In clinical trials, the most
critical safety information is the adverse event (AE). There are numerous
guidance and guidelines regarding the AE collection. However, there
are still a lot of confusions. The very basic question is when to start the AE
collection and when to stop the AE collection. For example, here are some discussions:
When to start the AE collection?
It is a very common practice in industry-sponsored clinical
trials that AE record keeping begin after informed consent. Adverse
events will be collected even for those patients who signed informed consent, but subsequently
failed the inclusion/exclusion criteria during the screening period. If we
attend the GCP training, it is very likely we will be told this is the way we
are supposed to do for adverse event collection in order to be compliant with GCP.
However, the AE definition in
the
ICH E2A guidance document suggests that adverse event can be recorded at
or after the first treatment, not the signing of the informed consent form (ICF).
The
ICH E2A defined the AE as:
Adverse Event (or Adverse Experience) Any untoward medical
occurrence in a patient or clinical investigation subject administered a
pharmaceutical product and which does not necessarily have to have a causal
relationship with this treatment. An adverse event (AE) can therefore be any
unfavourable and unintended sign (including an abnormal laboratory finding, for
example), symptom, or disease temporally associated with the use of a medicinal
product, whether or not considered related to the medicinal product.
A. Commonly, the study period during which the investigator
must collect and report all AEs and SAEs to the sponsor begins after informed
consent is obtained and continues through the protocol-specified post-treatment
follow-up period. Since the ICH E2A guidance document defines an AE as “any
untoward medical occurrence in a patient or clinical investigation subject
administered a pharmaceutical product…” This definition clearly excludes the
period prior to the IMP’s administration (in this context a placebo comparator
used in a study is considered an IMP. Untoward medical occurrences in subjects
who never receive any study treatment (active or blinded) are not treatment
emergent AEs and would not be included in safety analyses. Typically, the
number of subjects “evaluable for safety” comprises the number of subjects who
received at least one dose of the study treatment. This includes subjects who
were, for whatever reason, excluded from efficacy analyses, but who received at
least one dose of study treatment.
There are situations in which the reporting of untoward
medical events that occur after informed consent but prior to the IMP’s
administration may be mandated by the protocol and/or may be necessary to meet
country-specific regulatory requirements. For example, it is considered good risk
management for sponsors to require the reporting of serious medical events
caused by protocol-imposed screening/diagnostic procedures, and medication
washout or no treatment run-in periods that precede IMP administration. For
example, a protocol-mandated washout period, during which subjects are taken
off existing treatments (such as during crossover trials) that they are
receiving before the test article is administered, may experience withdrawal
symptoms from removal of the treatment and must be monitored closely. If the
severity and/or frequency of AEs occurring during washout periods are
considered unacceptable, the protocol may have to be modified or the study
halted. Some protocols may also require the structured collection of signs and
symptoms associated with the disease under study prior to IMP administration to
establish a baseline against which post-treatment AEs can be compared. In some
countries, regulatory authorities require the expedited reporting of these
events to assess the safety of the human research.
For a specific study, the screening procedure and the
potential injury of the screening procedure should be considered when deciding
when to start the AE collection. For a study with very minimal or routine screening
procedure (such as phase I study / clinical pharmacology study in healthy
volunteers at phase I clinic), it may be ok to collect the AE starting from the
first treatment. For a study with
comprehensive screening procedures or with invasive screening procedures, it is advised that the AE collection should start once the subject signs the ICF. For
example, in a study assessing the effect of a thrombolytic agent in ischemic
stroke patients, the screening procedures include CT scan and arteriogram to assess the location and size
of the clot – which can cause
adverse effects / injuries to the study participants. In this situation, it is strongly advised
that the AE is collected at the ICF signing.
If the AE is collected from the ICF signing, during the
statistical analysis, the AEs can be divided into non-treatment emergent AE and
treatment emergent AEs (TEAE). Non-TEAEs are those AEs occurred prior to the first study treatment and TEAEs are those AEs with onset date/time at or after the first study treatment. Non-TEAE and TEAE will be summarized
separately and the extensive safety analyses will be mainly based on the TEAE.
When to Stop the AE collection?
It is even more murky in terms of when to stop the AE
collection because the end of the study is trickier than the start of the study. A study may have
a follow-up period after the completion of the study treatment. A subject may discontinue the
study treatment earlier, but remain in the study to the end.
There is no clear guidance how long after the last study
treatment the AEs need to be collected. In practice, it is common to continue
reporting AEs following the last study treatment – the period for post study
treatment may be 7 days following the last treatment or 30 days following the
last treatment. The decision of AE
collection during the follow-up period should be based on the half life of the
study drug, whether there are AEs of special interest related to the study drug
in investigation, and whether it is in pediatric or adult population.
In oncology clinical trials, it is typical not to collect
the adverse events during the long-term follow-up period. Adverse events may
just be collected for short period after the last treatment, for example 30 days or 3 months or 6 months following the last study treatment. During the long-term follow-up period, only
the study endpoint (tumor related events) such as death, tumor progression, or
secondary malignant event will be collected.
QUESTION: What are the investigator's responsibilities in
terms of reporting the post-discontinuation adverse events? On one hand, since
the patient discontinued from the study, some think that the investigator has
no right to review the patient's clinical record under HIPAA (authorization
terminated) or informed consent regulations (consent withdrawn) and consequently
has no authority or responsibility to report the adverse events. On the other
hand, there does not appear to be any variances to an investigator's IND
obligations (even when a patient discontinues from the study) with respect to
reporting adverse events according to 21 CFR 312.64. Also, would the
investigator's reporting responsibilities be the same for Situation A and
Situation B?
ANSWER:
FDA has stated that clinical investigators need to capture
information about adverse effects resulting from the use of investigational
products, whether or not they are conclusively linked to the product. The fact
that a subject has voluntarily withdrawn from the study does not preclude FDA's
need for such information. In fact, withdrawal is often due to adverse effects,
some already realized and others beginning and that will later progress. For
your first scenario, that is obviously not a real problem since the
investigator is also the individual's private physician and obviously has this
information. While you are correct to worry about privacy issues in both
scenarios, the public welfare is a larger issue. Failure to capture and report
adverse effects, particularly serious adverse effects, will not only be a
problem for the individual in question but potentially for other actual and
potential study subjects. It is also essential to capture the information so
that the total picture is available to FDA when a marketing decision is
imminent. The individual in question may be one of very few who would evidence
the particular adverse effect, particularly given the limited number of
individuals included in a study. However, this information could have major
ramifications for the potentially large population of users of the drug once
legally marketed. How to best go about collecting the details of the adverse
effect is obviously a different issue.
In summary, the AE collection can be depicted as the following where TEAE stands for treatment-emergent adverse event:
