ON MARCH 28, 2011, the U.S. Food and Drug Administration (FDA) issued its “final rule” about new safety reporting requirements for pharmaceutical manufacturers involved with clinical trials.¹ The rule lays out clear definitions and standards to help ensure that critical safety information about an investigational new drug is accurately and rapidly reported. The purpose of adverse event reporting is to enable FDA to develop a meaningful safety profile of the drug.² In an effort to identify real threats to human safety, FDA issued the final rule not only to obtain the pertinent information but also to lessen the “irrelevant” information sponsors were submitting.³ As FDA recognized, irrelevant information is a “drain on resources for FDA, investigators, and institutional review boards,” and it does not “meaningfully contribute” to FDA’s reporting efforts.⁴ According to FDA, over-reporting of serious adverse events for which there is little reason to believe that the drug caused the event complicated and delayed FDA’s ability to detect a safety signal.⁵ FDA claims that its final rule will provide more effective surveillance by improving the quality of safety reports and better protect people participating in clinical trials of drugs.⁶

New Reporting Requirements

An Investigational New Drug Application (IND) is the vehicle through which a pharmaceutical manufacturer (sponsor) advances drug development through clinical trials. Because the drugs being tested are investigational and their adverse effects on people are not completely known, appropriate safety reporting is an important part of the clinical trial process. This reporting is done by the sponsor submitting an IND safety report.⁷ The final rule requires that certain safety information that previously had not been required to be reported to FDA now be submitted within 15 days of becoming aware of an occurrence. These reports include:

• findings from clinical or epidemiological studies that suggest a significant risk to study participants;
• serious suspected adverse reactions that occur at a rate higher than expected;
• serious adverse events from bioavailability studies which determine what percentage and at what rate a drug is absorbed by the bloodstream; and
• serious adverse events from bioequivalence studies which determine whether a generic drug has the same bioavailability as the brand name drug.

The Adverse Event

An adverse event is an “untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.”⁸ The final rule defines new terms that help clarify when an adverse event should be rapidly reported to FDA.⁹ The four types of events include: (1) life-threatening adverse event (or suspicion thereof); (2) serious adverse event (or suspicion thereof); (3) suspected adverse reaction; and (4) unexpected adverse event.¹⁰ The final rule requires expedited reporting (within 15 days) of an adverse event “only when there is a reasonable possibility that the drug caused the adverse event.”¹¹ The adverse events that must be reported within 15 days of discovery are those that are “both ‘serious’ and ‘unexpected’” and also a “suspected adverse reaction.”¹² This requirement has been called an “intermediate level of suspicion” because even if no causal relationship has been proven but there is reason to believe it might exist, the event should be reported.¹³ In an effort to clarify the identification of a causal connection, the final rule provides for sponsors to better understand when rapid reporting of an adverse report is necessary.¹⁴ For example, a serious adverse event is when a participant develops “drug dependency” or an “allergic bronchospasm” which may or may not result in hospitalization.¹⁵

Sponsors must identify all previously submitted safety reports regarding a similar suspected adverse reaction at the time a 15-day report is submitted. Sponsors must also submit an analysis of the significance of this report in light of other similar reports.¹⁶ In some instances, the final rule requires reporting in the aggregate as compared to a control group, rather than a report of a single adverse event, so that the adverse event reporting will have more context.¹⁷ FDA has provided some guidance documents for methods of interpreting pooled data, but recognizes that it is impossible to completely avoid “noise” in the reporting system.

So what is exempt from rapid reporting requirements? In an FDA-issued reporting guide, FDA listed a few events that need not be reported: (1) death or serious injury that were “likely to have been manifestations of the underlying disease;” (2) events that “commonly occurred in the study population independent of drug exposure;” and (3) events “that were study endpoints,” meaning that “the study was evaluating whether the drug reduced the rate of these events.”¹⁸

Effect on the Blind Study

When the rule was in the proposed stage, it seemed to require that a blind clinical study be “broken” while the causal connection is identified. FDA recognized that the risk could “compromise the integrity of well-regulated clinical investigations, lead to fewer patients completing a trial, necessitate larger patient enrollment, and lengthen the timeline for new product development, possibly leading to higher costs for marketed drugs.”¹⁹ Sponsors immediately raised concerns about breaking the trial, arguing that it would ruin the results of the study.²⁰

In response to these comments, FDA noted that “where the serious, unexpected, suspected adverse reaction must be reported expeditiously, the agency expects the blind to be broken.”²¹ This is not to say that a study designed with a specific endpoint, such as heart attack or stroke, should generally be broken upon the event happening if the event was disclosed in the study protocol.²² Accordingly, FDA made changes in the final rule that allow for alternative reporting methods which do not require breaking the blind when proposed by the sponsor and accepted by FDA.²³ In this protocol, the sponsor must disclose any serious adverse events for which the blind will not be broken and plans for alternative reporting and further observation.²⁴ FDA’s acceptance of such plans will hinge on whether “patient safety can be assured without breaking the blind.”²⁵

Concerns and Solutions

The rule would appear to make clear a sponsor’s reporting requirements about which types of adverse events need to be reported to FDA and how they are to be reported. In essence, a pharmaceutical company will have to decide, based on FDA rules, which cases need to be reported on an individual basis and which adverse events needs to be reported on an aggregate basis. Pharmaceutical manufacturers are also faced with the reality that any approved drug may be the subject of future litigation. A decision by a pharmaceutical manufacturer that it need not report certain adverse events (or not report them within 15 days) can have long-lasting implications in lawsuits. One should assume that a plaintiff’s attorneys will request and scour adverse events and whether they were reported to FDA. Similarly, one should assume that they will look at whether adverse events were reported in an expedited manner, if required.

The FDA itself has some suggestions as to how a pharmaceutical manufacturer can comply with the rules. It suggests that “sponsors should have processes in place to periodically review and analyze their entire safety database, not only for IND safety reporting purposes, but also to update investigator brochures with newest safety information.”²⁶ Additionally, sponsors should consider having a system, with clear protocols in place, to ensure that all decisions as to which “adverse events” are not reported are fully documented, as well as to the reasoning behind the decisions. A similar protocol as to who decides which reports need to be made within 15 days will also helpful. Everyone involved in the clinical study should be given the information necessary to make sure that these protocols are followed. Since each 15-day adverse event has to be accompanied by other similar adverse events and an analysis of that information, the sponsor may find that having a database that can be quickly accessed to determine other similar adverse events will make following the requirements of the rule easier to follow.

Conclusion

Although sponsors may believe the rule will make the process of bringing new drugs to market slower and more burdensome, the goal is just the opposite. Reviewing and evaluating uninformative individual safety reports places a tremendous burden on FDA’s resources without an accompanying benefit. By reducing the current number of uninformative individual safety reports, sponsors, FDA, investigators, and institutional review boards can focus more time and resources on safety issues that affect patients and, ultimately, public health.

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[1] FDA. Q&A: Final Rule: New Safety Reporting Requirements for Investigational New Drug Applications (INDs). Last updated Sept. 28, 2010. Available at <http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/
ApprovalApplications/InvestigationalNewDrugINDApplication/ucm226365.htm>. Last accessed Feb. 16, 2012.

[2] 75 FR 59936.

[3] Id.

[4] Draft Guidance for Industry and Investigators Safety Reporting Requirements for INDS Studies, Sept. 2010, p. 3. The recommendations in such guidances are nonbinding but contain the FDA’s thoughts and comments as to the topics that are the subject of the guidance.

[5] Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans 75 FR 59935, 59936.

[6] Id. Another stated goal is to harmonize the regulations with recommendations by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and by the World Health Organization’s Council for International Organizations of Medical Sciences (CIOMS), and which have been adopted by the European Union (EU).

[7] FDA. Q&A: Final Rule: New Safety Reporting Requirements for Investigational New Drug Applications (INDs). Last updated Sept. 28, 2010. Available at <http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/
ApprovalApplications/InvestigationalNewDrugINDApplication/ucm226365.htm>. Last accessed Feb. 16, 2012.

[8] 21 C.F.R. § 312.32(a).

[9] Id.

[10] 21 C.F.R. § 312.32.

[11] Id.

[12] 21 C.F.R 312.32 (c)(1).

[13] Id.

[14] 21 C.F.R. § 312.32.

[15] Id.

[16] 21 CFR § 312.32 (c).

[17] FDA. Final Rule: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans. 2010 WL 3997257, *3. Last updated June 10, 2011. Available at <http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDev
elopedandApproved/ApprovalApplications/InvestigationalNewDrug
INDApplication/ucm226358.htm>. Last accessed Feb. 16, 2012.

[18] Id.

[19] 75 FR at 59940.

[20] 75 FR at 59947.

[21] Id.

[22] Id.

[23] Id.

[24] Id.

[25] 75 FR at 59947.

[26] Id.

Finis