DHHS proposed rule on clinical trial registration and results submission

The Department of Health and Human Services (DHHS) has announced a proposed rule on clinical trial registration and results submission. It proposes requirements for sponsors or principal investigators submitting registration and summary results information, including adverse event information, for specified clinical trials of drugs (including biological products) and medical devices, and for pediatric postmarket surveillances of a medical device, to ClinicalTrials.gov (CT.gov). This proposed rule provides for the expanded registry and results data bank specified in the FDA Amendments Act of 2007 (FDAAA) to enhance patient enrollment, provide a mechanism to track subsequent progress of clinical trials, provide more complete results information and enhance patient access to and understanding of clinical trial results. The executive summary is presented here.

Purpose: This proposed rule clarifies and expands requirements for the submission of clinical trial registration and results information to CT.gov. It implements FDAAA provisions to improve public access to information about certain clinical trials. Those responsible for specified clinical trials of FDA-regulated products have been required to submit registration information to CT.gov since 2007, summary results information for clinical trials of approved products since 2008, and adverse events information since 2009.

This proposed rule does not impose requirements on the design or conduct of clinical trials or on the data that must be collected during clinical trials. Instead, it specifies how data that were collected and analyzed in accordance with a clinical trial’s protocol are to be submitted to CT.gov. No patient-specific data are required to be submitted by this proposed rule or by the law this proposed rule is intended to implement.

The following is a summary of the major provisions of the regulatory action.

Applicable Clinical Trial: This proposed rule specifies for which clinical trials information must be submitted to CT.gov. This proposal specifies an approach for determining whether a particular clinical trial or study is an applicable clinical trial, based on descriptive information that would be submitted at the time of registration.

Responsible Party: There must be only one responsible party for submitting information about an applicable clinical trial. The sponsor would be considered the responsible party, unless and until the sponsor designates a qualified principal investigator (PI). This proposed rule specifies the approach for determining who would be considered the sponsor of an applicable clinical trial under various conditions, what qualifies a PI to be designated a responsible party by a sponsor and how responsibility reverts to the sponsor if a designated PI is unable to fulfill the requirement to submit information to CT.gov.

Registration: Registering applicable clinical trials at CT.gov would require the responsible party register an applicable trial not later than 21 days after enrolling the first participant. The rule specifies the data elements of trial information that must be submitted at the time of registration, including the descriptive information, recruitment information, location and contact information and administrative data elements listed in section 402(j) of the Public Health Service (PHS) Act, as well as additional data elements proposed under the DHHS Secretary’s authority to modify the requirements for clinical trial information due at registration as long as such modifications improve, and do not reduce, the clinical trial information available to the public on CT.gov. DHHS considers the proposed additional data elements necessary to enable the agency to implement other statutory provisions, indicate the status of human subjects protection review of the trial, facilitate the public’s ability to search and retrieve information from CT.gov and help ensure entries are unambiguous. Some of these additional data elements were included on CT.gov before FDAAA was enacted.

Expanded Access Information: Section 402(j) of the PHS Act requires the submission of information on how to obtain expanded access to investigational drugs used in applicable clinical trials, if the drugs are available through expanded access programs to patients who are not participating in relevant clinical trials. For an applicable clinical trial of a drug available under expanded access, this proposed rule would require the submission of a separate expanded access record containing details about how to obtain access to the investigational drug. If an expanded access record already has been submitted in conjunction with a different clinical trial of that same drug, the responsible party for the new clinical trial could link to the existing expanded access record rather than create a new one.

Results Submission: This proposed rule implements the requirement for the submission of summary results information for applicable clinical trials. It also proposes to extend the requirement for results submission to applicable clinical trials of drugs, biological products and medical devices not approved, licensed or cleared by the FDA. This proposed rule would require the submission of tables of data summarizing demographics and baseline characteristics of the enrolled participants and primary and secondary outcomes, including results of any scientifically appropriate statistical tests.

In general, this proposed rule would require the submission of results not later than one year after completion of the trial, which is defined as the date of final data collection for the primary outcome measure studied. Results submission could be delayed for up to two additional years with certification that either an unapproved, unlicensed or un-cleared product studied in the trial is still under development by the manufacturer or that approval will be sought for a new use of an approved, licensed or cleared product being studied in the trial. This proposed rule also permits responsible parties to request extensions for “good cause.”

Adverse Events: This proposed rule would require the responsible party to submit summary information of the number and frequency of adverse events experienced by participants enrolled in a clinical trial, by arm and organ system. It would require submission of two tables of information: one with summaries of all serious adverse events; the other with summaries of other adverse events that occurred with a frequency of 5% or more in any arm of the clinical trial, regardless of whether they were anticipated or unanticipated.

Updates and Other Required Information: This proposed rule would require all submitted information to be updated at least annually if there are changes to report. More rapid updating would be required for several data elements to help ensure users of CT.gov have access to accurate, up-to-date information. This proposed rule also requires timely corrections to any errors.

Costs and Benefits: Based on DHHS cost estimates, this regulatory action is not expected to have a significant impact on the economy. The costs consist primarily of the time needed to organize, format and submit to CT.gov information that was prepared for or collected during the clinical trial. The benefits include greater public access to information about and evidence from applicable clinical trials (and other clinical trials) and greater clarity about what is required for those subject to the legal mandate to submit information to CT.gov.

To ensure DHHS considers comments before it begins work on the final rule, submit written or electronic comments on the proposed rule no later than Feb. 19. Individuals and organizations interested in submitting comments, identified by RIN 0925-AA52 and Docket No. NIH-2011-0003, may submit electronic comments at http://www.regulations.gov/. Follow the instructions for submitting comments. NIH is no longer accepting e-mail comments. Submit written comments by fax at (301) 402-0169, or by mail/hand delivery/courier (for paper, disk, or CD) to Jerry Moore, NIH Regulations Officer, Office of Management Assessment, 6011 Executive Boulevard, Suite 601, MSC 7669, Rockville, MD 20852-7669. All written comments must include the agency name, Docket No. and RIN. Do not include any personal information; it may be disclosed to the public. Reference in your comments the applicable number assigned to each key issue discussed in the proposed rule.

FDA draft guidance on pediatric clinical pharmacology studies

The FDA has announced availability of a draft guidance document titled General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products, intended to assist sponsors of New Drug Applications (NDAs), Biologics License Applications (BLAs) and supplements to such applications who are planning to conduct clinical studies in pediatric populations.

Effectiveness, safety or dose-finding studies in pediatric patients involve gathering clinical pharmacology information, such as that regarding a product’s pharmacokinetics and pharmacodynamics pertaining to dose selection and individualization. This draft guidance addresses general clinical pharmacology considerations for conducting studies so dosing and safety information can be sufficiently characterized, leading to well-designed trials to evaluate effectiveness.

During the past two decades, the FDA has worked to address the problem of inadequate pediatric testing and inadequate pediatric use information in drug and biological product labeling. The FDA Modernization Act of 1997 established incentives for conducting pediatric studies on drugs while exclusivity or patent protection exists. Congress subsequently passed the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA).

Both BPCA and PREA were made permanent by FDASIA. Under BPCA, sponsors of certain applications and supplements can obtain an additional six months of exclusivity if, in accordance with the statute’s requirements, they submit information responding to a written request from the DHHS Secretary relating to use of a drug in the pediatric population. Under PREA, sponsors of certain applications and supplements are required to submit pediatric assessments, unless they receive an applicable waiver or deferral. If applicable, sponsors must submit a request for a deferral or waiver as part of an initial pediatric study plan.

This draft focuses on the clinical pharmacology information (e.g., exposure-response, pharmacokinetics and pharmacodynamics) needed to support findings of effectiveness and safety and helps identify appropriate doses in pediatric populations. The draft describes the use of quantitative approaches (i.e., pharmacometrics) to employ disease and exposure-response knowledge from relevant prior clinical studies to design and evaluate future pediatric studies. The draft guidance does not describe: (1) standards for approval of drugs and biological products in the pediatric population, (2) criteria to allow a determination that the course of a disease and the effects of a drug or a biologic are the same in adults and pediatric populations, or (3) clinical pharmacology studies for vaccine therapy, blood products or other products not regulated by the FDA’s Center for Drug Evaluation and Research.

Submit written or electronic comments by Feb. 9. Submit electronic comments to http://www.regulations.gov or written comments to the Division of Dockets Management (HFA-305), FDA, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. It is only necessary to send one set of written comments. Identify comments with Docket No. FDA-2013-D-1275.

The Regulatory Update is excerpted from Research Practitioner, Volume 16, Number 1, January-February 2015.