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 should one report adverse event?
- GCPHelpDesk: Adverse Events & Serious Adverse Events
- Adverse Event Reporting: During the Study
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.
In “Good Clinical Practice: A Question & Answer Reference Guide 2017” by Barnett International, the following answer was provided:
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.
Should adverse events be collected for subjects who discontinued the study treatment earlier? There is a good question and answer discussion at firstclinica.com “AE Reporting for Discontinued Patient”
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:In summary, the AE collection can be depicted as the following where TEAE stands for treatment-emergent adverse event:
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.