Despite this openness, there are some who argue that more information about adverse events in gene therapy clinical trials should be submitted to the RAC and made public. The investigation of the death of the patient in the clinical trial at UPenn has led to a series of stories in the press that imply that gene therapy is dangerous and that the industry is operating in secret and hiding adverse events. This, according to some, puts the public at risk because the true dangers of gene therapy are not being disclosed.
This pressure for disclosure has culminated in a new proposal from the RAC. Through a proposed amendment to the NIH guidelines, the RAC "clarified" its expectations for access to adverse event reports from institutions and investigators that receive NIH funding. The proposal was published in the Federal Register on November 22, 1999. Under the proposal, NIH would request reporting to the RAC of serious adverse events – whether or not the event was associated with or expected from the intervention – using a specified format and within a specified time frame. It would also request that the reports not contain trade secret or confidential commercial or financial information.
Upon review of this proposal, BIO has the following concerns: the standards outlined for expedited reporting are inconsistent with currently recognized standards; the SAE reporting format is inconsistent with current FDA regulatory standards; the context of disclosure for safety reports by RAC is not defined; and the required disclosure conflicts with current federal confidentiality statutes.
We propose an alternative approach for reporting of adverse event data by sponsors. Our proposal would constitute an agreement between the key federal agencies and industry that will provide the RAC with safety data while ensuring that patient confidentiality and trade secret data is protected.
Our proposal has been agreed to by all the members of BIO engaged in gene therapy research. The proposal sets a standard that all these companies will meet. The substance of the proposal will substantially increase the data that will be transmitted to the NIH and therefore to the RAC. We believe that this will effectively reassure patients and the public regarding the safety and efficacy of gene therapy clinical trials, enhance the ability of researchers to enroll patients in these trials, and enhance the RAC’s role in the process. At the same time, it is consistent with the industry’s FDA obligations and confidentiality rules.
The proposed reporting guideline would inappropriately recommend immediate reporting of unrelated serious adverse events.
According to 21 CFR 312, sponsors are required to notify FDA and all participating investigators of any "serious" and "unexpected" adverse event associated with the use of the drug being tested in the clinical trial within 7 days of notification of the event if the event was fatal or life-threatening, or 15 days for other serious and unexpected associated events. ("associated" refers to reasonable possibility of causation) This process ensures that federal regulators have the information they need to make a timely determination about the progress of a trial and whether patients are in danger. It also ensures that participating investigators are aware of important safety information. If patients are in danger, the FDA has the authority to place a clinical trial on hold or prohibit new enrollments. SAEs that are unrelated to the intervention are reported to FDA as part of the annual IND report submitted by sponsors because there is no imminent safety risk. This reporting structure is applicable to the development process for all drugs and biologics.
The NIH proposal defines "immediate" reporting as no later than 15 calendar days after the adverse event occurred. However, FDA regulations specify that the sponsor must report within 15 calendar days of receiving notification from the investigator that the event has occurred. It is therefore important to acknowledge the distinct and separate responsibilities of an NIH funded investigator and an FDA regulated sponsor of clinical trials.
A reporting system that entails the reporting of all SAEs in an expedited manner is inappropriate and unnecessary. The public is already protected by the immediate reporting of related events that alert FDA and all participating investigators to any dangers to patients in clinical trials. Additionally, the FDA has the mandate at any time during the course of a clinical study to require the sponsor to provide full information and analyses on all observed adverse events. Adverse events may occur during a trial that have nothing to do with the intervention. Public reporting of them, however, in the absence of full contextual information on the investigational agent, can result in premature and potentially misleading perceptions of a product’s profile. This could be detrimental to the development of potentially life-saving new therapies.
The proposal creates another reporting format that is unnecessary and duplicative.
The format for reporting SAEs is well established in federal regulations. 21 CFR describes in detail the process and information to be used by sponsors submitting adverse event reports. To create a new format would simply create additional burdens that would not enhance the understanding of a potentially important safety event.
Since the report requested by NIH would by definition contain trade secret and commercial confidential information and private patient information, the RAC cannot lawfully disclose its contents.