Risk & Resources to Shape Trial Operations

The high cost of drug development, declining pharma revenues, and concerns about unclear and conflicting regulations are generating calls for major changes in clinical research practices. Sponsors complain that the Food and Drug Administration's risk-averse nature leads to larger, more costly studies that delay access to promising therapies. FDA points to the notable jump in approvals for new molecular entities last year as evidence that the agency does not keep important new medicines from patients. FDA also seeks to collaborate more with other regulatory authorities, academia, and industry and is encouraging development of "personalized" medicine to provide more effective treatments based on individual response. It remains to be seen if the spike in approvals last year is a fluke, or a sign of progress on the innovation front, as FDA and the research community address many difficult issues in the coming months.

Jill Wechsler

Global challenges

Regulators and researchers are struggling to deal with the continued rise in clinical trials conducted in foreign countries due to increased demand for vital medicines and vaccines in other regions, along with industry's search for more efficient research operations. More public-private partnerships are tackling tropical diseases, malaria, and tuberculosis, further expanding the volume of overseas research.

The trend is driving efforts to harmonize conflicting regulations for ensuring ethical research and compliance with standards. An October 2011 report from the Center for Global Development proposes to accelerate research on treatments for neglected diseases by establishing systems for diverse regulatory authorities and ethics committees to evaluate and approve protocols at the same time. Similarly, pharmaceutical companies are implementing recommendations of the Multi-Regional Clinical Trials Project to establish common policies and practices for conducting research in different geographical regions.

Regulatory authorities also seek to expand collaborative efforts to monitor far-flung research activities more efficiently. FDA and the European Union are continuing a joint program on good clinical practice (GCP) inspections based on positive results reported in July 2011 from a pilot program to share inspection information and to conduct joint inspections. The current participants are looking to form similar cooperative programs with other regulatory authorities and in additional regulatory areas.

Ethics and disclosure

The growth in international research raises important ethical issues that are under scrutiny on a number of fronts. The Obama administration has called for an assessment of US regulations protecting human subjects by the President's Commission for the Study of Bioethical Issues. The aim is to evaluate whether current research policies are sufficient to prevent any recurrence of the ethical violations associated with 1940s research in Guatemala on sexually transmitted diseases, which the commission critiqued in a September 2011 report. The panel issued its report last month, which found that current rules do protect research participants from harm, while noting the need for improvements in methods for compensating people injured during research and better tracking and disclosure of federally funded studies.

The commission's work will help shape an ambitious administration effort to enact broad changes in the "Common Rule" governing federally funded biomedical research. The initial reform plan proposes central IRB review for multi-center trials, improved informed consent procedures, standardized collection of safety data, and stronger protections for individually identifiable information from research programs. Interested parties have filed more than 1,000 comments about the proposal, a volume that may make it hard for government officials to meet their plan for issuing a revised reform proposal this year.

While the Common Rule does not apply directly to studies regulated by FDA, the reform initiative could boost public confidence in the pharmaceutical R&D process by eliminating redundant and wasteful regulatory practices and strengthening protections for research participants. Moreover, Common Rule standards could extend to more investigators involved in commercial studies if the policy is expanded to cover all research studies conducted at institutions that receive any federal funding for human subject research.

Federal agencies also are strengthening financial disclosure requirements to address perennial concerns that economic interests could compromise research results. FDA seeks to update its 10-year-old conflict-of-interest policy for investigators to clarify that reporting applies to some early studies and that a broader range of compensation should be disclosed. The National Institutes of Health (NIH) is implementing a controversial new financial disclosure policy that reduces the reporting threshold to $5,000 and seeks to expand disclosure of payment information.

Risk and regulation

The drive for more transparency in biomedical research continues to expand postings for clinical trials and summary results on the http://clinicaltrials.gov website, which now lists more than 100,000 studies. Further growth may be shaped by clarification of the need to register observational studies, to disclose results from trials that are halted or fail to support product registration, and whether sponsors should have to post detailed clinical trial data—not just summaries.

At the same time, new "Sunshine" requirements for disclosing pharma payments to health professionals raise concerns that clinical investigation activities will become even less attractive to practicing physicians. The proliferation of rules requiring public disclosure of research activities and funding may drive efforts to establish international common standards for research transparency.

Limited government resources, along with pressure to better ensure the integrity and proper conduct of clinical trials, will continue to focus attention on risk assessment and risk management in FDA regulatory policies. Agency officials are examining factors likely to precipitate safety problems and patient harm in scheduling clinical site inspections and establishing strategies for study monitoring and evaluation. Such approaches may be extended to inspection programs for institutional review boards (IRBs) and for bioequivalence studies.

In evaluating risk, FDA emphasizes that the ultimate responsibility for ensuring adherence to GCPs and safety standards lies with sponsors, and cannot be handed over to the investigators and contract research organizations they engage. Agency officials want industry to build quality into clinical trials through appropriate study design, data verification, and oversight of critical activities.

FDA also hopes to move forward with required electronic submission of applications for drugs and biologics over the next five years. The agency plans to issue guidance defining standards and formats for e-filings and to develop common terminology for clinical data. A majority of new drug applications now come in electronically, but most INDs (investigational new drug applications) still use paper. Electronic submissions will support an FDA electronic data system with capacity to validate, store, and extract study information. Ultimately, this will assist agency reviewers in evaluating interventions and comparing the effectiveness of different treatments, and will link to electronic health records and to broader health IT systems to support more consistent, rigorous, and timely reviews.

Spurring innovation

Widespread concern about the low productivity of today's drug development process is prompting multiple initiatives to identify biomarkers and other tools that can streamline clinical research, particularly for complex conditions such as weight loss and Alzheimer's. The Predictive Safety Testing Consortium organized by the Critical Path Institute is developing markers for kidney, liver, and skeletal muscle injury. Another consortium is devising electronic methods for collecting patient-reported outcomes data. There is growing enthusiasm for "adaptive" clinical trials, illustrated by the I-SPY-2 study, a broad collaboration managed by the Foundation for the NIH that is examining how different subtypes respond to certain breast cancer therapies. IT initiatives also may make clinical trials more efficient, such as using social medical to recruit patients and establishing secure websites for research subjects to report results.

The new Patient-Centered Outcomes Research Institute (PCORI) is slated to have a $500 million annual budget by 2014 to invest in research on effective treatments for important conditions. PCORI plans to finalize priorities for its research agenda by March, and its Methodologies Committee is scheduled to report in May on research methods and standards for this field. "Patient centeredness" will continue to shape a range of regulatory and research initiatives, as FDA encourages sponsors to incorporate patient needs and opinions into clinical trial protocol design, patient recruitment, drug delivery, and safety evaluation.

Finalizing fees

All these initiatives will be shaped by legislation to reauthorize the Prescription Drug User Fee Act (PDUFA), which has to be enacted by September 30 for FDA to continue to collect fee revenue. FDA and manufacturers have agreed on a revised PDUFA program for drugs and biologics, as well as fees for biosimilars and generic drugs. PDUFA renewal has strong support on Capitol Hill, but individual legislators could hold up action on the bill to add pet programs to the package. In these times when Republicans and Democrats find it hard to agree on most important policies, it will take considerable political skill for a balanced PDUFA bill to make it through the legislative process in time to prevent an FDA collapse.

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