INSTRUCTIONS ON THE METHOD OF SAFETY REPORTING WITHIN THE CLINICAL TEST
This guide defines how to collect, check, and report adverse events and adverse events
(side effects) that occur in clinical trials.
METHOD OF NOTIFYING TESTING ORDERS FROM RESEARCHERS ABOUT ADVERSE EVENTS AND SERIOUS ADVERSE
EVENTS
Adverse event is an adverse event that occurred during the period of drug administration and for which a cause-and-effect relationship with
the use of the drug does not have to be proven. Unwanted experience is any unintended and unwanted sign
(eg, abnormal laboratory findings), a symptom or disease, temporally associated with the administration of the drug.
A serious adverse event1 is an adverse event that results in death, immediate life threat,
disability, hospital treatment, extension of existing hospital treatment, congenital anomalies, or defect
discovered at birth, or requires intervention to prevent the aforementioned consequences.
The researcher records and records adverse events or laboratory abnormalities that are planned for the clinical setting
tests listed as crucial to the safety assessment and shall be reported to the contracting authority
in accordance with the notification requirements and within the time limits set by the clinical trial plan.
The researcher records and records all adverse events unless otherwise provided by the clinical plan
testing. The researcher informs the research client of any serious adverse events that occur
to the respondent treated by the investigator during the clinical trial, unless otherwise provided by the plan
clinical trial.
The researcher informs the client without undue delay and within 24 hours of finding out about them
trials on serious adverse events, unless, for specific adverse events, a clinical plan
no urgent reporting was found to be necessary. If necessary, the researcher shall send to the client
a follow up report to enable the testing contractor to determine if it is affected
a serious adverse event on the benefit-risk relationship of the clinical trial.
1 These consequences must be taken into account at the time of the event. For example, in relation to a life-threatening event, it does
refers to an event in which the respondent was at risk of death at the time of the event; it does not refer to an event that
it can hypothetically cause death if it is more severe.
In cases where reporting is not required immediately, the investigator shall submit the report as appropriate
of the timeframe, taking into account the specifics of the trial and the severity of the adverse event, according to
the deadlines set out in the protocol or booklet for researchers.
After completing the clinical trial, the researcher should not actively monitor the subjects he / she treated at
with respect to adverse events, unless otherwise specified in the clinical trial plan.
If the researcher detects serious adverse events that may be causally related to the drug used in
clinical trial, and occur after the end of the clinical trial in the subjects treated by the researcher,
the investigator informs the trial client of a serious adverse event without undue delay.
The test client shall keep detailed records of all adverse events investigated by the investigator
informed.
ADVERSE REACTIONS OF THE MEDICINAL PRODUCT AND ASSESSMENT OF THE INCURRENCE, CAUSATION AND EXPECTATION
A side effect (side effect) of a drug is any adverse and unintentionally triggered reaction that may occur with
therapeutic dose of the drug. The definition also covers errors in the administration of the drug and the use of the drug beyond the scope of what
is provided for in the clinical trial plan, including misuse and misuse of the product.
A serious side effect (side effect) of a drug is a harmful and inadvertently triggered reaction to
medicine resulting in death, immediate life threatening, disability, hospital treatment (if not
either necessary), extension of hospital treatment or congenital anomaly, or birth defect.
An unexpected side effect (side effect) of a drug is that of a drug whose nature,
weight2 or outcome are not known or described in the Summary of Product Characteristics or in the Research Leaflet for
drugs that are in clinical trials and cannot be expected based on known pharmacological properties of the drug.
It is the responsibility of the test client to ensure that all reported adverse events are cumulative,
- have a reasonable possibility of causation with the product under test (IMP)
- are "serious" and
- are "unexpected".
2 The term “weight” is used here to describe the intensity of a particular event. This should be different from the term
"Serious."
ASSESSMENT OF THE INCIDENCE
An assessment of whether an event is serious is usually made by the investigator's rapporteur.
CAUSATION ASSESSMENT
In determining whether an adverse event is a side effect, consideration is given to whether there is a viable possibility
establishing a causal link between the event and the investigational drug based on an analysis of the available evidence.
The assessment of whether there is a reasonable possibility of a causal relationship is usually made by the researcher.
In the absence of information provided by the investigator-rapporteur on causality, the investigator shall consult
with the investigating rapporteur and encourages him to express his views on the matter. Investigator
does not diminish the value of the causality assessment given by the researcher. If the contracting authority does not agree with
the investigator's causality assessment reports the unexpected serious side effects of both.
ASSESSMENT / EXPECTATION ASSESSMENT
When determining whether an adverse event is unexpected, it considers whether the event adds significant information about
specificity, increase in frequency or severity of a known serious adverse reaction that has already been documented.
The expectation of adverse effects is determined by the client of the test in the reference safety information.
Expectancy is determined on the basis of previously observed events with the active substance and not on the basis of expected events
pharmacological properties of the drug or events related to the respondent's disease.
The safety reference information provided in the Product Features Summary (SmPC) or brochure for
researchers (IB). A cover letter indicates where the reference safety information is located
within the documentation regarding the request. Investigator of the test as a reference security
the information selects the summary of product characteristics that is most appropriate for safety
respondents.
Reference safety information may change during the conduct of a clinical trial. For reporting purposes
of the unexpected serious side effects the version of the reference safety information that is
valid at the time of the occurrence of unexpected serious adverse reactions. Therefore, changing the security reference
the information influences the number of side effects to be reported as suspected unexpected serious side effects.
The expectation assessment is usually done by the contracting authority. If the investigating rapporteur has provided
expectation information, the contracting authority shall take them into account.
METHOD OF NOTIFICATION OF THE AGENCY AND ETHICAL COMMITTEES BY THE CONTRACTING AUTHORITY ABOUT SUSPECTING Unexpected DANGEROUS
SIDE EFFECTS
06.35 Suspected Unexpected Serious Adverse Reactions -SUSAR
The client of the clinical trial conducted in BiH submits all relevant information on
suspects the following unexpected serious side effects:
• any suspected unexpected serious adverse reactions to the investigational drugs that occur
during that clinical trial;
• any suspected unexpected serious side effects associated with the same active substance, regardless of
pharmaceutical form and strength or indication under investigation, u
investigational drug and occurring in a clinical trial conducted (exclusively) outside BiH, if clinical
testing commissioned by:
- that client; or
- different client who is part of the same parent company as the client clinical
trials, or who jointly develops a drug with the clinical trial client3
on the basis of a formal agreement;
• any suspected unexpected serious side effects of the study drug that occur in any of the subjects in
the clinical trial, to be determined or to be seen by the client at the end of the clinical trial.
Deadline for notifying the Agency and the Ethics Committees of suspected unexpected
The serious side effect was determined depending on the severity of the side effect and amounts to:
a) in the case of life-threatening or life-threatening suspicion, of unexpected serious adverse reactions occurring during that period;
clinical trial in BiH as soon as possible and in any case not later than seven days after
the client learns of a side effect; if necessary, ensure timely reporting, the contracting authority
may submit an initial incomplete report followed by a full follow-up report,
within eight days at the latest;
b) in the case of non-lethal SUSARs or suspected unexpected serious, non-life-threatening side effects which
occur during that clinical trial in BiH, not later than 15 days after the client becomes aware of a side effect;
c) in case of suspected unexpected serious adverse reactions occurring during that clinical trial in
BiH, which were initially considered non-lethal and life-threatening and turned out to be deadly or
life-threatening, as soon as possible, and in any case not later than seven days after
the client learns that the side effect is deadly or life-threatening;
d) in case of suspected unexpected serious adverse reactions occurring during that clinical trial outside
BiH, even in case of suspected unexpected serious side effects related to the same active substance, regardless
to pharmaceutical form and strength or
3 Obtaining the investigational drug or safety information to a prospective potential marketing authorization holder
marketing is not considered a joint development.
the indication being investigated, in the investigational drug, and which appear in the clinical trial being conducted
(exclusively) outside BiH, if the clinical trial was commissioned by that client or by a different client
of the same parent company, the client of the clinical trial is obliged to the Agency at least once every six months
to submit a linear list of all SUSARs for the observed period, with the accompanying clinical client report
examinations on major security issues.
SUSAR MONITORING REPORT
If the initial report of suspected unexpected serious adverse reactions (fatal or life-threatening) is incomplete, (at
example: if the contracting authority did not provide all the information within seven days), the contracting authority within
an additional eight days submit a full report based on initial information.
The countdown for submission of the initial report (day 0 = Di 0) starts as soon as the contracting authority receives it
information containing minimum reporting criteria.
If the trial contractor receives significant new information on a case already recorded,
the countdown starts again from zero, that is, when the new information is received. This information is provided in
follow-up report within 15 days.
If the initial report of suspected unexpected serious adverse reaction initially considered to be
not deadly or life-threatening, but turned out to be deadly or life-threatening,
incomplete, it should be reported as soon as possible, but within seven days of learning that the side effect is
deadly or life-threatening. The contracting authority shall submit a completed report within an additional eight days.
In cases where SUSAR, which was initially considered not to be life-threatening or life-threatening, turns out to be
lethal or life-threatening, a joint report shall be drawn up if the initial report has not yet been submitted.
DETERMINING THE IDENTITY OF THE ALLOCATED TREATMENT
The researcher discovers the identity of the assigned treatment of the subjects while conducting the clinical
examinations only if identity disclosure is relevant to the respondent's safety.
When reporting to the Agency and the Ethics Committees on SUSAR, the client reveals the identity of the treatment
assigned to the respondents to whom SUSAR refers.
If there is a possible suspicion of an unexpected serious side effect, only the contracting authority shall disclose
identity only for that respondent. The drug still remains masked to other persons responsible for
continuous conduct of clinical trials (such as administration, monitors,
researchers) and those persons responsible for analyzing the data and interpreting the results after completion
clinical trial, such as biometric personnel.
The information disclosed is available only to those persons who are required to participate in the security reporting to the
clinical trials or persons who continuously perform safety assessments during the clinical trial.
However, if for clinical trials conducted in diseases with high morbidity or high
mortality, where the ultimate indicators of efficacy could also be the suspicion of unexpected serious side effects, or
when the ultimate indicator of clinical trial effectiveness is death or other
A "serious" outcome (which could potentially be reported as suspected unexpectedly serious
side effect), systematic disclosure of the identity of the study drug could compromise the integrity of the clinical
testing. In these and similar circumstances, the trial client points out in the clinical trial plan which ones are serious
events should be treated as disease-related and not susceptible to systematically revealing the identity of the subject
drug and accelerated reporting.
If, after discovering the identity of an investigational drug for an event, it turns out to be SUSAR, the rules apply
for reporting suspected unexpected serious side effects.
SUSAR RELATED TO ACTIVE COMPARATOR OR PLACEBO
Comparators and placebo are IMPs. Therefore, the same requirements for SUSARs associated with an active comparator apply
reporting as for the IMP test. Placebo-related events do not usually meet the criteria for SUSAR
and thus for emergency reporting. However, where SUSARs are associated with placebo (eg reaction due to ancillary
substance or impurity), the contracting authority should report such cases.
ANNUAL REPORTING OF SAFETY TENDERER
With regard to the medicines tested (except for placebo), the study sponsor is obliged to submit annually
a report to the Agency and the Ethics Committees on the safety of each study drug used in the clinical trial
to which he is the client.
In the case of a clinical trial involving the use of more than one study drug,
the trial contracting authority may, if provided for in the clinical trial plan, submit one report on
safety for all investigational drugs used in that clinical trial.
The annual report contains only aggregate and anonymous data.
The annual reporting obligation begins with the first approval of the clinical trial and ends with the completion of the last
clinical trial conducted by the client with the investigational drug in BiH.
The report in the appendix contains the security reference information in effect at the beginning of the period of which
is being reported.
The security reference information in effect at the beginning of the reporting period serves as a
reference safety information during the reporting period.
If the reference security information changes significantly during the reporting period, then
the changes are stated in the annual safety report. Moreover, in this case the security reference is revised
the information is submitted in addition to the report, with the security reference information in force at
the beginning of the reporting period. Despite the change in the reference security information, the reference
security information in place at the beginning of the reporting period serves as a reference
security information during the reporting period.
Details on annual security reporting, including rules on identity disclosure,
it is prescribed in the ICH E2F - Development Safety Update Report 'DSUR' guidelines.
POSTMARKETING CLINICAL STUDIES SAFETY NOTIFICATION
Safety notification from post-marketing clinical studies is done in accordance with the Rules of Procedure
reporting, collecting and monitoring adverse drug reactions ("Official Gazette of Bosnia and
Herzegovina ", No. 58/12).
METHOD OF SUBMISSION OF SECURITY INFORMATION IN CLINICAL TRIALS
Who submits to the Agency the following documents related to clinical trials: suspected serious unexpected side effects
(SUSAR), SUSAR Linear Lists, Development Safety Update Report
- DSUR) and other safety information related to the drug in the clinical trial?
The clinical trial client or the representative of the clinical trial client shall submit it to the Agency
clinical trial documents. If the client of the clinical trial is not based in BiH, as
the representative must be authorized by a natural or legal person established in BiH.
How to submit safety-related documents in clinical trials:
• SUSAR registration is done through the Licensee's Adverse Reaction Form, which can be found at
the Medicines Agency website: www.almbih.gov.ba or through the CIOMS-I form, with the accompanying document to which
to which the following should be indicated:
a) the Agency's protocol number;
b) the name of the clinical trial;
c) the designation of the clinical trial plan;
d) information on the investigator-rapporteur;
e) suspected unexpected serious adverse reaction;
f) possible investigational drug (including name-code number of the active substance);
g) causality assessment.
The completed form with the accompanying act can be submitted to the Agency in one of the following ways:
- by mail, to the Agency for Medicinal Products and Medical Devices of Bosnia and Herzegovina, Veljka
Mlađenovica bb, Banja Luka;
- by fax: 051 / 450-301;
- by e-mail (e-mail: klinicka@almbih.gov.ba)
• The linear list shall be submitted by electronic mail on CD with the accompanying document to be indicated
name and designation of clinical trial plan (s) with study drug in BiH.
• The DSUR shall be submitted by electronic mail on a CD, accompanied by a statement stating the name and
the designation of the clinical trial plans (s) with the study drug in BiH.
ADVERSE REACTIONS OF MEDICINES NOT RECEIVED AS SUSAR
In particular, there is no need for testing contractors to report as SUSAR (but may require some
other actions as described below)
• side effects not related to IMP but to additional drugs (non-IMP) and not resulting from interactions with IMP;
• SUSAR in a non-sponsor clinical study;
• adverse reactions to medicines occurring outside BiH beyond the clinical trial, exclusively used as an IMP in
BIH.
NOTIFICATION OF ADVERSE REACTIONS RELATED TO ADDITIONAL MEDICINES (NON-IMP)
Safety notification regarding additional medicines is done in accordance with the Regulations on the method of reporting,
of collecting and monitoring adverse drug reactions (Official Gazette of Bosnia and Herzegovina, No. 58/12)
.
OTHER IMPORTANT SAFETY INFORMATION THAT DOES NOT COVER SUSAR - OTHER MEASURES
Events may occur during a clinical trial that do not fall within the definition of SUSAR and are therefore not subject to
reporting requirements for SUSARs, although they may be relevant in terms of respondent safety.
For example, new developments related to the study or development of IMP may affect security
respondents, such as:
- A serious adverse event that could be related to study procedures and that could modify implementation
studies;
- Significant risk to the population, such as lack of efficiency in the IMP used for
treatment of a life-threatening illness;
- A major safety breakthrough from a recently completed animal study (such as
carcinogenicity);
- Suspension of the study for safety reasons, if the study is conducted with the same examinee
a medicinal product in another country by the same sponsor;
- Recommendations of the DSMB (Data and Safety Monitoring Board), if any, where relevant to the safety of the respondents.
These events / observations may not be reported as SUSAR, but they may require others
actions such as:
- Emergency security measures and their notifications;
- Significant amendments;
- Early interruption of testing.
In addition to the examples above, it is recommended that the contracting authority inform the Agency and the Ethics Committees
on any other security issues that could significantly alter the current assessment of the benefit-risk balance
of the tested product.
Safety information related to medicines currently under trial in BiH needs to be provided
To the Agency, in paper form, within the shortest possible period of time.
SUBMITTING RELEVANT INFORMATION
The contracting authority must report any information that is 'relevant', that is, information that is
necessary to:
- check that the expected therapeutic and public health benefits continue to justify the foreseeable risks, and
- Administratively processed the report.
In identifying irrelevant and relevant information, medical and
scientific assessment.
In particular, new administrative information that might affect the processing of the report should be considered
'relevant'. One example is information that can help identify potential duplicates.
It may turn out, after initial reporting, that the event is not SUSAR, for example, due to a deficiency
causation, seriousness or unexpectedness (hereinafter referred to as "downgrade"). Downgrades should be considered
relevant information.
Examples of irrelevant information are minor date changes or typographical error corrections
the previous version of the report.
INFORMATION OF THE RESEARCHER BY THE TESTING ORDER
The investigator will also inform all investigators.
The client of a clinical trial conducted in BiH shall report all relevant suspected information
unexpected serious adverse reactions to the investigational drugs that occur during that clinical trial in BiH.
The deadline for notification of suspected unexpected serious adverse reactions is set depending on
of the severity of the side effect, and is:
a) in the case of life-threatening or life-threatening suspicion, of unexpected serious adverse reactions occurring during that period;
clinical trial in BiH as soon as possible and in any case not later than seven days after
the client learns of a side effect; if necessary, ensure timely reporting, the contracting authority
may submit an initial incomplete report followed by a full follow-up report,
within eight days at the latest;
b) in the case of non-lethal SUSARs or suspected unexpected serious, non-life-threatening side effects which
occur during that clinical trial in BiH, not later than 15 days after the client becomes aware of a side effect;
c) in case of suspected unexpected serious adverse reactions occurring during that clinical event
interrogations in BiH, which were initially considered non-lethal and life-threatening, and for which
they turn out to be deadly or life-threatening, as soon as possible and in any case the furthest away
within seven days after the client learns that the side effect is deadly or dangerous
life.
The information should be concise and practical. Therefore, whenever possible, information on SUSARs should be consolidated
in the form of a linear list of SUSARs over periods determined by the nature of the research project / clinical development project and
volume of SUSARs generated. The linear list should be accompanied by a concise review of the development security profile
of the investigated drug.