The US Food and Drug Administration (FDA) today announced it will keep open a comment period for a relatively little-noticed but potentially important document on the partial release of clinical trials data by the agency.
Background and Basics
The proposal, Availability of Masked and De-identified Non-Summary Safety and Efficacy Data, was first announced by FDA on 3 June 2013 and proposed permitting regulators to partially release data to certain outside researchers.
The notice followed a lengthy push by FDA Commissioner Margaret Hamburg to improve how FDA leverages regulatory science to the benefit of product applications. That push, known as the Regulatory Science Initiative, is specifically meant to "enhance the science and knowledge critical to improving the development, manufacture, evaluation, and safe use of critically needed new therapies," FDA explained in the announcement.
And that's where preclinical and clinical study data comes into play, FDA continued. The agency explained that data from one study may be useful to addressing "key hurdles in drug development" such as the development of new valid endpoints for trials, the predictive value of preclinical models, a deeper understanding of how products affect different diseases, and whether new clinical designs could be used. In one cited example, data studied by the agency resulted in cutting the clinical development time in half for one hepatitis C candidate.
Safety issues, too, can often be addressed more easily when data is pooled. FDA said an analysis of 199 trials of 11 antiepileptic drugs identified an increased risk of suicidal ideation and behavior for patients. Other trials have provided key data on which biomarkers predict hepatic toxicity.
All of this serves to benefit both patients and companies alike, FDA said. Patients would benefit from having earlier access to safer medicines, while companies would be able to save money and get an earlier return on their investment.
There's just one problem, says FDA: While it has considerable expertise in analyzing this type of data, it says it wants to bring in additional, outside review resources in the form of independent experts.
As with other clinical trials transparency efforts, the toughest question remains how FDA can bring in outside experts without violating the privacy rights of patients involved in the studies while at the same time protecting the commercial investments of sponsors.
Despite those difficult issues, FDA says it intends to move forward with its proposal with an open ear toward the concerns of sponsors. "FDA intends to consider the extent and nature of public availability of de-identified and masked subject level data necessary to achieve specific aims," it wrote in its Federal Register posting-data that is neither linkable to a specific product nor a specific application or individual patient.
How the agency will mask data is not yet certain, but it said it is considering a range of strategies, including making limited data available to researchers via a random sample or a subset, restricting data analysis to limited data fields, and pooling data to obscure the products.
FDA's proposal has received sharp pushback from industry, most notably from the Pharmaceutical Research and Manufacturers of America (PhRMA).
Something Old, Something New...
PhRMA said it believed the best avenue for disclosing the data would be through "Data generators"-i.e. the pharmaceutical companies themselves-"rather than through agency data disclosure."
"Such an arrangement, when properly executed, can provide unmasked data in a manner that protects both patient privacy as well as incentives for investment in biomedical research," PhRMA wrote, adding that an industry-led initiative would have the added benefit of involving companies that might not have any interaction with the agency.
That industry effort is, not coincidentally, the Principles for Responsible Clinical Trial Data Sharing-a plan released in August 2013 and co-sponsored by PhRMA and its EU equivalent, the European Federation of Pharmaceutical Industries and Associations (EFPIA). The principles, which have been endorsed by all PhRMA and EFPIA member companies, call for each company to permit "qualified" researchers to access de-identified data so long as they conduct "legitimate" research.
The proposal, however, would notably only apply to new trials-not older ones.
But what's more, PhRMA contends FDA already has a statutorily-mandated program that could accomplish its goals more easily.
In comments submitted to FDA in August, PhRMA wrote that the 2007 Food and Drug Administration Amendments Act (FDAAA) already contained provisions to allow FDA to release "Action packages describing the basis for approval of new medicines"-authority the agency has not yet enacted through rulemaking.
"PhRMA believes that companies' commitments to responsible data sharing, combined with full implementation of ClinicalTrials.gov, are the best means to advance FDA's stated objectives," it said.
As to FDA's proposal, PhRMA said it has "significant concerns," noting that the proposal could permit the "wide release" of data to researchers and even "the entire public" depending on the agency's definition of "other interested parties."
In the past, PhRMA has maintained that public release of similar information could result in harms to the public, noting that an incorrect reading of the raw data could be misinterpreted and lead to incorrect assumptions or conclusions. The same argument was advanced in its most recent correspondence to FDA, in which it adds that non-contextualized data analysis by non-experts could lead to second-guessing of FDA's regulatory conclusions, undermining the approval process and faith in the regulatory system.
A Matter of Competition and the Constitution
PhRMA also advanced the argument that the release of data could result in competitors using data to "address key hurdles in drug development," reducing the incentives to invest.
"Analysis of masked data could allow the submitter's competitors to abbreviate their development programs," it wrote. "These competitors might even be able to patent inventions derived from the data and exclude the original submitter from using them." Further, if data was able to be "un-masked"-something PhRMA spends considerable time showing is possible (if also extremely difficult) in the correspondence-"competitors could obtain the reports of investigations in an application and re-submit them to regulators to gain approval of competing drugs."
As a result, PhRMA said it is "concerned that FDA's proposal is inconsistent with existing legal protections for raw data. Because the data would continue to have competitive value after masking, they would remain trade secret and/or confidential commercial information."
And under the Federal Trade Secrets Act and Section 301(j) of the Federal Food, Drug and Cosmetic Act (FD&C Act), such confidential commercial information would thus be illegal to release, requiring a statutory change to permit its release.
Even if that were done, though, PhRMA said the release would constitute a "taking" of submitted data, making it illegal under the Fifth Amendment-an argument recently advanced by the Washington Legal Foundation (WLF) in a similar trade case.
Additionally, PhRMA said that FDA's already-strained resources might be further diverted if the proposal were to be enacted, taking away from its statutorily-defined mission in pursuit of an optional one.
FDA: Let's Discuss This More
Regardless of the merit of industry's arguments, FDA seems ready to discuss the matter more fully.
In a 30 September 2013 Federal Register notice, the agency said it is prepared to reopen the comment period for the notice, which had previously closed on 3 August 2013.
FDA said it had received and considered several comments that the existing comment period "did not allow sufficient time to develop a meaningful or thoughtful response."
In light of these comments, FDA is now granting an additional 30 days for comments. It is unclear whether this timeframe would be extended should a shutdown of the government--and the Federal Register--occur.
Federal Register Notice