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Practical aspects of the “new” IND Rule

Posted on May 23rd, 2016 by in Pharmacovigilance


The FDA IND reporting rule[i], mandatory since March 2011, has had a major impact on the sponsor’s responsibilities to report safety information representing a potential change in the risk profile for products that are under investigation. Beyond the change in the definition of a suspected adverse reaction (“any adverse event for which there is a reasonable possibility that the drug caused the adverse event”) are other more challenging obligations. For instance, it is now necessary to report to the FDA within 15 days when there are one or more occurrences of an event that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug. Other occurrences that must be reported in such a timely manner include the imbalance of occurrence of significant AEs between two arms of a trial, findings from other studies or from pooled data, animal or in-vitro results suggesting a significant risk to humans, and increased rates of occurrence of serious AEs compared to the investigator brochure or protocol.


Several guidance documents (2012[ii],[iii] and 2015[iv]) provide recommendations on the operational and decisional processes to support compliance with this new rule. These changes have generated a significant debate, as they represent a deviation from ICH or non-US regulations. The intent here is to reduce the burden of processing non-significant safety information for FDA and investigators, and to push for more proactive signaling activities and decision-making approaches for sponsors.
The need for proactive and ongoing monitoring of safety signals (individual or aggregate data) during clinical trials is well established (see CIOMS VI, or the work done by the different working groups[v],[vi]) and is expected to already be in place for all pharmaceutical companies. However, a survey[vii] highlighted that, a few years after the new IND rule effective date, a significant number of companies had not yet changed their practices to align with the new FDA standards. Though the situation may have improved since, let us look at a few factors which could explain this delay:

  • Pharmaceutical companies are risk adverse for understandable reasons. They want to minimize the liability exposure and reduce the risk of operational complexity by sticking to their established practices, such as never overriding the investigator causality assessment.
  • Small companies do not always have the resources or expertise to set up a robust governance model for handling and deciding on potential signals. They might be tempted to build the process as they go (or as issues start to arise) rather than to build a quality system from the start and execute through it.
  • The responsibility of safety during the development phase is often viewed as a core expertise and prerogative of the clinical research team. The pharmacovigilance team is not always as involved as it should be in the development phase of products. Some organizations do not have quick access to a team of pharmacovigilance and pharmacoepidemiology experts to contribute as needed to the investigator brochure and protocol preparation.
  • When dealing with aggregate information, identifying when the clock starts for reporting is not easy. There can be a natural temptation to keep looking for more evidence of a safety issue, which sometimes unnecessarily delays critical decisions and reporting.
  • The management of masked/unmasked information can be a challenge in small structures, where maintaining a solid firewall between masked/unmasked teams or individuals is not practical. In such small organizations, organizing an independent internal or external Safety Assessment Committee for reporting decisions, as suggested in the FDA Draft 2015 Guidance, can be difficult.
  • Defining a quantitative framework to guide the medical review and safety monitoring of accumulating data requires a significant contribution from statisticians and epidemiological experts in order to predict the rates of anticipated serious adverse events and to establish comparison guidelines. This can be a struggle for some.
  • Last but not least, the enforcement of these rules through FDA inspections might be delicate. While compliance to hard metrics (date of receipt/date of submission, compliance to an expected format, etc.) is straightforward, the assessment of the logic, efficacy, or sensitivity of the company’s qualitative/qualitative framework can be more difficult. Multiple variations of these frameworks and safety governance models exist across the industry; some are probably more relevant than others on patient safety, and none is defined by regulations. The FDA guidelines are helpful but are not binding (contrary to the EMA GVPs), and it should not be a surprise that the industry and the FDA still spend a lot of time communicating on the implementation of a rule that’s been mandatory for some five years.

In spite of this, many companies have successfully implemented frameworks and processes maximizing their compliance to the rule and their commitment to patient safety. A significant amount of references and expertise is within reach for all other companies to design and implement a clear, transparent, and documented safety governance model that meets both recognized standards and FDA IND regulations. We should expect that the remaining compliance gaps will be greatly reduced in the near future.



[i] 21CFR312.32(c)(1)

[ii] FDA Guidance for Industry and Investigators, Safety Reporting Requirement for INDs and BA/BE studies, Dec. 2012

[iii] FDA Guidance for Industry and Investigators, Safety Reporting Requirements for INDs and BA/BE Studies-Small Entity Compliance Guide, Dec. 2012

[iv] FDA Draft Guidance for Industry, Safety Assessment for IND Safety Reporting, Dec. 2015

[v] Crowe B et al, Recommendations for safety planning, data collection, evaluation and reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting team, Clinical Trials 2009; 6:430-440

[vi] Wittes J et al, The FDA’s Reporting Rule on Expedited Safety Reporting: Statistical Considerations, Statistics in Biopharmaceutical Research, 7:3, 174-190

[vii] Archdeacon P et al, Therapeutic Innovation & Regulatory Science 2013, 00(0) I-8

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J.-P. Clement MD

Executive Pharmacovigilance Consulting

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