymous prior to publication. However, the choice of
p.000070: anonymisation techniques to use, while retaining a maximum of scientifically useful information, is left up to the
p.000070: company.
p.000070: It is up to the pharmaceutical company, taking due account of the ultimate purpose and use of the clinical reports,
p.000070: i.e. publication in EMA’s website, and on the basis of the guidance made available to decide which option to use, i.e.
p.000070: demonstrate that after anonymisation all three criteria are fulfilled (singling out, linkability and inference) or to
p.000070: perform a risk assessment.
p.000070: EMA understands that in an initial phase redaction techniques are likely to be used by applicants/MAHs, taking into
p.000070: account that for a certain period, pharmaceutical companies will have to anonymise their data retrospectively (reactive
p.000070: data anonymisation), i.e. after the clinical report has already been submitted for scientific review. Importantly,
p.000070: redaction alone is more likely to decrease the clinical utility of the data compared to other techniques.
p.000070: Therefore, EMA is of the view that applicants/MAHs, after experience has been accumulated in the de- identification of
p.000070: clinical reports, should transition to other anonymisation techniques that are more favoured in order to optimise the
p.000070: clinical usefulness of the data published (proactive data anonymisation). Pharmaceutical companies are encouraged to
p.000070: use these anonymisation techniques as soon as possible, whilst ensuring data anonymisation is achieved.
p.000070:
p.000070: 5.2. Rare diseases, small populations and low frequency events
p.000070:
p.000070: Clinical trials conducted on rare diseases and on small populations may have a high risk of re- identification.
p.000070: Therefore, specific attention should be given to these scenarios. Measuring the risk of re- identification and a
p.000070: thorough risk assessment should be performed in these cases and anonymisation of the data should be adapted to the
p.000070: identified risk. In addition, a quantitative approach to the measurement of the risk of re-identification should be
p.000070: favoured (see Section 5.4). This approach is also applicable to genetic information and low frequency events (e.g. rare
p.000070: events, extreme values, unusual treatments, pregnancy outcomes).
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
p.000070: Page 40/99
p.000070:
p.000070: 5.3. Specific recommendations to MAHs/applicants for the anonymisation of personal data of trial participants
p.000070:
p.000070: The anonymisation techniques described in this guidance are applicable only to trial participants15. Personal data in
p.000070: relation to investigators, sponsors and applicants/MAHs should be redacted as described in section 6.
p.000070:
p.000070: 5.3.1. Anonymisation criteria
p.000070:
p.000070: For clinical data, retaining the linkability of multiple records belonging to the same trial participant within the
p.000070: same document is important to understand the safety and efficacy profile of a medicinal product. In addition, inference
p.000070: is important in view of the scientific utility of the data, and emphasis should be made on the potential impact of
p.000070: inferred data on the trial participants. Therefore, since in order to achieve a maximum usefulness of the data
p.000070: published, it is unlikely that for clinical reports all three criteria can be fulfilled by any anonymisation solution,
p.000070: it is EMA’s view that a thorough evaluation of the risk of re-identification needs to be performed (see section 5.4).
p.000070:
p.000070: 5.3.2. Anonymisation techniques
p.000070:
p.000070: It should be noted that each anonymisation technique has its own strengths and weaknesses. The robustness of each
...
p.000070: electronic datasets and allow the anonymisation of the copy of the CSR for publication using the underlying clinical
p.000070: data which has already been anonymised. This may facilitate the anonymisation process and maximise the information
p.000070: included in the copy of the CSR anonymised for publication. It does not mean that anonymisation will take place before
p.000070: the scientific review of the data for the purposes of the clinical trial and marketing authorisation assessment. None
p.000070: of these processes should undermine the submission of the full, pseudonymised clinical reports and underlying data.
p.000070: Most importantly, it needs to be demonstrated that these techniques can ensure that the risk of re-identification is
p.000070: acceptably low and in line with requirements for public disclosure and that the data transformation resulting from the
p.000070: applied anonymisation techniques will not lead to a different interpretation of the study results.
p.000070:
p.000070: 5.3.2.1. Anonymisation of Direct Identifiers
p.000070:
p.000070: Direct identifiers are elements that permit direct recognition or communication with the corresponding individuals.
p.000070: Direct identifiers generally do not have data utility, with the exception of the patient ID.
p.000070: Clinical reports submitted to EMA mostly consist of pseudonymised aggregated data and therefore it is unlikely that
p.000070: direct identifiers are present in the reports. Nonetheless, any direct identifiers still present should be redacted,
p.000070: e.g. name, email, phone number, signature and full address. Patient ID numbers (including randomization/treatment
p.000070: number or safety case ID) can be either redacted or recoded.
p.000070: Recoding or pseudonomysing direct identifiers have been demonstrated to reduce the risk of re- identification16.
p.000070: However, having a pseudonym means that information for the same individual can be linked which is likely to increase
p.000070: the risk of re-identification. On the other hand, the value of the data is significantly reduced where the ability to
p.000070: follow a patient across visits and events is broken. The risk of linking the information for the same individual can be
p.000070: measured and net effect on risk can be determined. A decision on whether to redact or recode patient ID should be made
p.000070: on a case-by-case basis based on the impact on the risk. Moreover, it should also be considered that for any extension
p.000070: to the initial marketing authorisation application study, the same patients will be recoded differently from the
p.000070: initial marketing authorisation study. EMA recognises that in such situations data utility may be suboptimal since this
p.000070: creates a problem of linkability between the initial study and the extension study.
p.000070:
p.000070: 5.3.2.2. Anonymisation of Quasi Identifiers
p.000070:
p.000070: Quasi identifiers are variables representing an individual’s background information that can indirectly identify
p.000070: individuals. Unlike direct identifiers, information from quasi identifiers increases the scientific usefulness of the
p.000070: information published. Geographical location is an important variable since clinical practice can vary from country to
p.000070: country and this can impact on the outcome. Relative dates relating to individual patients are also important due to
p.000070: the potential impact on the outcome of the trial. Patient
p.000070:
p.000070:
p.000070: 16 David Carrell, Bradley Malin, John Aberdeen, et al. “Hiding in plain sight: use of realistic surrogates to reduce
p.000070: exposure of protected health information in clinical text”. J Am Med Inform Assoc 2013;20:342–348.
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
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p.000070:
...
p.000070: identity of individuals19. It is therefore important to protect the quasi identifiers as well as the direct
p.000070: identifiers.
p.000070: Classification of variables into categories of personal data
p.000070:
p.000070: There are three conditions for a variable to be considered an identifier (direct or quasi), i.e. replicability (the
p.000070: variable values must be sufficiently stable over time so that the values will occur consistently in relation to the
p.000070: data subject), distinguishability (the variable must have sufficient variability to distinguish among individuals in
p.000070: the data) and knowability (an adversary must know the identifiers about the data subject in order to re-identify them).
p.000070: If a variable is not knowable by an adversary, it cannot be used to launch a re-identification attack on the data (see
p.000070: below for further details on adversaries and attacks).
p.000070:
p.000070: 17 PhUSE De-Identification Working Group, “De-Identification Standards for CDISC SDTM 3.2,” 2015.
p.000070: 18 Institute of Medicine (IOM). 2015. Sharing clinical trial data: Maximizing benefits, minimizing risk. Washington,
p.000070: DC: The National Academies Press. Appendix B.
p.000070: 19 BMJ 2015; 350: h1139 Anonymising and sharing individual patient data.
p.000070:
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p.000070: medicinal products for human use
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p.000070:
p.000070: Once a variable has been determined to be an identifier it is necessary to establish whether it should be classified as
p.000070: a direct identifier or a quasi-identifier. This is important because the techniques used to protect direct identifiers
p.000070: are different from those used for quasi identifiers.
p.000070: PhUSE has defined a set of rules developed to facilitate the assessment of direct and quasi identifiers in the data.
p.000070: These rules help pharmaceutical companies to establish the various categories of personal data that can be found in the
p.000070: clinical reports.
p.000070: 2. Identification of possible adversaries and plausible attacks on the data
p.000070:
p.000070: For public data release, adversaries are most likely interested in showing that an attack is possible (demonstration
p.000070: attack). The following potential scenarios of re-identification can be conceived in the context of the publication of
p.000070: clinical trial data:
p.000070: • An organisation sees a financial interest in finding out who are the trial participants in the clinical trial.
p.000070: Usually it would require some strategy to identify accurately a fair number of trial participants
p.000070: • One trial participant is of particular public interest and is focussed on by the press or other body
p.000070: • A group or individual, possibly for academic reasons, in order to embarrass the data controller, or to undermine
p.000070: the public support for release of data, wishes to identify just one trial participant without regard to which trial
p.000070: participant it might be
p.000070: • A random event in which an individual happens to examine a report including data on a trial participant with
p.000070: whom they are well acquainted to the extent that they can accurately guess that certain information relates to that
p.000070: trial participant.
p.000070: Each of the scenarios described above reflect possible adversaries and plausible attacks, having different risk
p.000070: implications. Applicants/MAHs should identify possible adversaries and plausible attacks on the data and evaluate the
p.000070: impact on the risk of re-identification.
p.000070: 3. Data utility considerations
p.000070:
p.000070: This is an important requirement that MAHs/applicants need to consider carefully when selecting the anonymisation
p.000070: methodology. If anonymisation of the data results in clinical reports that are no longer useful for their intended
p.000070: secondary purposes, data utility is compromised. Furthermore, anonymisation of clinical reports results in the data
p.000070: being perturbed in some way. Ensuring that the analysis results produced after anonymisation are similar to the results
p.000070: that would be obtained from the original clinical reports is critical. Therefore, the amount of distortion should be
p.000070: minimised. Ultimately, a balance must be reached in order to obtain an acceptably low probability of re-identification
p.000070: and a high utility data.20
p.000070: 4. Determining the risk of re-identification threshold and evaluation of the actual risk of re- identification
p.000070: Measuring the risk of re-identification involves selecting an appropriate risk metric, a suitable threshold and the
p.000070: actual measurement of the risk in the clinical data information to be disclosed. The choice of a metric depends on the
p.000070: context of data release. For public release it is advisable to use the maximum risk.
p.000070: Setting an acceptable threshold encompasses evaluation of the existing mitigation controls (none in the context of
p.000070: public disclosure), the extent to which a particular disclosure would be an invasion of privacy to the trial
p.000070: participant and the motives and the capacity of the attacker to re-identify the
p.000070:
p.000070: 20K. El Emam, Kald Abdallah. “De-identifying Clinical Trials Data”. Applied Clinical Trials, Mar 20, 2015.
p.000070:
p.000070:
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p.000070: medicinal products for human use
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p.000070:
p.000070: data. Once a threshold has been determined, the actual probability of re-identification can be measured. If the
p.000070: probability is higher than the threshold, anonymisation of the data needs to be performed. Otherwise, the data can be
p.000070: considered to have a very small risk of re-identification and to be fully anonymised.
p.000070: Based on the recommendations made in the IOM report and the available precedents for public release of health data, EMA
p.000070: believes that it is advisable to set the threshold to a conservative level of 0.09. However, it is up to the
p.000070: applicant/MAH to decide on the most appropriate threshold for public disclosure of the clinical reports at stake, and
p.000070: if a different threshold is selected a justification shall be provided.
p.000070: The most appropriate way to measure the risk of re-identification for an entire dataset, in the context of public
p.000070: disclosure, is through the maximum risk, which corresponds to the maximum probability of re-identification across all
p.000070: records.
p.000070: Further information about the methodology to calculate the risk of re-identification is available in the literature,
p.000070: such as for instance that the probability of re-identification of a record in a data set is 1 divided by the frequency
p.000070: of trial participants with same category/value of a set of the quasi identifiers (group size).
p.000070: It is acknowledged that initially anonymisation will involve reactive data anonymisation where the assessment of risk
p.000070: of re-identification may be mostly qualitative. The approach to be taken in the case of a qualitative risk assessment
p.000070: is very similar to that of a quantitative approach, the difference being that rather than having a probability and
p.000070: measure of the risk as numerical values there is instead a qualitative scale (e.g. high, medium, low risk).
p.000070: Applicants/MAH are encouraged to use quantitative methods to measure the risk of re- identification as soon as they are
p.000070: in a position to do so.
p.000070: Applicants/MAH may not follow, in an initial phase, an analytical approach, and therefore it will not be necessary to
p.000070: calculate the risk of re-identification. In such cases step 4 of the anonymisation process could be omitted.
p.000070: 5. Anonymisation methodology
p.000070:
p.000070: Applicants/MAH should identify the most suitable technique (or combination of different techniques) to establish an
p.000070: adequate anonymisation process and should describe how they reduce the risk of re-identification. In addition,
p.000070: justification should be provided for the data that is altered and the choice of anonymisation techniques used.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
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p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
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p.000070: medicinal products for human use
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p.000070:
p.000070:
p.000070: 6. Documenting the anonymisation methodology and process
p.000070:
p.000070: Documenting the methodology used is an important step as it provides information not only on the techniques that have
p.000070: been used to anonymise the data but also the rationale for using them. It should also be described how the clinical
p.000070: reports have been rendered anonymous either by measuring and managing the risk of re-identification, or by
p.000070: demonstrating that the three criteria for anonymisation have been fulfilled.
p.000070:
p.000070: 5.5. Reporting on the anonymisation process
p.000070:
p.000070: The anonymisation methodology used by applicants/MAHs must include a way of demonstrating adequate anonymisation of the
p.000070: reports and have a repeatable process to follow. The methods and outcome of the anonymisation process must be
p.000070: documented.
p.000070: Applicants/MAHs should therefore describe the anonymisation process followed in an anonymisation report. In addition,
p.000070: the report should describe how the risk of re-identification has been measured and managed, or if the three criteria
p.000070: for anonymisation have been fulfilled.
p.000070: As recommended by the Art. 29 WP, data controllers should disclose the anonymisation technique(s) being implemented in
p.000070: the case of public release of the anonymised data. Therefore, the anonymisation report will be published by EMA,
p.000070: together with the clinical reports.
p.000070:
p.000070: 6. Redaction of personal data of investigators, sponsor staff and applicant/MAH staff
p.000070: Personal data of individuals other than patients, i.e. investigators, sponsor staff and applicant/MAH staff will not be
p.000070: published with the following exceptions:
p.000070: • The sponsor and coordinating investigator signatories of the clinical study report and the identities of the
p.000070: investigator(s) who conducted the trial and their sites.
p.000070: However, their contact details and signature should be redacted. Personal data relating to all other clinical study
p.000070: personnel should also be redacted. Data pertaining to the above exceptions in other parts of the CSR will be redacted
p.000070: as they may give away geographical information (e.g. site number, site address, investigator names) that could be
p.000070: linked to patients and hence may enable their identification.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
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p.000070: medicinal products for human use
p.000070: EMA/90915/2016
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p.000070:
p.000070: Chapter 4
p.000070:
p.000070: External guidance on the identification and redaction of commercially confidential information in clinical reports
...
p.000070:
p.000070: If the patient ID is redacted from the clinical reports it is less likely to link information relating to an
p.000070: individual. A combination of quasi identifiers reported in several sections of the report could also lead to linking
p.000070: information relating to one individual.
p.000070: c. Information cannot be inferred concerning an individual
p.000070:
p.000070: The value of an additional variable concerning an individual can be inferred from a narrative that has not been
p.000070: suitably anonymised.
p.000070: [If this section has been completed and the three criteria have been met, there is no need to complete the next section
p.000070: on the risk assessment]
p.000070:
p.000070: 1.2.2.1.2. Risk assessment
p.000070:
p.000070: The aim of the risk assessment is to determine how much de-identification/anonymisation is required in order to reduce
p.000070: the risk of re-identification to an acceptable level.
p.000070: • Identification of possible adversaries and plausible attacks on the data - for public data release, adversaries
p.000070: are most likely interested in showing that an attack is possible (demonstration attack).
p.000070: • Evaluate the risk of re-identification
p.000070:
p.000070: - Choose qualitative or quantitative approach and provide justification
p.000070:
p.000070: - Set threshold
p.000070:
p.000070: ✓ qualitative: low; justify the selected level
p.000070:
p.000070: ✓ quantitative: numerical value; justify the selected threshold
p.000070:
p.000070: - List variables that will be used for the risk calculation
p.000070:
p.000070: ‒ Calculate risk
p.000070:
p.000070: ✓ qualitative: calculate the level of risk (e.g. high, medium, low) based on the characteristics of the source data
p.000070: (e.g. prevalence of the disease, trial sample size, number of sites)
p.000070: ✓ quantitative: calculate the probability of uniquely identifying an individual
p.000070:
p.000070: - Check that the re-identification risk is lower than the pre-defined threshold
p.000070: - De-identify data until the risk of re-identification is lower than the set threshold. De- identification can be
p.000070: an iterative process until anonymisation of the data is reached.
p.000070: [If the applicant/MAH decides to perform a risk assessment, there is no need to complete section 1.2.2.1.1]
p.000070:
p.000070: 1.2.3. Data utility considerations
p.000070:
p.000070: A balance must be reached in order to obtain an acceptably low risk of re-identification and high utility data, taking
p.000070: into consideration that the protection of personal data is of paramount importance.
p.000070: Applicants/MAHs should state that they have carefully considered the impact of the anonymisation methodology used on
p.000070: data utility.
p.000070:
p.000070: External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for
p.000070: medicinal products for human use
p.000070: EMA/90915/2016
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p.000070:
p.000070: 1.2.4. Conclusion
p.000070:
p.000070: On the basis of the information provide above, there should be evidence that the re-identification risk, after the data
p.000070: has been anonymised, is below the pre-defined threshold, or that the three criteria listed under 1.2.2.1.1 have been
p.000070: fulfilled.
p.000070: [NAME OF THE COMPANY] declares the anonymisation report has been prepared following the guidance made available by EMA,
p.000070: and the anonymisation techniques have been applied consistently in the preparation of the documents comprising the
p.000070: Redaction Proposal Version.
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
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p.000070:
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p.000070: medicinal products for human use
p.000070: EMA/90915/2016
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p.000070:
p.000070: 1.3. Template for list of documents submitted
p.000070:
p.000070: Module 2.5
p.000070:
p.000070: - document 1
p.000070:
p.000070: - doucment2
p.000070:
p.000070: Module 2.7
p.000070:
p.000070: - document 1
p.000070:
p.000070: - document 2
p.000070:
p.000070: Module 5
p.000070:
p.000070: - document 1 – [CSR1] body
p.000070:
p.000070: - document 2 – [CSR1] Appendix 16.1.1
p.000070:
p.000070: - document 3 – [CSR1] Appendix 16.1.2
p.000070:
p.000070: - document 4 – [CSR1] Appendix 16.1.9
p.000070:
p.000070: - document 5
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
...
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| access | Access to Social Goods |
| age | Age |
| authority | Relationship to Authority |
| children | Child |
| drug | Drug Usage |
| ethnicity | Ethnicity |
| family | Motherhood/Family |
| healthy volunteers | Healthy People |
| influence | Drug Usage |
| officer | Police Officer |
| opinion | philosophical differences/differences of opinion |
| party | political affiliation |
| placebo | participants in a control group |
| property | Property Ownership |
| race | Racial Minority |
| single | Marital Status |
| substance | Drug Usage |
| union | Trade Union Membership |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| drug | ['influence', 'substance'] |
| influence | ['drug', 'substance'] |
| substance | ['drug', 'influence'] |
Trigger Words
capacity
consent
cultural
harm
justice
protect
protection
risk
sensitive
Applicable Type / Vulnerability / Indicator Overlay for this Input