Providing an investigational drug outside of a controlled trial carries inherent development risks, but it can also be a win-win proposition for patients and sponsors when managed well, veterans of "expanded access" programs say.

According to the FDA's broad definition, "expanded access" could mean a one-time supply of a drug to a particular patient, or a program that serves tens of thousands of patients (see chart: " ¹ Three Ways To Access Investigational Drugs In the U.S. "). Globally, the terms "early access" and "compassionate use" are also used for similar programs.

Demand for access to investigational drugs is on the rise for a number of reasons. For one, it's become much easier for patients to access information about trial drugs and also to publicize their own experiences through social media. The globalization of the biopharma markets and a growing focus on development of treatments, including biologics, for less common disorders are also driving interest, said Carol Collins, corporate vice president of the Peri-Approval Clinical Excellence program at Parexel.

Another key factor is the evolving regulatory environment. FDA has widely publicized guidance on three paths toward gaining access outside of trials for patients who do not qualify for ongoing studies (² Also see "FDA Rules On INDs May Embolden More Patients To Ask For Trial Drugs" - Pink Sheet, 17 August, 2009.).

"The FDA has become more explicit in encouraging submission of early access programs. To hear them comment about it publicly used to be a rare thing," said Robert Erwin, director of the Marti Nelson Cancer Foundation at a seminar on access programs held by the Center for Business Intelligence in March.

More recently, at the end of April, the agency held a public meeting with drug developers to discuss expanded access to novel hepatitis C treatments (³ Also see "Sponsors Caution Against Premature Expanded Access For Novel HCV Drugs" - Pink Sheet, 1 May, 2010.).

Benefits of an expanded access program for sponsors include satisfying consumer demand and creating a buzz for a product prior to commercial launch, developing good relationships with disease advocates and doctors, and gaining knowledge early on about effects in a wider population. Among the ranks of expanded access veterans that say they would do it all over again are Genentech, BioMarin, and EpiCept.

But there are inherent risks. In written testimony for the HCV meeting, Vertex Chief Medical Officer Robert Kauffman said that his company was open to working with the FDA to expand access to its Phase III telaprevir, with "some cautions."

Unanticipated safety issues and drug-drug interactions could arise, Kauffman noted. Overall, there is a risk that a "promising therapy for thousands of patients could be derailed" by significant safety and other events that may be population specific, particularly if these occur before a solid body of safety data for the compound has been obtained."

"There are certainly examples from the past where premature expanded access has frustrated the goal of maximum benefit brought about by earliest and widest availability through marketing approval," Kauffman commented.

Patients who are on a waiting list for a liver transplant have few options and stand to benefit from expanded access to HCV drugs. Assurances from FDA about how adverse events in this type of population would be reported on the label could help "de-risk" an expanded access program in this setting, said GlobeImmune Chief Medical Officer David Apelian, who attended the HCV meeting.

Oncology A Likely Target

Up to now, expanded access programs have been more common in particular disease areas - notably HIV/AIDS - where the stakes were very high and advocates became very effective in pressuring companies to supply drugs. As awareness grows, industry sources expect higher demand for access to treatments of life-threatening diseases for which no alternatives are available and/or which seem to be game-changers, based on early trial results. Oncology is seen by many as the most likely area to be targeted.

Still, there are many obstacles to implementation of FDA's recent expanded access regulations (⁴ Also see "Access To Investigational Drugs Remains Challenge Despite New FDA Rules" - Pink Sheet, 29 March, 2010.). For example, physicians must be on board, but they may fear liability.

The American Society of Clinical Oncology and FDA are rolling out a new collaborative educational program to inform professionals about the process for accessing investigational drugs for individual patients. The initiative was unveiled June 4 at the start of ASCO's annual meeting.

FDA Principal Deputy Commissioner Joshua Sharfstein and Office of Oncology Drug Products Director Richard Pazdur were on hand to underscore FDA's flexibility in granting access for patients without other options. But Pazdur also stressed the importance of enrollment in clinical trials, saying "we believe the best access is through approval."

Lessons Learned From Expanded Access Veterans

An expanded access program could actually help a new drug application, said Gerard Kennealey, former vice president of clinical oncology at AstraZeneca. While working at the firm, Kennealey was involved with a 20,000-patient-strong expanded access program for the EGFR inhibitor Iressa (gefitinib) in non small-cell lung cancer. Safety data for so many patients gave the NDA a boost, he said at the CBI seminar.

The Iressa program was offered to patients in reasonably good health, to help avoid safety issues that could derail approval, Kennealey said: "It was a difficult decision but we felt it was appropriate."

AstraZeneca kept expanded access separate from its clinical development program. A patient advocacy group helped field patient requests and a contract research organization was hired to manage the program and work with physicians. The drug was provided free of charge. Kennealey currently is VP of Business Development at Cephalon.

In the U.S., companies are permitted to charge for agents provided via expanded access but only to recoup their direct costs, not their development expenses (⁵ Also see "Sponsors Can Charge For IND Drugs If They Offer "Significant Advantage"" - Pink Sheet, 17 August, 2009.). Few, if any, will be willing to tip their hand about costs and/or set a price that could later be used as a benchmark by payers.

Compassionate use programs are highly customized and costs vary widely, depending on many factors, including the cost of making the drug itself, the number of patients treated and the extent of safety monitoring, said Parexel's Collins. Some companies will want to go beyond the minimum regulatory requirements for reporting serious adverse events. Such was the case with the Iressa program.

Outside the U.S., companies may charge market rates, though they are often operating in environments with price controls. Cognizant that prices could set benchmarks for payers, companies seek to charge rates that are in line with plans following commercialization.

Also speaking at the CBI conference, EpiCept CEO Jack Talley said that following ex-U.S. approval in many countries of Ceplene (histamine dihydrochloridein) in acute myeloid leukemia, but prior to finding a commercialization partner, his company opted to offer the treatment for compassionate use. That drug is set to be filed in the U.S. soon and EpiCept is hopeful about getting priority review, due to high unmet need.

Based partly on the charging situation, EpiCept said it opted to make Ceplene available almost everywhere in the world - except the U.S. The company's early access program was motivated by many factors, including high unmet medical need, ethical obligation and extensive knowledge of the drug's activity and toxicities, Talley said. Compassionate use is "no substitute for commercial launch," but it does help pave the way.

"I do believe that this is an excellent means to build, refresh and broaden thought leader support," he said. "Having Ceplene available through this mechanism is going to be a very key component to the commercial introduction of the product."

EpiCept now has a commercial partner on board outside the U.S. and the compassionate use programs will be phased out.

Drug Promotion By Any Other Name

Unapproved drugs cannot be advertised or commercially promoted, but expanded access is nevertheless a way to get a foothold in the market. such was the case in the early days of HIV treatment, commented Richard Klein, HIV/AIDS program director at FDA's Office of Special Health Issues.

Contacted by e-mail, Klein recalled that as marketing approvals were being finalized for HIV drugs, thousands of people were using expanded access. People became familiar with a particular drug and heard stories about patients who were benefiting. It was one way to potentially promote a drug without "promoting it," Klein wrote.

"That's a side benefit, but from FDA's perspective, the [main] benefit is to those patients who were able to bridge their therapy until the new drug became commercially available," he added.

A Long-term Commitment

BioMarin opted to provide an expanded access program for its Kuvan (sapropterin dihydrochloride)for the rare genetic disorder phenylketonuria prior to approval, covering all costs, including institutional review board expenses. But it didn't offer the program until it had submitted its NDA and believed it had a very good shot at approval, as well as an accelerated six-month review.

BioMarin's Chief Business Officer Stephen Aselage said expanded access was a good experience worth repeating. If the company offers access for another drug in the future, it will aim to give more notice to sites to allow time for the IRB review.

However, in other situations where the regulatory pathway and/or data sets are less clear, expanded access could present problems. One concern expressed is that FDA could make up for the slipping review deadlines through expanded access programs, and that the compassionate use could become a sort of substitute for approval.

In that case, the regulator could have a conflict of interest. Delays could drag on for two or three years and companies could wind up "on the hook" to provide free goods to patients long-term, Aselage commented. Patient advocates at the CBI meeting said that companies offering expanded access should be prepared to continue the drug supply for life to those who benefit, even if drug development is terminated. Cutting people off could trigger a "firestorm of negative publicity," they warned.

When Cell Therapeutics received a complete response letter in April for its non-Hodgkin's lymphoma drug Pixuvri (pixantrone), FDA presented early access as an option in the meantime (⁶ Also see "CTI's Pixuvri Strategy After FDA Rejection: Pursue Expanded Access, Start Combination Trial" - Pink Sheet, 9 April, 2010.). The same month, the agency offered to work with Australia-based ChemGenex to develop an early access program for AML treatment Omapro (omacetaxine mepesuccinate), also after a complete response letter.

Miracle Drugs In High Demand

Drug companies are certainly not obliged to provide early access, as the FDA rules make clear. But in cases of dramatically good trial results, there could be intense pressure from patients and serious public relations damage if access is denied. In the 1990s when Herceptin was performing well in trials, patients and their advocates picketed the Genentech campus, demanding early access, which was ultimately provided.

Kennealey said that AstraZeneca's program for Iressa starting in 2000 was prompted in part by the 7,000 requests for treatment that flooded in following dramatic early trial results and media reports of a miraculous 'Lazarus' response.

Having adequate supply is a concern, particularly for companies developing complex biologics. A lottery system might be required and if this is necessary, involvement of patient advocates can help ensure fairness and ward off negative PR. Advocates at the CBI meeting also noted that it's perfectly acceptable to offer expanded access at existing trial sites only, as opposed to providing sweeping geographic coverage.

The Marti Nelson Cancer Foundation's Erwin recalls that after Genentech began to offer an expanded access program for Herceptin, the company came under fire for not having enough supply. But by that time, disease advocates had evolved from critics into allies and helped communicate supply limitations, Erwin said.

"When the more aggressive, anti-business reporters focused on a single patient's emotional story and wanted to write a piece trashing Genentech, I would talk to them with the credentials of having been a hostile party in the beginning," Erwin said. "I could say, 'Yes, they are telling the truth: they are acting honorably.'"

Developing close ties with advocacy groups can also help get a drug approved more quickly, which has financial benefits down the line for the sponsor post-approval, Erwin added.

Making Way For "Super Herceptin"

A spokesman for Genentech said the key lesson learned was the importance of working closely with the community you are trying to help, including doctors, patients and their advocates. Secondly, the company learned how to address limited supply and make sure treatments were distributed in a fair and ethical way.

Since the early days with Herceptin, Genentech, now part of Roche, said that it has become part of the development process to consider whether an expanded access will be needed. Drugs that serve a high, unmet need and/or produce a very strong response in trials could be prime candidates. Treatments must be backed by reasonable safety data and have potential for efficacy. The company said it does not provide access to single patients to ensure equity and provides drugs in a very organized manner with good safety monitoring, via trial sites.

In May, Roche began to offer an expanded access program for its next-generation breast cancer product for HER-2 positive women: trastuzumab-DM1 (T-DM1), partnered with ImmunoGen. That drug is now going to be submitted for accelerated approval following a Phase II trial in third-line HER-2 positive metastatic breast cancer (⁷ Also see "Roche To File NDA For T-DM1 This Year" - Pink Sheet, 15 April, 2010.).

The access program, listed as an open-label study on clinicaltrials.gov, is open only to women who have failed at least four therapies, including two HER-2 positive targeted drugs. Based on the inclusion criteria, other trials should not be adversely affected. Genentech is running a Phase III study of the drug in the second-line setting and a randomized Phase II trial in women who have not received prior chemotherapy.

Chat room boards are buzzing with news about "Super Herceptin." In April, a visitor to the breastcancer.org website made this comment about news of Roche's plans for an accelerated U.S. filing of TDM-1, based on Phase II data: "That IS good... Finally we are getting some speediness. We should get away from the old school that everything takes 20 years to get approval and another 10 to figure out which patients get the most benefit."

But not everyone sees it that way. The grassroots disease organization Breast Cancer Action has cried foul. In a March 23 letter to FDA officials, available on the group's website, Executive Director Barbara Brenner applauded the company's plans for expanded access, while also voicing concern that the company intends to use what they are calling an "Expanded Access Study" as a substitute for a Phase III trial.

"The Expanded Access program will not provide Phase III data. The FDA must insist on sufficient randomized results before approving TDM-1 for the market," she wrote.

In an interview in May, Brenner noted that the TDM-1 trial listed as an expanded access program on the clinicaltrials.gov site is very limited. As opposed to offering true access to patients, it appears to mainly be a means for the company to collect additional data for a particular group of patients who have already received numerous treatments, she said.

Access: At least Two Sides To Every Story

The T-DM1 case illustrates a conundrum for FDA. On one hand, it faces demand to approve drugs more quickly, but it also gets raked over the coals for its industry ties when adverse events surface for approved drugs. There's also reason to believe expanded access could work better in some diseases than others. In HIV, drugs knock down viral load, and result in measurable changes and benefits to patients, observed FDA's Klein. But in other diseases, like cancer, benefits are harder to measure,

After getting on the market, Iressa turned out to be useful for only 10 percent of patients who had a particular genetic mutation. The Abigail Alliance has been one of the strongest voices for expanded access, following the death of Abigail Burroughs, whose parents sought unsuccessfully for her to receive Imclone Systems' drug Erbitux (cetuximab). But based on the drug's track record in head and neck cancer since it's been on the market, it's reasonable to question the assumption that Abigail would have lived if only she had access, which had been denied by the company, Klein commented.

Voicing his personal opinion and not the FDA's official position, Klein observed that patients may assume that what's not on the market is better than what is available. The promise of a particular investigational drug may be magnified in the eye of a desperate patient - but many don't seem to be as miraculous after they reach the market.

"It's one of the issues that raises personal concerns for me about the growing interest in expanded access right now," Klein observed. "They [investigational drugs] can offer hope when patients exhaust other options, but I wonder if that presumed promise is always, or usually, in proportion with the benefit realized."

The answer to that question could become evident over time, as expanded access programs are more widely applied.

- Emily Hayes ( ⁸ e.hayes@elsevier.com )

Making Expanded Access Programs Work For - Not Against - Your Trial Drug

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