Regulatory Update, April 2017
FDA Draft Guidance on Multiple Endpoints in Clinical Trials
In the January 13, 2017, Federal Register, the FDA announced the availability of a draft guidance titled, “Multiple Endpoints in Clinical Trials.” This draft provides sponsors and review staff with the FDA’s thinking about the problems posed by multiple endpoints in the analysis and interpretation of study results and how these problems can be managed in clinical trials for human drugs, including drugs subject to licensing as biological products. The purpose of this guidance is to describe various strategies for grouping and ordering endpoints for analysis and applying some well-recognized statistical methods for managing multiplicity within a study to control the chance of making erroneous conclusions about a drug’s effects.
The FDA’s International Conference (now Council) on Harmonization (ICH) guidance for industry “E9 Statistical Principles for Clinical Trials” is a broad-ranging guidance that includes discussion of multiple endpoints. This draft guidance provides greater detail on the topic of multiple endpoints.
Failure to account for multiplicity when there are several clinical endpoints evaluated in a study can lead to false positive conclusions regarding the effects of the drug. The regulatory concern regarding multiplicity arises principally in the evaluation of clinical trials intended to demonstrate effectiveness and support drug approval; however, this issue is important throughout the drug development process.
The focus of this draft is control of the Type 1 error rate for the planned primary and secondary endpoints of a clinical trial so that the major findings are well supported. Multiplicity adjustments provide a means for controlling Type 1 error when there are multiple analyses of the drug’s effects. The issues of multiplicity and methods to address them are illustrated in the draft with examples of different study endpoints. Both the issues and methods that apply to multiple endpoints also apply to other sources of multiplicity, including multiple doses, time points or study population subgroups.
Once a trial is successful (demonstrates effectiveness or “wins” on the primary endpoint(s)), there are many other attributes of a drug’s effects that may be described. Analyses that describe these other attributes of a drug can be informative and are often included in physician labeling. Such descriptive analyses are not the subject of this draft guidance and are not addressed in detail.
Identify comments with Docket No. FDA-2016-D-4460.
Final Rule Updating Common Rule Published—Effective: Jan. 19, 2018
In the January 19, 2017, Federal Register, the current update to the Federal Policy for the Protection of Human Subjects (the Common Rule) was published. It was published concurrently on behalf of 16 federal departments and agencies. Readers of Research Practitioner have seen several articles on proposed changes to the Common Rule since the Notice of Proposed Rulemaking was published in September 2015. Based on the review of 2100 comments made to that NPRM, substantial changes were made and are presented in the Final Policy. Future articles will highlight in more detail some of the important changes that occurred between proposed and final rule but in summary, the final rule ultimately did not adopt several controversial proposals seen in the proposed rule. They were:
- The final rule did not adopt the proposal to require that research involving non-identified biospecimens be subject to the Common Rule, and that consent would need to be obtained in order to conduct such research.
- The final rule did not expand the federal policy to cover clinical trials that are not federally funded.
- The final rule did not include the proposed standardized privacy safeguards for identifiable private information and identifiable biospecimens.
- The final rule did not adopt the most restrictive proposed criteria for obtaining a waiver of the consent requirements relating to research with identifiable biospecimens.
Further, the final rule did make the following significant changes to the Common Rule:
- Establish new requirements regarding the information that must be given to prospective research subjects as part of the informed consent process.
- Allow the use of broad consent from a subject for storage, maintenance and secondary research use of identifiable private information and identifiable biospecimens. Broad consent will be an optional alternative that an investigator may choose instead of, for example, conducting the research on non-identified information and non-identified biospecimens, having an institutional review board (IRB) waive the requirement for informed consent, or obtaining consent for a specific study.
- Create a requirement for U.S.-based institutions engaged in cooperative research to use a single IRB for that portion of the research that takes place within the U.S., with certain exceptions.
- Remove the requirement to conduct continuing review of ongoing research for studies that undergo expedited review and for studies that have completed study interventions and are merely analyzing study data or involve only observational follow up in conjunction with standard clinical care.
The Regulatory Update is excerpted from Research Practitioner, Volume 18, Number 02, March/April.