Expanded access (compassionate use) clinical trials aren’t as straightforward as they seem, and applications to expand access for cannabinoid drug trials are even more complicated. “Although the application process outlined on the FDA website seems very clear, the reality, unfortunately, is not like that,” according to Ricardo Alvarez, M.D., director of cancer research at Cancer Treatment Centers of America’s Southeastern Regional Medical Center in Atlanta and clinical assistant professor at Georgia Regents University. “I typically see eight- to 10-page applications,” Alvarez says, “but they take too much time. They’re the equivalent of filling out the paperwork for CDER (Center for Drug Evaluation and Research) trials involving two companies. That requires a lot of staff support.”
To participate in expanded access trials, Alvarez says physicians need the support of a team, including a care manager, to contact the pharmaceutical company and to fill out the necessary forms. The current application form, FDA 1571, requires 26 data points and seven attachments. Filing for FDA permission to launch an expanded access trial is much the same as filing to participate in investigational new drug (IND) trials. Physicians must obtain a letter of authorization from the pharmaceutical company allowing the IND to be used for expanded access for their specific patients, and they also must develop trial inclusion and exclusion criteria, a patient protocol, and patient exposure data. Additionally, the patient must be examined by the physician applying for the trial and sign a consent form that clearly outlines the risks and potential benefits.
Once the paperwork is filed, physicians say it takes about 15 days to gain FDA approval, although emergency approval is possible within a few days. Historically, the FDA approves 99.5% of all compassionate use requests.
A STREAMLINED FDA APPLICATION
In February 2015, the FDA issued a draft guidance proposing a new form for expanded access trials to replace Form FDA 1571. The new form, FDA 3926, is not yet finalized, but it is expected to streamline the application process for physicians enrolling patients in expanded access trials.
Form FDA 3926 asks for, among other things, clinical information, treatment information, letter of authorization from the drug’s manufacturer, physician’s qualifications, physician’s contact information and the physician’s IND number (which differs from the manufacturer’s IND number), request for authorization to use draft from FDA 3926 rather than Form FDA 1571, and a certification statement and the physician’s signature.
FDA documents say the new form should take about 45 minutes to complete. When finalized, it is expected to have eight data points and require only one attachment.
PHARMA — NOT THE FDA — PREVENTS EXPANDED ACCESS TRIALS
“Getting approval from a pharmaceutical company is the biggest hurdle to gaining access to expanded use trials,” says Steve Jensen, SVP of the regulatory consulting practice at the Weinberg Group. The reason, he says, is fear. “Pharmaceutical companies don’t want to generate data that doesn’t need to be generated.” There’s no motivation, therefore, for them to allow expanded access trials.
“Compassionate use really is a clinical trial,” notes Paul Lyons, M.D., Ph.D., medical director at Virginia Comprehensive Epilepsy Program. “In the past, compassionate use medications were open label and unregulated. Expanded access trials have become more rigorous, however, and require physicians to report patient data and adverse effects just like other clinical trials.”
Pharmaceutical companies with early-phase trials may restrict expanded access because of limited information about the drug’s safety, mechanism of action, or efficacy. “Other times, the issue is supply. Many companies — especially smaller companies in early-stage investigations — don’t have much drug on hand. Alternatively, requests for expanded access may be for indications the company hasn’t investigated,” says Robert Church, partner at the international law firm of Hogan Lovells. “Any of these factors could make a company reluctant to participate.”
Alvarez notes that sometimes companies are flexible, but it depends on the compound. “For example, when the clinical trials for Gleevec (imatinib mesylate) became fully enrolled, Novartis opened an expanded access program.” Novartis doesn’t routinely allow expanded access trials when its planned trials are fully enrolled, however. He says the reasons for denials aren’t always clear.
Persuading a pharmaceutical company to allow an expanded access trial takes time. Gaining approval from the FDA and the pharmaceutical company took a total of about 50 days for each of the two trials Alvarez requested in 2014.
“The landscape for expanded access trials has changed over the past decade so that drug companies are taking greater steps to make investigational drugs available,” Church says. “At the outset,” he continues, “companies with drugs that treat serious or novel conditions often sense that people will ask for expanded access. They typically develop internal guidelines to determine when in the developmental cycle to make a drug available. If the drug or patient request doesn’t meet those guidelines, the company may decline individual requests unless enough pressure is brought to bear by patient advocates.”
PATIENTS LOSE PATIENCE WITH DELAYS
A patient’s continued commitment to an expanded access trial also often wanes during the application process. At the onset, patients are briefed on the course of action and what that means to them in terms of potential risks and benefits. They also are asked to meticulously log their symptoms and reactions to the medication, attend follow-up appointments, and allow additional blood draws.
In Alvarez’s experience, patients abandon the expanded access process because of the lengthy paperwork and time spent waiting for approval.
FOR CANNABINOIDS, THE DEA IS THE HOLDUP
The process for gaining expanded access to cannabis-based therapeutics (cannabinoids) is significantly more complex. An article (“Boy Interrupted”) in Wired magazine last July brought attention to this issue, citing 100-page applications and very long approval time frames.
In this case, manufacturers aren’t a barrier. “Cannabinoid manufacturers want to make their compounds available to prescribers, to move those compounds from the shadows to the mainstream,” Jensen says.
Instead, the challenge is to get approval from the Drug Enforcement Agency (DEA), he continues. “The FDA and DEA are struggling to get their heads around the cannabinoid issue. As a Schedule 1 drug, the missions of these two agencies are diametrically opposed.”
The FDA’s mission is to bring effective therapeutics to patients. But, according to the DEA, Schedule 1 drugs have “no currently accepted medical use and a high potential for abuse.”
Lyons knows the challenges firsthand. He recently added three patients to an expanded access trial for the cannabinoid Epidiolex, by GW Pharmaceuticals.
“It took me 13 months to get a Schedule 1 license,” says Dr. Lyons, who then had to meet state requirements for inventorying and dispensing the drug. “That required bolting a 40- to 50-pound safe into the office.”
The second hurdle was persuading the manufacturer to supply the patient with medication. “This is a small barrier. Most pharmaceutical companies are happy to do this,” he says.
The third barrier, he says, was bureaucratic. “To add patients to my existing expanded access trial, I had to submit brand-new applications, as if nothing ever had been submitted. I’m trying to run a placebo, double-blind trial for the same drug, with the same nurses, same disease state, same doctor, and same program, yet I had to submit a new application to the DEA and the FDA,” Lyons says. After three months, a DEA field agent informed him the three patients were accepted into the expanded trial.
"Expanded access trials have become more rigorous."
Paul Lyons, M.D., Ph.D.
Medical Director, Virginia Comprehensive Epilepsy Program
KEY RESOURCES TO TAP INTO
From a patient’s perspective, hiring a consultant to speed access to an expanded access trial is unnecessary, both Lyons and Alvarez say. Some pharmaceutical companies, however, find consultants helpful in writing trial protocols that meet the combined concerns of the DEA and FDA.
For example, GW Pharmaceuticals in the U.K. hired consultants to work with the FDA and DEA to help write protocols for its Epidiolex orphan drug program. Lyons says, “I doubt I would have succeeded in gaining access for my patients without their support.”
Some of the simplest resources for patients and physicians seeking to gain access to expanded access trials are the Web pages of the American Cancer Society (ACS), the National Cancer Institute, and now, the FDA. As Alvarez explains, “These sites translate the process into plain language and tell patients what to anticipate.” They include information about costs, how to access drugs and trials, and how to get additional information. The ACS site also tells patients what to ask their physicians about unapproved medications.” The new FDA compassionate use Web page (www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse) specifically for physicians also has detailed information on topics such as how to apply for expanded access to an investigational drug under a single patient IND and what to expect after submitting that request.
Clearly, it’s becoming easier for physicians to launch expanded access trials, as these sites show. Nonetheless, overcoming pharmaceutical companies’ objections is still the greatest hurdle.