On December 14, 2018, the FDA floated plans in Biocentury, to launch a new program in 2019 to help more patients access unapproved therapies through Expanded Access.
The FDA should be commended for recognizing there is a problem with the current system for giving patients with severe or immediately life-threatening disease or condition access to promising new therapies. In 2016, there were over 1.8 million disease related deaths in the United States, yet only 1,300 patients received access to an investigational new product (.07%) through an Individual Patient IND – FDA’s mechanism.
For years, the FDA has pointed to high approval rates (99% of all requests received) as evidence the FDA committed to making investigational products available to patients in need. When considered alone, this data can be misleading. The problem with the program has not been with the number or timing of FDA approvals. The program struggles with the burden of administrative and regulatory requirements and a perceived lack of incentives for manufacturers to participate.
It is time-consuming and expensive for physicians and patients to make Individual Patient Expanded Access requests. The process has been additionally stressed by manufacturers hesitant to approve requests. Companies have a desire to carefully control their clinical development program. Manufacturers may deny requests because they do not want development efforts adversely affected by safety events that occur under Expanded Access, cost of the investigational product is high, the manufacturer has not produced sufficient amounts of investigational product for use outside of approved clinical trials, or simply because of a lack of resources to support those applications. Expanded Access can further be of limited benefit to biopharmaceutical companies as actionable data is rarely collected on use and outcomes in these cases.
Right-to-Try laws addressed risks manufacturers face when approving compassionate use requests, namely use of clinical outcomes to delay or adversely affect review/approval of investigational drugs, indemnification for manufacturers, sponsors, physicians, clinical investigators, and hospitals, and liability for refusing to provide access to an investigational drug for any patient or group of patients.
A great deal of political and societal pressure has now been placed on the FDA.
In response to this pressure, FDA plans an initiative to facilitate access to investigational treatments through Expanded Access. The agency proposes to field telephone requests from physicians and patients streamline the application process (by completing forms like the FDA 3926 form), forwarding requests to manufacturers, and collecting data on outcomes. The process is designed to keep the various players in the process to tight timelines, and gather important data so that FDA can respond to policy to address these hurdles with a clear picture of the barriers that are preventing access today.
The FDA proposal is remarkable in a number of ways.
The first is that this proposal places FDA in the position of practicing medicine. I have direct experience with this. Having run IRBs at the University of Maryland, the University of California at Los Angeles (UCLA) and the Department of Defense (DoD), I have been a member of committees fielding Expanded Access requests. It was common for IRB members to discuss therapeutic alternatives as a part of the review of Expanded Access cases. These discussions were always difficult.
FDA will need to receive clinical information from patients and physicians to ensure they are appropriately “matched” to potentially beneficial investigational products. In cases where multiple investigational drugs are in development, the FDA will inevitably be involved in decisions about the right investigational product for the right situation. The FDA has said it is “considering whether staff who field calls should provide advice about availability of clinical trials or other approved or unapproved drugs.”
I would argue the FDA is going to need to do this for the proposed initiative to provide value. It will also be required because FDA cannot be in the position of facilitating Expanded Access requests only to have them denied by manufacturers because the investigational product is not appropriate, the patient’s clinical case makes access to the investigational product unsafe or an open and accruing clinical trial is available. FDA cannot be both facilitator and regulator in these cases. Conflicts will inevitably arise as new relationships are formed between FDA and companies that approve Expanded Access requests. It will be difficult for FDA to deny marketing approval for products that it has advised patients to use in Expanded Access cases. Direct involvement in individual patient Expanded Access requests has the potential to taint FDAs opinion of investigational products. Successful outcomes could encourage FDA marketing approval for new products and failures could encourage additional FDA caution.
Second, the proposal offered by FDA boils down to cost shifting from patients/physicians to the government. Anova estimates physicians need to spend approximately 100 hours to prepare an Individual Patient Expanded Access request at a cost of approximately $18,000. The physician must explain the patient’s condition, describe the approved products and treatments used to date, name the specific investigational product the patient is seeking to use, attest that all currently approved treatments have been used (or are unlikely to prolong the patient’s life), and describe the potential best and worst outcomes of the proposed treatment. A treatment plan/protocol and consent form must be drafted. Discussions with the manufacturer must be had and key documents (e.g., Investigators Brochure, Pharmacy Manual) must be reviewed to ensure the investigational product can be safety received, compounded and administered. Of course, Institutional Review Board (IRB) review and approval must be obtained, written informed consent secured and serious adverse events reported. FDA is proposing shifting cost from the physician to the FDA. The FDA will describe the patient’s clinical condition, the FDA will draft a treatment plan/protocol and consent form, the FDA will populate the FDA 3926 form, the FDA will draft a Letter of Authorization (LOA). Setting aside whether the FDA could actually lend efficiency to this process, it is a bad idea for FDA to be involved in both drafting materials and then reviewing/approving them as the responsible regulatory authority. It will be difficult for a reviewer at FDA to feel comfortable denying a request prepared by a FDA peer, supervisor, etc.? Just the act of supporting a request implies FDA clinical approval of a particular product in a specific situation.
As a third point, I worry about the impact this approach would have on the relationship between the FDA and manufacturers. Dr. Gottlieb is quoted as saying “There are advantages for patients for FDA contacting the sponsor. We can have a different conversation [with a drug company] than an individual patient or physician.” I am not a fan of what this implies. Biopharmaceutical companies are wholly dependent upon the FDA to approve investigational new products for marketing. Manufacturers receiving requests “facilitated” by the FDA are clearly going to experience pressure to approve these requests. That may not be a good thing when the safety profile of an investigational product is less than fully understood, when product supplies are tight, when manufacturing costs are high or when the clinical details surrounding these cases are not quite right for the product being requested.
Finally, it is unclear to me how meaningful data can be collected from this activity. FDA has not proposed structuring treatment plans/protocols so that consistent data is collected from similar cases. There is no electronic data capture tool being offered to facilitate safety reporting or outcomes. It is not clear that there are even fair descriptions to be used to describe reason(s) why manufacturers deny submitted requests.
At this year’s FDA/CMS summit Dr. Janet Woodcock discussed FDA efforts to convert the FDA from a paper based entity to an electronic one. She astutely pointed out that there are no longer tractor trailers full of essential documents arriving on the FDA’s doorstep. Unfortunately today’s electronic paper process results in the loss of knowledge as actionable data is squashed down into PDF documents. This Expanded Access proposal appears destined to use old technology and approaches (telephone calls and forms) to accelerate a process that helps few today. It is hard to imagine how the suggested approaches could enable 5,000, 10,000 or 20,000 patients to access investigational treatments under Expanded Access.
Some might argue that I am being too hard on the FDA. The FDA is in a difficult situation. The agency is being unjustly accused of being obstructionist and unfair to patients despite a great deal of evidence to the contrary. Shouldn’t the FDA be encouraged to offer this sort of solution if it can help even one patient?
I believe the answer is no. The FDA should encourage the public sector to provide tools to physicians and patients to fix this process, or facilitate a third-party to provide the solution developed for public interest. These tools should do a better job of ensuring qualified patients get access to qualified investigational products at the right time. Quality data should be collected from 100% of these cases…and the FDA should remain an independent regulatory agency providing oversight with the distance required to ensure the welfare and rights of patients in difficult situations.
