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FDA published in December 2012 a final guidance on IND and BA/BE reporting along with a brief Q&A accompanying it. See: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf and www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM332846.pdf respectively.

Continuing with the review of the key points in FDA’s guidance.  This is the final part.

Aggregate Reports of SAEs as a 15 Day IND Safety Report

FDA discusses this in detail.

An IND safety report based on aggregate data must be in narrative format and must include a description of the suspected AR, all relevant information e.g. summary information about symptoms, concomitant medications, demographics, comorbid conditions, past history, pertinent laboratory test results, timing of events (onset and duration), and duration of treatment. Data from previously submitted individual case IND safety reports should be included, if applicable.

Finally, the narrative report should describe the characteristics and results of the analysis, including a description of the databases, how the conclusion was reached, who reviewed the analysis, any planned changes in monitoring or to study documents (e.g., informed consent, IB), and any planned further analyses.  Individual cases described in the submission must also be included as 3500A forms.  If some individual cases were previously submitted as IND safety reports, they should be resubmitted and clearly identified as duplicates. Before submission, each individual case report should generally be unblinded.

The sponsor should determine an appropriate approach for reporting subsequent occurrences of the same event to FDA and all participating investigators, and the sponsor should include a description of this approach in the initial expedited narrative IND safety report.

Editorial Comment:  This is a complex undertaking and basically becomes a sort of white paper or expert report of the case series.  There are some nuances here that not all sponsors are necessarily aware of including the requirement to submit (or resubmit) the individual cases. Presumably this means these cases should be resubmitted in this narrative report (say in an appendix) and not as individual 15 day reports.  The FDA comment on reporting to investigators is nebulous but does have the advantage of allowing the sponsor to make a rational and informed choice.  Whatever choice is made, it should be documented (probably in an SOP or Working Document) and be consistently adhered to.

Other Reports

FDA requires narrative reports (presumably in a similar format and content as above) for reports of overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies.  If the findings are published a copy of the publication should be included.

Where and How to Submit

The report must be transmitted to the CDER or CBER review division that has responsibility for review of the IND and these reports should be submitted to all the sponsor’s INDs under which the drug is being administered.  Reference all INDs to which the report is submitted and identify the specific IND under which the suspected AR occurred.  FDA accepts electronic submission of 15-day IND safety reports in eCTD format to the IND application if the IND is in eCTD format or if the sponsor intends to convert the IND to eCTD format.

Editorial Comment:  This is a bit of a surprise.  Many companies submit only to the IND under which the investigator is doing the trial and not to all open INDs.  FDA wants the case to go to all the INDs under which the drug is being administered with reference to the “primary” IND in each submission.  Companies should ensure that they are doing this.

7 Day Reports

FDA recommends that sponsors submit 7-day IND safety reports electronically in eCTD format.  Also acceptable are other rapid communication methods: phone, fax, email.  Sponsors should contact FDA to arrange this and to obtain a secure email account with FDA if email is used.

Editorial comment: No surprises.

Reporting Time Frames

Day 0:

15 Day Reports: The time frame for submitting an IND safety report to FDA and all participating investigators is 15 calendar days after the sponsor determines that the suspected adverse reaction or other information qualifies for reporting (day 0). Exceptions are for aggregate or increased frequency reports where the first case may well have been much earlier than 15 days.

7 Day Reports: These reports, if complete, do not require an additional submission at 15 days if the case is complete at 7 days.

Editorial comments: FDA is not clear here but presumably this refers to a 3500A form sent in by day 7.  The rapid communication (e.g. phone) is not sufficient.  A written report (MedWatch/CIOMS I) must be sent.  If sent by day 7 that suffices (presuming no further information comes in); if a MedWatch/CIOMS I is not sent in by day 7 then it must be sent in by day 15.

Follow-Up Information

In a clinical trial in a controlled environment it is expected that follow up information is generally readily available.  The sponsor must seek out such information and maintain records of efforts made to get this information.

Editorial comments: To put it less diplomatically, as the sponsor is controlling the study (and paying for it usually) the sponsor has the leverage (read: power) to compel follow-up and must do so.

Bioavailability/Bioequivalence (BA/BE) Studies

All SAEs (whether considered drug related or listed in the IB or labeling or protocol or in the investigational drug or control group) must be reported to FDA and all participating investigators within 15 days.  Follow up must be done if information is missing and submitted as a Followup Bioavailability/Bioequivalence Safety Report within 15 days.  CDER must be notified of all fatal or life-threatening AEs within 7 days (fax, phone, email).

BA and BE studies done in the in the United States that are exempt from the IND requirements under part 312 must report any SAEs from the study to FDA and to all participating investigators.  Such events from exempt BA/BE studies done ex-US are exempt from IND reporting.  However, AE information from foreign clinical studies must be included in the abbreviated new drug application (ANDA) submission

Editorial comment:  This change was made by FDA in the last regulations rewrite.  FDA considers any and all SAEs in a BA/BE trial to be critically important because the likelihood of an SAE in a small trial (e.g. perhaps no more than 20 people) who are usually healthy volunteers is miniscule.  Thus any SAE that does appear is not likely to be due to chance and must be evaluated.  So all SAEs – even if incomplete, not fully meeting all four validity criteria and even if felt to be unrelated to the drug  – must be reported as 15 (or 7 day if appropriate) reports.

The comments about foreign studies are a bit surprising (and confusing) as one would think that significant findings from abroad that are relevant would want to be known by FDA rapidly.  Presumably though, as the sponsor is doing continuing surveillance and life cycle risk management, a finding from a non-reportable study would alter the benefit-risk analysis and would alter the other trials underway and/or IB and/or consent and would reach the FDA.

Closing Comments

A good and useful document that clarifies several matters that may have been ambiguous to some.  Companies should review their SOPs and actual processes to be sure that they are compliant with these requirements.

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