FDA Publishes Draft Guidance Documents

Although the dates for submitting comments to some of these will have passed before publication, interested parties should still consider submitting comments on these drafts as instructed, with the indicated Docket Number included in the comments.

Developing BCG-Unresponsive Nonmuscle Invasive Bladder Cancer Treatments

In the November 18, 2016, Federal Register, the FDA announced availability of a draft guidance for industry titled “Bacillus Calmette-Guerin (BCG)—Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment.” It aims to assist sponsors in developing drugs and biologics to treat patients with a high-risk form of bladder cancer, nonmuscle invasive bladder cancer (NMIBC). The alternative is radical cystectomy, a surgical procedure with significant morbidity and mortality. This guidance helps overcome some obstacles in conducting the studies needed to establish efficacy of drugs and biologics for these patients with an unmet medical need. It focuses on the subset of patients with BCG-unresponsive disease. Also, the pathological diagnosis and staging, risk stratification and trial design, including assessment of appropriate clinical endpoints, are discussed. The preferred trial design for demonstrating efficacy of drugs developed to treat NMIBC is a randomized, controlled trial with a time-to-event endpoint of recurrence-free survival. Single-arm trials are appropriate in clinical settings for which a randomized, controlled trial is either unethical or not feasible. Therefore, single-arm trials of patients with BCG-unresponsive carcinoma in situ with or without papillary disease using an endpoint of complete response rate (and duration) may be appropriate.

Submit comments as instructed by February 16, 2017. Identify comments with Docket No. FDA-2016-D-3456.

Format and Content of Physiologically Based Pharmacokinetic Analyses

In the December 2, 2016, Federal Register, the FDA announced availability of a draft guidance for industry titled “Physiologically Based Pharmacokinetic Analyses—Format and Content.” It recommends to drug sponsors the format and content for submitting physiologically based pharmacokinetic (PBPK) analyses to the FDA to enable efficient and consistent review. A PBPK analysis uses models and simulations that combine physiology, population and drug characteristics to describe pharmacokinetics and/or pharmacodynamics of that particular drug in humans. Throughout a drug’s life cycle, PBPK analyses can be used to support decisions on whether, when and how to conduct certain clinical pharmacology studies, inform dosing recommendations and enable prescription drug labeling. Standardizing the content and format of the analyses can facilitate the FDA’s efficient assessment, consistent application and timely decision making during regulatory review. The guidance does not address methodological considerations and best practices for the conduct of PBPK modeling and simulation or the appropriateness of PBPK analyses for a particular drug. Submit comments by January 31, 2017. Identify comments with Docket No. FDA-2016-D-3969.

FDA Publishes Final Guidance Documents

Interested parties may submit electronic or written comments on these final guidance documents at any time, as instructed for the first document and with the indicated Docket Number included in the comments.

Use of Electronic Informed Consent—Questions and Answers

In the December 15, 2016, Federal Register, the FDA and the DHHS Office for Human Research Protections (OHRP) announced availability of a final guidance titled “Use of Electronic Informed Consent—Questions and Answers.” It is intended for institutional review boards (IRBs), investigators and sponsors engaged in or responsible for oversight of human subject research under DHHS and/or FDA regulations.

This guidance makes final the draft titled “Use of Electronic Informed Consent in Clinical Investigations—Questions and Answers” issued in March 2015. It has recommendations on the use of electronic systems and processes that may employ multiple electronic media to obtain informed consent for both DHHS-regulated human subject research and FDA-regulated clinical investigations of medical products, including human drugs, biological products, medical devices and combination products.

The guidance provides recommendations on procedures that may be followed when using an electronic informed consent (eIC) to help: (1) ensure protection of the rights, safety, and welfare of human subjects; (2) facilitate the subject’s comprehension of the information presented during the eIC process; (3) ensure appropriate documentation of consent is obtained when electronic systems and processes that may employ multiple electronic media are used; and (4) ensure the quality and integrity of eIC data included in the FDA applications and made available to the FDA during inspections.

The FDA received many comments on its draft. In response, the FDA further clarified: (1) how to present information in the eIC to the subject; (2) how and where to conduct the eIC process; (3) how and when questions from subjects should be answered; (4) steps that may be taken to facilitate the subject’s understanding; (5) how to convey additional information to the subject during the course of the research; (6) how to use electronic signatures to document eIC; (7) how to verify the identity of the subjects who will be electronically signing the informed consent; (8) how to use electronic informed consent for pediatric studies; (9) how to provide copies of the eIC to the subject; (10) steps that may be taken to ensure privacy, security and confidentiality of the eIC information; (11) how to obtain Health Insurance Portability and Accountability Act authorizations for research electronically; (12) what eIC materials the investigator should submit to the IRB; (13) what the IRB’s responsibilities are in the eIC process; (14) the eIC documentation required for the FDA submission with applications; (15) steps to ensure that eIC materials are archived appropriately for the FDA-regulated clinical investigations; and (16) what eIC materials or documents the FDA will require during an inspection.

IDEs for Neurological Devices Targeting Disease Progression and Clinical Outcomes

In the November 7, 2016, Federal Register, the FDA announced availability of a final guidance titled “Clinical Considerations for Investigational Device Exemptions (IDEs) for Neurological Devices Targeting Disease Progression and Clinical Outcomes.” This guidance aims to assist sponsors who intend to submit an IDE to the FDA to conduct clinical trials on medical devices targeting neurological disease progression and clinically meaningful patient centered outcomes. It makes final a March 2016 draft.

The FDA believes that neurological devices intended to slow disease progression and improve clinical outcomes that are meaningful may represent a revolutionary option for patients. The guidance aims to aid industry and FDA staff in considering the benefits and risks of medical devices that target either the cause or progression of a neurological disorder or condition such as Alzheimer’s disease, Parkinson’s disease or Primary Dystonia, rather than the symptoms. It applies to neurological medical devices that are designed to slow, stop or reverse the progression of disease and result in clinically meaningful patient outcomes. It provides general study design considerations for clinical trials that investigate neurological devices using biological markers and clinical outcome assessments. Submit comments as instructed above. Identify comments with Docket No. FDA-2016-D-0539.

Non-Inferiority Clinical Trials to Establish Effectiveness

In the November 8, 2016, Federal Register, the FDA announced availability of a final guidance titled “Non-Inferiority Clinical Trials to Establish Effectiveness.” This document provides guidance to applicants submitting investigational new drug applications, new drug applications, biologics licensing applications or supplemental applications on the appropriate use of non-inferiority (NI) study designs to provide evidence of the effectiveness of a drug or biologic. The guidance gives advice on when NI studies demonstrating effectiveness can provide interpretable results, how to choose the NI margin and how to test the NI hypothesis. This guidance consists of four parts. The first is a general discussion of regulatory, study design, scientific and statistical issues associated with the use of NI studies to establish the effectiveness of a drug or biologic. The second focuses on some of these issues in more detail, notably the statistical approaches used to determine the NI margin and to test for non-inferiority. The third addresses commonly asked questions about NI studies. The fourth includes four examples of successful and unsuccessful efforts to define NI margins and test for non-inferiority.

It makes final the draft guidance for industry, “Non-Inferiority Clinical Trials,” published in 2010, and it supersedes the guidance for industry, “Antibacterial Drug Products: Use of Noninferiority Trials to Support Approval,” also published in 2010, which will be withdrawn. Submit comments as instructed above. Identify comments with Docket No. FDA-2010-D-0075.

Effective Date for NIH Policy on Single Institutional Review Board for Multi-Site Research Extended

On December 16, 2016, the National Institutes of Health (NIH) of the Department of Health and Human Services (DHHS) extended the effective date for the NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research from May 25, 2017, to September 25, 2017. A copy of the NIH Policy (published June 21, 2016) is available at https://www.gpo.gov/fdsys/pkg/FR-2016-06-21/pdf/2016-14513.pdf.  Guidance and Frequently Asked Questions to assist in the implementation of the policy will soon be available at http://osp.od.nih.gov/office-clinical-research-and-bioethics-policy/clinical-research-policy/models-irb-review.  For further information, contact the NIH Office of Science Policy, at (301) 496-9838. 

The Regulatory Update is excerpted from Research Practitioner, Volume 17, Number 01, January/February 2017.