FDAAA and clinical trial data bases

The recently-enacted FDA Amendments Act (“FDAAA”) has lots of requirements that may have impact on statistical analysis and programming. It is not new that the study information needst o be registered in clinicaltrials.gov database. However, a major change to the clinical trial database is that not later than December 25, 2007, the database must include links to information on clinical trial results. The term “results” is used fairly broadly in FDAAA to include summary information FDA has posted from an advisory committee meeting that considered a particular study, FDA public health advisories, FDA’s application review documents, Medline citations to any publications focused on the results of the trial, and the drug entry in the National Library
of Medicine database of structured product labels (if available).



The results requirements include demographic and baseline characteristics of the study participants, results values for each of the primary and secondary outcomes for each arm of the study, point of contact for scientific queries, and information on sponsor agreements with investigators that could restrict their ability to discuss or publish trial results.



What makes the results requirement most complicated is the format in which the results must be submitted: rather than uploading study results that have already been compiled into a clinical study report for example, using Clinicaltrials.gov's online Protocol Registration System (PRS), sponsors must first create results tables and then enter the data and statistical analyses.


This requirement means that the statistician needs to step in when the study information needs to be entered in the correct way.

Some of the statements in the amendment act are worth attention. The act stated that only applicable drug clinical trials are required to have results published. "IN GENERAL.—The term ‘applicable drug clinical trial’ means a controlled clinical investigation, other than a phase I clinical investigation, of a drug subject..." This seems to imply that the phase I study can be exempted from this requirement. However, the assignment of the study phases sometimes is arbitrary especially when a phase I study is conducted in the patients rather than the healthy volunteers.

The requirement of presenting the results for all primary and secondary could provide the misleading information to the reader if the readers have no knowledge about the interpretation of the results. Not everybody can read the results of scientifically appropriate tests of the statistical significance. Statement says ‘‘(ii) PRIMARY AND SECONDARY OUTCOMES.—The
primary and secondary outcome measures as submitted under paragraph (2)(A)(ii)(I)(ll), and a table of values for each of the primary and secondary outcome measures for each arm of the clinical trial, including the results of scientifically appropriate tests of the statistical
significance of such outcome measures."

Regarding the AE and SAE reporting, the statement says ‘‘(I) SERIOUS ADVERSE EVENTS.—A table of anticipated and unanticipated serious adverse events grouped by organ system, with number and frequency of such event in each arm of the clinical trial.
‘‘(II) FREQUENT ADVERSE EVENTS.—A table of anticipated and unanticipated adverse events that are not included in the table described in subclause (I) that exceed a frequency of 5 percent within any arm of the clinical trial, grouped by organ system, with number and frequency of such event in each arm of the clinical trial." The confusion from this is that there is no clear definition for anticipated and unanticipated SAE and AE. Perhaps for the future study protocols, the anticipated SAE and AE need to be listed in the protocol. Subsequently, the summary table of SAEs and AEs need to be separated for anticipated events and unanticipated events.

Further readings on this topic can be found from:
http://www.fda.gov/oc/initiatives/advance/fdaaa.html
http://www.fda.gov/oc/initiatives/hr3580.pdf
http://prsinfo.clinicaltrials.gov/fdaaa.html
http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2008/02/fdaaa-enforceme.html