Modernizing Eligibility Criteria: Precision Eligibility For Precision Medicine

Searching for a clinical trial can be as much work as a full time job, and often a not very rewarding one at that. In fact, even after finding a trial that seems like a good fit, many patients are overwhelmed by administrative hurdles or prevented from enrolling because of an exhaustive list of exclusionary criteria. (That’s why letting the clinical trial navigators at Cure Forward do the work for you is so great!)

Why Are Trials So Exclusive?

While many patients look to clinical trials as a way to gain access to the latest drugs, it is important to remember that the real purpose of a clinical trial is to determine the safety and efficacy of an investigational drug. That exhaustive list of exclusionary criteria was originally designed to protect patients — keeping the sickest patients off a trial protected them from unexpected adverse effects that could be magnified by their condition. It was also designed to produce clear evidence of a drug’s safety and efficacy to enable regulators to make appropriate decisions. In order to be sure that any effect (good or bad) was due entirely to the investigational drug, many patients were routinely excluded. It is becoming clear, however, that while these exclusions were designed with patient safety in mind, they may be keeping a good drug from patients who could derive benefit. In addition, once approved, these drugs will be used extensively in the same patients who were excluded from the original trials, and so doctors will not have realistic safety data to help patients make treatment decisions.

Drug Development Stakeholders

There are many stakeholders when it comes to drug development. Of course, academics are aware that they need to publish their studies, industry researchers know they need to make a profit, and regulators are concerned with the integrity of their process. But overall, they have the same goal: Get good drugs to patients as quickly as possible, without letting any bad drugs slip through. And, of course, that’s what most patients want, too. The hard part is getting everyone to agree on how to best accomplish that goal.

Clinical trials are designed by trial sponsors. Though government agencies such as the National Institues of Health (NIH), and academic medical centers sometimes design and sponsor a trial, the pharmaceutical company who makes the drug is usually the trial sponsor. The U.S. Food and Drug Administration (FDA) plays a big role in the approval of a drug, but doesn’t actually design clinical trials.

While exclusionary criteria were initially developed to protect patients, too many trial sponsors are using an outdated list of exclusionary criteria as a template, failing to give appropriate and thoughtful consideration to the patients who can enroll in a trial. Many sponsors cite concerns that lifting restrictions might jeopardize or delay approval.

The FDA Does Its Part

To alleviate some of those concerns, Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence, and two of his colleagues authored a perspective in the New England Journal of Medicine: Reevaluating Patient Eligibility Criteria in Oncology Trials.

The article addresses four of the most commonly excluded populations in oncology trials, and cites evidence to support the claim that these routine restrictions should not be adopted universally in trial design. It also gives solid suggestions for data analysis to ensure that inclusion of additional patient populations doesn’t interfere with the regulatory process. The authors also discuss potential benefits to the pharmaceutical companies for including more of the routinely excluded populations. For more information, please see this article in Bloomberg BNA.

Of course, making changes takes time, and this system will not change fast enough for many looking for trials today. Yet, this publication reveals the willingness of the FDA to work with trial sponsors who are interested in finding ways to include more patients in clinical trials without jeopardizing the approval process.

Passing The Torch To Pharma

The New England Journal publication from the team at the FDA demonstrates the agency’s commitment to ensuring the inclusivity of clinical trials, yet the decision on exclusionary criteria falls solely to the trial sponsor. It is safe to say that people working at pharmaceutical companies genuinely care about patients, but they need to be profitable to continue making drugs to help patients. Patients will surely benefit from more thoughtful exclusionary criteria: many previously ineligible patients will be able to get potentially life-saving drugs. But appropriately expanding their trial population will benefit trial sponsors as well:

  • Fewer exclusions mean faster enrollment. The sooner a drug is approved, the sooner it can make money for the company.
  • More patients equals more data. Now, patients who are excluded are forced to make a request for compassionate use if they feel a drug might help them. When these requests are honored, the patients are treated outside the clinical trial, so data about their response and adverse effects may not be appropriately captured.
  • Doctors and patients will know what to expect once the drug is approved. While the sickest patients are routinely excluded from trials, they are usually some of the first patients to be offered a new drug once it is approved. Knowing what to expect, both in terms of response and adverse effects, would help a patient more confidently choose a new drug.
  • More label indications. A drug’s label can only indicate its use in the same setting as the trial that gained its approval. Since heavily pretreated patients and those with brain metastasis are routinely excluded from clinical trials, newly approved drugs are rarely indicated to treat those individuals. Doctors are free to prescribe any approved drug in an “off-label” capacity, but insurance companies are reluctant to pay for off-label prescriptions. If the insurance company won’t pay for a drug, few people have the extreme wealth to be able to afford cancer drugs out-of-pocket, leaving the company with either a lost sale or to provide the drug free of charge to the patient.

What If I’m Ineligible NOW?

A changing tide is good, but what if you’re in need of a trial now, and can’t wait for trial sponsors to start adopting some of the new recommendations? While the “right to try” legislation is being discussed widely, and is under consideration in the Senate, there is already a mechanism for patients to get investigational drugs when they don’t qualify for a trial. The FDA has established a protocol that your doctor can complete to get a single patient Investigational New Drug application (IND) for compassionate or emergency use. While the FDA approves nearly every single patient IND application they receive, the sticking point is usually getting the pharmaceutical company to agree to provide the drug. (Remember, they’ll be giving you the drug but not getting the complete data in return. Maybe they should just include you in the trial!)

Precision Eligibility In The Era Of Precision Medicine

In the era of precision medicine, clinical trial sponsors need to rethink their use of a boilerplate list of exclusionary criteria. More precise selection of trial populations means that the drug has a better chance of success. But there are fewer patients who will qualify for the treatment based on a precision biomarker or mutation, so reducing exclusionary criteria will allow the timely completion of a trial. In addition, more precise treatments bring with them the promise of lower toxicities, which reduces the risk of causing excessive harm to more compromised patients.

While patient protection should remain a priority in the design of clinical trials, determining eligibility merits the same thoughtful consideration that goes into the rational design of today’s precision medicines. Such thoughtful consideration will benefit not only the patients on the trial, but future patients and company stockholders, too.

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Jamie Holloway Precision Medicine Advocate

Jamie Holloway

Jamie Holloway is a both a scientist and a survivor, earning her PhD in tumor biology from Georgetown University a few years before her own breast cancer diagnosis. Now living with no evidence of disease after treatment for early stage triple negative breast cancer, she bridges the gap between scientists and researchers as a Precision Medicine Advocate for Cure Forward and as the Patient Advocate for the Metastatic Breast Cancer Project at the Broad Institute. She works with researchers as part of the Georgetown Breast Cancer Advocates and writes about her personal experience with cancer on her blog, Run Lipstick Chemo, and as a contributor to the Cure Magazine community.

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