Getting with the Program: Expanded Access Programs

Henry Sacks was a stoic, self-reliant man all of his life, but one day, several years after the start of his battle with colon cancer, his oncologist told him he didn’t know of any further options for treatment. Sacks, if he wanted to survive, would have to start researching on his own.

For a 72-year-old who predated the Internet revolution, this was a tough challenge. He didn’t know how to navigate the maze of websites about medical trials or understand the terminology that obscured every pathway toward information about his stage 4 cancer.

So he called his daughter, Janis Berglas, and pleaded for assistance. “He said to me, ‘I don’t know anything about computers. Is there anything you can do on the Internet?’”

The cry for help deeply affected Berglas. “I suddenly felt I had to save my father’s life,” she says. But the task was almost as overwhelming for her.“

because I couldn’t figure it out,” Berglas says. “I’m a college-educated woman, and yet I had no idea what was promising. I would call and find that (the trial)

was already over or there were some criteria that I didn’t understand that my father didn’t meet.”

After helping her father enroll in an expanded access program, Janis Berglas became convinced that there should be more such programs, and that they should be easier for patients and their doctors to find. Photo by Susan Farley.

Eventually, a friend in the pharmaceutical industry put her in touch with an oncologist who thought Sacks would be an ideal candidate for a few drugs undergoing testing at the time.

What worked in her father’s favor was that one of the pharmaceutical companies doing testing was accepting patients for an expanded access program (EAP), an opportunity created on rare occasions to give patients access to investigational drugs showing early signs of effectiveness—outside the structure of clinical trials. That meant that though the clinical trial of the drug was closed, the EAP would enable her father to receive the same medicine. Better still, the EAP was accepting patients through Greater Baltimore Medical Center, just 30 minutes from where they lived.

In 2002, Sacks began taking the drug Erbitux (cetuximab), which has since been approved for the treatment of both colorectal and head and neck cancers. The drug extended Sacks’ life by two years, giving him what his daughter described as genuine quality time. “He definitely responded very well in the beginning,” she says. “He golfed, rode his bicycle, went to Florida. He just kept busy, and when he couldn’t anymore, the boys would come over and play poker.”

I had no idea where to begin. I found that there were various trials, all posted, but they were posted in doctor speak, and by the end of the day I was in tears

Yet the family’s near-miss in finding the program convinced Berglas that EAPs, which seemed to have such potential for helping patients, were too rare and too hard to find.

“There is not only need for more expanded access programs, but a simplified means for those in need and their doctors to find them,” Berglas says. “After we experienced the relief of seeing my father enrolled in such a program and responding well to the medication, my husband and I had many conversations about our fears that people with fewer resources and less tenacity than we had could be suffering needlessly.”

BENEFITS FOR PATIENTS AND DRUG DEVELOPERS

Expanded access programs involving cancer drugs have been around since the mid-1990s, when one was created to allow patients with HER2-positive breast cancer access to the targeted drug Herceptin (trastuzumab). While they remain difficult to start or join due to process and patient eligibility issues, the concept has since matured, with the Food and Drug Administration (FDA) giving EAPs— known in the industry vernacular as “compassionate use” programs—enhanced regulatory status in 2009.

Essentially, they are run in conjunction with late-stage clinical trials so that promising investigational drugs can get into the hands of patients who stand a good chance of benefiting from them and who have exhausted their other treatment options, including clinical trials. EAPs can include either individuals or groups of patients. To open, they must be requested by a drug developer or a treating physician, and then approved by the FDA.

As opposed to clinical trials, which test drugs for safety and efficacy, EAPs primarily have a treatment function, and do not involve close monitoring of, or reporting about, patients. Thus, the way patients respond to drugs administered through EAPs does not factor much into the FDA’s determination about whether to approve the medications and how they should be labeled—unless serious side effects occur that can be correlated directly to the use of the product, says Richard Klein, director of the FDA’s Patient Liaison Program.

According to Klein, companies may decide to open an EAP—if they believe their application meets government standards—because there is a reasonable assurance of a drug’s safety and efficacy and a great need for the treatment before it is approved by the FDA.

An EAP in progress until very recently involved Ibrance (palbociclib), an inhibitor of cyclin-dependent kinases 4 and 6 that was being studied in combination with letrozole in post-menopausal women who have advanced, estrogen-positive, HER2-negative breast cancer; the drug was approved for that indication on Feb. 3.

Pfizer opened the EAP after completing enrollment in two phase 3 trials of Ibrance and submitting a new drug application to the FDA. Its aim was to “provide a mechanism by which eligible women who may benefit from treatment with palbociclib can gain access to this investigational therapy at this time,” Mace Rothenberg, Pfizer’s chief medical officer for medical oncology, said at the time. Treatment under the EAP took place at a number of specific locations around the United States.

Opening EAPs can benefit drug developers by generating good will among patients and providing a preview of any safety issues that might come up in a real-world group of patients, rather than in a group selected specifically for a clinical trial.

As a result, when possible, companies often find it worthwhile to open EAPs, despite drawbacks including increased costs. For instance, in many EAPs, these companies foot the bill for their medications—as Pfizer did with Ibrance. Although the FDA allows drug companies to charge, cost recovery for investigational drugs is tightly regulated. The cost of providing such drugs is often considered proprietary information, and the companies would rather offer the drugs for free than establish pricing for an EAP program.

This works out well for patients, since health insurers don’t typically cover the costs of investigational medications administered in an EAP.

Despite the potential benefits for both drug developers and the chronically ill, the number of patients enrolled in EAPs each year is just a small proportion of the total undergoing treatment for cancer and other diseases. In 2013, just 974 patients were enrolled in EAPs. That number was 936 the previous year. And the actual number of open EAPs for cancer treatments represents a tiny sliver of the more than 10,000 cancer clinical trials that are currently open. In early December 2014, there were just 29 expanded access programs enrolling patients, according to ClinicalTrials.gov, a primary resource for patients, doctors and others seeking information about ongoing medical research.

FEW AND FAR BETWEEN

So, why are EAPs so rare?

When a drug succeeds in trials it can create industry buzz, and patients and their advocates often ask the FDA to prompt the creation of an EAP. However, only a minority of all clinical trials generate early positive results that are sufficiently strong to merit the opening of an EAP, and a drug developer may refuse to apply if it believes its product doesn’t meet that standard.

Even when that standard is met, the drug development company has the right to nix an EAP based on safety concerns or whether sufficient quantities of a drug are available to serve both the purposes of the clinical trial and a wider EAP population. A company might also be concerned that the FDA, upon a drug’s approval, will add labeling requirements based on patient outcomes from an EAP population when they seem directly related to the treatment; that’s a concern because those outcomes could be worse than those recorded in clinical trials, due to the typically frail condition of patients who enroll.

Sometimes researchers are concerned that patients may flock to enroll in an EAP and avoid the related clinical trial. This is because all patients who enroll in an EAP will have access to the investigational drug, whereas those in the clinical trial may be given a “comparator” or currently approved drug instead of the investigational drug. Such an enrollment shift would be a worry because many clinical trials are already under-enrolled, and some close early as a result.

It can be labor-intensive to try to get an EAP created, particularly on the part of physicians and their staff members, who must spend time and effort doing paperwork and other tasks to open such a program without the reimbursement they would receive if participating in a clinical trial.

And then there are medical concerns. Even if an interested patient has exhausted all other options for treating his or her illness, the potential benefits of taking the experimental treatment must also outweigh the potential risks for that patient. Access can be denied if the patient’s disease stage does not match the criteria for acceptance, or if the researchers determine in advance that the drug will have no efficacy for the patient in question. Sometimes, newly discovered safety issues or a comorbid condition may make it too risky for the patient to take the drug.

If a patient meets all the conditions and an EAP is requested, the next question is whether the program will be approved.

The FDA operates with the awareness that many patients are in dire need and are very willing to try an experimental medicine, despite the potential risk involved, Klein says. Over a three-year period from the time the FDA started keeping records in 2009, the agency approved 99.4 percent of requests for EAPs, he says. While that is a seemingly high percentage, many other EAP requests from patients and their doctors are turned down by drug developers, say advocates for cancer patients including Frank Burroughs, founder of the Abigail Alliance for Better Access to Developmental Drugs.

As a result, those advocates contend, the FDA needs to find new ways to increase patient access to investigational drugs.

STEPPING UP THE PACE

Burroughs backed numerous drugs for wider access over more than a decade, and he says that all of them eventually were approved by the FDA. He believes this demonstrates that good drugs can be identified earlier, and that the federal agency is being overly cautious.

He began his advocacy organization after his daughter, Abigail Burroughs, who was diagnosed at 19 with head and neck cancer, was turned down in 2001 for access to two cancer treatments that were investigational at the time—Erbitux, approved in 2006 for head and neck cancer, and Iressa (gefitinib), which has since been approved for the treatment of non-small cell lung cancer.

The efforts to obtain the drugs through EAPs were unsuccessful, and Burroughs’ daughter died that same year.

The Abigail Alliance contends that tens of thousands of other cancer patients have died for lack of access to drugs that could have significantly improved their outcomes. One reason patients aren’t getting access to these drugs is that doctors are overwhelmed by the work involved in helping them, Burroughs says.

“When an individual patient applies to get a drug, there’s a convoluted process that each patient needs to go through,” he says. “And it takes a lot of time. There’s so much incredible paperwork that most doctors couldn’t do it. The only way they could do it is if they stopped treating some of their patients who are fighting for their lives.”

To change things at the FDA, the Abigail Alliance is backing the Compassionate Freedom of Choice Act (H.R. 4475), which “mandates that you’ve got to get these drugs to people sooner,” Burroughs says. Under the act, terminally ill patients with no other medical options would be granted access to investigational drugs upon a physician’s recommendation, and after giving their informed consent. The FDA could not require data collection about outcomes or side effects for patients getting the drugs in this way, and drug developers would not be liable for loss, damages or injuries incurred by these patients.

BALANCING SAFETY WITH DEMAND

According to Klein, there are some misconceptions about his agency’s efficiency when it comes to accommodating EAP requests. Klein has denied that the paperwork for requesting an EAP is very time-consuming, saying it takes about two hours per case, and that FDA staff are available to help. He adds that the agency typically processes these applications in two to four days—or in just hours in emergency cases.

Further, the FDA responds that the existence of programs to accelerate the drug approval process shows that it is, in fact, speeding things up. Such programs include Priority Review, Breakthrough Therapy, Accelerated Approval and Fast Track.

Even so, Klein says, the agency cannot always move as quickly as patients would like when it has to balance safety with demand for access. “If you’re on a time clock and you’re in the 11th hour, nothing’s moving fast enough, and so it seems to be moving at a molasses pace. And if you’re a scientist reviewing data and thinking about all these consequences of using the drug, I don’t think it’s necessarily slow. I think people at the FDA are trying to move as quickly as they can.”

While genetic biomarkers give researchers a better understanding of what may work for patients, it’s still not a time to put zeal ahead of caution, Klein adds. “Having drugs that are targeted genetically opens new doors to problems, because a lot of these drugs have very severe side effects,” he says. “If you give them to people who are not going to respond, then you’re putting people unnecessarily at dramatic risk.”