Fraud, Abuse, and Consent

Clinical studies of new drugs and medical products have been growing exponentially, spurred by a steady surge in federal funding of biomedical research, and by increased investment in R&D by pharmaceutical and biotech companies. A major expansion in NIH grants has focused the attention of federal investigators and oversight agencies on the clinical research enterprise and how well it protects human participants in clinical trials.

The Office of the Inspector General in the Department of Health and Human Services continues to examine the adequacy of protections for study participants, while regulatory agencies are expanding programs and policies to ensure compliance with the rules. Sponsors of studies regulated by the FDA face added rules governing clinical trial conduct, as well as new threats of litigation from government and private attorneys.

Law enforcement officials are concerned that the increase in the number of clinical trials is prompting sponsors and CROs to sign up a broader spectrum of physicians, clinics, and hospitals as clinical investigators, many with little experience in research rules and practices. They question whether this growing pool of researchers is adhering to requirements for recruiting trial participants, ensuring informed consent, documenting clinical responses, and filing information on adverse events. Hospitals and physicians are eager to expand research activity to boost incomes squeezed by the tighter reimbursement policies of HMOs and government health care programs. However, they now find themselves in a whole new world of regulation and compliance requirements.

Both government officials and private attorneys maintain that the goal of heightened enforcement and regulation is to ensure that study participants are safe and fully informed of the risks of participating in research programs. This is not about compliance, but about our desire to protect human research participants, says Mark Yessian, an OIG (Office of the Inspector General) regional inspector general for evaluation and inspections. All parties aim to restore public confidence in biomedical research that has been damaged by deaths and harm due to inadequate research oversight. The question is whether efforts by sponsors and researchers to avoid lawsuits and regulatory problems are imposing excessive controls on R&D and wasting resources.

Cracking down
The search for fraud and abuse in the clinical research arena is a prime interest of Justice Department attorneys. Assistant U.S. attorney James Sheehan reports that he is focusing more on clinical trial activities as they proliferate in the Philadelphia area.

Misrepresentations in grant applications to NIH or in filings with FDA could generate scrutiny, noted David Hoffman, another assistant U.S. attorney from Philadelphia. Speaking at the Medical Research Summit in Washington, DC in March, Hoffman noted that a study sponsor or investigator could get into trouble by failing to provide meaningful and full disclosure to patients of research risks and conflicts of interest, failing to report adverse events properly, publishing biased or slanted research results, or falsifying information or records.

Plaintiffs and prosecutors increasingly bring charges involving medical research under the False Claims Act (FCA), which prohibits intentional submission of false claims to the U.S. government. Many of these cases have been initiated by whistle-blowerssuch as nurses at clinical sitesand most have been brought against academic research institutions for fraud related to the misuse of NIH grants.

Penalties for FCA violations can be stratospheric, commented attorney Paul Kalb (of Sidley Austin Brown & Wood) at the research summit. He explains that the sponsor of a clinical trial could be liable under FCA if a government health program such as Medicaid pays for a drug or medical product that is approved by FDA based on fraudulent filings with the agency. In December 2000 Johnson & Johnsons LifeScan subsidiary agreed to a $60 million settlement with plaintiffs who argued that FDA would not have approved LifeScans glucose monitoring kit if the company had fully reported adverse events to the agency. The two company whistle-blowers who brought the case collected multimillion-dollar awards and set an example for other concerned insiders.

Another looming concern for study sponsors is the possibility that payments to physicians for research services could violate the federal antikickback statute. That law imposes heavy penalties on any party that pays someone to induce the purchase of goods or services paid for by a government program. A clinical trial sponsor or CRO could run afoul of this policy if found to pay physicians excessive fees for conducting bogus studies. While preapproval trials that undergo review by FDA and an IRB are unlikely to appear as shams to channel money to heavy prescribers, Kalb notes that the issue can arise with Phase 4 studies.

Former Justice Department official John Bentivoglio (now with Arnold & Porter) advises pharma companies to look behind their arrangements with clinicians to see whether they are legitimate or could be regarded as a way to transfer payments to influence prescribing.

A third source of concern for sponsors and investigators is the growing number of trial lawyers filing suits on behalf of individuals harmed through participation in clinical trials. Most of these cases have involved universities and research centers, but CROs or manufacturers that directly oversee subjects in studies could become parties to such suits. The deep pockets of pharmaceutical companies make them ready targets for plaintiffs attorneys.

Probes expanding
Many of the cases brought by the Justice Department and private plaintiffs arise from OIG investigations. This investigative arm of the Department of Health and Human Services (HHS) put the spotlight on inadequacies in the nations research oversight system in a June 1998 report documenting the shortcomings of IRB operations. Subsequent OIG studies have raised concerns about human subject recruitment and the proliferation of foreign clinical trials. More recently the OIG has been looking at how well sponsors monitor clinical trials, whether pharma company payments to providers violate the antikickback law, and how human subjects are recruited for clinical trials.

A new report that is expected in June will evaluate how well clinical trial Web sites convey to the public useful information about research opportunities. The OIG has examined 22 Web sites with 110 clinical trial listings to see if Internet communication provides a vehicle that can help the public understand research issues and promote informed consent, Yessian explained. He noted that many of the clinical trial listings hyped benefits but said little about risks. Some sites touted trials as a way for individuals to obtain experimental drugs or to make money. These shortcomings may spark interest in standards or accreditation of Web sites, as well as requirements for IRB oversight.

Congressional concerns
These developments are prompting lawmakers to examine ways to strengthen federal policies governing clinical research. The Senate Health, Education, Labor, and Pensions (HELP) Committee has held hearings on clinical research issues to assist committee chairman Ted Kennedy (Democrat, Massachusetts) and Senator Bill Frist (Republican, Tennessee) develop legislation on the issue. The senators seek to enhance IRB capabilities and to address conflicts of interest and informed consent requirements.

In the House, Representatives James Greenwood (Republican, Pennsylvania) and Diana DeGette (Democrat, Colorado) back legislation to apply the Common Rule of 1986 (which governs research funded by federal agencies) to all research, including that which is privately funded. The legislators also may seek to expand the HHS Office of Human Research Protections (OHRP) into a broader agency that would oversee all research involving human participants supported by federal government agencies. Congress currently is focused on several other biomedical research issues, which are likely to sideline adoption of new laws to enhance human research protections. The legislators have been involved in a heated debate over measures to ban human reproductive cloning, which also could curb research on therapeutic cloning of human embryos. The House and Senate also have to resolve differences in bioterrorism bills approved last year, which include some provisions related to medical research involving toxic agents.

FDA weighs in
While Congress studies these issues, FDA is offering new policies to enhance the ability of IRBs to assess study protocols. One plan in the works for more than a year is to require that all IRBs register with the agency. Registration is considered a basic step for FDA and HHS toward getting better information on the range and scope of the IRB community and being able to communicate to that community about policies and requirements.

Another proposal aims to address OIG concerns about IRB shopping by sponsors and investigators. In March, FDA issued a request for comments (through 6 June 2002) on a proposal to require that medical researchers inform IRBs about prior assessments of a protocol by other review boards (Federal Register, Vol. 67, No. 44, p. 10115-6, 6 March 2002). The agency wants to know if sponsors and researchers consider IRB shopping a significant problem and whether it is more common for certain products and situations. If disclosure is warranted, FDA would like suggestions on who should provide information on prior review, how and what should be disclosed, whether a sponsor should reveal both favorable and unfavorable reviews, and whether this information also should be disclosed to FDA.

One question is whether disclosure is useful without full information on the basis of a prior IRB decisionbut requiring that IRBs explain their reasons for approving or rejecting a study plan would add to their already overburdened agendas. Although the proposal aims to prevent companies from hiding unfavorable IRB decisions, FDA acknowledges that there are situations where it may be appropriate for a sponsor to challenge an IRB decision and seek a second opinion. In such cases, however, the regulators believe that IRBs should be informed of all the facts.

SIDEBAR: Should subjects decide instead of consent?
The research community is now talking about encouraging informed decision making by research participants, instead of informed consent. Greg Koski, director of the Office of Human Research Protections (OHRP), commented recently that the term informed consent presumes that the individual will give consent; informed decision making, instead, implies that a decision is based on full understanding of the risks involved.
Jill Wechsler, Washington Editor

What do you think?
Does it seem to you that informed decision making is a more informative way to describe the process of obtaining consent from potential research subjects? Do you think that the term informed consent carries a built-in presumption that individuals will consent?

Do you believe that a new term is desirable to help ensure that subjects are fully informed of their rights and protections? If so, would you choose informed decision making, or would you like to see the clinical research community adopt some other language?

With your participation and suggestions, this discussion will continue in future issues of Applied Clinical Trials. Wed like to hear from you by fax (541 984-5250) or email (jganter@advanstar.com).
Jane Ganter, Editor-in-Chief