HHS Announces Planned Rules Affecting IRBs and Clinical Trials

May 14, 2018

HHS is planning to publish several new rules affecting IRBs and clinical trials over the next several months, according to the spring OMB Unified Agenda.
Direct Final Rule: Institutional Review Board Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations – Scheduled for this month, this final rule will permit an Institutional Review Board (IRB) to waive informed consent under certain conditions for minimal risk clinical investigations. According to the announcement, this will “facilitate certain minimal risk clinical investigations to support the development of new products to diagnose or treat disease and will harmonize with the HHS Common Rule waiver provision that has been adopted and successfully employed by other agencies.”
Proposed Rule: Responsibilities for the Initiation and Conduct of Clinical Investigations – Due in April 2019, the FDA will propose rule updates to investigational new drug application (IND) regulations to define and clarify the roles and responsibilities of persons engaged in the initiation, conduct and oversight of clinical investigations subject to IND requirements. “The proposed changes would better protect the rights, safety and welfare of subjects and help ensure the integrity of clinical trial data. The proposed rule should help reduce study misconduct and ensure the integrity of clinical trial data (benefits) while requiring additional documenting, reporting and recordkeeping for clinical investigators (costs),” according to the announcement.
Proposed Rule: Institutional Review Boards; Cooperative Research – Expected last year but now slated for December 2019, this proposed rule would replace current FDA requirements for cooperative research such that “any institution located in the U.S. participating in multisite cooperative research would need to rely on approval by a single IRB for that portion of the research that is conducted in the U.S., with some exceptions. This proposed rule also would also establish an IRB recordkeeping requirement for research that takes place at an institution in which IRB oversight is conducted by an IRB that is not operated by the institution.”

FDA Advises on Clinical Trials for Uncomplicated UTI Treatments
The FDA invited comments from stakeholders on a new draft guidance for clinical trial designs and drug development programs to support indications for uncomplicated urinary tract infection (uUTI) treatments. The draft guidance only discusses uUTI treatments and does not apply to treatments for complicated urinary tract infections. The FDA’s document provides guidance on the size of the clinical trial population, and advises that the size of the database should be discussed with the agency during clinical development. Patients showing signs of systemic illness, such as a fever greater than 100.4 Fahrenheit, shaking chills or other clinical manifestations suggestive of uUTI should be excluded, as well as patients being treated with other antibacterial drugs effective in treating uUTI. The document also provides guidance on trial design and other considerations for patient enrollment.

Clinical Trial Studying Kidney Transplants Between HIV Patients Begins in U.S.
The National Institutes of Health announced the launch of the first large-scale clinical trial to study kidney transplants between individuals with HIV. The HOPE in Action Multicenter Kidney Study will take place in multiple clinical centers across the U.S., to evaluate kidney recipients for potential transplant and HIV-related complications occurring post-surgery and determine the safety of the kidney transplantations. The study will track the clinical outcomes of 160 kidney transplants. Half will get kidneys from deceased donors with HIV, while the others will receive kidneys from HIV-free deceased donors that serve as the control group.

Precision Medicines Get FDA Approval Based on Smaller, No-Frills Trials
Precision medicines are approved faster than other drugs on the basis of smaller and less frequent clinical trials, according to new research published in the journal Health Affairs. Researchers led by Aaron Kesselheim, director of the Program on Regulation Therapeutics and Law (PORTAL) at Brigham and Woman’s Hospital, analyzed FDA reviews of precision medicines from 2013 to 2017 and found precision medicines go through the process nearly two years faster than similar drugs. While this was largely due to the regulatory fast tracks available to such drugs, including the “breakthrough” designation, researchers also found that the drugs are approved based on fewer pivotal trials involving fewer subjects and less likely to involve placebos, randomization or blinding, which limits the data that serve as the basis for FDA approvals.

MHRA Cites Data Management and Integrity Issues in GCP Inspection Report
Problems with inaccessible trial master files and confusing questionnaires are among the nonconforming practices cited in the latest GCP inspection report from the UK Medicines and Healthcare Products Regulatory Agency Annual Report and Accounts. From April 2016 to March 2017, the agency inspected 16 commercial and eight non-commercial organizations, recording 10 critical findings among seven businesses. Of the non-commercial organizations inspected, which comprised three universities, four National Health Service (NHS) trusts and a charity, only one critical finding was logged. One critical recordkeeping issue involved a firm retaining several essential documents in different electronic systems that were not defined as part of the trial master file (TMF) and were not accessible by inspectors. In addition, the TMF presented did not contain all the essential documents needed to reconstruct trial events and show compliance with regulations and the firm’s quality system. In addition, the report cited data management shortcomings such as incorrect eDiary data that was used in analysis, but could not be changed. eDiary devices used by subjects also had no audit trail to verify their authors or entry dates. The portal used to manage data clarification forms also had no audit trail. The inspections also revealed critical data integrity issues. For example, one site’s eligibility and primary endpoint data questionnaires contained confusing language and medical terms difficult for patients to understand. The forms were meant to be completed by a healthcare professional, the report stated, but investigators could not confirm that a healthcare professional had completed or overseen its completion, bringing into question the accuracy and quality of the data. During the site inspection, it also became evident that electronic health records (EHRs) and paper source data used in the trial had several notable deficiencies. For example, it wasn’t possible to verify who completed them, when they were completed, who made changes to them and why the changes were initiated. Read the full MHRA report here:

FDA Issues Advice to Sponsors of Pediatric HIV Drugs
Developers of pediatric HIV drugs should enroll clinical trial subjects in cohorts based on weight rather than age, according to new draft guidance issued by the FDA. Sponsors should begin developing pediatric formulations as soon as the adult dose is selected based on results from the Phase II trial. For nonadolescent pediatric subjects, or those between 4 weeks and 12 years old, sponsors should enroll parallel rather than series cohorts within clinical studies. Phase III efficacy trials should include adolescents along with adults, as dosing recommendations for antiretroviral products are typically the same for adults and adolescents, the agency said. During non-adolescent pediatric trials, sponsors should enroll subjects based on weight rather than age and base the selected weight-bands on World Health Organization (WHO) standards, according to the guidance. When sponsors are seeking approval for a new pediatric formulation, they should conduct bioavailability/bioequivalence studies in adults to demonstrate that the two formulations are comparable. If bioavailability is not comparable, they may need to instead support it through dose adjustments, an additional trial or scientific rationale to support the difference. The agency encourages sponsors to “have early discussions with the WHO, nongovernmental organizations, the FDA and others regarding pediatric plans to facilitate the development of drug products to meet the needs of pediatric patients (e.g., selection of formulation, strengths and dosage of a drug product).”