For a while now, the awareness of Expanded Access Programs has been on the rise. Expanded Access – for those largely unaware – is the use of investigational new drugs (IND) outside clinical trials. It extends a lifeline to patients with life-threatening diseases enabling them to use INDs because they didn't meet the enrolment criteria of a clinical trial. The benefits of expanded access were highlighted recently in an article by Jess Rabourn, Managing Director of the ALS Emergency Treatment Fund. Below he sits down with CTA to explain how the perception of expanded access has progressed over the last few years.

Clinical Trials Arena: What are the biggest challenges you face with Expanded Access programs?

Jess Rabourn: There are common challenges for any program that brings an investigational drug into the clinic, whether it's for research or for expanded access. But you weigh the costs and hazards against the benefits of engaging patients – benefits to the body of knowledge about the drug's affect on people, and also the benefits to physicians and their patients who are otherwise restricted in their medical decision making. One important challenge for expanded access is that it's often not commercially feasible, especially for the small drug companies bringing cutting edge treatments through trials in tough diseases like ALS and Alzheimers. These companies have a job to do. They're hired by their shareholders to advance a product toward marketing approval. They weren't hired to spend their resources on humanitarian access programs. We have to note that access programs in the U.S. are prohibited from recovering any money above direct costs, and that's a deliberate safeguard against the possible incentive a company may have to skip the research and just sell a drug before it's approved. You can't do that here, and that's a good thing.

There are a few other issues with expanded access. My organization is focused on class-level expanded access trials, which enroll hundreds or thousands or patients at a time, just like research trials. It's for the patients who can't take part in research, which is often a huge proportion of the disease population. But many in this country have become preoccupied with the single-patient variety, since that is one lever that can be pulled by patients and doctors. Drug companies who haven't prepared for expanded access at a class level have been struggling in their attempts to answer the one-off requests that come in. Can you give it to some and not others? For any condition affecting more than a handful of individuals, the single-patient channel is totally inappropriate and virtually impossible to use in an ethical way. So we've been working with drug companies to help them devise ethical large-group access programs that are planned in advance and have consistent enrollment criteria at all participating sites.

CTA: Can Expanded Access programs and clinical trials for the same drug run in conjunction with one another?

JR: Expanded Access can absolutely run in parallel with research. That's exactly how it was envisioned in the 1980s when new antiretroviral drugs were provided to tens of thousands of AIDS sufferers who were too sick to enter the research trials of those same drugs. But there's a narrative out there that says that Expanded Access competes with research trials for precious resources, and can therefore derail drug development for a disease. The narrative extends to the preferential enrollment of single-arm access trials, in which patients know they will get the medicine, as opposed to a randomized trial, in which they may spend six months of their remaining life on placebo. But this old narrative gets way too much air time. Upon closer inspection, there is very little evidence to suggest access programs have impacted trial enrollment. Best practices have evolved and require that either the enrollment periods or the inclusion criteria are dislocated so that there is no competition between research trials and access trials. FDA requires you to demonstrate some control of this issue as well. It's more of a good management issue than an essential risk.

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Expanded access may actually boost enrollment and retention in research trials. In highly publicized access programs for breakthrough cancer drugs like Gleevec and Iressa, participants of randomized Phase 2 research studies were given the option to crossover to the access program at the end of the study period, but only if they had complied with the protocol. In other words, enrol in the study and don't drop out. Those two programs admitted thousands of patients, while fully enrolling and completing their respective Phase 2 trials.

CTA: In your experience, have you found there to be a danger that pharma companies might become, as you say, disincentivised to pursue research trials in favour of Expanded Access programs? What is to stop them from going down this route?

JR: One thing that stops it is the U.S. regulatory statute that requires sponsors of access programs to show progress toward marketing approval. You're simply not allowed to proceed if doing so is expected to imperil the drug's full development.

The economic gains from expanded access are indirect. You can learn from patients and you can build outcomes measures into your protocol that may help you plan your next research trial, but you cannot profit directly by sponsoring an access trial. FDA allows some cost recovery, because otherwise the drug company is asked to shoulder a huge burden for a community good. But, (a) the company is not allowed to charge more than its out-pocket-cost, and (b) it is very hard to charge patients for unapproved medicine, for a lot of reasons. These factors form a huge disincentive for companies to bother with expanded access at any meaningful level. And that's what our organization was built to address.

CTA: Switching track slightly, with Expanded Access programs, is funding a constant issue?

JR: Funding is always an issue, but that boils down to awareness and understanding amongst the clinics, disease foundations. Expanded Access is not a very well understood space, although that's been changing over the last few years. Even the improved understanding people have of Expanded Access today is not entirely clear. We've had a spate of high profile stories of patients struggling with paperwork required to launch their own single-patient IND; the takeaway should have been that companies need more help to launch ethical top-down access programs for whole sections of the population where appropriate. But instead, our media and activist groups have mistakenly blamed the regulatory agencies for the difficulties they face. There really is no regulatory barrier; it's all about the economics.

There needs to be a clear distinction between the single-patient channel and classic group-level expanded access. A lot of people don't know there is a difference and many push for something that's not usually appropriate in the first place. Single access programs are only really for exceptional cases, so education here is really vital.

CTA: To follow on from that, with awareness of Expanded Access slowly on the rise, for the people who may be running out of options as far as treatments are concerned, do they know Expanded Access is a lifeline for them?

JR: I think it's better than it was in the past. Obviously it's moving in the right direction, but we haven't reached a watershed moment where the patient communities get it. You still see a tremendous misunderstanding. Nearly every published article I've seen on this in the last few years – lay and professional – confuses the inadequacies of single patient (or named patient) access for shortfalls of expanded access in general. That's a problem, and it's holding back some real groundbreaking solutions.



*Jess Rabourn is the Managing Director of the ALS Emergency Treatment Fund