Compliance with FDAAA 801. Are trial results being reported on time?

In 2007, the US Congress enacted the Food and Drug Administration Amendments Act of 2007 (FDAAA)1. According to its Section 801, also known as FDAAA 801, responsible parties are required to post basic results of completed clinical trials to Clinicaltrials.gov. Submitting the results became available from September 2008, when the ClinicalTrials.gov results database was launched.

FDAAA 801 does not apply to all clinical studies, but only to those that meet the FDA definition of an ‘Applicable Clinical Trial’2. In general, this term includes all interventional studies of drugs, biologics, or medical devices, which

  • have at least one research site in the United States, or are conducted under an FDA investigational new drug application or investigational device exemption, or involve medical product that is manufactured in the United States and exported for study in another country
  • are not phase I trials or device feasibility studies

FDAAA 801 does not require results submission for drugs and devices not approved by FDA. Moreover, it does not apply to trials that were ongoing as of September 27, 2007, and reached the primary completion date before December 26, 2007. Nevertheless, any trial may be subject to the Voluntary Submissions provision.

Results of applicable studies must be submitted no later than 1 year after the date of completion or early termination. This deadline can be extended up to 2 years under certain circumstances related to marketing approval of novel products. In this case, a certification to delay submission or an extension request must be provided. For not complying with FDAAA 801 requirements, penalties have been established that include:

  • civil monetary penalties of $10 000 a day
  • withholding grant money

Attempts to assess the rate of timely reporting

Since the law came into force, numerous studies have been conducted to assess compliance with FDAAA 8013-9,11 as well as to elucidate key factors associated with reporting rate3-8,10. These studies differed in search algorithms and time intervals analyzed. Some of them were focused on overall compliance with mandatory reporting4-6,8, while others were restricted to a certain product type3,7,9,11. Not surprisingly, differences in a study design yielded differences in estimates. Nonetheless, despite inconsistency in results, the main conclusions were generally the same:

  • industry-funded trials are much more likely to report results than trials with academic funding
  • later phase trials are more compliant with FDAAA 801 than phase II trials
  • compliance with mandatory posting the results is far from being optimal

Anderson et al.8 analyzed the period from 2008 through 2013, and provided the following estimates: among the studies that were required to submit the results, only 13.4% reported them on time, and 6.1% had a legally acceptable delay. Trials funded by industry met disclosure requirements in 17.0% of cases. At the same time, reporting rates for trials funded by the National Institutes of Health (NIH) and other institutions were 8.1% and 5.7%, respectively.

The study by Anderson et al. was well-designed. To identify highly likely ‘Applicable Clinical Trials’, they used algorithm based on input from the National Library of Medicine. Furthermore, they scanned 5 databases to determine whether a product was approved by the FDA. However, the question “which trial to include in the analysis” was still a stumbling block that caused a lot of criticism regarding some earlier studies. ClinicalTrials.gov results database does not have fields to define whether a trial is covered by FDAAA 801. Thus, making precise estimates was a really difficult task.

Concerns were expressed that the analyzed trials could have contained the following studies:

  • completed before the law came into effect
  • trials of unapproved products
  • trials which have submitted the results, but have not yet been verified by the FDA
  • studies that have requested a delay to submit results

Besides this, it was shown that data obtained could be confounded by a wrong interpretation of FDAAA 801 requirements. So, in some cases, the violation of FDAAA 801 was concluded to be overestimated and needed to be re-analyzed. This was done with respect to the study by Miller et al.9 A further study by Lassman et al. provided an independent analysis based on a deeper insights into a more complete dataset11. They revealed a significantly higher overall FDAAA 801 compliance rate for drugs sponsored by large companies (86% vs. about 70%).

Much public attention was drawn to the study conducted by Prayle et al.4 According to their calculations, compliance with federal law was 22% for all trials, 40% for industry-funded trials, and 9% for trials not solely funded by industry. Members of the US Congress demanded an explanation from the NIH and the FDA. In response to this claim, the NIH performed an unofficial analysis and reported on-time reporting rates of 52% for industry, 21% for NIH-based sponsors, and 14% for NIH-funded academic sponsors12.

Prayle commented this reassessment, “I think that although we may argue about the specific percentages, it appears clear that the majority of trials didn’t report on time, even with the unofficial NIH analysis.”13

What are the reasons for poor compliance?

Several reasons for low disclosure rates have been proposed:

  • collaborations, mergers, and acquisitions can cause problems with taking responsibility to report9
  • despite the severe penalties established, they have never actually been imposed14
  • some FDAAA 801 requirements are unclear and ambiguous, that leads to conflicting understanding of which trials are subjects to the law and what are the actual reporting timeframes

Lassman et al.11 wrote, “For example, is a ‘certificate of delay’ (COD) required if a clinical trial is completed before initial approval of an investigational drug? If the drug is not approved for any indication, there arguably is no 1 year deadline to post trial results because FDAAA does not require results posting for trials of unapproved drugs. And if there is no deadline, there arguably is no need to submit a COD to ‘delay’ that deadline. In light of this ambiguity, some companies took the position that a COD was not required for trials of unapproved drugs, but they nevertheless complied with the spirit of FDAAA by submitting results to ClinicalTrials.gov within 30 days after initial approval of the drug.”

The Final Rule

The Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11)15 was released in September 2016. It is applicable to clinical trials initiated on or after January 18, 2017. The Final Rule aimed to clarify the FDAAA 801 requirements and interpret ambiguous statutory provisions. A step-by-step checklist16 was developed to evaluate whether a study is an ‘Applicable Clinical Trials’ under 42 CFR Part 11.

In order to further increase transparency, The Final Rule provided additional requirements for trial registration and results submission. In particular, results disclosure became mandatory for all trials regardless of the FDA approval status. Changes from the previous rule were summarized in a corresponding document17.

For today, it is too early to judge how successful this initiative is and whether it can improve timely reporting. Nevertheless, it seems to be an important step towards promoting the public availability of clinical trial information.

 

References

[1] Food and Drug Administration Amendments Act of 2007. Accessed 3 April 2018. https://www.gpo.gov/fdsys/pkg/PLAW-110publ85/pdf/PLAW-110publ85.pdf

[2] Elaboration of Definitions of Responsible Party and Applicable Clinical Trial. Accessed 3 April 2018. https://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf

[3] Law MR, et al. Despite law, fewer than one in eight completed studies of drugs and biologics are reported on time on ClinicalTrials.gov. Health Aff 2011;30:2338–45.
http://dx.doi.org/10.1377/hlthaff.2011.0172

[4] Prayle AP, et al. Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study. BMJ 2012;344:d7373–d7373.
http://dx.doi.org/10.1136/bmj.d7373

[5] Gill CJ. How often do US-based human subjects research studies register on time, and how often do they post their results? A statistical analysis of the Clinicaltrials.gov database. BMJ Open 2012;2:e001186. http://dx.doi.org/10.1136/bmjopen-2012-001186

[6] Gopal RK, et al. Research without results: Inadequate public reporting of clinical trial results. Contemp Clin Trials 2012;33:486–91.
http://dx.doi.org/10.1016/J.CCT.2012.02.001

[7] Nguyen TAH, et al. Public Availability of Results of Trials Assessing Cancer Drugs in the United States. J Clin Oncol 2013;31:2998–3003.
http://dx.doi.org/10.1200/JCO.2012.46.9577

[8] Anderson ML, Peterson ED. Compliance with Results Reporting at ClinicalTrials.gov. N Engl J Med 2015;372:2370–1.
http://dx.doi.org/10.1056/NEJMc1504513

[9] Miller JE, et al. Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012. BMJ Open 2015;5:e009758. http://dx.doi.org/10.1136/bmjopen-2015-009758

[10] Shamliyan T. Reporting of results of interventional studies by the information service of the National Institutes of Health. Clin Pharmacol Adv Appl 2010;2:169.
http://dx.doi.org/10.2147/CPAA.S12398

[11] Lassman SM, et al. Clinical trial transparency: a reassessment of industry compliance with clinical trial registration and reporting requirements in the United States. BMJ Open 2017;7:e015110.
http://dx.doi.org/10.1136/bmjopen-2016-015110

[12] Wadman M. FDA says study overestimated non-compliance with data-reporting laws. Accessed 3 April 2018.
https://www.nature.com/news/fda-says-study-overestimated-non-compliance-with-data-reporting-laws-1.10549

[13] Hawkes N. FDA disagrees with BMJ study that found clinical trials were not being reported. BMJ 2012;344:e3277.
http://dx.doi.org/10.1136/bmj.e3277

[14] Lynch HF. It’s time to levy penalties for failing to report clinical trial results. Accessed 3 April 2018. https://www.statnews.com/2018/01/17/time-levy-penalties-failing-report-clinical-trial-results/

[15] Clinical trials registration and results information submission. Accessed 3 April 2018.
https://www.federalregister.gov/documents/2016/09/21/2016-22129/clinical...

[16] Checklist for evaluating whether a clinical trial or study is an Applicable Clinical Trial (ACT) under 42 CFR 11.22(b) for clinical trials initiated on or after January 18, 2017. Accessed 3 April 2018.
https://prsinfo.clinicaltrials.gov/ACT_Checklist.pdf

[17] Changes from current practice described in the Final Rule. Accessed 3 April 2018. https://prsinfo.clinicaltrials.gov/FinalRuleChanges-12Dec2016.pdf