In May of this year, the US Food and Drug Administration (FDA) released a Guidance for Industry on group-level “Expanded Access” for unapproved drugs. Journalists and investors reacted with wide speculation as to what these “new rules” might mean for drug development. The answer is: not much; the rules are not new at all. Today's regulations on Expanded Access in the US have been the same since 2009, when two minor modifications were made (one relating to cost recovery, the other relating to distinct authorization criteria for intermediate size and large size group programs.) The FDA periodically issues ‘Guidance for Industry’ documents on various regulatory topics. They clarify existing rules, rather than set new ones. Furthermore, the recent Guidance on Expanded Access was released in its draft form in 2013, meaning those who are interested or already involved in the practice have had plenty of time to familiarize themselves with the information. But there is a lot more to Expanded Access than regulatory policy.
Expanded Access programs are "treatment use" clinical trials in serious unsolved diseases, and they are intended for enrolling groups of patients who cannot get into the "research trials" of a particular investigational drug. In the last 24 months, reporters have issued a heavy dose of headlines on the topic, first telling the story of terminally ill patients who had tried and failed to access investigational drugs through a single-patient form of Expanded Access. Then – in response to these human stories – more highlighted several governmental efforts to make single-patient Expanded Access easier for patients to apply for, and then, more recently, reporting various market perceptions of Expanded Access, including an investor sell-off of drug maker Sarepta following FDA’s new Expanded Access Guidance.
With the media hoopla, one would be forgiven for thinking that shifting FDA policy was a major part of the early access landscape in the US But it is not. In fact, the regulations have remained largely the same since first enacted in 1987, and in the following three decades FDA has been consistently liberal in granting the requests of drug makers and other sponsors seeking to enroll patients in Expanded Access programs. But, here is the crux: while a drug's availability through Expanded Access has had almost nothing to do with FDA policy, it has nearly everything to do with the disease community and the business conditions in which the drug company operates.
The task of any commercial enterprise – including drug companies – is to use its resources in ways that maximize the odds of economic reward while minimizing the risk of loss. For small, cash-light ventures in breakthrough drug development, this means carefully selecting activities that will move an asset closer to payoff. Management teams are paid to do this by using traditional practices, not by risking capital on interesting new strategies that are probably foreign to its board members. In larger companies, resources are less scarce but share price can be hyper-reactive to perception, especially the perception of wrongdoing. These obstacles are what stand in the way of greater use of Expanded Access trials in the US. So, how can these obstacles be overcome?
First, do no harm. That is, be mindful of the cost and risk that any clinical program could put on its sponsor. The primary goal of treatment-use trials is a humanitarian one, so it is hard to expect a commercial company to willingly shoulder the entire burden alone. So, how do we do no harm? The simplest way is for patient advocacy organizations and other foundations to help defray the fiscal costs. Additionally, make sure that participating trial sites are functioning as partners in the program and not as fee-for-service providers. In the early 2000s, top research centers were invited to treat their cancer patients within large Expanded Access trials for new receptor-inhibitor cancer drugs like Gleevec, Iressa, and Tykerb. The drug companies provided the drug product, the protocol, site trainings and monitoring standards to the sites, as well as data collection tools and sometimes patient-assistance funding for patients who could not pay their treatment costs. But they did not include a research budget for the site’s study team; that is, no profit margin. Unlike research trials, Expanded Access programs have primarily humanitarian objectives and the business relationships – under best practices – have reflected that. Unfortunately, some recent high profile Expanded Access programs have neglected that lesson and have acquiesced to substantial fees paid to participating sites.
Second, make partners out of the beneficiaries. Since early access to unapproved or off-label treatment is a matter of public good and is – in some diseases – considered standard medical practice, we might re-think which parties should manage it. Some unmet needs are recognized as too important or too difficult to leave for the marketplace to figure out. For example, global outbreaks of SARS, Ebola, and Zika prompted governments and NGOs, such as the World Health Organization and Medecins Sans Frontieres to build new distribution networks for treatment. Non-profits like OneWorld Health and PATH have built a supply-chain to bring best-in class medication to underserved parts of the world. Similarly, solving the economics of Expanded Access in the US and other regions may involve one or more specialty non-profit organizations or a public private partnership (PPP) between the non-profit sector and government. If done correctly, a central platform for Expanded Access could partner with individual disease communities and with the leading drug companies operating in each space to sponsor meaningfully sized, responsibly designed access trials for patients who otherwise have no hope for treatment.
Third, add value. Group Expanded Access programs are open label clinical trials that enroll a wider spectrum of patients than research trials do. Engaging larger numbers and wider ranges of patients can generate important treatment outcomes data within the targeted indication. When combined with consented biosamples from the same patients, these data can help researchers identify subgroups that appear to respond best, enabling more-targeted clinical research of the study drug. In 2002-2003, a collection of Expanded Access trials for gefitinib (Iressa) enrolled over 24,000 sufferers of advanced and chemo-sensitive lung cancer patients. The data supported findings of ethnic, gender, and comorbidity factors of treatment response. The large program also disproved a theory that the treatment increased patients’ risk of interstitial lung disease. With the reduced costs of modern assay and informatics technologies, wide access trials may soon reveal molecular signatures of disease variants that respond best (or worst) to a particular treatment.
It would be wrong to completely dismiss opportunities for government agencies to make early access programs more feasible. For example, the Center for Medicare and Medicaid Services (CMS) could establish more accommodative policy for covering leading investigational-stage treatments for dying patients who are not candidates for research trials. Already, under Medicare Part B, treatment expenses for clinical trial participation are often covered, but it is unclear how treatment-use clinical trials fit into this. And some argue that FDA should revisit its policy for the sponsor’s cost recovery, perhaps to give up the intrusive requirement of disclosing a company’s cost structure. Nevertheless these factors do not solely determine the feasibility of access programs. A more functional business model is needed – one that aligns the charitable, scientific and medical interests for wider patient engagement.
*Jess Rabourn, Chartered Financial Analyst, is a co-founder and managing director of WideTrial, a non-profit platform to support Expanded Access clinical trials. He has six years experience consulting on the regulations and business practices of early access programs and is a principal partner of Ax-S Pharma, LLC