An Rx for the System: Gaining Access to Investigational Drugs


Expanded access programs 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.

R. Ruth Linden is an independent health advocate and bioethicist who prides herself on publicly avowing her opinions. On the issue of expanded access programs (EAP) for investigational drugs, she comes down squarely on the side of “not good enough.”

EAPs 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 U.S. Food and Drug Administration.

But the programs come too late in the game for many cancer patients, and many more are simply unable to participate, says Linden, who holds a PhD in sociology and is president of Tree of Life Health Advocacy of San Francisco, California.

As a result, she and other patient advocates are calling for dramatic changes to FDA policy designed to get experimental drugs much more quickly into the hands of patients who may benefit from them.


Linden has been a part of the battle to widen access to experimental drugs since the mid-1990s.

In those days, HIV/AIDS patients were dying in droves and had nothing to lose by seeking every means possible to compel drug companies to grant them broad access to promising new drugs. Civil disobedience and dramatic protests were key to their modus operandi, but their efforts also could make it difficult to impossible for drug companies to recruit patients for clinical studies.

“The HIV/AIDS activists had tremendous power because they could shut down a trial,” Linden says.

Seeing how successful they were, a coalition of breast cancer activists took a leaf out of the same playbook and in December 1994 marched on Genentech’s campus in South San Francisco in an attempt to force wider access to an experimental formulation they thought could save lives.

“A small cadre of breast cancer activists worked with HIV/AIDS activists to adapt their methodologies to a very promising biological that Genentech was developing—Herceptin (trastuzumab). They did civil disobedience on the Genentech campus, handcuffing themselves to a building and driving onto the campus honking horns and shouting through bull horns and carrying portable sirens to make a great spectacle—because women were dying who had a chance at life extension if they had access to this investigational therapy,” Linden says.

It worked by bringing Genentech to the bargaining table, and an expanded access arm of the clinical trial was created using a lottery, becoming the first EAP for any cancer drug, according to Linden.

Though EAPs have come into broader use, they remain a poor solution to the problem of getting promising treatments into the bodies of those who need them in a timely manner, says Linden. Many patients who gain access to such medications do so when their bodies are already severely ravaged by disease or by highly toxic chemotherapy.

Typically cancer patients try approved drugs first, but in some cases those drugs are “contraindicated” or not appropriate for particular patients. Participating in a clinical trial may involve being given a placebo, rather than the investigational drug itself, and some patients may not meet the criteria for inclusion in the trial, giving them the option to participate in an EAP. By then, a patient’s cancer may have developed a resistance to medications, making it harder to treat.

“By the time a person tries to get therapy on an EAP, she or he is very ill,” Linden says. “Patients with devastating illnesses stand a much greater chance of surviving or extending their lives or even experiencing total disease remission—otherwise known as cure—the sooner they get treatment.”


Drug companies have the last word about whether to expand access to an experimental medication outside of a clinical trial, and even patients with the strongest arsenals of resources sometimes fail to persuade them to allow an EAP.

In 2014, for example, Forbes magazine followed the case of Mikaela Knapp, a 25-year-old woman with metastatic renal cell carcinoma who had exhausted all FDA-approved drugs for treating her disease. Though her family was media savvy and waged a huge campaign to gain access to any of three PD-1/PD-L1 therapies then in development—including Keytruda (pembrolizumab), which has since been approved for the treatment of melanoma—Knapp could not survive the wait and succumbed in April 2014.

“Her case would be a model for how to mobilize social media as well as the public relations machinery to persuade and arm-twist decision makers to lend a sympathetic ear to a patient’s legitimate request for an experimental therapy. Mikaela and her family did everything right, and yet she was denied the therapy that might have bought her some time," Linden says.

David Kroll, who had written about Knapp’s campaign for Forbes, suggested in a May 2014 article that drug developers did not offer her the therapies because she was already too sick to benefit from them.

Richard Klein, director of the FDA’s Patient Liaison Program, noted that the agency approves nearly every request it receives to open an EAP, but that many other EAP requests from patients and their doctors are turned down by drug developers.

To change things for the better, says Linden, both drug developers and the FDA will need to be involved. What’s needed is a reevaluation of the efficiency and effectiveness of the clinical trials process, says Linden, who believes change should be effected much further “upstream” to benefit a far greater number of patients in need of effective medication.

“Therapies are fast-tracked all the time. We need to have more strategies like fast-tracking, expanded access, and continuation protocols that benefit the clinical trials subjects who are also patients with lives on the line. We need to have a national conversation about the design of clinical trials,” she says, “because expanded access is an adjunct to a much more complex problem. The problem is the drug development and approval process in the U.S. Expanded access is not really a fix.”

The FDA responds that the existence of programs to accelerate the drug approval process shows that the agency is already 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.

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.”


Members of the Abigail Alliance for Better Access to Developmental Drugs have battled for years to expand access to trial drugs and to get the FDA to revamp the drug approvals process so that promising drugs can get into the hands of patients sooner, and so that the drug trials process is modernized to reflect newer science and understanding.

Steve Walker, a cofounder of the alliance, says that his first wife, Jennifer McNeillie, was delayed in entering a clinical trial for the drug Erbitux (cetuximab) due to required testing procedures he considered outdated. By the time she entered in 2002, she was already severely weakened by a desperate fight with colorectal cancer using other medications. Erbitux, which was approved for the treatment of her disease two years later, dramatically improved her condition for six months, but then protocol required that she be removed from the trial because she developed a small lesion on her liver. Her disease quickly progressed, and she died within a couple of months at the age of 47, leaving Walker to wonder how much time the delay in enrollment had cost her.

He adds that enrolling in a trial in the hope of getting a promising investigational drug is often equivalent to a roll of the dice.

Randomized drug trials in which patients receive placebos or “comparator” medicine—whose degree of efficacy is already well documented—instead of the investigational drugs do patients an injustice by prolonging suffering and raising the death toll, Walker says. “We have this sort of sense in this country that if you make a movie you shouldn’t kill the animals—you know, in war scenes they should not be injured—but some of what we do (to humans) to get drugs approved seems criminal,” he says.

The FDA does consider trials without a comparator arm in limited circumstances, Klein points out. However, the best way to find out exactly how well, or whether, a drug is effective is to compare it to a known therapy, allowing analysis that demonstrates the “net difference,” he says. There are so many variables in responses of patients to a therapy, and even in the absence of therapy, that the most effective way to judge and assess the effect is to compare it to a known result, he says.

Advocates for FDA reform say the federal agency is not well-equipped to fix the drug approvals process on its own or to make EAPs more widely available. The agency is hog-tied by bureaucracy, political interests and staffing and funding shortages that render it virtually incapable of better complying with its congressional mandate to serve the public’s best interest, they contend.

“The FDA needs guaranteed funding and staffing at a level adequate to perform its mission,” Linden agrees. “Dollars and staff are the first steps in initiating a national conversation about drug development and approval.”

Adequate funding is certainly a part of having the resources — particularly the human resources -- to do rapid, effective reviews of study data, Klein agrees. That is the purpose behind PDUFA, which, along with accelerated approval and breakthrough therapy, has significantly reduced review time for new products, he says.


Linden is calling for an examination of the FDA Safety and Innovation Act, which was created in 2012 to encourage innovation and speed patient access to safe and effective products. “The FDA has established a three-year implementation plan, but who is overseeing the plan’s progress? What initiatives actually have been proposed or launched and with what consequences for people with cancer and other life-threatening diseases?” she asks.

In response, Klein points again at the breakthrough program, saying it has had a big impact by putting a high priority on promising new drugs, helping sponsors with their trial designs and consulting along the development timeline to ensure that trials are designed to provide the necessary data to effectively analyze the safety and effectiveness of new drugs and biologics.

He adds that the Patient Focused Drug Development program “has given voice to patients with a variety of serious illnesses and conditions, which will be valuable to the FDA and industry in pinpointing the outcomes that matter most to patients. This, in my opinion, cannot help but result in trials that are designed with endpoints that are appropriate to the needs of patients.”

But Linden wants more. “Congress or the president should direct the Institute of Medicine (IOM) to study the drug development and approval process in a series of reports,” she says, “in the same way that medical error was studied in the late 1990s, resulting in the IOM’s renowned volume, To Err is Human (1999)”—a report that started a national conversation about medical error and safety. “Something comparable is needed to address the drug approval process.”

“Diving deeper, we need experts, including consumers, advocates and activists, to review the oft-stated claim that double-blind placebo controlled trials are the best design for determining an experimental agent’s superiority over the standard of care,” she says. “Other clinical trials designs that may, under certain conditions, be comparable or superior need to be evaluated for their benefits on ethical and therapeutic grounds. But this would only be the tip of the iceberg. The entire approval process needs to be carefully and objectively scrutinized, not only for its inefficiencies but also for innovations that could be introduced. In short, we need to adopt a new model.”

Walker, of the Abigail Alliance, agreed that the canvas has to be stretched out flat before the picture can be improved.

“You’ve got to get to what’s really causing it, and that involves this process of putting everything on the table, having no sacred cows and everything up for a cold-eyes review and potential elimination,” he says. “And that’s something the government, and especially agencies like the FDA, do not do well at all. They’re so bound up in their institutionalized way of doing things.”


The Abigail Alliance has a history of legal and legislative battles designed to improve the odds for patients desperate to obtain promising treatment. Of more than 20 drugs it has backed for wider access, all were eventually approved by the FDA, which the advocacy group says is proof that there are ways early on to prove that certain experimental drugs are worthy of wider distribution prior to completion of the FDA approval process.

In 2006, the alliance took its case to the U.S. Court of Appeals and won a judgment that terminally ill patients had a right to access trial drugs not approved by the FDA. But in 2007 a larger panel of appellate judges overturned that decision, and the Supreme Court declined to hear the case.

Alliance cofounder Frank Burroughs says more expanded access could be enormously valuable to the public because of the additional data on patient response that could be gathered.

“Let’s say you have a drug and it’s getting to more people because of the EAP, and you find that it had some deadly side effects that you didn’t see in the smaller clinical trial, or that a lot of people excluded from the primary trial were obviously benefiting from it. Wouldn’t you want to know that before it was out there even more?” Burroughs asks.

Currently, the Abigail Alliance is backing “Right to Try” legislation in many states that would allow terminally ill patients to try experimental drugs without FDA approval. The legislation has been approved in several states, including Arizona, Colorado, Michigan, Missouri and Louisiana. The Goldwater Institute has been backing “Right to Try” laws and aims to get them passed in all 50 states.

Critics of “Right to Try” laws contend they circumvent the FDA role of ensuring that investigational drugs are safe, that drug companies are still not obligated to make the drugs available, and that there is no provision to make funds available for the purchase of investigational drugs.

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