Federal mandates calling for transparency of clinical trial information have been in place in the United States since 1997, but a recent move will finally give the current FDA (Food and Drug Administration) law some teeth to enforce compliance. In September of 2012, the US Department of Health & Human Services (HHS) transferred authority from HHS control to the FDA to oversee information that is filed to ClinicalTrials.gov (“clinical trial registry data bank”), and seek out those who fail to file, or file misleading or false data, according to a statement in the Federal Register.(1)
Why is this transfer of responsibility important? As we travel over the last 15 years and look at deficiencies in the laws governing disclosure, assessing how these deficiencies may have contributed to the existing lack of compliance in disclosure reporting, it is easy to conclude that laws are only as good as the people who enforce them. Important to also note that historically the FDA has been an enforcement agency (2), whereas the HHS/NIH is not.
The Food and Drug Administration Modernization Act (FDAMA) of 1997, Section 113, is responsible for establishing the ClinicalTrials.gov databank. It was the first US trial disclosure law designed to provide the public with information about ongoing and completed clinical trials, specifically for serious or life-threatening diseases or conditions where available treatment options were limited. However, with no penalties or enforcement built into the law, compliance was low.
A FDA analysis discovered in 2002 that only 48% of trials of cancer drugs were being registered and trials for other serious diseases registered less than 10% of the time. (3) Aside from these small targeted analyses being conducted and showing low percentages for compliance, another problem existed in that agencies had no overall mechanism in place for tracking compliance and identifying studies that should have been registered, but were not.
In 2007, the Food and Drug Administration Amendment (FDAAA) Act, Section 801, expanded the clinical trial reporting requirements to include the registration of most interventional studies (not just limited to serious or life-threatening diseases or conditions) and added the posting of results for applicable clinical trials.
This new law had a mechanism for tracking compliance through a form submitted with every FDA application/submission that certifies compliance was being met under Public Law, including a list of each applicable study through an assigned NCT Number(s) on the form. It also has penalties described (e.g., up to $10,000/day) for non-compliance along with enforcement being defined as the following two-step process:
- Notice to Director of NIH: FDA notifies the NIH about change in status of a drug applications (e.g., approval, non-approval, withdrawal) for studies accompanied by a certification
- Notice of Compliance: NIH notifies sponsors if their information in the databank is non-compliant under FDAAA; requesting a remedy within 30 days of notification.
However, as of 4Q2009 (two years after the law went into effect) there was still no system in place for the FDA to notify NIH and no enforcement plan yet established. (4) It should be noted though that this law does include steps for additional rulemaking to take place that will help workout many of these issues, and in the meantime, FDA has communicated that they expect “good faith compliance” with the statutory requirements and expect that researchers will put internal procedures in place to ensure compliance. (4) Let’s look at how trial sponsors continued to comply with law following 4Q2009:
- In August 2010, the NIH sent notices to the responsible parties of approximately 21,000 (9,000 industry and 12,000 non-industry) trials that appeared to be missing data or lacking results in ClinicalTrials.gov. This act resulted in the NIH only receiving responses and/or the data corrections for about 30% of these studies. And even though the pharmaceutical and medical device industries seem to get the most negative publicity from the media when it comes to transparency of trial information, the NIH had found that academic institutions were compliant with FDAAA results postings less than 5% of the time. (5)
- In February 2012, three House lawmakers (Reps. Henry Waxman(D-CA), Ed Markey (D-MA), and Diana DeGette (D-CO)) issued letters to FDA Commissioner Dr. Margaret Hamburg and NIH Director Francis Collins expressing their concern over a report published in the British Medical Journal (“BMJ”) documenting the underreporting of results of clinical studies on ClinicalTrials.gov. A database search of trials registered on ClinicalTrials.gov showed that of the 738 trials that were classified as subject to mandatory reporting, only 22% had reported results.(6) FDA and NIH both disputed some aspects of the study, but as Andrew Prayle an author of the BMJ paper followed up saying, “it is not surprising that they reached different conclusions (than the study), but can they account for all of the 78% of trials which were not reported?”(7)
As seen above, compliance continues to struggle. Even with laws that establish mechanisms for tracking compliance along with the defining of penalties, it is still important that laws are enforced.
The FDA has stated that it can enforce FDAAA from the statute when warranted. But this has only been apparent when other compliance issues are the driving force, such as a string of corporate integrity agreements (CIAs) with the U.S. Office of the Inspector General (OIG) in which clinical trial data disclosure requirements were included along with other compliance issues.(8)
So what message can be sent with this delegation of authority? Current law says that if there is a finding of noncompliance, the sponsor or investigator of an applicable clinical trial has 30 days to reconcile. If there is still noncompliance after 30 days, FDAAA added language for penalties up to $10,000 for each day out of compliance.
In these dismal economic times there is doubt that the federal government has the funding necessary for adding resources to conduct this oversight; however, fining one of the wealthiest industries in the world could more than cover this shortfall (and possibly fund a few other government programs)? Is this delegation of authority setting up the framework for bringing in new government revenue while at the same time addressing a chronic problem and boosting transparency in clinical research?
- Federal Register
- HHS Delegates FDA Authority to Enforce ClinicalTrials.gov Reporting Requirements
- Clinical Trials Reporting and Publication, Congressional Research Service for Congress
- FDAAA Title VIII (PL 110-85, Section 801) Expanded Clinical Trials Registry and Results Database – An FDA Update; Drug Information Association (3rd Annual Clinical Trials Disclosure Workshop), October 7, 2009.
- gov Registration and Results Reporting: Updates and Recent Activity. Journal of Clinical Research Best Practices. Vol 7, No. 2, February 2011.
- BMJ Article on Clinical Trial Reporting Foments Discontent on Capital Hill
- FDA says study overestimated non-compliance with data-reporting laws
- Clinical Trial Data Disclosure: The Pace Quickens, Journal of Clinical Research Best Practices, Vol 8, No 10, October 2012