Working Group on Compassionate Use and Pre-Approval Access
The NYU School of Medicine Working Group on Compassionate Use and Pre-Approval Access (CUPA) was founded in 2014 to explore the ethical issues surrounding access to investigational products before they’ve received U.S. FDA approval, including: the fairness and transparency of access decisions, the role of social media, and legislative efforts to sidestep regulation of pre-approval access. Today CUPA continues to work to advance knowledge about this topic, identify best practices, and bring to the forefront important ethical issues that need further attention.
Who we are
CUPA is chaired by Arthur Caplan, PhD, founding director of the NYU School of Medicine’s Division of Medical Ethics, and Alison Bateman-House, PhD, assistant professor in the Division of Medical Ethics. Members, listed at right, represent a wide variety of fields, including medicine, law, academia, bioethics, government, industry, and patient advocacy.
What we do
CUPA’s main responsibilities, activities, and accomplishments include:
- Working with patient groups to help demystify pre-approval access and create community-specific resources.
- Publishing hundreds of articles in peer-reviewed journals and mainstream publications (click on the links at right for articles and interviews, as well as resources for patients and other stakeholders). Members have received extensive coverage in major media outlets including the L.A. Times, STAT, Harper’s Magazine, Forbes, and NPR, among others, and they speak frequently at conferences and seminars.
- Serving as the go-to resource for issues related to pre-approval access. In addition to publications and resources, CUPA’s website features an educational module on pre-approval access and information on legislative and industry activities.
You can find the group’s 2016 annual report outlining the breadth and variety of its work here.
- What is “compassionate use”?
- What is an unapproved medical product?
- Who is eligible for pre-approval access?
- I've heard that FDA approval is very slow. What about people who need access to the new medical products before approval?
- What can you ask for through pre-approval access?
- Is pre-approval access a clinical trial?
- So, are patients in expanded access programs in a clinical trial or are they receiving the drug through pre-approval access?
- Who is in charge of pre-approval access decisions?
- If it’s “compassionate,” why does the issue generate so much controversy?
- How else could granting a dying person access to an unapproved medical product harm an ongoing clinical trial?
- What are “right-to-try” laws?
- How many patients have been helped by right-to-try laws so far?
- Who could possibly object to dying people trying any means available to save their lives?
- Still, given the length of time it takes the FDA to approve new therapies, why not remove the middleman—the FDA—from the compassionate use equation?
- If the FDA permits more than 99% of compassionate use requests to proceed, do we really need it to review these proposals?
- If right-to-try laws don’t help get treatments to sick patients, then why are supporters pushing them so hard?
- Why do so few people in the U.S. get access to experimental drugs via pre-approval access? Just over a 1,000 people per year in our entire country versus thousands in France, a much smaller country?
- Who is on the NYU School of Medicine Working Group on Compassionate Use and Pre-Approval Access, and what do they hope to accomplish?
- Does the Working Group talk with legislators or other policy makers?
- Has the Working Group found any positive proposals to make for those seeking compassionate use?
- Who pays for the Working Group?
- What publications have Working Group members issued?
- The Working Group’s co-chairs, Dr. Arthur Caplan and Dr. Alison Bateman-House, are part of NYU School of Medicine’s Compassionate Use Advisory Committee (CompAC). Is this a conflict of interest?
- If I’m interested in gaining compassionate use access to a drug or device, what should I do?
“Compassionate use” is the same thing as “expanded access” is the same thing as “pre-approval access.” Regardless of the name you use, it is a pathway by which patients may be granted access to a drug or device that hasn’t been approved for sale or use in the United States by the Food and Drug Administration (FDA). Compassionate use is the term typically used by the media, and expanded access is the legal term used by the FDA. We prefer the term pre-approval access because we think it makes clear what is being discussed: access to a medical product that is not approved for use. Outside of the U.S., there are additional terms used, like “named patient programs” or “named patient supply.” We recently wrote a paper arguing for one term to be used everyone to prevent confusion.
Normally patients in the U.S. have access to such unapproved medical products only by enrolling in a clinical trial. Pre-approval access does not involve enrolling in a clinical trial. (This is a little complicated, and we discuss it more thoroughly below.) Terminally ill patients who have no other treatment options may seek this type of access. So might those with debilitating non-terminal diseases or conditions, such as blindness, multiple sclerosis, or chronic pain.
Some high-profile cases have brought pre-approval access into public awareness. In 2001, the Abigail Alliance for Better Access to Developmental Drugs was launched in memory of Abigail Burroughs, a 21-year-old cancer patient who died while trying to access an unapproved drug. In 2013, Andrea Sloan sought compassionate use of an ovarian cancer drug. Her request was initially denied; she appealed, and she died shortly after a company agreed to provide the drug. And in March 2014, the family of seven-year-old Josh Hardy waged an aggressive media campaign to secure pre-approval use of an antiviral drug from a small manufacturer. Although the company refused to grant the drug to Hardy via compassionate use, it created a new clinical trial that enrolled him as a subject. He survived and returned home. These were all individual-patient cases of pre-approval access, which we describe in more detail below. There are also cases of pre-approval access for groups, which we also talk about below.
Outside the U.S., policies for pre-approval use vary by country. This FAQ pertains only to the United States.
In the U.S., medicines and medical devices are available for sale or use only after they are approved by the FDA, the federal agency charged with making sure medical products have been shown to be relatively safe and effective before they can be placed on the market. (If evidence arises later that a medical product is not as safe or effective as thought, the FDA can withdraw it from the market.)
When a company has a new drug or device that it wants to sell or use, the company needs to follow the FDA’s rules about how to get its product approved. Normally this involves going through a series of tests, both of safety and efficacy. Only after this testing (which typically entails clinical trials) is completed and the data collected from the testing is sent to the FDA for review will the agency decide whether to approve the product.
FDA regulations specify two groups of people who are eligible for compassionate use when no alternative treatment is available: (1) those with life-threatening diseases or conditions for whom “there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment”; and (2) those with serious diseases or conditions associated with “morbidity that has a substantial impact on day-to-day functioning.” More information can be found in the first section here.
I've heard that FDA approval is very slow. What about people who need access to the new medical products before approval?
Whether FDA approval is slow or not is a matter of debate and will not be covered here. But for patients who seek access to unapproved medical products, there are several possible routes of access. The most common one is to enroll in a clinical trial. You can get more information about that here. The less common one is pre-approval access. And in some states, it is theoretically possible to access drugs via something called Right to Try laws, which we discuss below.
Unapproved medical products: drugs (including biologics) as well as devices. More information can be found on the FDA website.
The pre-approval access scenario that we are most familiar with from the media, movies, and the like is a request from a single patient. Individual-patient compassionate use is not a clinical trial. The purpose of an individual-patient compassionate use protocol is to treat a patient, not to collect data. For more information on this type of compassionate use, see the Code of Federal Regulations, §312.310.
The type of pre-approval access that we, as a society, are less familiar with deals with groups of patients with a similar disease or condition, such as boys with muscular dystrophy. For more information on this type of pre-approval access, see CFR §312.315. Individuals within the defined group can sometimes gain access to an unapproved medical product by means of an “expanded access program” created by the company developing the product. For example, if a new drug to treat a deadly disease is nearing the end of the clinical trials testing process, and data suggest that the drug is safe and effective, the company may start an expanded access program to make the drug available to those who cannot wait for it to receive final FDA approval. Also, there is frequently a time lag between FDA approval of a new drug and when it starts showing up in pharmacies, or when insurance companies agree to start paying for it. During that time, patients can access the (now approved) drug through expanded access programs. (Expanded access programs close down once a drug is available in pharmacies.)
Some of these expanded access programs are types of clinical trials. They do not have many of the features that we think of as typical of clinical trials (for example, patients know what drug they are receiving; they are not randomized to receive other treatments or a placebo; etc.); however, these programs do involve the collection of clinical data about the participating patients. Patients who seek pre-approval access are typically in worse health than patients in clinical trials. By collecting data on patients in an expanded access program, the company developing the drug or device can get an idea of how the new product works on sicker patients. This information is often useful in predicting how the product will work in the “real world,” after it has been approved by the FDA.
So, are patients in expanded access programs in a clinical trial or are they receiving the drug through pre-approval access?
Expanded access program have elements of both clinical trials and compassionate use programs. As in clinical trials, there are rules about who is eligible to enroll. And patients’ physicians must report to the company certain information about the drug, including about any side effects and how well it is working. The rules about who is allowed in an expanded access program are frequently not as strict as those about who may be allowed to join a clinical trial, and the main goal of the expanded access program is to help the patients in it, rather than the development of knowledge. If, for whatever reason, a patient is not able to access a drug through an expanded access program, he or she may then ask to get it through single-patient compassionate use.
In the U.S., the companies developing the new medical product are the key decision-makers about whether to allow access to an investigational drug or device. Physicians channel requests to the appropriate company and provide information about the requesting patient. If the company agrees to provide a product to a physician for a particular patient, two more approvals must be secured: the FDA's and an institutional review board's (IRB).
The FDA reviews proposed use of experimental medical products to make sure there is biological plausibility of the proposal and no evidence that the attempt will be obviously unsafe. The FDA does not "approve" pre-approval proposals, allows them to proceed or not. Over 99% of these proposals are allowed to proceed. However, in some circumstances the proposal is altered in response to feedback from the FDA. Jarow et al. looked at a random sample of 150 proposals and found that 11% were altered in response to FDA input. Such alterations were along the lines of changing the proposed dosing schedule.
Several reasons. Access to investigational medical products is not always fairly granted. For example, those with the financial resources or special medical or political connections may seek and gain preferential access. Those who know how to utilize social media may have an advantage over those who don’t. (The Josh Hardy case is a good illustration of this.) Similarly, not every doctor, much less patient, knows about compassionate use or how to request it.
Another key issue is the risk that pre-approval access poses to the clinical trial process and the timeline for FDA approval. Granting individuals access to investigational medical products can jeopardize an ongoing clinical trial that may eventually produce a treatment that could help many future patients. If some of a drug is diverted to compassionate use, there may not be a sufficient amount left to permit a clinical trial to be done, thereby delaying the trial, possible FDA approval of the new drug, and, ultimately, the general availability of the new drug for months or years.
Finally, because the investigational medical products being sought by patients have not been thoroughly tested (unless someone is seeking access to a drug that is in Phase 3 clinical trials), their effects and side effects are often unknown, especially in very sick people. As such, the treatments may cause further harm and suffering, or even hasten death. Negative outcomes in patients could have serious repercussions for the investigational medical product, which could be blamed—even if the poor outcome happened because the patient was seriously ill. The FDA says it will not hold adverse events associated with compassionate use against a drug unless it is reasonable to do so, but some companies are afraid to take this risk and, as a result, avoid compassionate use.
How else could granting a dying person access to an unapproved medical product harm an ongoing clinical trial?
Several ways. If patients learn that pre-approval access is a possibility, they may not be willing to enroll in a clinical trial, fearing they’ll receive a placebo or standard-of-care treatment instead of the desired product. If people had a choice to receive the investigational medical product they wanted through a compassionate use program or by entering a clinical trial, it is not surprising that they would choose the compassionate use program—after all, they would know for sure what they were receiving. While that may be the most rational choice for an individual, it could imperil the availability of patients for clinical trials, which would have dire consequences for the drug development process and for future patients.
Many manufacturers have limited supplies of their investigational products, and granting compassionate use access can threaten those supplies. If they run out of supplies, manufacturers may have to scale back or suspend clinical trials. Especially with biologics, it is no easy task to “just make more drug.” Some biologics can take more than a year to produce, and there are limited numbers of manufacturing facilities that can perform these complex tasks. Other drugs are hugely costly to make.
Legislation has been introduced in the U.S. at the state and federal level that purports to grant terminally ill people access to investigational drugs and devices. Three federal right-to-try (RTT) laws have been proposed: S.204 - Trickett Wendler Right to Try Act of 2017, H.R.878 – Right to Try Act of 2017, and H.R.1020 – Compassionate Freedom of Choice Act of 2017. The Goldwater Institute, a libertarian think tank, created a model bill (under "Resources," here) for states to use in crafting right-to-try laws. Most of the laws and bills follow the model bill closely, although there are differences. For example, four states don't allow inpatients to request drugs under right to try, something not specified in the model bill, and several bills' definition of "terminal illness" differs from the model's.
RTT laws have generated a lot of attention since the first one was enacted in Colorado in May 2014. They are now on the books in 34 states. The popular press praises these laws for ostensibly throwing a lifeline to terminal patients, but the laws don't require a manufacturer to provide investigational medical products upon request — so, in actuality, they are no more of a guaranteed lifeline than is the FDA program that RTT seeks to undercut. A recent article by working group members Lisa Kearns and Alison Bateman-House analyzed the variations in provisions among 32 of the state RTT laws and found that right-to-try laws provide few tangible benefits to patients, despite their patient-centric rhetoric.
The laws' backers claim that they speed up the process of getting investigational medical products to patients by removing the FDA from the pathway to access. But cutting the FDA out of the picture by means of state laws is almost certainly illegal, which is why RTT advocates are now pushing for federal legislation. Furthermore, although companies may wish to respond to patient requests, they may see no upside to giving access to their investigational products without FDA approval. If the products work, companies want to be able to use that information when they seek marketing approval from the FDA, and if the products do not work, companies want to be able to say that there was oversight of the use of their investigational product on a sick or dying patient.
According to the Goldwater Institute and Dr. Ebrahim Delpassand, the founder of Excel Diagnostics and Nuclear Oncology Center, 80 patients have gained access to an agent called Lutathera under the Texas right to try law. Yet because Lutathera was already available via pre-approval access, we do not accept this claim as evidence of one or more patients receiving otherwise unavailable drug(s) because of a RTT law. Rather, to the best of our knowledge, no patients have been helped by right to try laws.
People in states with right-to-try laws are receiving access to investigational medical products, but this is done under the FDA's "expanded access" provisions, which predate right-to-try laws. And the FDA isn't the problem right-to-try supporters make it out to be. Over the past six years, the agency has granted more than 99 percent of all pre-approval requests, and approval for drugs to treat rare or life-threatening diseases are, as the New York Times put it, "the rule, not the exception" (see the article, and a chart showing the agency's approval trajectory since 1990, here). The FDA responds to pre-approval access requests on average within four days, and it responds to emergency requests on average within 24 hours. And in June 2016, the agency released significantly revamped paperwork, reducing the time needed to complete it to less than an hour. Not only the FDA review typically speedy, it can be helpful to patients. Jarow et al. looked at a random sample of 150 proposals and found that 11% were altered in response to FDA input. Such alterations were along the lines of changing the proposed dosing schedule.
Right-to-try laws raise an important ethical concern: They create false hope in desperately ill people that they can obtain something they may, in fact, not be able to get.
No one, but you can certainly object to falsely raising patients' hopes that they have a right to investigational medicine. You can object to patients experiencing increased suffering or possibly an earlier death if they were not fully informed of the risks they were taking or aware of conflicts of interest that might be impacting the advice they are being given. Also, many of right to-try-laws and bills stipulate that if patients receive access to an unapproved medical product, they are at risk of losing hospice care, home healthcare, or even insurance coverage. These provisions are not well publicized, so patients may not understand what they risk.
Many people might also object to granting individual requests at the expense of enrolling participants in clinical trials, which could result in finding treatments that have the potential to help larger numbers of future patients. PhRMA (Pharmaceutical Research and Manufacturers of America), a trade group representing companies in the pharmaceutical industry in the United States, has expressed concerns about the legislation, both because it threatens the integrity of clinical trials and because it considers FDA oversight of investigational products to be in the best interest of patients.
It is also the case that unscrupulous health care providers might try to take advantage of right-to-try laws to sell nostrums and quack cures to desperate patients and their families. Right-to-try legislation requires only that a Phase 1 safety study has been done, and that's flimsy protection from shysters and crooks. Despite the fact that Phase 1 studies are often called "safety studies," the completion of a Phase 1 study does not guarantee that an experimental drug is safe. Most Phase 1 studies use paid, healthy volunteers to determine the appropriate dosage for future studies, and, as such, there is little information available about how these experimental drugs may work in patients. While patients, particularly the terminally ill, may be understandably willing to take on risk to try a new treatment, we need to ensure that they understand that even Phase 1 studies are no guarantee of safety and that prior to the completion of Phase 2 studies, there is no information about a drug's efficacy. Thus, using a drug before the completion of Phase 1 and Phase 2 truly in a leap into the unknown.
Still, given the length of time it takes the FDA to approve new therapies, why not remove the middleman—the FDA—from the compassionate use equation?
First, there's a real reason for FDA oversight. In 1962, the thalidomide incident spurred legislation that forces drug companies to prove to the FDA that their products are safe and effective before they can be approved. And bear in mind that there will always be hucksters and snake oil salesmen peddling anything as a cure to desperate people. This sadly exists in the unregulated arena of stem cell "therapies," which have been portrayed as cures for nearly everything in some nations. The FDA helps prevent an increase in attempts to manipulate and exploit those desperate for a cure or treatment for their ailments.
Importantly, the FDA review can be helpful to patients. Jarow et al. (link) looked at a random sample of 150 proposals and found that 11% were altered in response to FDA input, including, for example, changing the proposed dosing schedule. When trying an investigational drug, a patient's doctor is working with very limited knowledge, so the more insight provided about how to use the drug and how to treat any side effects, the better.
If the FDA permits more than 99% of compassionate use requests to proceed, do we really need it to review these proposals?
Yes. While the FDA almost always permits a compassionate use request to go forward, FDA personnel weigh in on aspects of the proposal, such as the dosage to be used, the dosing schedule, and the like. Based on the FDA's knowledge of the experimental agent and how it worked in any previous usage in people, the agency can help the physician to adjust the proposed treatment plan. This is an important step in trying to help patients because the FDA employs expert scientists and physicians who specialize in clinical research protocols, while a patient's treating physician may not have this experience. So, FDA approval is not a “rubber stamp”; it is a necessary collaboration between experts in the administration of investigational products and a patient's treating physician.
If right-to-try laws don’t help get treatments to sick patients, then why are supporters pushing them so hard?
The prevailing theory is that interested parties want to try to force federal action—that is, federal legislation that would limit the FDA’s oversight of the entire drug approval process through generating a groundswell of state activity. The Yale Law Journal made just this case in December 2014. A federal right-to-try bill was first introduced in July 2015, lending more weight to this theory.
Why do so few people in the U.S. get access to experimental drugs via pre-approval access? Just over a 1,000 people per year in our entire country versus thousands in France, a much smaller country?
Comparing the numbers of patients treated with experimental agents in the U.S. and France is an apples-to-kumquats comparison. It is inappropriate to compare these two countries for one simple reason: France has a national healthcare system and our country does not. Not all Americans have access to centers of clinical excellence and research specialty care. It would be a miracle for a patient in a safety net hospital to be given the option of trying an unapproved drug via compassionate use. These hospitals rarely participate in clinical trials, do not have the infrastructure necessary to treat patients with experimental drugs, and, more to the point, see a tremendous volume of patients, even for complex specialties like oncology. There is no institutional support for anything but standard care, and patients have no option to leave there and go to a private hospital. As such, an entire economic class is ruled out. This has nothing to do with FDA rules about access to experimental drugs; it has to do with a system that was never set up to provide every patient with cutting edge, including experimental, treatment. It is not fair that access to unapproved drugs is only for those who know about the possibility; can afford the "right" physician and hospital; and can pay costs associated with the process that insurance may not pay or are lucky/appealing enough to find themselves the beneficiaries of a charitable endeavor. Thus, a sensible way to help patients would be to deal with these systemic inequalities.
Despite the fact large numbers of Americans are not situated so as to be able to seek experimental drugs for compassionate use, there are still many patients who both seek this access and receive it. The FDA gets over 1,000 requests a year, but a request can be for either one patient or many patients. For example, from 2014 to 2015, the FDA permitted 1,256 compassionate use attempts; 1,194 of these permitted requests were for single patients, but 62 were for multiple patients. Of these 62, 54 of the permitted requests were deemed "intermediate" (defined as more than one but less than many) in size, and 8 were deemed large. Without knowing the names of the drugs, we cannot know the number of patients involved in these intermediate and large requests; however, it is not unheard of to have more than 1,000 patients in a large compassionate use program. So, nobody knows exactly how many patients receive pre-approval access in our country, but it is certainly more than just the number of pre-approval requests permitted by the FDA.
Who is on the NYU School of Medicine Working Group on Compassionate Use and Pre-Approval Access, and what do they hope to accomplish?
Members of the Working Group are listed here. The Group works to raise awareness of the many ethical issues surrounding compassionate use and other efforts to facilitate access to investigational medical products prior to their approval by the FDA. In order to do this, and to understand the perspectives of all of those involved in this issue, the Group works closely with patient advocacy organizations, large and small pharmaceutical and biotechnology companies, venture capitalists who fund such companies, and a host of other organizations, including the FDA and various trade organizations. The Group is currently working to develop connections with physicians and IRB professionals in order to better understand compassionate use and pre-approval access from the perspectives of those groups.
Where it sees room for improvement, the Working Group also seeks to effect policy changes that will make the process more realistic, more equitable, and more transparent for those seeking access to investigational medical products.
The Working Group talks with anyone who has insight into pre-approval access or ideas about how to improve the process for those seeking access to investigational medical products. We have communicated with both state and federal legislators and FDA leadership. When we do so, we are not advocating for particular legislation or pushing an agenda. We answer questions, share what we have learned, and seek to provide education. Neither these conversations nor this document represents an official view of NYU or any employer or other institutional affiliation of any Working Group member. However, Working Group members are not precluded from speaking their own minds in an individual capacity or from writing editorial or position papers.
The Working Group has also provided input and advice on pre-approval access to patient advocacy groups and pharmaceutical companies, as well as legislators and others. Some of those whom we have advised include: State Sen. Ted Kennedy Jr. (CT), U.S. Sen. Tom Carper (DE), the ALS Emergency Treatment Fund, Janssen Pharmaceuticals, the Hyundai Hope on Wheels Thought Leader's Summit, Assemblywoman Linda Rosenthal (NY), U.S. Rep. Michael McCaul (TX), BIO, and the Florida Dept. of Health.
We are currently working on developing “big-picture” proposals. In the meantime, we have a number of recommendations for best practices. These are interim measures that will not have a huge impact but will make the situation of current patients less taxing. For instance, we call upon those companies developing medical products to create compassionate use policies. Companies may decide that a medical product under development should not be made available for pre-approval access; our concern is that they proactively develop policies concerning compassionate use.
For those companies that allow access to their unapproved medical products, we call upon them to make those policies publicly accessible (for example, on their corporate websites). We call upon these companies to make publicly available a telephone number, email address, or other designated point of contact to which requests for compassionate use should be directed. We call upon companies to commit to a set time frame for making a decision on a request, to convey this time frame to requestors, and to report decisions to requestors in accordance with this time frame. These recommendations were adopted by legislators and incorporated into the 21st Century Cures legislation passed in December 2016.
All of these interim measures deal with the manufacturers of the investigational medical products. Our Working Group’s final recommendations will be more comprehensive, with recommendations for industry, the FDA, legislators, healthcare providers, and others.
Working Group members receive no compensation for their work on this committee. Overhead costs and other expenses are paid by the Division of Medical Ethics at the NYU School of Medicine, which receives income from a variety of sources including private gifts and contracted projects.
Members of the Working Group have written and spoken extensively about compassionate use, pre-approval access, and related subjects, including FDA regulations, right-to-try laws, and more. You’ll find a link to these articles here.
The Working Group’s co-chairs, Dr. Arthur Caplan and Dr. Alison Bateman-House, are part of NYU School of Medicine’s Compassionate Use Advisory Committee (CompAC). Is this a conflict of interest?
CompAC, which was formed by the NYU School of Medicine, is independent from the Working Group. The idea for CompAC came from discussions that occurred in part among Working Group members, but the two are separate entities.
Talk to your physician. Although you can research compassionate use for your desired drug or device online, you will need to work with your physician to make the request.
If you or your physician need guidance about the process, you can call the FDA's Expanded Access Program Liaison at 301-796-8460.
If you or your physician need someplace to get started, search on ClinicalTrials.gov using the keywords “expanded access,” “compassionate use” and “pre-approval access.”
If you are interested in a particular product-in-development, search the website of the manufacturer of that product for the company's access policy. By law, many drug companies are now required to make such policies public.
The Working Group sends out occasional updates about compassionate use and pre-approval access. To receive these updates, please contact Beba Blagojevic. For media inquiries, please contact Beba Blagojevic (Division of Medical Ethics) or Elaine Meyer (Institutional Communications).