Hope Meets Reality

A desire for access to experimental medications often conflicts with the need for safe and widely available new drugs.

When her ovarian cancer did not respond to available treatments, Andrea Sloan was advised by her physicians at MD Anderson Cancer Center in Houston that an investigational drug, manufact­ured by BioMarin pharmaceutical company, was her best shot at survival. Patients normally access investigational medicines by enrolling in a clinical trial, but Sloan was ineligible for trials. The gregarious Texas lawyer and her supporters mounted a multi-pronged campaign to convince BioMarin to supply her with the drug. They reached out to legislators and others with political clout, spoke to the press, and marshaled social media. Despite these efforts, she never convinced BioMarin to give her its drug, which may or may not have helped her. A different drug company made a competing drug available to her, but it was too late for any interventions to help, and Andrea Sloan died.

Sloan devoted the end of her life to trying to reform the way patients obtain potentially beneficial investigational drugs. The Food and Drug Administration (FDA) calls this expanded access, but many are more familiar with the term, “compassionate use.” Compassionate use comes into play when patients who are unable to access investigational drugs by enrolling in clinical trials because they are too sick, too far away, or excluded due to participation in a prior trial are able to try those drugs through their doctors. Investigational drugs have not been approved by the FDA, so they can’t be sold in pharmacies. However, when a dying or seriously ill patient has no other option, a company can provide a drug to the patient’s doctor so that the doctor may try it on the patient. This is not a clinical trial. Indeed, in most cases, no data is collected unless a serious adverse event occurs. Rather, compassionate use is a therapeutic long shot that is offered only if a patient, his or her doctor, the doctor’s hospital, the FDA, and the company developing the drug all agree to pursue it.

“Compassionate use is a therapeutic long shot that is offered only if a patient, his or her doctor, the doctor’s hospital, the FDA, and the company developing the drug all agree to pursue it.”

When a patient and his or her doctor decide to seek an investigational drug, the doctor contacts the company that makes the drug and explains the situation. If the company agrees to make the drug available, the doctor submits a form to the FDA, which reviews the planned use of the drug. If the FDA agrees, the company sends the drug to the doctor, who, in the meantime, must seek permission from the institutional review board (IRB) of the hospital or practice. While compassionate use is not research, it involves drugs that are still being studied. The IRB works with the doctor to ensure that the patient understands this and that using an investigational drug may result in good or bad outcomes.

This process has been criticized for taking too long. Patients who are dying may not have time to survive the process. Unfortunately, there is no system in place to track how long a compassionate use request takes, how many of these requests are made to drug companies, or what the outcomes of requests are. Sometimes a request can take a day, or it can take longer, especially if the request involves using an adult medicine on a pediatric patient or shipping a drug overseas. The part of this process that has been criticized the most is the requirement for FDA review. Opponents claim that it can take up to 100 hours just to complete the FDA paperwork. This complaint has no basis in fact, but in June 2016, the FDA did release a revised form, to remove any confusion about requirements.

While no one knows how many of these requests are made to drug companies, the FDA does report how many requests it receives. From October 1, 2013, through September 30, 2014, the agency received 1,882 requests. Of those, the FDA approved 1,873, an approval rate of over 99 percent. Unfortunately, it is impossible to know how many patients received drugs via compassionate use. The FDA reports the number of approved plans, and some of these plans are for only one patient, while other plans can be for hundreds. Whether patients are helped, harmed, or not noticeably affected by these drugs remains unknown.

Furthermore, we do not know anything about the patients who are able to obtain access. Given that many physicians are unaware of compassionate use or, if they’ve heard of it, they do not know how to request it, we can assume that only certain patients are being offered the option. Anecdotally, we hear of patients who are related to, or who have access to, drug company executives having had success getting these drugs.

In Sloan’s case, she was a patient at one of the nation’s best hospitals. When she was denied access to the experimental drug, she asked people in her government and legal circles for help. Making use of social capital is a time-honored tradition. However, it means that people without connections are shut out.

“Most Americans support compassionate use. They also want their drugs, devices, and vaccines to be safe and effective. Sometimes, these two desires conflict.”

There are several proposals about how to improve compassionate use. One is the Andrea Sloan CURE Act, which seeks to address the inequity of access to investigational drugs by mandating that certain pharmaceutical companies be required to publicly post their compassionate use policies. If a company is willing to consider providing its drugs, it must then post contact information and say when a decision can be expected once a request has been submitted. The act was incorporated into legislation called the 21st Century Cures Act, which has passed the federal House of Representatives and is under consideration in the Senate.

Another proposal, from the libertarian think tank the Goldwater Institute, suggests that stripping the requirement for FDA approval would allow patients to access drugs faster. It wrote a model bill in which state governments nullify that requirement. So far 31 states have enacted such bills, and federal legislation has been proposed.

However, there is no validated report of any patient getting a drug through a “Right-to-Try” state law. Setting aside constitutional concerns over FDA authority, there are several reasons patients have not been able to obtain drugs via these laws. First, the ultimate power to give access to an experimental drug rests with the drugmaker. Second, a drug company, which takes its investigational drugs before the FDA for approval, would not want to damage its relationship with the agency by handing out its investigational drugs without the agency’s blessing, regardless of what state law may permit. And finally, it is illegal to market unapproved drugs, so informing patients and their doctors of the existence of a compassionate use program is difficult.

Another proposal is a navigator system that would help patients and their physicians find investigational medicines available for compassionate use and offer guidance on how to lodge a request. But navigation search engines are only as effective as the data they search. Existing public databases, such as the National Institutes of Health’s, are very limited in their scope and accuracy, and much data about ongoing clinical trials remain in private, commercial hands. In this context, even a very good navigator is not likely to have a huge impact on access.

Neither the status quo nor these three proposals ensures equitable access. But they may expand and perhaps diversify the pool of individuals seeking investigational drugs outside of clinical trials. While right-to-try state laws do not appear to have assisted any patients so far, the publicity about these laws seems to have increased awareness of the issue.

Most Americans support compassionate use. They also want their drugs, devices, and vaccines to be safe and effective. Sometimes, these two desires conflict. If companies are overly generous with compassionate use, they risk undermining enrollment in the very trials that demonstrate safety and efficacy and thus the wide availability of their drugs. However, if companies help no one, not even those who cannot qualify for a clinical trial, they show no respect for the needs of the very sick and dying. Finding the right balance will require more than legislation or a navigator. Companies, advocacy groups, regulators, investors, and physicians need to fine-tune drug approvals so that the desperate are helped while the general public is protected.