FDA’s finalization of its expanded access policies illustrates the can't-win pressures that the agency often finds itself under from various stakeholders.

The cause of the most recent agency heartburn revolved around the timing of the release of three final guidances on expanded access which lead to fevered investor speculation about what it augurs for orphan drug approvals.

The June 2 release of the guidances (see box) is part of a broader agency effort on the issue of expanded access programs that included a recent forum about the creation of a clearinghouse for the programs and potential additional reforms Also see "Expanded Access Programs Need FDA Policy Changes To Really Expand" - Pink Sheet, 23 May, 2016..

FDA Expanded Access Guidances

The agency has been under political and stakeholder pressure to encourage expanded access – sometimes called compassionate use – programs, and the agency's announcement came from none other than Commissioner Robert Califf, demonstrating the importance of the issue to the agency.

So far so good, right? With the move, FDA is making it somewhat easier for desperately sick patients to access potentially helpful medicines, and showing Congress that it can finalize guidances, a long-standing concern of many who oversee the agency ([A#14150430003]).

Actually not so good for Sarepta Therapeutics Inc., whose proposed Duchenne treatment eteplirsen is awaiting a final decision amid a negative advisory committee decisions and FDA concerns.

The company announced May 25 that the agency had said it would miss the product’s review goal, although that was seen by some as a positive sign ([A#14160525002]).

Sarepta, which already saw its stock sink on the negative FDA advisory committee on eteplirsen, and a subsequent run-up following news that the agency would miss the review goal, saw shares plummet again after the final expanded access guidances were released. Speculation at the time was that the guidelines were another step toward a “complete response” letter for eteplirsen even though FDA stated emphatically that the two were unrelated.

Finalizing guidances little changed since 2013 brings woe to Sarepta, but it could actually help patients on BioMarin's product as the trials wind down.

The theory of why the guidances were bad news for Sarepta goes like this: FDA is under tremendous pressure to approve eteplirsen but is unconvinced by the data, so it wants to reject the application, but also wants to make sure that patients can still have access to the product, so it finalized the guidances to ensure that company could keep patients in drug even as it handled a complete response letter.

It's not airtight logic – why would Sarepta focus on getting patients into a compassionate use program instead of into more registration trials that could win it approval? – but then again the stock run-up after the review delay isn't exactly unimpeachable either, given the agency's history with Duchenne product applications.

FDA fervently insisted that the timing of the guidance release had nothing to do with eteplirsen, and the announcement did not mention Duchenne. But Califf said in the second sentence that as a doctor, he understood “the importance of being able to access investigational treatments for a patient when there are no other options to treat their serious disease or condition.”

Sarepta declined comment on whether it has an expanded access program in place for eteplirsen.

Regardless what that happens with that particular product, the incident exemplifies the damned-if-you-do, damned-if-you-don't aspects of FDA policymaking: Keeping guidances in draft form makes Congress angry, but finalizing them gives Wall Street the vapors.

Few Changes In Finalization

Despite the hoopla, FDA made only a few changes to the expanded access draft guidances it released in 2013, and had received few comments about them.

The Pharmaceutical Research and Manufacturers of America said in comments on the draft guidance that it should be made clear that safety data collected on a drug through expanded access should not be used in risk-benefit calculations in part because the population is not randomized and collection may lack data integrity features. The industry group said the data should not factor into an approval decision unless previously discussed with the sponsor. PhRMA also called for FDA to create an online tool to help providers submit expanded access applications.

The Biotechnology Innovation Organization said in its comments that there should be more clarification on how expanded access protocols should be designed so they can yield new and vital information.

The agency is hoping the shorter request form, which it expects to take 45 minutes to complete, and system clarifications will make it easier to submit expanded access applications.

FDA tends to approve almost all expanded access applications, but advocates have argued that it still is too difficult to make the requests Also see "FDA Expanded Access Guidances Fail To Achieve Détente With Advocates" - Pink Sheet, 27 May, 2013..

Darcy Olsen, president of the Goldwater Institute, a proponent of so-called “right-to-try” laws, said in a statement that FDA’s efforts are laudable, but “there shouldn’t be an application process in the first place.”

“FDA’s shortened form does nothing to address the other choke points in its expanded access program or the systemic disincentives the FDA has created for drug companies to offer treatments to the terminally ill" outside of FDA-sanction clinical trials, Olsen said.

Several states have passed laws mandating patients’ right to try certain therapies if they have no remaining options Also see "Sarepta's Eteplirsen Is Centerpiece Of Senate Hearing On Expanded Access" - Pink Sheet, 26 February, 2016..

Guidances May Help BioMarin

While most of the attention around the compassionate use policies has been focused on Sarepta, the guidances could in fact wind up as the backbone for the Duchenne muscular dystrophy community to continue access to BioMarin Pharmaceutical Inc.'s drisapersen after the firm announced that it was ending development of its Duchenne treatment.

The company said May 31 (two days before FDA released the guidances) that discussions with the European Medicines Agency’s Committee for Medicinal Products for Human Use appeared headed toward a negative decision, just as was reached by FDA.

Drisapersen received a “complete response” letter from FDA in January after a negative advisory committee recommendation and a review delay Also see "BioMarin's Drisapersen 'Compete Response' Shows FDA Flexibility Still Limited" - Pink Sheet, 14 January, 2016..

BioMarin has decided to stop its drisapersen program as well as the follow-on BMN 044, BMN 045, and BMN 053 development programs, which are in Phase II for distinct Duchenne forms, but the company is not abandoning development in the disease altogether, it said.

Like eteplirsen, drisapersen was targeting Duchenne patients with a genetic mutation amenable to exon 51 skipping.

'Transition Plan' Being Created As Trials Wind Down

Patients now receiving drisapersen and potentially those also receiving eteplirsen may have to turn to the expanded access program in order to continue receiving the treatment.

BioMarin is in the process of creating a “transition plan” as it winds down its ongoing clinical trials for drisapersen.

The company told the Pink Sheet that patients will still have access to the drug while the plan is established. Regulatory authorities, along with physicians and advocates, will have input, the company said.

FDA facilitates and reviews requests for expanded access to products. While the agency cannot force sponsors to make drugs available to patients who want them, it does set up the system to allow it to occur.

BioMarin does not have an expanded access program in place now, and only has clinical trials ongoing. A spokesperson offered no information on how much product is left or how much longer patients would be able to stay on the drug.

Transition plans typically do not follow a common formula. Each situation can depend on the number and type of trials that are open, the adequacy and cost of the drug supply, company finances and even whether the product in question has other potential uses in the sponsor’s portfolio.

BioMarin also said that individual investigators, along with patients, ethics committees and institutional review boards, will have to decide whether to continue treatment.

For those patients and families that believe in drisapersen’s effectiveness at stemming the effects of Duchenne, the expanded access program could be a temporary lifeline.

A number of patients testified to drisapersen’s positive effects during the Peripheral and Central Nervous System Drugs Advisory Committee meeting on the product, such as retaining the ability to climb stairs or get into a car unassisted.

Parent Project Muscular Dystrophy, a Duchenne patient advocacy group, said in a June 1 blog post that while the decision is not entirely unexpected, the group was still “heartbroken” at BioMarin’s decision.

“We were all hopeful it would work and we saw that for many it did,” the group wrote. “We were hopeful for future developments, additional exons, possibilities for many.”

Cost Recovery Outlined

The structure of BioMarin's transition plan remains unsettled, but it's doubtful that the firm will seek to recover costs from patients, even though such an element is described in FDA guidance. Firms almost never charge patients for expanded access use, and it is clear FDA's policy is intended to ensure that such a program is not a money-making venture.

But it may become relevant in the case of drisapersen. BioMarin will write down about $580m in the second quarter because of its decision to stop development.

FDA must authorize the sponsor to charge for the drug, which requires meeting a number of requirements.

The guidance also states that sponsors generally will be allowed to charge for the product for a year or less before having to regain agency authorization, or the length of the clinical trial that in which the drug is used.

Sponsors are allowed to recover direct costs of making a drug available to patients, according to the guidance.

In programs for larger patient populations, sponsors also are allowed to recover the cost of monitoring the expanded access IND or protocol, complying with IND reporting requirements, and other administrative costs directly associated with expanded access use.

Third-party administration fees also may be recovered by the sponsor in that setting, according to the guidance.

For individual patient expanded access, sponsors are not allowed to charge to cover indirect costs, such as those associated with developing the treatment protocol and informed consent documents or corresponding with the IRB and FDA, according to the guidance.

FDA Can't Win On Guidances: Expanded Access Policy, Duchenne Worries Collide

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