The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the “Draft Guidance on Drug Safety Information—FDA’s Communication to the Public.”
BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.
A. Safety Information should be Communicated in the Balanced Context of Benefit/Risk, Health Outcomes, and Scientific Uncertainty:
BIO believes that the Draft Guidance makes some important clarifications in FDA’s risk communication policies that will benefit the public health. For example, the Draft Guidance states that a Drug Safety Communication (DSC) generally communicates the following information (lines 272-276):
A summary of the safety issue and the nature of the risk being communicated
The established benefit or benefits of the drug being discussed
Recommended actions for health care professionals and patients, when appropriate
A summary of the data reviewed or being reviewed by FDA
Since all drugs carry both benefits and risks which must be carefully evaluated by patients and their physicians, we support FDA’s recognition that new safety information must be communicated in the context of the drugs intended use and benefit. As stated in the Draft Guidance, “FDA recognizes the potential public health implications of providing emerging drug safety information, and we are particularly concerned about possible unintended consequences, such as inappropriate modification or discontinuation of useful treatment.” (lines 155-157) BIO fully agrees with this statement so that patients in consultation with their doctor have the full context of a drug’s benefits and risks when making important decisions about their health. The public health is not necessarily advanced by communication of drug risks in the absence of a discussion of known benefits or the context of other commonly accepted risks.
BIO also supports the conclusion that FDA communications should be outcomes focused with clear advice for patients and healthcare providers on how to manage a risk, rather than just focusing on dissemination of facts or conclusions.
We appreciate the communication will also include a summary of the data reviewed or being reviewed by FDA. BIO recognizes the dual, and occasionally competing, goals of timely and relevant communication with the public and the need to ensure that the scientific findings are verified and accurate. However, we note that publication of analyses that have not been verified by quality systems to ensure accuracy of conclusions can lead to greater patient confusion in the long term. Uncertainty in a known or emerging risk is not well described in the guidance as a factor in when to communicate a safety issue to the public or in how the issue is assessed. We request that FDA please describe how the communication might differ based on the level of certainty about a specific risk. In addition to a summary of the data source, we encourage FDA to communicate the level of uncertainty associated with the safety signal and the type of evidence used to support the claim.
B. Communication with the Sponsor Prior to a Risk Communication
Adequate communication among FDA, regulated industry, and the public is a critical component of an FDA public health intervention. The Draft Guidance states that “FDA strives to notify the relevant Sponsor at least 24 hours before the first public communication that emerging safety information about its drug will be posted on the FDA Web site.” (lines 478-480) In the event of a safety issue or enforcement action, we recommend that FDA notify the company involved earlier than 24 hours prior to any external FDA communication so that the company may develop complementary communications to the public and healthcare providers, or work collaboratively with FDA to establish a joint communication plan. We suggest FDA engage with Sponsors at least 48-72 hours in advance of communicating emerging safety information or results of manufacturing site inspections (Form 483) which have implications for patient safety, tothe public. Companies need to prepare to respond to inquiries from media, international health authorities, advocacy groups, and consumers that will be triggered by FDA public announcements.
For example, although MAPP 6700.4 states the Office of New Drugs (OND) safety regulatory project manager will notify the Sponsor once a DARRTS Tracked Safety Issue (TSI) has been created, it does not state that FDA will communicate to the Sponsor regarding FDA web posting of alerts or communication on this topic. In addition, MAPP 4151.6 on the Drug Safety Newsletter states that Sponsors of products discussed in the newsletter will be notified by fax only 24 hours before posting of the newsletter.
There is need for more communication and coordination between FDA and Sponsors to minimize the potential for conflicting information and provide multiple channels of communication to better inform patients and physicians.
C. Communicating when a Safety Issue is Resolved
The guidance does not outline when and how FDA will communicate a decision that a potential safety issue is no longer deemed “potential” or an issue altogether. We request the addition of details regarding such communication.
Additionally, the guidance does not outline how it determines when to remove safety-motivated restrictions (for example, no longer requiring restricted distribution as part of a REMS program) and how that decision is communicated. We suggest that this information be added to the guidance.
Section 11 also addresses how drug safety information is updated and archived. It is helpful that FDA plans to identify updated information in DSC’s with the month and year in which it was identified. Creating a permanent archive (still publicly available on the Web) for all DSCs, however, will create a situation where very old and stale safety communications, that have since been resolved, may be inadvertently accessed as a “live” issue. More fundamentally, permanently retaining old safety communications is at odds with the primary purpose for DSC’s – informing patients and HCP’s about emerging drug safety information. Once the issue has been resolved, the DSC is no longer a “timely communication” (line 52) – it is outdated. For important drug safety information, patients and HCPs should use the approved product labelling as their resource. Retaining closed out DSCs in a permanent archive that is still publicly accessible runs a real risk of misleading the public and creating an information overload, such that the important safety information – that which is found in the product’s labelling – can become obscured.
While an issue is still under study, such as when clinical trials are still ongoing (lines 451-452) or evaluation of a complex issue is still underway (lines 450-451), then it may be appropriate to keep an archive of all DSCs involved with that particular issue. Once an issue has been resolved or the label has been amended appropriately, however, such as when FDA finds “sufficient evidence that a drug is not associated with a safety concern previously described by FDA as an emerging drug safety issue” (lines 439-440, emphasis added), then the entire DSC thread for that issue should be removed from the DSC page, as it is no longer a “timely” communication of an “emerging” safety issue. Similarly, it is unclear what independent utility closed out DSC’s would have for the public absent any regulatory action (line 445). Rather than a catch-all catalogue of information (which, by its very nature, could be incomplete or not substantiated), FDA should ensure that the DSC page remains focused on its stated purpose – providing timely information on emerging safety issues – and leave other regulatory vehicles, such as the product labelling or www.clinicaltrials.gov
for ongoing trials – to serve their purposes. In 5, 10, 15 years time, the permanently archived reports will not provide any benefit to HCPs or patients due to their outdated nature and will only serve to be at most, distracting, and at worst, misleading, about a product’s safety information.
FDA should revise Section 11 to reflect a “close-out” process for when a Drug Safety Communication has been effectively addressed and resolved, such that it no longer will reside in the Drug Safety Communications archive. In the Final Guidance, FDA should remove the sentence “Updated DSC’s, like all DSC’s, are permanently archived on the Web site,” (Lines 442-443) and replace it with a policy that will more accurately track to the purpose of DSC’s and provide meaningful, as opposed to potentially misleading, incorrect information to patients and HCP’s. It may also serve as a resource to document the strengths and limitations of the signal evaluation process. What was the result of all this risk communication? Was public health served?
D. Definitions of “Risk” and “Regulatory Action”
FDA should define what is meant by risk. In general, it seems to mean an adverse event or serious adverse event or medication error, but elsewhere it seems to imply other things, such as off-label use. We note that risk and signal evaluation are not necessarily interchangeable.
In addition, throughout the document, the term “regulatory action” is used, but not defined. For example, the Draft Guidance states that “In recent years, FDA has begun making information on potential drug risks available to the public earlier — often while the Agency is still evaluating the data and determining whether any regulatory action is warranted.” For the sake of clarity, please provide examples of “regulatory action”. FDA can take a number of regulatory actions in response to new safety information, including label changes, Risk Evaluation and Mitigation Strategies (REMS), market withdrawal, recalls, etc.
E. Addressing Sentinel Findings
We request that FDA clearly state and/or recognize that results from the FDA Sentinel Network should follow the processes outlined in both Draft Guidances before communicating Sentinel findings to the public. The FDA Sentinel Initiative falls under the active surveillance evaluations, which is mentioned in both guidances as a source of new, more serious adverse drug reactions.
F. Communicating Other Safety Issues
If off-label use, non-adherence, loss of efficacy, and counterfeit medications are important safety issues, these should also be included in “What this guidance is about,” along with a description of how these issues would be communicated.
BIO appreciates this opportunity to comment on the “Draft Guidance on Drug Safety Information—FDA’s Communication to the Public.” Specific, detailed comments are included in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.