On February 14, 2012, the House of Representatives Committee on Energy and Commerce issued a letter to the Honorable Margaret A. Hamburg, Commissioner of the U.S. Food and Drug Administration (“FDA” or “the Agency”), as well as a companion letter to the Director of the National Institutes of Health (“NIH”). The letter to Dr. Hamburg laid out concerns raised by a recent British Medical Journal report evaluating compliance with the regulatory requirements to register clinical trials and post-clinical trial data in the ClinicalTrials.gov database. This study found that investigators, industry, and government agencies conducting in-house research routinely fail to post results of clinical trials in the database, as required by law.

The framework of regulations that governs clinical trial transparency has evolved over the past several years, and FDA’s enforcement authority has been strengthened. These developments have been due to a call for greater transparency by the clinical trials community, the public, and Congress in order to better ensure that unsafe or ineffective drugs do not reach or remain on the market.

A Brief Background on Clinical Trials Transparency Regulations
The Food and Drug Administration Modernization Act of 1997 (“FDAMA”) amended the Public Health Service Act of 1944 to require that clinical trials be registered in a national database. FDAMA mandated the creation of a basic registry in order to alert the public to the existence of drug and biologics trials for serious and life-threatening diseases or conditions. It allowed for, but did not require, the reporting of clinical trial results. FDAMA tasked NIH with implementing the registry for both federally and privately funded trials.

Following enactment of FDAMA, the recall of, or increased warnings for, several popular prescription drugs garnered attention in the national media. For instance, in September 2004, Vioxx was abruptly recalled by Merck after a data safety monitoring board overseeing a long-term study of the drug recommended that the study be halted due to an increased risk of serious cardiovascular events associated with the drug, including heart attack and stroke.

In May 2007, FDA required a boxed warning for Avandia in response to a meta-analysis published in the New England Journal of Medicine analyzing 42 previous studies of Avandia. The clinical data originally submitted to the Agency supporting approval of Avandia indicated that the drug did not pose an increased risk of cardiovascular events. The review, however, raised concerns of a heightened risk of heart attack and death associated with the drug, prompting FDA to require the boxed warning. Both events received considerable national media attention.

In September 2007, Congress enacted the Food and Drug Administration Amendments Act (“FDAAA”). Section 801 of FDAAA was a response to perceived clinical trial reporting failures contributing to continued marketing of dangerous or ineffective drugs, such as Vioxx and Avandia. Section 801(a) expanded the registration requirements for clinical trials, included device trials, and mandated the posting of more detailed trial information and basic study results. This section also required that a certification form accompany certain human drug, biological, and device product submissions made to FDA. Submission of this form certifies the submitter’s compliance with all applicable clinical trial registry and results posting requirements.

FDAAA also created more severe punishments for violators of its transparency provisions. Section 801(b) contained conforming amendments to the Food, Drug, and Cosmetic Act (“FDCA”) which established several new prohibited acts at FDCA 301(jj):

1. Failure to submit certification of compliance or knowingly submitting a false certification;
2. Failure to submit required clinical trial information; and
3. Submission of clinical trial information that is false or misleading in any way.

Additionally, section 801(b) created civil money penalties at FDCA 303(f)(3) for engaging in one of the 301(jj) new prohibited acts. Violators may be penalized as much as $10,000 for all violations adjudicated in a single proceeding. If violations are not corrected within 30 days of notification, additional penalties of as much as $10,000 per day may be assessed until the violation is corrected.

Congressional Concerns with FDA’s Enforcement
Despite the clear grant of enforcement authority to FDA by FDAAA, the Committee’s recent letter to Commissioner Hamburg registered “concerns about whether FDA is adequately enforcing the law requiring such reporting.” The letter continues, “We are also concerned that these publication delays may allow ineffective or dangerous drugs to remain on the market, resulting in significant harm to patients and waste in the health care system.”

The Committee cited the British Medical Journal report, noting that of the 738 trials that were completed in 2009 for which posting was mandatory under FDAAA, only 22% had posted results within one year of trial completion, and that for a staggering 575 of 738 clinical trials, there was a complete failure to provide the trial results mandated by the Act. The authors of the article acknowledged that their study had certain limitations, particularly related to identifying which studies were subject to FDAAA. They wrote that their results were a worst-case analysis, potentially leading to an underestimation in the percentage of clinical trials. Nevertheless, they believed that their general conclusions were still sound even if they could not be sure that they were completely accurate. The Committee letter emphasized that these reporting failures were at the heart of why Section 801 was enacted, registering its disapproval that the Agency apparently failed to make use of the more extensive enforcement power that was specifically created for this very purpose.

The Committee requested that FDA provide answers to four questions:

1. Whether the findings of the study correspond with FDA’s internal data on compliance with the reporting requirements of FDAAA Section 801, and a request for a summary of FDA’s internal compliance data.
2. Whether FDA had issued any warning letters, imposed any fines, or otherwise initiated any enforcement actions related to the reporting requirements.
3. Whether the Agency has adequate resources and authority to enforce the reporting requirements.
4. Whether FDA believes additional statutory changes are necessary to address the issues of underreporting of clinical trial data and non-compliance with the reporting requirements in FDAAA Section 801.

Anticipated Effect of the Committee’s Attention
If recent history is any indication, the effect of the letter will most likely be an increase in enforcement actions taken by FDA against violators of the post-FDAAA clinical trial regulatory requirements. Historically, we have seen a ramping up of FDA enforcement actions when driven by government scrutiny. For instance, in January 2010, the Government Accountability Office (“GAO”) released a report critical of FDA’s oversight of its Office of Criminal Investigations (“OCI”). The very next year, FDA took measurable action.

OCI has the primary responsibility for all investigations conducted by FDA, including suspected tampering incidents and suspected counterfeit products. Similarly, OCI has primary responsibility for all law enforcement and intelligence issues pertaining to FDA-regulated products. As a key element of FDA’s oversight of OCI, FDA’s assessment of OCI’s six field offices is intended to ensure compliance with investigative policies. However, GAO found that these assessments were not being implemented in accordance with prescribed time frames. Of the twenty-four total office assessments that should have been completed during the period under review, only seven, or about 30%, were completed, and one office had not been assessed in over ten years. In addition, the GAO report found that FDA lacked the necessary performance measures to assess OCI’s overall success.

In response to the GAO report, Commissioner Hamburg sent a letter to Sen. Charles Grassley (R-IA), laying out the steps FDA planned to take to correct the shortcomings highlighted by the report. Among other things, Commissioner Hamburg pledged to revamp the criteria used by OCI to select cases for prosecution, indicating that corporate investigations also would include an element of individual prosecution. The plan emphasized FDA’s commitment to increasing the use of misdemeanor prosecutions as a deterrent to executives in the healthcare industry.

The Agency made good on its promise. The healthcare industry did in fact see more enforcement actions taken against corporations following the GAO report. In 2011, prosecutors secured prison terms ranging from five to nine months for four Synthes executives who pled guilty to one misdemeanor count each for their role in the alleged off-label promotion of a bone cement product. Also in 2011, Forest Laboratories pled guilty to a misdemeanor in connection with its marketing of two prescription drugs and was ordered to pay a fine of $313 million. FDA threatened to take enforcement action against Forest’s chief executive officer, but ultimately did not do so.

The healthcare industry should prepare for FDA to take this recent Congressional criticism to heart. In the wake of the Committee’s February 14 letter, we can expect clinical trial registration and reporting enforcement actions in the months and years to come.

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Gary Messplay (gmessplay@hunton.com) is a partner in the Washington, D.C. office of Hunton & Williams LLP and is co-chair of the Firm’s Food and Drug Practice. Allison Reschovsky (areschovsky@hunton.com) and Adele Gilpin (agilpin@hunton.com) are associates in the Washington, D.C. office of Hunton & Williams LLP, in the Firm’s Food and Drug Practice.