15

Expedited and Aggregate Reporting in Clinical Trials

There are multiple different safety reports that pharmaceutical companies and other sponsors must submit to health authorities. This chapter reviews the key reports that are required now by most health authorities.

Certain serious adverse events (SAEs) must be reported to health authorities within 7 or 15 calendar days. Most countries use “calendar days” rather than “business or working days,” as holidays and working days are not the same everywhere. Some countries still retain different rules for local cases, but by and large, thanks to ICH, CIOMS, and common sense, most countries have standardized on the same timing, format, and content of expedited (also called “alert”) reports.

Another way to express “clinical trial reporting” is reporting for drugs that are not yet marketed (no Marketing Authorization or New Drug Approval (NDA) yet or for the indication in question). Although this refers primarily to clinical trials, it may also refer to SAEs found in named patient use, compassionate use, solicited SAEs, epidemiologic trials, and other “nonclassic” trials and studies.

Most countries require that SAEs, which are unexpected (not labeled), that is, do not appear in the product labeling that is usually the Investigator Brochure, and that have some possibility (even if small) of being caused by the study drug in question, be reported in 15 calendar days from the first notification of anyone in the company (or organization), including its agents, business partners, contractors, distributors, and vendors. This is called a “15-day report,” “an expedited report,” or “an alert report.” Note the triple requirement: serious, unlabeled, and possibly related.

A subcategory of this is the “7-day report.” In a 7-day report, the patient in question has died or had a lifethreatening SAE, which is also unexpected and possibly related (same as above). This report must be sent to the health authorities within 7 calendar days. Note that all 7-day reports are also 15-day reports. Thus, if a report is communicated as a 7-day report, it must also be followed up as a 15-day report. The 7-day report may be communicated as a phone call, fax, or some other less formal communication compared with the more formal 15-day report (a CIOMS I, MedWatch form, E2B transmission). If the 7-day report is “informal,” then it must be followed up with the usual 15-day “formal” report. If the 7-day report is the CIOMS I, MedWatch form, or E2B, it will cover both requirements. Thus, the 7-day report becomes a 15-day report with the same requirements for follow-up and further reporting (see below).

The Investigator’s New Drug Application (IND) obligations are found in 21CFR312. An IND is usually opened and held by a pharmaceutical company, but academics, universities, and individuals may also do so. The term that the FDA uses for the IND holder is generally “the sponsor.” The sponsor is obliged to “review and evaluate the evidence relating to the safety and effectiveness of the drug as it is obtained from the investigator” (21CFR312.56(c)). This includes 7- and 15-day expedited reports (21CFR312.32) and annual reports (21CFR312.33). In March 2011, updates to these regulations went into effect.

Serious, unexpected (unlabeled), adverse events from clinical trials for which there is a reasonable possibility that the drug caused the event must be reported. Each report identifies all similar reports sent to the FDA, and the sponsor analyzes their significance.

Specifically the FDA regulations state 21CFR312(c) (1): “The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting.” In each IND safety report, the sponsor must identify all IND safety reports previously submitted to FDA concerning a similar suspected adverse reaction, and must analyze the significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information.

In each expedited report, all previously submitted expedited reports of similar suspected adverse reactions must be noted and analyzed in light of previous, similar reports or any other relevant information. This analysis may be included in the narrative.

Note that only previously submitted expedited reports need be included in the analysis. However, many companies look at all similar non-expedited SAEs and NSAEs if appropriate. Although not required, this is a wise practice.

Expedited reporting must be done for findings from animal studies, epidemiological studies, pooled analysis of multiple studies, or clinical studies, whether or not conducted under an IND and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug (312.32(c)(1)(ii)). Data from in vitro studies (e.g., microsusceptibility, drug interaction, or genotoxicity) are to be sent as 15-day IND reports if a significant risk in humans is determined (312.32(c) (1)(iii)).

Any clinically important increase in the rate compared to that in the IB or protocol of a serious suspected adverse reaction must be submitted as a 15-day expedited report. FDA realizes this may not always be available. When it is available, a judgment of “clinical importance” should be based on the study population, nature and seriousness of the AE, magnitude of the increase, and other appropriate factors.

• The report must be made no later than 15 calendar days after the sponsor’s initial receipt of the information (which is day zero and is considered the “clock start date”). Under older regulations the clock start began when there was sufficient information that the three criteria were met (serious, unexpected, associated) for an expedited report and that the report had the four criteria (reporter, patient, AE, drug) to be valid. FDA has changed these rules:
  
  
  
  • Because the four elements of the minimum data set are generally readily available in the clinical trial setting, the agency has determined that the definition and the requirement for the minimum data set are unnecessary and has decided not to require a minimum data set for IND safety reports.
    
  • The reporting time clock starts (i.e., day zero) as soon as the sponsor determines that the information qualifies for reporting. For a serious and unexpected suspected adverse reaction from a clinical trial, this would be the day the sponsor receives information from the clinical investigator.
    
  • If any information necessary to evaluate and report the suspected adverse reaction is missing or unknown, the sponsor should actively seek such information.

Thus when a study site reports any SAE information, the clock starts–even if the information is incomplete or does not meet the minimum requirements. The sponsor must then rapidly obtain the rest of the (minimum) information needed for the expedited report.

If the case has a serious outcome of fatal or life-threatening (i.e., serious, unexpected, associated, and fatal or life-threatening), the case is to be reported as a telephone or fax report within 7 calendar days of the first receipt. All 7-day reports are automatically 15-day reports and must then be processed and submitted as expedited reports by day 15 unless the 7-day report was a MedWatch or E2B expedited report. Follow-up reports (also expedited reports) are submitted if new information arrives.

For expedited reporting there must be sufficient evidence to suggest a causal relationship between the drug and the SAE, thus creating a “Suspected Adverse Reaction (312.32(c)(1)(i)). FDA does not want to receive as expedited reports those cases that are not likely to be related to the drug.

The FDA has clarified that it requires the investigator to report serious AEs rapidly to the sponsor along with a determination of seriousness/life-threatening as well as a determination of causality (“reasonable possibility”). The sponsor only determines expectedness. The most conservative viewpoint prevails. That is, in terms of seriousness and causality, if either the investigator or sponsor feels a case is serious and that there is a “reasonable possibility” the SAE was due to the drug, it should be expedited.

The events should be submitted on a MedWatch 3500A form or, if already arranged with the FDA, as E2B transmissions, though the FDA has not officially started accepting IND reports electronically at this writing. Animal reports and other nonindividual case reports (e.g., epidemiologic studies) are usually submitted as narratives rather than on MedWatch forms. Most companies do not want to put animal data into their clinical safety database. Non-U.S. cases may be submitted on MedWatch or CIOMS I forms.

All SAEs from bioavailability and bioequivalence studies must be reported as expedited reports whether labeled (in the investigator brochure or not) or related to the drug (causality).

The sponsor must also notify all participating investigators of these reports. The investigators in turn notify the investigational review boards (21CFR312.32(c)(i and ii)). The notification procedure has become a bit more complex recently, as not every single individual report goes to the investigators and IRBs. Rather important reports or those that alter benefit/risk should be reported. FDA has issued a guidance on this: “Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting—Improving Human Subject Protection” (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf). The sponsor is also required to report information to the FDA from any source, foreign or domestic; clinical, animal, or epidemiologic investigations; commercial marketing experience; literature reports; unpublished papers; and foreign regulatory authorities (21CFR312.32(b)). The FDA retains the right to change the format and frequency of the reports. For marketed drugs, reporting to the IND is not required unless that case is from an IND clinical trial.

Follow-up is required on all safety information received by the sponsor and submitted as a follow-up to the original (initial) 15-day report. Follow-up information is handled with the same 15-calendar-day clock. If a case is received and does not meet the criteria of a 15-day report (e.g., reported as a nonserious case initially) and only later does the receipt of follow-up information show the case to meet the reportability criteria, the clock starts when the follow-up information is received. If a case becomes nonexpedited on receipt of follow-up information, the sponsor should submit this new information as a follow-up 15-day report and indicate that the case no longer meets the criteria for expediting.

Other information the sponsor receives that does not quite fall into these categories but which the sponsor wishes to report should be reported as an information amendment or in the annual report. The FDA notes that reporting of a case by the sponsor does not mean that the FDA or the sponsor believes that the report was necessarily due to the drug. This point may prove to be important in any potential litigation in which the sponsor might become involved (21CFR312.32(c)(3, 4)). Postmarketing trials should be submitted to the IND (whether conducted under an IND or not) only if the case meets the three criteria (serious, unexpected, possibly related) as determined by the sponsor.

The FDA also notes that in some trials, the sponsor and FDA may reach an agreement to be noted in the protocol whereby certain study endpoints (e.g., a particular SAE such as a myocardial infarction or death) which would normally be expedited cases will not be reported as 7- or 15-day reports but rather periodically or at the end of the trial. This must be customized for each situation and FDA must agree to it. Expedited reports should be unblinded and placebo cases should not be reported.

In summary, the sponsor (whether an individual, institution, or company) must submit to the FDA as a 15-day expedited report all clinical trial AEs that are serious, unexpected (not in the Investigator Brochure or Package Insert, depending on which one is used: Investigator Brochure for nonmarketed drugs or new indications of marketed drugs and the package insert—usually—for marketed drugs and postmarketing studies), and reasonably associated with the study drug. As noted above, epidemiologic, animal, and other studies may also generate expedited reporting. If the case is a death or is life-threatening, a 7-day report (phone or fax) must also be made in addition to the 15-day report.

Stay updated, free articles. Join our Telegram channel

Join