IV. Assistance to Try to Obtain an Investigational Drug Outside of a Clinical Trial

By far, the most common way that patients get investigational drugs is by taking part in a clinical trial. However, a clinical trial may no longer be open to new patients and not everyone is eligible to participate in trials that are open. Some patients do not fit the exact requirements for clinical studies, some have rare forms of cancer for which only a limited number of studies are underway and others are too ill to participate.


Working with the National Cancer Institute and other sponsors of investigational drugs, the FDA has established special conditions under which patients and their doctors can apply to receive cancer treatments that have not yet made it through the approval process. In the past, these special case applications for new treatments were handled under rules for compassionate uses. More recently, the grounds for such applications have been expanded to include more patients and more categories of investigational treatments.

Today, subject to the approval of the sponsor of an investigational drug, a patient may receive an investigational drug through an expanded access protocol or a special exception or compassionate exemption if the following criteria are met:

  • There must be substantial clinical evidence that the drug may benefit persons with particular types of cancer.
  • It must be possible to give the drug safely outside a clinical trial.
  • The drug must be in sufficient supply for ongoing and planned clinical trials.
  • There is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition.
  • The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated.
  • Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.
  • The patient’s physician must determine that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition.

The purpose of an expanded access protocol is to make investigational drugs that have significant activity against specific cancers available to patients before the FDA approval process has been completed. Expanded access protocols thus may allow a larger group of people to be treated with an investigational drug.

The sponsor must apply to the FDA to make the drug available through an expanded access protocol and the FDA must determine if there enough evidence from studies already completed to show that a drug is likely to be effective against a specific type of cancer and that it does not have unreasonable risks. The FDA generally approves expanded access only if there are no other satisfactory treatments available for a patient’s disease.

Patients who do not meet the eligibility criteria for a clinical trial may ask their physician to request a special exception or compassionate exemption. The doctor must contact the sponsor of the investigational drug and provide the patient’s medical information and treatment history. The sponsor (the National Cancer Institute or a drug company) evaluates requests on a case by case basis and must determine if there is reasonable expectation that the drug will prolong survival or improve quality of life.

Not all investigational drugs are available through an expanded access protocol or special exception or compassionate exemption. The sponsor decides whether to provide an investigational drug outside a clinical trial and availability may be limited by drug supply or other factors.

Every cancer patient has the right to request treatment with an investigational drug. It’s not hard to imagine the circumstances that lead cancer patients to seek an investigational drug. However, those very difficult circumstances still raise some important questions that should be asked and answered.

Important side effects may be acceptable in exchange for a clinically meaningful benefit. But even small harms may outweigh any benefit in a surrogate outcome.

In an editorial published in the Journal of the National Cancer Institute in 2006, Steven Woloshin, M.D and Lisa Schwartz, M.D. offered some cautionary advice for physicians and patients to consider before pursuing an investigational cancer treatment based on the results of preliminary research.

"Moving fast is appealing. It means being on the cutting edge of medicine. It means bringing new hope to patients. There is a presumption that newer treatments are better than older ones. And all sorts of forces encourage the rapid adoption of new, so-called breakthrough treatments and technologies, including investigators with professional and financial interests, pharmaceutical companies, an uncritical news media, aggressive disease advocacy groups and desperate patients with progressive disease and no good options...

"The point is that moving fast is a gamble. When preliminary findings turn out to be true, patients benefit. When the findings are not true, patients get hurt: They are exposed to ineffective or harmful treatments, or they forego good alternatives...

"[P]hysicians need to approach preliminary research cautiously. [Here is] a series of questions to help clinicians decide whether to encourage patients to gamble on preliminary results.

"First, did the research show an important clinical benefit? By “clinical benefit,” we mean interventions that affect how patients feel or function or whether they survive, as opposed to surrogate outcomes such as a change in tumor size or lab findings. The patient’s clinical state matters a lot. Patients who feel well or have a good prognosis already (i.e., with standard treatment) should demand more benefit than patients who are sick or dying.

"Second, are there important downsides to using the new regimen? Judgments about benefit need to be made in the context of harm. Important side effects may be acceptable in exchange for a clinically meaningful benefit. But even small harms may outweigh any benefit in a surrogate outcome.

"Third, how strong is the evidence for the findings? Results from large, long-term randomized trials are more compelling than results from small trials or controlled observational studies and much more so than the results of a case series.

"Fourth, how does the new research fit with prior work? Contradictory findings are generally an indication of caution; however, the first good randomized trial data may be sufficient to trump a body of observational work...

"Finally, do effective treatment alternatives exist? It makes little sense to risk exposure to a new, therapeutically equivalent drug when safe and effective alternatives with longer track records are available." (8)

8. Woloshin S et al. What’s the Rush? The Dissemination and Adoption of Preliminary Research Results. J Natl Cancer Inst. 2006;98:372.