Pre-approval access: Walking a moral, ethical financial tightrope

The needs of the many outweighing the needs of the one might seem the acme of logic, at least for a Vulcan. For humans, it's not so simple, and it's only one of several thorny problems industry, government and society must resolve to establish clear guidance to provide dying patients with compassionate use access to experimental drugs.

Aiming to spur development of such guidance, the NYU Langone Medical Center, which has established a working group on compassionate use and pre-approval access, recently conducted a two-day conference to discuss, as NYU bioethicist Arthur Caplan phrased it, "the pull and tug" of various parties, from patients and their families to drug development companies and their investors to the FDA and its well-established clinical trial and regulatory system that several panelists suggested is in dire need of an overhaul.

Compassionate use, or expanded access – the FDA uses the former term for medical devices and the latter for drugs and biologics – has been around for years, noted Caplan, who had served on institutional review boards (IRBs) during some of the early HIV drug trials. But the explosion of genomics and proteomics discoveries, the rise of the internet and social media and the trend toward patient-centric health care all have combined to push the difficulties and inequities of compassionate use to the forefront. That's been evidenced in the number of right-to-try laws that have cropped – 24 states and counting – and last year's Twitter-storm when parents of 7-year-old Josh Hardy sought access to an investigational antiviral drug for their dying son. (See BioWorld Today, March 13, 2014, and Oct. 1, 2015.)

And polls have indicated that most people view it as a moral obligation to make sure dying patients have access to any potential life-saving treatments, even if economic efficiencies are the trade-off. That makes it easy to blame drug companies if they deny requests, though firms are under no obligation, either regulatory or legal, to provide access to their investigational drugs. It's also easy to point the finger at the FDA as a barrier, but the agency has noted that it actually approves most of the expanded access applications that come through – the FDA's Richard Klein, in fact, noted that an average of 1,200 applications are submitted each year, both for single- and multipatient access, and "99.4 percent year after year have been allowed to go forward and proceed."

As it stands now, all parties are frustrated. CEOs feel "put upon, angry about being vilified," NYU's Caplan told conference attendees during his introductory remarks. "Regulatory people are feeling misunderstood. . . . IRBs are confused about what to do." And management and investors at companies end up "feeling sideswiped when requests come in," particularly those smaller firms that might boast promising candidates but have limited resources.

Patients, too, are often daunted by the process of seeking access to investigational drugs. Even panelist Marc Boutin, of the National Health Council, detailed the difficulties he had negotiating the paperwork to get his dying father access to investigational drugs, despite his industry connections.

And compassionate use is the only option for patients unable to get into clinical trials. Enrollment criteria exclude many patients for various reasons – either they are too early stage to show a clear halt in disease progression or they are the sickest patients whose advanced disease would prevent evaluation via FDA-approved endpoints. Pat Furlong, of Parent Project Muscular Dystrophy, ran into both of those trying to enroll her two sons with Duchenne muscular dystrophy into drug trials.

"If 10 is too old and 6 is too young, you are outside the bus with no opportunities," she said.

Furlong also raised another issue: Patients receiving treatment on a compassionate use or expanded access basis are guaranteed to get the active drug; those enrolled in a clinical study risk ending up in the placebo arm. "Most of these people who are sick don't deserve a placebo effect," she said.

And therein lies the rub, since eventual FDA approval for many drugs is based on data from placebo-controlled studies. Therefore, the question becomes how to balance the needs of a dying patient who can't wait for approval with the needs of future patients who could be helped by the drug if it reaches market.

COMPETING WITH THE REGULATORY SYSTEM

"This is a tough issue from industry perspective," acknowledged Fritz Bittenbender, executive vice president of public affairs at the Biotechnology Industry Organization (BIO), who said the No. 1 goal of the industry group "has to be getting patients access to medicine as soon as possible."

BIO's member companies have to follow FDA's current system. The approval hinges on a drug completing a prescribed clinical program, he added, "and we need patients to be able to do that."

The problem, according to Steve Walker, of the Abigail Alliance, a group lobbying for earlier access to drugs, is that the compassionate use process ends up competing with the regulatory system, to the detriment of both. But, of the two, he suggested it's the regulatory process that needs to change, to accommodate the greater understanding of disease and disease markers and the continuing shift of focus from the disease to the patient.

"Fundamentally, what's wrong with the way we innovate today is that our system is built to learn how to treat a population," Walker said. "The end goal is to produce a statistic, this really meaningless metric called a "p" value – [which is] arbitrarily 0.05; no one knows why – so we know how to treat the average patient."

The problem is that most patients enrolled are not "average" patients, he added. Medicine is "not population-based," and the existing process "is futile; it's not going to work."

And Walker wasn't alone. Several other panelists cited an outdated regulatory system as one of the barriers to getting drugs to patients.

Considering the pace of discovery today, "it is wrong to think that all the systems we built 30 to 40 years ago are going to be up to the task," said pediatric oncologist Peter Adamson, of the Children's Hospital of Philadelphia. "The clinical trial system isn't up to the task, our regulatory system isn't up to the task, industry isn't up to the task," he added. And that's where changes in rules and legislation at the government level will have to come in.

"Unless we have a legislative component to help drive this, we have a lot of interesting discussions but that's all we end up with," Adamson said.

Some suggestions offered during the conference include allowing for provisional approval of certain drugs, after phase I or phase II, which would allow access to patients while providing value to companies, so they can continue attracting backers for further investment in the drug. Other suggestions include putting in place a mechanism for gathering data from compassionate use cases so that information can add to the research.

As for the right-to-try laws, many in industry foresee little impact – the laws address neither funding nor logistics for treatment – but the FDA's Klein noted that though "they don't really add anything" to the FDA's current compassionate use process, they do "remove the guardrails that provide safety."

More than one panelist bemoaned the lengthy paperwork for compassionate use applications, something Klein said is "in the process of being revised" to make it less cumbersome, while still providing all the necessary information. Informed consent is "one of the big, big concerns at the FDA," he said. It's important that patients and/or their caregivers understand the risks.

And there are risks. Drugs can be sought for compassionate use after the phase I stage. Phase I is a "very tiny, very short" trial to establish dose and pharmacokinetics, but "it's not the answer to safety," Klein noted. Patients should be aware of that fact.

If any answers were forthcoming at the end of the two-day meeting, it was that compassionate use within the current framework is the equivalent of "a square peg that doesn't fit into any of the holes," as Abigail Alliance's Walker put it. Resolving the compassionate use equation will require effort on all parties – companies, regulators, doctors and patients.

As Adamson noted, "This is a topic that has a lot of moving parts to it, and we shouldn't try to simplify."

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