Trial Modernization Key to Innovation

Amidst the clamor to reduce the cost and time of drug development and thus speed more new products to patients, a lead strategy is to reform the clinical research process. Proposals are proliferating for the Food and Drug Administration (FDA) to adopt more "pro-innovative" approaches for testing and regulating medical products as user fee legislation moves forward on Capitol Hill. FDA itself is soliciting new ideas for reducing the burdens imposed by trial oversight and data collection requirements.

Separately, the national "Bioeconomy Blueprint" from the White House Office of Science and Technology Policy, issued in April, includes improvements in clinical research as one of many strategies for promoting economic growth and improving public health through biotechnological advances. This grab-bag of ideas also supports public/private partnerships to "repurpose" approved drugs, the cross-government effort to revise the Common Rule governing human subject research, and greater utilization of FDA's vast repository of drug safety and efficacy data to speed drug development.

Jill Wechsler

In addition, a blue-ribbon Institute of Medicine (IOM) panel has called for a major transformation in the US clinical research enterprise to incorporate clinical research into community-based systems of care. This report posted in April summarizes a November 2011 workshop that discussed how a "learning healthcare system" would have doctors who care for patients also serve as clinical investigators so that collaboration across the healthcare system will generate useful information on effective treatments ("View from Washington," February 2012). The result would be increased support for new biomedical discovery from the public and from healthcare providers and payers.

Another IOM report on "Ethical and Scientific Issues in Studying the Safety of Approved Drugs," which we will discuss further next month, lays out concerns related to conducting randomized controlled trials on marketed therapies, along with a discussion of preapproval clinical safety issues that warrant further study of new drugs.

Adding to PDUFA

Looming Congressional action on legislation to reauthorize the Prescription Drug User Fee Act (PDUFA) and several other new and old FDA user fee programs has generated a host of proposals for reforming clinical trial oversight. The PDUFA agreement negotiated by FDA and industry includes provisions to spur development of new treatments for rare diseases and more biomarkers and research tools to streamline clinical studies. A key provision calls for FDA to approve more applications in the first review cycle through greater interaction with sponsors during the review process.

One important, but less noticed, PDUFA provision requires sponsors to file all INDs and applications for new drugs and biologics in a standard, electronic format within five years. The user fee agreement maps out a process for accomplishing this goal: first FDA will issue draft guidance on standards and format of e-submissions by the end of this year; final, binding guidance will be published in another year; and the standards will become binding in two more years. This tight implementation timeframe is spurring FDA and industry collaboration through the Clinical Data Interchange Standards Consortium and the Pharmaceutical Users Software Exchange (PhUSE), which have formed working groups to define terms and to develop standards for reporting and sharing clinical and preclinical data.

In addition to the agreed-on PDUFA plan, a host of additional legislative "enhancements" before Congress aim to spur medical product innovation by making the regulatory process less burdensome and more predictable. Several bills offer incentives for the development of new antibiotics by providing additional exclusivity to sponsors of new therapies, as well as leeway for FDA to use priority review and fast-track approval strategies to speed new treatments to market. Other measures aim to loosen up rules governing FDA advisory committees to allow scientific experts to serve on these panels even if they have conflicts of interest. One proposal wants FDA to clearly explain to sponsors its reasons for rejecting an application so that innovators understand what is needed to get to market.

A key goal of patient and research groups is to expand the FDA's use of the accelerated approval process. At the April annual meeting of the Food and Drug Law Institute (FDLI), FDA commissioner Margaret Hamburg voiced support for legislative language that would provide "clarity to industry and the public" on the use of accelerated approval for "a wide variety of diseases and conditions, including rare diseases." Hamburg also backed proposals to codify the concept of "breakthrough drugs"—products that elicit such a dramatic response early in clinical trials that they warrant market approval based on limited clinical evidence.

Yet, Hamburg doesn't want overly proscriptive legislation. She said nothing about appointing an FDA "chief innovation officer" with authority to ensure that the FDA accepts data from a clinical trial that employs an innovative study approach previously approved by the agency. The aim of such requirements is to protect sponsors from later objections from agency reviewers to streamlined study methods, innovative protocols, or reduced oversight by institutional review boards (IRBs).

The FDA also opposes another industry proposal to expand the agency's mission statement from "promoting the public health" to include "spurring economic growth" through the approval of new medical products. Agency officials say it's impossible to calculate how approval or rejection of a new drug or medical device would affect jobs, as one sponsor might gain from approval, but a competitor could lose.

Hamburg expressed concern that the strong "anti-government and anti-regulation sentiment" expressed in some legislative proposals could "lower FDA's high public health standards that have served patients, consumers, industry, and the public health for so long, and so well." High standards for safety and efficacy, she said, "will ensure that innovations actually help patients," and that they receive coverage from third-party payers.

Setting priorities

In describing the top priorities for the Center for Drug Evaluation and Research (CDER) at the FDLI meeting, Deputy Director Douglas Throckmorton included reinvigoration of drug development on the list. New drug development remains fairly flat, while the cost of conducting clinical trials continues to rise, he said, and "CDER has an obligation to help reverse that trend."

The FDA provided an opportunity for sponsors and the research community to propose new ways to streamline and strengthen the flawed clinical research system at an FDA public hearing in April. The agency sought to build on the multiple initiatives launched over the last decade in part to help improve oversight of clinical research, including the Critical Path Initiative of 2004; the Bioresearch Monitoring Initiative announced in 2006; and the Clinical Trial Transformation Initiative, a collaboration between FDA and Duke University formed in 2007 to carry out specific clinical research improvement projects.

Despite some progress, there was a sense among the fairly few participants at the meeting that these efforts have not greatly reduced the time and money needed to test new medical products.

Participants reiterated well-known recommendations for change: streamline the IRB review process by centralizing IRB functions for multi-center trials; simplify consent forms, which now average 22 pages; harmonize regulations to limit conflicting interpretations; and reduce the need for investigators to send adverse event reports to all investigators and IRBs involved in a study.

Marta Fields, Director of Compliance and Quality Systems at Seattle Genetics, admitted that sponsors tend to over report adverse events, overwhelming investigators with information from all clinical sites because FDA rules are not clear as to what has to be reported to whom. Andreas Koester, Head of Clinical Trial Innovation for the Janssen Pharmaceutical Companies of Johnson & Johnson, proposed that the FDA endorse a standardized investigator training module so that sponsors don't have to retrain investigators for every new research project. More transparency and information sharing on investigator enrollment and dropout rates, moreover, could help sponsors and CROs assess sites and investigators.

Several speakers acknowledged that recent FDA guidance was encouraging trial operators to adopt risk-based approaches to clinical site monitoring. Sponsors are moving away from visiting every site every month, said Koester, but he and others remain wary that the new policy will stick.

Few of these reform projects, however, qualify as "transformative," complained Doug Peddicord, Executive Director of the Association of Clinical Research Organizations. Instead of producing more white papers, he and others urged research to see how a reform proposal actually affects a trial, such as comparing the impact on trial subjects of a five-page informed consent form versus the 22-page one. Peddicord also backed an FDA chief innovation officer able to negotiate binding agreements on innovative ways to test products and move them through the approval process. Sponsors will try faster, cheaper ways of conducting research, he said, if they have assurance a new approach won't be rejected later.

Jill Wechsler is the Washington Editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com