In a time when evidence-based prescribing and clinical guidelines are hot topics in medicine, trying to access a not-yet-approved drug to use in a patient can feel like navigating uncharted waters. Many physicians are unaware that the US Food and Drug Administration (FDA) allows the use of unapproved drugs outside of clinical trials and — even if they did know it is possible — have no idea how to access such investigational drugs for their patients.
This knowledge is largely sequestered into certain clinical specialties, such as oncology or rare disease, and it is not taught in medical school or during residency: instead, is largely self-taught. Thus, while some physicians have become very accustomed to requesting pre-approval access to drugs, the majority lack this knowledge. In this essay, I use a fictional case to trace the process for requesting access to an unapproved drug. I hope to explode several myths about the process, such as the notion that the FDA is the primary actor in granting access to unapproved drugs and the belief that physicians must spend 100 hours or more completing paperwork for pre-approval access.
Imagine you are a physician, and you have a pregnant patient who has tested positive for Zika. While she is only mildly ill, she’s terrified that her unborn child may be impacted by the virus, which has been provisionally linked with microcephaly and other abnormalities. She’s so concerned that she is contemplating an abortion, even though she and her husband have been trying to have a child and were overjoyed to learn she was pregnant.
Last night, you saw a news story about a pharmaceutical company testing a drug that, in theory, could minimize the impact of Zika on the developing fetus. The story, while focused on the hope of a way to prevent fetal harm from Zika, had also discussed some of the ethical concerns raised by the prospect of testing a new drug on pregnant women and their unborn children. Watching the story, you had thought it might be impossible to ethically test this drug in people, but now, with a distraught patient before you, you wonder if you can find a way for her to try this investigational drug.
In the best-case scenario, you’d remember the name of the company testing the drug; you’d learn it is enrolling patients in a well-designed clinical trial; and you find that your patient is eligible for the trial, is interested in participating, and there is a trial site convenient to her. She enrolls in the trial and has a healthy child — either because of the drug or because the infection did not affect the fetus — and her participation in the trial aids in the development of a drug that may help others who find themselves in her situation. There are numerous reasons, however, why this best-case scenario may not come to pass. You may be unable to recall or figure out what company was testing the drug you heard about; your patient may be uninterested in participating in a clinical trial; she may be interested but may be ineligible because of medical factors, etc.
For the purpose of this essay, let us imagine that your patient is interested in trying the drug and that she is eligible for the trial; however, the closest trial site is three states away. Financially, there is no way she would be able to met the requirement of three prenatal and two postnatal visits to the trial site; thus, due to geography and its attendant difficulties, she cannot enroll. Nevertheless, she is consumed with the idea that the trial drug may be able to help her child. She decides that, unless she can get access to the trial drug, she will abort the fetus for fear for bringing into the world a disabled child that she and her husband feel they would be ill-equipped to care for and raise.
You know the FDA allows expanded access (its term) or compassionate use (the more colloquial term) of investigational drugs in such situations, but you have heard that it is complicated and that it takes a lot of time, so you wonder if it is even a possibility for your patient, who would need to take the drug quickly. Nevertheless, you decide to try, so you do an internet search for “FDA expanded access” and send an message to the email address turned up by your search. You quickly get a response informing you that you need to contact the company to see if it is willing to provide its drug in an expanded access/compassionate use context. You do an internet search to find a phone number for the company, then you call it to see if the company would be willing to make their investigational drug available to your patient. Whoever answers the phone at the company directs you to its ongoing clinical trial, but you explain that your patient is unable to participate in the trial because of distance and expense. You ask to be transferred to whomever it is that you’d need to speak with to ask for your patient to receive the drug via expanded access.
Unfortunately, some companies respond to such requests by simply not responding to inquiries. Other companies do respond, conveying a decision made by the company’s chief medical officer, its regulatory liaison, its CEO, the head of the team developing the new drug, the legal team, or some other company staff member. Just as there is no industry-wide consensus on who ought respond to such requests, there is no consensus on what the answer ought be. Some companies feel strongly that they ought not provide unapproved drugs to patients outside of clinical trials, while other companies are willing so long as such compassionate use does not interfere with the conduct of their clinical trials. Some companies may be willing to provide access in theory but do not have enough drug to make provision a reality. Other companies may have policies that access will only be granted after a certain point in the clinical testing of the drug — for example, after it has been proven relatively safe in a Phase 1 trial, after it has been proven relatively effective in a Phase 2 trial, or perhaps after the clinical trials are complete and the request for the drug to be approved is under review by the FDA. Yet another area where there is no industry-wide consensus is what to do with patients who appeal a denial. These are the patients who turn to the media, online petitions, and Twitter and Facebook to try to pressure a company into granting access to its unapproved drugs.
In your case, you are lucky — the company has received so many requests for their drug that they have decided to open an expanded access program (EAP). This is like a clinical trial, in that it collects some data, but its inclusion criteria is less demanding than that of the company’s “real” trial, meaning that women who did not qualify for the clinical trial may be able to enroll in the EAP. More important for your patient, she would not have to travel across state lines — because the data being collected is so much less, the prenatal and postnatal visits can be conducted at your hospital.
Just as you are breathing a sigh of relief about how easy the process turned out to be, you get bad news from the company. The EAP is in the process of being set up, but it will not be started in time for your patient, who needs treatment urgently if she is to avoid having an abortion. The company informs you that it is still willing to provide their drug to your patient, but you will need to go through what is called the single patient IND route. Your contact at the company directs you to form FDA 1571. This is the form that you’ve heard can take 100 or more hours to complete, and your patient doesn’t have that kind of time, so you prepare to admit defeat. But the company informs you that the 100-hour estimate applies to them, when they completed the form prior to beginning their clinical trials. You are only responsible for filling out about eight or so questions, which they identify for you. As you look through the form together, your contact tells you that the FDA is revising this form, pulling out only those questions someone like you need. The new, shorten form, called FDA 3926, is still under review but will come into effect later this year and is estimated to take only 45 minutes to complete.
Once you complete the form, you send it to the FDA, which will review the request to see if it raises any red flags. By law, the FDA has no more than 30 days to respond. However, understanding that these requests are often time-sensitive and pertain to patients who oftentimes have no other therapeutic options, the FDA’s screen is done as quickly as possible and is not concerned with the possibility of minor harm. The company tells you that historically the FDA has approved the vast majority of requests for expanded access. Looking on the internet you find the FDA’s statistics and see that, from 10/2014–9/2015, of the 779 “single patient IND” requests like yours received, the FDA approved 774. That seems promising but, as you see no data about how quickly the requests are reviewed, you are still worried if you can get an answer in time to be of use to your patient.
The next morning you learn that the FDA has approved the request to try the investigational drug on your patient and her fetus. However, there is one more step to take before you can provide the drug to your patient. Specifically, you need permission from your hospital’s institutional review board (IRB) before you can use any investigational, unapproved drug on your patient. The IRB is charged with reviewing research projects proposed to be conducted at the institution, making sure they are ethically unproblematic before subjects can be enrolled in them. In this case, what they are reviewing is not a research project (even though it involves an investigational drug) but clinical care, albeit of a new, innovative sort that may not actually work. As such, you are not sure how to present your plan to try this investigational drug on your patient and her fetus to your institution’s IRB.
When you call the drug company for advice, they offer to send you their clinical trial consent form. You modify that form, removing language about the trial but keeping information about the potential risks and benefits of the drug to mother and fetus. You then call your hospital’s IRB and explain that you have an compassionate use request for one of your patients, the drug company is willing to provide the investigational drug, and that the FDA has approved the proposal but that you know you need the IRB’s approval. The IRB staff member tells you to send him your proposed informed consent form and that the IRB will try to review it as quickly as possible. You know it normally takes a while for your IRB to review submissions, and in this case you do not have time for that, so you are both relieved to hear that they will review it quickly and a bit skeptical. Before5pm, you call again to check on your submission and to emphasize its time sensitivity, and you are informed that you’ll have an answer tomorrow. You call your patient to update her and then you do the same to the pharmaceutical company, which tells you it will express ship the drug to you so you can use it as soon as you get approval from the IRB.
In our scenario, it all works out — the IRB approves your submission; the drug arrives on time; the patient consents to receive the drug and takes it with no problems; and eventually she delivers a healthy child. You have new, hard-won knowledge about how to request unapproved investigational drugs. Very likely you think the process was more complicated that it should be, especially given the time-sensitivity of such requests, and you are happy that the FDA has a new streamlined form coming into use soon. Overall, however, you are appreciative of the guidance provided by the company and the FDA, and your patient is grateful that you went above and beyond to try to help her have a healthy child.
The purpose of walking through the above scenario was to demystify the process of seeking access to an investigational drug outside of a clinical trial through the FDA’s expanded access program. Secondarily, the above scenario was intended to quash myths such as the FDA having ultimate control over access to investigational drugs via expanded access and the FDA’s paperwork requiring 100 or more hours of time from requesting physicians. However, it must be acknowledged that the above scenario is idealized. Physicians may not be able to figure out what company to contact for a specific drug, or they may be unable to get a response from a company to their request for pre-approval access to an investigational drug. In particular, smaller or newer companies may not have policies about how such requests are to be handled and may have never designated who among the personnel ought handle such requests. Misunderstandings about how to obtain access to investigational drugs outside of clinical trials may result in physicians spending time attempting to petition the FDA for access when, in reality, it is the companies that have the initial and most significant role in deciding whether to grant a request for access. And, as mentioned before, there is no industry-wide consensus on how to handle appeals, thus resulting in some patients turning to the court of public appeal, seeking to pressure or shame companies into providing the desired products.
One byproduct of the lack of understanding of how to seek pre-approval access is the recent proliferation of so-called “Right to Try” laws on the state level. These laws identify the FDA as the sticking point in patients’ efforts to obtain non-trial access to investigational medical products. Seeking to remedy the perceived problem, these laws state that FDA approval is not needed in order to use investigational medical products under certain circumstances (most commonly, in terminally-ill patients, with informed consent, and on a doctor’s recommendation). These state laws raise constitutional issues in their effort to wrest from the federal government the power to regulate the use of unapproved medical products. More importantly, these laws misunderstand that any obstacle to a patient achieving pre-approval access is far more likely to arise from companies being unwilling to give out their drugs than from the FDA refusing a submission. Supporters of the right to try laws frequently say that the FDA issue is not one of rejections but rather of foot-dragging: that patients are dead or too far gone by the time the FDA approves the submission. There does not appear to be data on the FDA’s turnaround times for expanded access submissions, and it is likely that there is a range in the FDA’s review times. However, by law, the FDA has no more than 30 days to respond, and anecdotally it appears the FDA responds much faster than that, sometimes within the same day as a submission being filed. The architect and main proponent of the Right to Try movement, the libertarian Goldwater Foundation, frequently cites the 100 plus hour assertion in explaining why it has targeted the FDA; however, as explained above, that is a misunderstanding of the fact that expanded access requests do not necessitate the completion of the entire IND (investigational new drug) form but rather only several sections of the form.
It may be that the main barrier to patients getting access to pre-approval drugs is lack of familiarity on their part and on the part of their physicians with how to navigate the process. Hopefully this essay has provided helpful illumination and has de-mystified the process. However, seeking investigational drugs outside of clinical trials will still be challenging, and there is still much work to be done: educating patients and physicians, guiding the pharmaceutical industry to develop best practices, assisting IRBs to be able to provide appropriate and timely reviews of compassionate use proposals, and collecting data about the timeliness of FDA review of expanded access submissions.
Alison Bateman-House acknowledges and appreciates the assistance of Richard Klein, director of the FDA’s Patient Liaison Program.