Earlier this year, the US Food and Drug Administration (FDA) made a quiet but important announcement: It would seek to engender limited clinical trials transparency in the US by releasing de-identified and masked data to select members of the public, but only after soliciting public input to see how the proposal might affect industry. Now the pharmaceutical industry's top trade group, the Pharmaceutical Research and Manufacturers of America (PhRMA) has submitted comments to FDA indicating support for FDA's goals but concern for its methods and legal status.
The proposal, announced on 3 June 2013, follows 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 in 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.
Regulators provided the example of a hepatitis C treatment, which had previously relied upon disease detection at 24 weeks. An analysis of data across 15 trials allowed FDA to determine that patient response at 12 weeks was just as indicative of the ultimate response, allowing companies to cut the trial time in half.
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. The answer, it postulated, lies in releasing marked, de-identified data to experts, hiding both patient identifiers and the identity of the particular drug product, allowing the agency to obtain deeper analysis.
PhRMA: Leave it to Industry
Now PhRMA, fresh off a transparency kick of its own, is weighing in on the proposal, calling its principles well-grounded but its methods concerning.
"PhRMA commends FDA's stated goals to protect patient privacy and preserve incentives for biopharmaceutical innovation," the organization wrote in a 24 July 2013 response to FDA provided to Regulatory Focus. "That said, we are concerned that implementation of this proposal could distract FDA from its primary mission to review marketing applications to bring new medical products to patients expeditiously; focusing on processing these data for outside analysis risks distraction and additional burdens on FDA's valuable resources."
Instead, 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 last week 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.
However, PhRMA wrote that the 2007 Food and Drug Administration Amendments Act (FDAAA) 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 is advanced in its 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.
The letter mentions vaccine products, among the safest products regulated by FDA that have nevertheless been subject to widespread public alarm after one now-discredited British scientist alleged to have found a link between their use and development of autism in children.
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 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.
The letter, when it is posted by FDA, will be available on this webpage.