Alison Bateman-House, contributor
Imagine you are dying of a disease or condition for which there is no treatment. Or imagine you are dying of a disease or condition for which cures exist, but they are not working for you. If someone said they had an experimental drug that wasn’t approved for sale or use in the United States but that might help you, you’d probably want to try it. You’d want the chance to live, even if only because your spouse or children would be desperate not to lose you.
If someone says to you, “We can’t guarantee the drug will work; in fact, we can’t even guarantee the drug is safe, and it might even kill you, though we don’t think that will happen,” you still might want to try it. You might say: “I’m dying anyway; what does it matter if this drug kills me? This is my only chance.”
This conversation happens more often than you might think. In many cases, the patient would then be enrolled in a clinical trial, where they’d get access to the experimental drug. It might be a Phase 1 trial, where the product is first being used in people and is given in increasing amounts until it causes toxicity in order for researchers to figure out what dose of the drug to use. Phase I clinical trials are commonly performed on healthy volunteers, not patients, but for certain very toxic drugs, like chemotherapies, the dosage-setting studies are done on patients because of the ethics of giving these drugs to healthy people.
However, clinical trials are not available to all people. Unfortunately, most clinical trials are conducted in university hospitals in cities, making them hard to access for those who live in remote areas. Having to travel back and forth to a trial site also makes clinical trials inaccessible to those who for whatever reason are unable to devote the necessary time and money. And because researchers are looking to enroll patients who, apart from the disease or condition of interest, are relatively healthy and able to answer the researchers’ questions — no secondary conditions, no developmental disorders like Down syndrome, no history of a serious condition like thyroid disease, no dementia — many patients would not be allowed into a clinical trial even if they wanted to join one.
How to handle compassionate use requests is not taught in medical school, nor do most young doctors learn it in residency. There is information available on the FDA website and on the website of the NYU Langone Health Working Group on Compassionate Use and Pre-Approval Access. Kids v Cancer, a patient advocacy group, offers a navigator service that will walk doctors through the process. Otherwise, learning how to make these requests is something individual doctors must figure out for themselves or learn by finding another doctor willing to teach them.
In essence, the process has four steps. First, the doctor and patient must identify a drug in development that they want to try. Second, the doctor must contact the company developing that drug and request it for the patient. If the company agrees to make the product available, the doctor must then complete a form for the FDA, which will review the proposed treatment plan. Finally, because the drug is not approved for sale or use in the United States, the doctor must get permission from her institution to use it on a patient. Once these steps have been completed, the drug may be used on the patient, provided the patient or a legally authorized surrogate decision maker gives informed consent.
Unfortunately, many of these steps are arduous for a doctor who has never done them before. Doctors, especially those not at the city hospitals affiliated with universities where most clinical trials are done, may not know all the drugs in development and may thus have difficulty figuring out which, if any, make sense to try.
Once a doctor has settled on an experimental drug, she needs to figure out how to send her request to the drug company. Fortunately, a law passed last year requires that drug companies make public their pre-approval access policies and information about how to make requests once any of their drugs in development enter the Phase 2 clinical trial stage. Companies are increasingly complying with this requirement by posting this information on their websites. For example, Janssen Pharmaceutical has a wonderful site with explanatory videos and specific information about how to submit requests for compassionate use access. (Disclosure: I work with this company on pre-approval access issues.)
But even if a company has not posted the information on its website, it may be available through another new resource, the Reagan-Udall Foundation’s expanded access navigator. By using this navigator and information posted by individual drug companies, doctors can hopefully find out how to submit a compassionate use request, as well as a timeline for when they’ll hear back from the company.
If the company says yes, the doctor (along with the company) submits to the FDA a form describing the patient and the proposed treatment plan. In light of complaints that the form was too complicated and confusing and took too long to fill out, the FDA released a streamlined form in 2016. Suitable only for when the doctor is treating one patient (as opposed to all of a doctor’s patients who have a certain disease but can’t get into clinical trials), the revised form consists of seven questions and is estimated to take 45 minutes to complete.
After the form is submitted to the FDA, staff members at the relevant part of the agency review the treatment plan. This review takes less than 24 hours in emergency situations; in non-emergencies, the review takes around four days. A recent report by the nonpartisan Government Accountability Office found that over 99% of the requests are approved, although perhaps with changes (for example, in the dosage of the drug to be used or in the dosage schedule). So contrary to claims that the FDA is an obstacle to patients seeking access to investigational drugs, this step is possibly the easiest part of the process to navigate.
Once the FDA has agreed to allow the compassionate-use request, doctors must gain the approval of their institution (although, in true emergencies, this step can be skipped and the institution merely informed of the situation within five days). All universities and research institutions have something called an investigational review board that reviews proposed research to make sure it is ethical. The IRB would need to give the doctor permission to use the experimental drug on the patient.
This step can be easy, with the IRB quickly reviewing the proposal and giving permission. Alternatively, this step can be difficult. Private hospitals that don’t conduct clinical trials may not have an active IRB, leaving the doctor searching for someone to authorize the experimental treatment. Hospitals with overwhelmed IRBs may not be able to review the proposal quickly. Or IRBs may charge for review, and the patient may be unable to pay this fee. For those last problems, there is a recent possible solution: The WCG Foundation, a public charity, will coordinate free, rapid IRB review for those who otherwise would not have access.
As noted, there have been many innovations in the compassionate use world recently: a streamlined FDA form; a new navigator; a law that requires transparency about pre-approval access policies; and a no-cost, rapid solution for IRB review. The intervention that would be most helpful at this point would be a multifaceted educational campaign to teach medical professionals, hospitals and patient advocacy groups about how to navigate the above path. Knowledge of this process is imperative for doctors, nurses and patient advocacy groups.
On the other hand, rather than trying to improve the compassionate-use system — which is supposed to be a rarely used safety net for those who cannot participate in clinical trials — we could work to improve the clinical trial system. Clinical trials need to be dispersed to areas of the country that do not currently have easy access. Institutions that conduct clinical trials need to be innovative about offering appointments beyond the 9-a.m.-to-5-p.m. window and need to offer services, such as childcare or eldercare, that would enable more people to be able to participate in clinical trials.
Furthermore, serious attention needs to be paid to the exclusion/inclusion criteria for clinical trials. While researchers like homogenous, relatively healthy groups of research subjects because they provide “clean” data showing the effect of the experimental treatment, it may be possible to widen trial eligibility to those who have been excluded on the grounds of age or medical condition without making the data too “messy” to be of use. Or a trial could be set up specifically for patients excluded from the “clean” trial, in order to get insight into how the drug would work in a real-world population, with all of its variability.