Complexities in Reporting SAEs: What Do the Regs Really Say?

“If a patient is randomized to the study but never receives study drug, must site staff report serious adverse events (SAEs) for this patient?”

This excellent question was recently asked in the CDM group on LinkedIn. The responses ranged from assertions that regulations require that either serious or all AEs must be reported starting at informed consent (IC), to suggestions that, in the absence of any internal company guidance, they should be captured as they can be eliminated from the analysis based on the “definitely not related” assessment.

I think the answer is probably “it depends”! As with most aspects of clinical research, deciding what to collect and to report requires understanding the risks associated with the different choices. That requires understanding, among other things, the context of the question, where and when the research occurred, and who intends to use the data and for what. Below you will find my thoughts on some of these factors.

(Incidentally, if anyone can point me to a place in a regulation where it defines “on study” as beginning with signing IC, and/or where it clearly states that SAEs must be captured beginning at IC, I’d be grateful. I was unable to locate any such statement, but my sources are primarily US regulation and guidances, ICH guidances, ISO standards, and some European regulations and guidances.)

The Question

The original question was whether SAEs occurring after randomization but before treatment must be reported. Because of the range of responses in the Group, I have also expanded the question to “Must all AEs and/or SAEs occurring on study be reported?”

There are two elements to consider here.

• The first is the meaning of “reported.” Does it mean that AE/SAEs must be reported on a CRF? Or does it mean that AEs/SAEs must be reported to regulatory authorities under the expedited reporting rules? Or does it mean that AEs/SAEs must be reported in the study report? Each of these is a valid question, and the answers depend upon a number of factors, some of which are discussed below.
  
• The second is the meaning of “on study.” Is it when IC is signed, or at randomization, or the beginning of baseline, or something else? One could use the term “enrolled” instead, but it turns out that neither term is clearly defined. It does imply that timing plays a role, and this is explored later in this article.
  

What Do the Regulations/Guidances/etc. Say?

As mentioned above, I did not find any regulations or guidances that defined when to start capturing AEs/SAEs beyond those potentially associated with study treatment. Here is what I did find that relates to this discussion.

ICH E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

• Focuses on the requirements for expedited reporting, rather than on determining the timing of what should be captured
  
• Lists the minimal information necessary to send a report, which includes a treatment having a plausible causal relationship with the event
  
• States that there are circumstances where certain SAEs may be exempt from routine reporting, such as when the SAE may be the primary outcome and expected. (KH: This indicates that there is no absolute rule that all SAEs must follow expedited reporting, although this does not speak to whether they are captured.)
  

Definition: Adverse Event (from ICH E2A):

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. (emphasis mine)

Different regulations/guidances have slightly different wording, but all require a potential association with treatment, so if the event occurred prior to treatment it cannot, by definition, be an AE. Thus, a sponsor could capture only those AEs beginning with study treatment and be technically completely compliant.

Definition: Serious Adverse Event (from ICH E2A):

During clinical investigations, adverse events may occur which, if suspected to be medicinal product-related (adverse drug reactions), might be significant enough to lead to important changes in the way the medicinal product is developed (e.g., change in dose, population, needed monitoring, consent forms). This is particularly true for reactions which, in their most severe forms, threaten life or function.

This is part of the definition of an SAE, and indicates some reasons why expedited reported should happen for SAEs. As SAEs are, by definition, a kind of AE, they too cannot occur prior to treatment initiation. In reality, there are times when treatment may not be the only factor to consider, especially with respect to SAEs.

ICH E3 Structure and Content of a Clinical Study Report

• 5.3 PATIENT INFORMATION AND CONSENT: How and when informed consent was obtained in relation to patient enrolment, (e.g., at allocation, pre-screening) should be described.
  
• 10.1 DISPOSITION OF PATIENTS: (…) It may also be relevant to provide the number of patients screened for inclusion and a breakdown of the reasons for excluding patients during screening, (…)
  

Item 5.3 suggests that IC and enrollment are not necessarily the same time point, and 10.1 reminds us that subjects can be excluded during screening, prior to treatment.

ICH E6 Consolidated Good Clinical Practices

• In section 6.9.2, it states that the clinical trial protocol should include The number of subjects planned to be enrolled. In multicentre trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
  

This implies that enrollment refers to the subjects needed for analysis, not those screened.

21 CFR Part 312.62

(b)Case histories. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. (…) The case history for each individual shall document that informed consent was obtained prior to participation in the study.

The regulation does not define what “participation” means, but since signing IC means agreeing to participate in the study, anything that happens after IC is, by definition, participating in the study. It’s a bit circular, but there it is!

ISO 14155.2 Clinical Investigation of Medical Devices for Human Subject – Good Clinical Practice

Definition 3.32: Point of Enrollment - time at which, following recruitment, a subject signs and dates the informed consent form

This brings up an interesting point:

1. Patients sign IC prior to participating in the study, meaning prior to any study procedures being performed (including those for screening)
   
2. Screening procedures are performed both to determine eligibility and, when appropriate, establish baseline values
   
3. If eligible, the subject continues. It is only at this point that the subject can be considered to be “on study.” Prior to this, eligibility has not been established, and so the subject must not be in the study, as GCP does state that ineligible subjects should not be included! (ICH E6 4.5.1 & 6.5.1)
   
4. Randomization may or may not occur at this point, depending upon the study design (there may be washout, baseline observation or other periods prior to randomization).
5. All of which means that the ISO definition of enrolment does not follow the same logic as the other regulations and guidances.
   

Even here it’s not completely clear, because later in the same standard, the Monitoring requirements state that the monitor should verify that:

f) signed and dated informed consent forms have been obtained from each subject at the point of enrollment and/or before any clinical investigation-related procedures are undertaken,
g) only eligible subjects as defined in the CIP are enrolled in the clinical investigation,

If only eligible subjects are enrolled, and enrollment happens at the time of IC, then all subjects who provided IC must be eligible, which cannot be true because screening procedures have not yet begun!

FDA’s Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use, April 2006

5.1.1.2 Other safety issues requiring expedited reporting Other safety issues also qualify for expedited reporting where they might materially alter the current benefit-risk assessment of an investigational medicinal product or that would be sufficient to consider changes in the investigational medicinal products administration or in the overall conduct of the trial, for instance: (…)
c) new events related to the conduct of the trial or the development of the investigational medicinal products and likely to affect the safety of the subjects, such as: - a serious adverse event which could be associated with the trial procedures and which could modify the conduct of the trial, - a significant hazard to the subject population such as lack of efficacy of an investigational medicinal products used for the treatment of a life-threatening disease, (…)
5.1.2 What should not be reported? Expedited reporting is not usually required: - for reactions which are serious but expected, - for non-serious adverse reactions whether expected or not. It is generally not necessary to report events that are considered unrelated to the investigational medicinal product.

This last part speaks particularly to the distinction between capturing the SAEs and doing the expedited reporting. Section c. above brings in the point that study procedures may also cause SAEs, and although SAEs by definition must occur during treatment, study procedures happening during pre-treatment periods may also be important.

The take-home message is that one has to think about the context of the definitions, the spirit of the regulations/guidances/etc., and the specifics of the trial in order to determine the best course.

The Importance of Context

Why do we capture AEs and SAEs in a trial? We are trying to determine if the treatment causes undesirable effects that outweigh its benefits. We want to tease out the relevant events from the “background noise.” If randomization has happened appropriately, and there are no other sources of treatment assignment bias, and the investigators understand how to identify treatment emergent AEs, then the incidence of any given non-treatment-related AE in each treatment group should be the same, as should the incidence of the AE in the pre- and during-treatment periods. This suggests that, absent any additional risk factors or protocol design requirements, it should be unnecessary to capture AEs prior to treatment.

The question then becomes what to capture and/or what should follow expedited reporting rules. The following are other factors to consider.

• Screening procedures: if the screening procedures are invasive or otherwise risky, capturing AEs/SAEs prior to randomization may be desirable, as it may influence the conduct of the trial, and/or the requirements for patient monitoring after the product is approved. Whether they should be subject to expedited reporting would depend upon an assessment of the other factors below.
  
• Indication/population: how severe is the indication? If the subject population is quite ill, and SAEs are expected, then it may be appropriate to capture the SAEs, but not do expedited reporting. This should be defined a priori in the protocol after discussion with regulatory authorities, the company’s regulatory affairs and clinical colleagues.
  
• Time frame: If the decision is to capture SAEs for subjects who were randomized but never receive treatment, what time frame should be used? Should they be captured only for subjects who didn’t receive treatment because of the SAE? Should the subjects be monitored for the same follow-up duration as treated subjects? Should the SAEs be subject to expedited reporting, considering that it is known the subject was not on treatment?
  
• How much is known? If very little is known about the indication, treatment, study population and/or expected SAEs, then it would be appropriate to capture and report more information, as it is more likely that an event would be unexpected. As noted above in the FDA’s AE reporting guidance Section 5.1.2, if certain SAEs are already known to occur and this is documented in the Investigator’s Brochure, expedited reporting may be unnecessary, even if they are still “reported” on the CRF.
  
• Geographic location: where is the study being conducted? The regulatory authorities in different regions may have different requirements or preferences for how much should be captured/reported.
  
• Study design: randomization does not necessarily happen when the subject is enrolled, meaning that IC is signed and all eligibility criteria are met, and the subject is cleared to continue in the study. There can be washout periods, baseline observation periods, or other epochs that occur prior to randomization, and collecting AEs and/or SAEs may or may not be necessary. Much depends on the procedures performed and whether there is interest in comparing AE/SAE incidence before and after treatment.
  

Consequences of Reporting and Not Reporting

There are other, perhaps less obvious, consequences to these decisions.

• Capturing SAEs: capturing SAEs requires providing considerably more information than is necessary for AEs. This is an additional burden on the site. It can also be a burden and expense for the sponsor, as it requires additional attention at each stage from data entry to data management to analysis and report writing.
  
• Reporting SAEs: The burden is even greater when the expedited reporting processes are followed, as this requires completing additional forms, informing the sponsor and also the Institutional Review Board (IRB)/Ethics Committee (EC). The IRB/EC can be swamped with reports of routine events, which reduces their effectiveness. Finally, the receiving regulatory authorities have to distinguish between important events and those that are reported because the site/sponsor/etc. is being ultra conservative. This impairs their ability to respond to the critical events.
  
• Analyzing the data: analysis and study reporting happen using the data that are captured. Whether SAES from randomized-but-not-treated subjects are included in the general intent-to- treat analyses or are put in a separate table is the choice of the biostatisticians, medical writers and clinicians responsible for the study report.
  

Bottom Line

I don't think it's possible to answer the overall question with an absolute statement of yes or no.

• It is usually appropriate to capture SAEs for subjects who have been randomized but not treated, but they generally don’t need to follow expedited reporting.
  
• It’s also usually unnecessary to follow expedited reporting for SAEs for subjects who have signed IC but have not been randomized (assuming randomization is when they are enrolled), but whether to capture them is more ambiguous.
• Generally, it’s not required to capture AEs for subjects who signed IC but weren’t randomized.
  

The caveat is that there are exceptions to every one of these cases, as suggested by the earlier discussions. Like so much of what we do, the decision requires judgement. Regardless of your decision, it is good practice to define clearly in the protocol what is meant by “enrolled,” “on study” and any other similarly unclear term.

In order to make the right decision,

• Educate yourself on the variables involved, and read the regulations
  
• Gather the relevant questions and information
  
• Talk to the other functional areas – this decision cannot (MUST NOT!) be made in a silo, because other perspectives and knowledge bases are required to ensure that all angles are covered
  

Your Regulatory Affairs group may have already spoken with the regulatory agencies about this; a good time to bring it up is at the early Phase 2 or end of Phase 2 meeting with the regulators. Whatever decision is made, be sure that it is documented fully, including the rationale for each element, because you may need that documentation later to justify the decision. There are few absolutes in our business, and nowhere is that more true than when dealing with regulations.

Many thanks to those who posed and responded to the question on LinkedIn. The thread was accessed on 6 December 2009 at http://www.linkedin.com/groupAnswers?viewQuestionAndAnswers=&discussionID=10132121&gid=7 7402&commentID=8843270&goback=.anh_77402&trk=NUS_DISC_Q-subject#commentID_8843270

Disclaimer: The author does not work for a regulatory authority, and the material in this article is based on reading the regulations/guidances and applying her own experience and observations. Each company should confer with their internal experts and the appropriate authorities to determine the best approach for their situation.