Working Group on Compassionate Use & Preapproval Access Frequently Asked Questions
At NYU Langone’s Working Group on Compassionate Use and Preapproval Access (CUPA), our list of frequently asked questions is an invaluable resource for learning about preapproval access and associated topics. The answers below pertain only to the United States. Policies for preapproval use vary by country.
General Questions About Preapproval Access
- What Is Preapproval Access?
- What Can You Get via Preapproval Access?
- What Does “Investigational” Mean?
- Why Use Preapproval Access?
- Who Is Eligible for Preapproval Access?
- Is Preapproval Access a Clinical Trial?
- How Can You Get Preapproval Access?
- What Is Right to Try?
- How Do Expanded Access and Right to Try Differ?
- Which Is Faster: Expanded Access or Right to Try?
- Why Might a Company Decide to Use Expanded Access Rather Than Right to Try, or Vice Versa?
- Who Makes Preapproval Access Decisions?
- Who Pays for Preapproval Access Drugs?
Questions Asked by Patients About Preapproval Access
Questions About Expanded Access
- What Is an Expanded Access Program (EAP)?
- How Many Patients Has Expanded Access Helped?
- Why Not Remove the FDA from the Expanded Access Process?
- Do We Really Need the FDA to Review Expanded Access Proposals?
- What Role Does an Institutional Review Board (IRB) Play in Expanded Access?
Questions About Right to Try
- What Are State Right to Try Laws?
- What Is the Federal Right to Try Law?
- How Many Patients Has Right to Try Helped So Far?
- What Role Does an Institutional Review Board (IRB) Play in Right to Try?
Questions About Public Engagement
- How Did Preapproval Access Become Mainstream?
- Why Does Preapproval Access Generate So Much Controversy?
- Why Might Someone Oppose Earlier Access to Investigational Medical Products?
Questions About CUPA
- Who Is on CUPA?
- What Does CUPA Hope to Achieve?
- Do CUPA Members Talk with Legislators and Other Policymakers?
- What Proposals Has CUPA Made?
- Who Pays for CUPA?
- What Has CUPA Published?
“Preapproval access,” “compassionate use,” “expanded access,” “right to try”: regardless of which name you use, these terms generally refer to the use of a medical product, for therapeutic benefit, that hasn’t been approved for sale or marketing by the country’s regulatory authority (the U.S. regulatory authority is the Food and Drug Administration, or FDA).
Most often, patients in the United States access unapproved—investigational—medical drugs, devices, or vaccines by enrolling in a clinical trial. Preapproval access is an umbrella term that encompasses access to investigational products both inside and outside of clinical trials. Compassionate use, expanded access, and right to try deal only with access to investigational products outside of clinical trials. We use the term preapproval access generally to refer to investigational medical products outside of clinical trials. Expanded access and right to try refer to specific pathways through which patients, via their physicians, may seek non-trial preapproval access.
Although compassionate use is a common term, CUPA avoids it because of its subliminal suggestion that not providing a requested unapproved medical product indicates a lack of compassion. There are certainly circumstances in which giving a patient a particular experimental product would not be very compassionate—for example, if it is likely to cause more harm than benefit. Outside of the United States, additional terms are used, like “named patient programs,” “named patient supply,” “managed access,” “special access,” or “early access.” CUPA members wrote a paper arguing for the adoption of a single term to reduce confusion; we prefer the term preapproval access. Because preapproval access includes access via clinical trials, we suggest using the term “non-trial preapproval access” instead of compassionate use.
In the United States, non-trial preapproval access operates via two pathways. Through the FDA’s expanded access pathway, a physician may seek access to investigational medical products on your behalf: drugs (including biologics), vaccines, and devices. Via the right to try pathway, a physician may seek access to investigational drugs that meet certain criteria.
In either case, the patient must request access through a doctor who is willing to administer the investigational treatment, and some doctors may be unwilling to do so. Neither expanded access nor right to try requires companies to provide their investigational products. Therefore, in either case, a patient (via a physician) has a right to ask for access but not a right to be provided the desired product.
In the United States, drugs (including biologics), vaccines, and medical devices are normally available for sale or use only after they have received marketing approval by the FDA, the federal agency charged with ensuring that medical products are relatively safe and effective. Before approval, the FDA refers to them as “investigational.”
When a company has a new product that it wishes to market, it normally needs to test that product first in humans, following the FDA’s rules. For drugs, vaccines, and some types of devices, marketing approval typically requires a series of tests intended to demonstrate that the product is both safe (i.e., its risks are reasonable in light of the benefits it offers) and effective. Only after these are completed, and the FDA has reviewed the data collected from these tests, does the agency decide whether to approve the product.
Products being developed and tested are called investigational. They may also be referred to as “experimental” or “unapproved” medical products.
In general, it takes at least 10 years for a drug to go through the development pipeline, from preclinical studies to approval. (Despite common misperceptions, FDA review and approval of investigational medical products constitutes only a small part of the time it takes to bring a new medical product to market.) Patients for whom there are no approved treatment options (or who have tried or are unable to try approved treatments) may wish to use products that are in development/not yet approved. Regardless of whether the drug is being tested in a clinical trial or the trials are completed and the FDA is reviewing trial data, patients who wish to try an unapproved drug must seek access to it via preapproval access. Not all patients can participate in a trial, or perhaps there is no trial available; for these patients, there is non-trial preapproval access—sometimes called compassionate use—which may be provided through the expanded access or right to try pathways.
FDA regulations specify two groups of people who are eligible to seek expanded access when no alternative approved treatment or clinical trial is available to them: (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 is available from the Code of Federal Regulations’ Expanded Access to Investigational Drugs for Treatment Use.
“Right to try” is restricted to patients with life-threatening diseases or conditions, as defined by the Code of Federal Regulations (CFR) Title 21, Part 312.81: (1) diseases or conditions where the likelihood of death is high unless the course of disease is interrupted; and (2) diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. The federal right to try law was enacted in May 2018, and little is known yet about how well it functions or how the provisions of the law will mesh with provisions of the various state right to try laws (which often have their own rules about which patients are eligible).
Preapproval access is an umbrella term, encompassing access to investigational products both in and outside of clinical trials. In this FAQ, the form of “preapproval access” being described is access to investigational products outside of a clinical trial, either through the expanded access or right to try pathways.
There are many types of clinical trials, and some look similar to expanded access programs. What makes something either a clinical trial or non-trial preapproval access is intent: Is the intent of the activity to treat patients or to conduct research?
The preapproval access scenario that we are most familiar with from the media and movies is an expanded access request for a single patient. Individual patient expanded access is not a clinical trial. The purpose of single-patient expanded access is to try to treat that individual patient, not to collect data for research. This does not mean that data cannot be collected—indeed, safety data must be collected—but it is not the primary purpose of the activity. For more information, see the Code of Federal Regulations (CFR), Title 21, Part 312.310.
Expanded access programs, which are established for groups of patients with a similar disease or condition, can have elements in common with clinical trials. Like trials, expanded access programs have rules about who is eligible to participate, and patients’ physicians must, at minimum, collect safety data. However, the rules stipulating who can participate in an expanded access program are frequently not as strict as those about who can join a clinical trial, as the main goal of the expanded access program is to treat patients, not to develop scientific knowledge. Thus, patients in expanded access programs may have fewer scans, lab tests, etc. than patients participating in clinical trials.
The 21st Century Cures Act, which went into effect in early 2017, may have resulted in expanded access and clinical trials becoming even harder to differentiate. Patients who seek non-trial preapproval access typically are in worse health than patients who participate in clinical trials; to be eligible for either expanded access or right to try, patients must be ineligible for clinical trials, and that is often due to the severity of their condition or to comorbidities. By collecting data on the patients in an expanded access program, the company developing an experimental medical product can gather evidence about how well the product works in patients sicker than those who participated in the clinical trials. This information might be useful in predicting how the product will work in the “real world,” as opposed to the cherry-picked world of a clinical trial. The 21st Century Cures Act promotes the use of real-world evidence (RWE) in evaluating medical products. If companies see expanded access programs as a source of valuable RWE, they may become more willing to run expanded access programs alongside their clinical trials. These expanded access programs would entail collection of at least some data because these data would be examined for RWE about the investigational medical product.
Currently, all that is known about the federal right to try law is what’s in the text of the law. However, it is safe to conclude that right to try is not a clinical trial, as its purpose is to try to treat a single patient, not to collect data.
If a patient meets the necessary criteria, he or she may be able to enroll in a clinical trial. The goal of a clinical trial is for researchers to evaluate the safety and efficacy of an investigational therapy in a group of participants similar to the patients that the therapy is intended to treat. Most clinical trials have four phases (I, II, III, and IV). In general, the goal of a phase I clinical trial is to determine whether a therapy has any intolerable side effects and to establish a safe dose for further testing, usually in healthy volunteers. Patients are sometimes participants in phase I research—for example, in oncology trials, where many of the treatments are too toxic to be ethically tried on healthy people. Investigational medical products that are tolerated well in phase I progress to phase II trials, which utilize a larger group of patients to gather information about safety and effectiveness (determining whether the therapy has a beneficial effect on the condition it is intended to treat). Phase III trials enroll an even larger group of participants to obtain more data about the therapy’s safety and effectiveness, possibly in comparison with an approved treatment or a placebo. Phase IV clinical trials are conducted to gather more information about a therapy’s safety after it has been approved by the FDA because sometimes side effects are not identified until after a product has been widely used.
In many trials, patients are randomly assigned to receive one of the possible interventions. Many trials are double-blinded, meaning that neither the participant nor the researcher knows which treatment the participant receives until the trial is over. Usually, researchers compare an accepted standard of care treatment with the investigational treatment; patients who receive the standard of care are in the “control” group. If there is no standard of care for a disease/condition, the investigational drug may be compared with a placebo to determine exactly what effect the investigational product has. These measures minimize bias, increasing researchers’ ability to evaluate the unapproved treatment accurately. This is a general overview of clinical trials; there are many types of trial design, and not all are randomized and/or double-blinded. Learn more about clinical trials.
Clinical trials will not accommodate all patients who have exhausted approved treatment options for their condition or for whom no other approved treatments exist. Patients may not be able to participate in a clinical trial because they live too far away from the trial site to make participation feasible; they don’t meet the trial’s enrollment criteria; the trial may be full; or there may be no trials for an illness/condition. To accommodate these patients, the FDA established expanded access, a pathway by which patients can use investigational medical products outside of a clinical trial. The intention of expanded access is to treat patients, not to gather information for research.
Through their doctors, patients may seek access to investigational therapies at any stage of development (including drugs not currently under development, or those that have been removed from the market), and they can request access to drugs, biologics, vaccines, and devices. Companies can establish expanded access programs (EAPs) to accommodate groups of patients, or individual doctors may seek access for individual patients. In “single-patient expanded access” requests, a patient’s physician identifies an investigational therapy and asks the company developing it to provide access. The company decides whether to provide the product and, if so, whether it will charge for it.
If the company agrees to provide its experimental product for that single patient, the physician then sends the request to the FDA, which reviews the proposed treatment plan to make sure it’s medically feasible and offers the patient a better chance of benefit than of harm. The FDA also confirms there are no existing clinical trials in which the patient could participate. The agency may alter the treatment plan based on the clinical judgment of its experts, for example, by amending the dosing schedule. After the FDA says it will allow the proposed treatment to proceed, the institutional review board (IRB) at the facility where the patient will be treated reviews the plan, to ensure that it is ethical and protects the patient’s interests. IRBs also review the informed consent document that will be used to ensure that the patient is well informed about the investigational nature of the product and the potential risks involved, as well as the possible benefits.
The Government Accountability Office has found the expanded access pathway functions well, although CUPA believes that all stakeholders would benefit from further education about what the pathway permits and how to utilize it.
Right to Try
The right to try pathway is essentially the same process as expanded access, except that there is no FDA or IRB review (unless the institution where the product will be used requires IRB review). However, there are several key differences between the two pathways. First, right to try applies only to drugs and biologics. Second, the investigational drugs that may be requested via right to try must have successfully completed a phase I clinical trial and be under active, ongoing development. Third, although patients must provide informed consent, the consent document is not held to the same standards as in expanded access and clinical trials. (For example, federal law requires that informed consent documents used in clinical trials and expanded access detail a patient’s rights; right to try has no such requirement.) Finally, right to try includes a liability provision that shields all parties involved in the use of an investigational product in a therapeutic attempt from lawsuits in most instances; the FDA’s expanded access pathway does not.
Right to try laws are U.S. state and federal laws that permit a patient to use an investigational drug that has completed phase I clinical testing without seeking prior approval from the FDA or an institutional review board (IRB). To date, 41 states have passed a right to try law, and a federal law was enacted on May 30, 2018.
The expanded access pathway can allow groups of patients to receive access to investigational medical products. Right to try does not. For an apples-to-apples comparison, we must compare right to try with single-patient expanded access. The process by which a patient would request access to an investigational product outside of a clinical trial is similar regardless of which pathway is being used. Both require that a physician identify a product suitable for his or her patient and then contact the company developing it to ask if it will provide it to the patient outside of a clinical trial. The patient may receive the product only if the company agrees: companies are the primary gatekeeper of access.
Expanded access requires two additional steps. If the company agrees to provide its product for that single patient, the physician must send the request to the FDA for review. Based on the judgment of its experts, the FDA may alter the treatment plan; for example, by amending dosing schedules. Once the FDA notifies the physician that a request may proceed (this happens in a matter of days, or hours in an emergency), an institutional review board (IRB) must review the request. IRBs are charged with protecting the rights and welfare of human participants in research studies and patients who will be treated with an investigational product. The IRB reviews the informed consent document to ensure it discloses the investigational nature of the treatment, the inherent “unknowns” in terms of benefits and risks, and other options available to the patient. IRBs also review expanded access requests to make sure that appropriate protections for patients are in place, including that the treating physician has the relevant training and experience and that the facility where the product will be used is able to properly treat and care for the patient in the event that problems arise related to the use of the product. Many, but not all, U.S. hospitals have an IRB; for those that do not, there are independent IRBs that can review expanded access plans. Due to concerns that the process may be too slow, in October 2018 the FDA commissioner changed the relevant rules so that IRB review of expanded access may be done by one representative of the IRB, rather than the entire committee.
Right to try applies only to drugs and biologics that have successfully completed a phase I clinical trial and are under active, ongoing development. Via expanded access, patients may seek access to investigational therapies at any stage of development (including drugs not currently under development, or those that have been removed from the market), and they can request access to drugs, biologics, vaccines, and devices.
In expanded access and right to try, the patient must provide informed consent; however, the consent document is not held to the same standards in right to try and expanded access. (For example, federal law requires that informed consent documents used in expanded access detail a patient’s rights; right to try has no such requirement.)
Finally, right to try includes a liability provision that shields all parties involved in the use of an investigational product in a therapeutic attempt from lawsuits in most instances; the FDA’s expanded access pathway does not.
It is not yet possible to compare the speeds of the two pathways because there have not been enough reported usages of the federal right to try pathway to make a fair comparison.
It is CUPA’s assessment that the slowest part of non-trial preapproval access likely occurs at the company level. Because both right to try and expanded access entail waiting for a response from the company developing the investigational product, both pathways will be affected by this time lag.
FDA review, which is required for expanded access but not right to try, is quick: same day for emergencies, and, on average, within four days for non-emergencies.
According to a survey conducted in 2018 by CUPA members on IRB professionals’ experiences with and perspectives on single-patient expanded access requests, 56 percent of 75 IRB professionals said that it takes the chair or designated member of their IRB 1 day or less to review a single-patient request after receipt. Another 28 percent responded that it takes 2 to 5 days, and 5.3 percent said it takes more than 5 days but fewer than 30. Lastly, 10.7 percent of respondents said they did not know how long it took to review single-patient requests. Although this data is from a small sample of IRB professionals, it is the first estimate of the time it takes chairs or designated members of IRBs to review single-patient requests. Institutions decide whether to require IRB approval for right to try requests; thus, it is an open question whether a right to try request will involve IRB review.
Regardless of whether right to try eventually proves to be a fast pathway, CUPA does not believe that any gain in speed is worth the loss of oversight by independent, expert third parties (the FDA and an IRB).
Many companies see no upside to providing their investigational products through right to try. If a product appears to be safe and/or effective in the expanded access setting, a company may wish to include that information in the paperwork submitted when it seeks marketing approval from the FDA. If a product appears to cause harm in the expanded access setting, a company will want to be able to say that there was FDA oversight of the product’s use outside of clinical trials.
The companies developing new medical products are the key decision-makers in determining whether to provide access to their investigational medical products. This is the case for both expanded access and right to try. Furthermore, companies that are willing to provide investigational products get to decide which pathway they’ll use. For example, a physician may seek access to a drug via right to try, but the company may inform the physician that it will provide it only via expanded access pathway, or vice versa.
In expanded access, a physician requests an investigational product from a company, providing information about the patient or patients who would receive the product. If a company agrees to provide it, two more entities must review the proposed treatment plan: the FDA and, unless use of the product is deemed an emergency, an institutional review board (IRB).
In right to try, a physician requests an investigational drug from a company, providing information about the patient who would receive it. If a company agrees to provide it, no FDA or IRB approval is required (unless the facility where the product will be administered requires IRB review).
According to federal regulations, drug companies are prohibited from charging patients more than the direct cost of manufacturing the investigational medical product.
In addition to this cost, companies that use the expanded access pathway are allowed to charge patients for the costs associated with shipping the product and, in some cases, monitoring/collecting safety data. The FDA requires companies to submit their cost calculations to the agency before charging patients for investigational products provided via expanded access. The FDA has more information on charging for investigational drugs. Currently, most pharmaceutical and biotech companies that provide their investigational products via the expanded access pathway do so for free.
It is unclear who pays the associated costs of using an experimental product—clinic or doctor visits, lab tests, imaging, and any additional monitoring and treatment the patient may need while using the product. The company developing the product might. Insurers might, although most private and public insurance companies do not pay for investigational medical products outside of clinical trials. Patients may be responsible for paying for all or a portion of these costs.
A company that provides its investigational drugs via the right to try pathway is similarly limited to charging patients only for the direct manufacturing costs. There is little public information regarding patients who have received investigational drugs through right to try, so we do not know whether companies will utilize this cost recovery option or provide their products for free. At this time, CUPA is aware of one patient who received an investigational drug for free. As with expanded access, it is likely that patients will be responsible for paying for all or a portion of the ancillary costs.
Talk to your physician. Although you can research investigational medical products online, you will need your physician to make the request.
If you or your physician needs guidance about expanded access, you can contact the FDA. Currently, the FDA has stated that questions about right to try should be directed to the company that is developing the desired product.
The Reagan-Udall Foundation for the FDA has developed an online Expanded Access Navigator that provides step-by-step instructions on how to identify available investigational medical products and how to apply for individual access. Sadly, participation in the navigator is voluntary, and many companies have chosen to not yet be listed. However, the site posts the non-trial preapproval access policies of a number of companies, along with information about who to contact at the company for information.
If you or your physician needs someplace to get started, search on ClinicalTrials.gov for what products are being studied to treat various diseases or conditions. The site also lists expanded access programs that may be available for certain investigational therapies. You may be able to participate in a clinical trial or find information about available expanded access programs.
If you are interested in a particular experimental medical product, search the website of the manufacturer of that product for the company’s preapproval access policy. By law, drug companies are now required to make such policies public once they have an investigational drug in a phase II clinical trial.
The Working Group sends out occasional updates about compassionate use and preapproval access. To receive these updates, please contact Beba Blagojevic, at firstname.lastname@example.org. For media inquiries, please contact Beba Blagojevic (Division of Medical Ethics) or Sasha Walek (Communications Manager, Department of Population Health, NYU Langone), at email@example.com. If your patient advocacy group or organization would like to host an “Ask an Expert” session or webinar on any of these topics, please contact Lisa Kearns, MS, MA, at firstname.lastname@example.org.
CUPA maintains a list of resources for patients, including links to resources published by CUPA members on preapproval access, FDA resources on single-patient expanded access and right to try, patient and physician navigators, patient advocacy websites, and more.
An expanded access program (EAP) allows a group of patients with the same disease/condition (such as boys with Duchenne muscular dystrophy) to access a medical product before approval. To qualify for an EAP, patients must meet certain criteria; however, these criteria are typically less rigid than those for clinical trials, as the purpose of an EAP is treatment, not research. For more information on expanded access programs for groups, see the Code of Federal Regulations (CFR), Title 21, Part 312.315.
For example, if a new drug is nearing the end of the clinical trials testing process and the trial data suggest that the drug is safe and effective, the company may open an EAP to make the drug available to those patients who will be harmed by waiting until the drug receives FDA approval to use it. Additionally, there is frequently a time lag between FDA approval of a new drug and when it is stocked in pharmacies (or when insurance companies agree to start paying for it). Patients may be able to access the now-approved but not yet easily available drug through an EAP during this time lag. Expanded access programs end once a drug is available on the market.
If no expanded access program exists or a patient does not qualify for an EAP, that patient, through a physician, may request the investigational product via single-patient expanded access.
Annually, the FDA releases the number of expanded access requests received and the number of requests that are allowed to proceed. While the agency gets approximately 1,000 expanded access requests a year, a request can be for one patient or many patients. The most recent data published by the FDA on the expanded access program shows that in fiscal years 2014 through 2018, the FDA allowed 8,620 expanded access requests to proceed. Of these requests, 4,898 were for non-emergency situations for single patients, 3,404 were for emergency situations for single patients, and 318 were for multiple patients. Of these 318 multi-patient protocols, 257 of the approved protocols were deemed to be “intermediate” (defined as more than one but less than many patients) in size, and 61 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 expanded access program. CUPA is aware of one large expanded access program that provided an investigational drug to more than 35,000 patients. No one knows exactly how many patients receive non-trial preapproval access in the United States, but it is certainly more than just the number of expanded access requests allowed to proceed by the FDA.
Here is a good example of why FDA oversight of drug safety is necessary. In 1962, thousands of children in dozens of countries (outside the United States) were born with severe birth defects to mothers who had taken thalidomide to treat morning sickness during pregnancy. This spurred FDA regulations requiring drug companies to prove that their products are both safe and effective before they would be approved. The thalidomide tragedy demonstrated the unexpected yet devastating potential toxicities associated with drug treatment. Bear in mind that there will always be hucksters and snake oil salespeople peddling “cures” to vulnerable people looking for treatment. (For a current example, look at the virtually unregulated field of stem cell “therapies,” which have been portrayed as cures for nearly everything.) The FDA tracks safety in addition to effectiveness of investigational treatments, helping to prevent an increase in attempts to manipulate and exploit those desperate for treatment.
In addition to having an oversight role generally, the FDA reviews expanded access requests to make sure there is sound medical reasoning behind them, that the proposed treatment plan offers more chance of benefit than risk of harm, and that the patient is not eligible for a relevant clinical trial. The FDA does not “approve” preapproval proposals; rather, it allows them to proceed (or not). More than 99 percent of expanded access proposals are allowed to proceed; however, in some circumstances a proposal is amended in response to feedback from FDA reviewers. Jarow et al. reviewed a sample of 150 proposals and found that 11 percent were revised in response to FDA input. Such revisions were along the lines of changing the proposed dosing schedule or requiring additional safety precautions. Because the FDA oversees all medical products and has access to clinical trial data, the agency may be aware of much more information than the treating physician.
When it comes to investigational drugs, particularly those in early development, doctors may be working with very limited information about how, and in which patient populations, the drug works. The more guidance provided about how to use the drug and how to prevent and treat side effects, the better. Once the product has been given to the patient under expanded access, the doctor has an obligation to notify the drug company and the FDA of any serious, unanticipated adverse events suffered by that patient. This, in turn, helps the FDA to be better able to evaluate future protocols.
Yes. Although the FDA almost always allows an expanded access request to go forward, agency personnel weigh in on aspects of the request, such as the dosage, the dosing schedule, and other criteria. Based on the FDA’s knowledge of the experimental agent and how it has worked in other patients, it can help the physician to adjust the proposed treatment plan. This is an important step in safeguarding patient welfare because the FDA employs expert scientists and physicians who specialize in clinical research protocols. A patient’s treating physician may lack this expertise. FDA permission is not a “rubber stamp” but rather a necessary collaboration between specialists in the administration of investigational products and a patient’s treating physician. Jarow et al. looked at a sample of 150 proposals and found that 11 percent had been revised in response to FDA input. Such revisions were along the lines of changing the proposed dosing schedule or requiring additional safety precautions.
In expanded access, physicians request investigational medical products from companies, providing information about the patients they will be treating. If the company agrees to provide a product, two more approvals are necessary: one from the FDA and, unless use of the product is deemed an emergency, another from an institutional review board (IRB). (For emergency requests, physicians have five days to notify, and submit paperwork to, their institutions’ IRBs after the initiation of treatment.) IRBs are responsible for monitoring the use of investigational therapies and protecting the welfare of patients who use them. When the IRB reviews an expanded access request, it is checking to make sure that the patient is informed about the investigational nature of the product and its unknown risks and benefits, in addition to ensuring the patient’s welfare while being treated.
Pursuant to Congressional legislation, in the fall of 2017 the FDA announced new rules, including allowing an IRB chair or designee to sign off on expanded access requests instead of a full board, as was previously required. This change is expected to significantly reduce the amount of time it takes for patients to receive investigational medical products via expanded access.
The Goldwater Institute, a libertarian organization, claimed several years ago that patients have problems obtaining preapproval access because of FDA bureaucracy. It proposed creating a second pathway, called “right to try,” alongside expanded access through which patients could access investigational drugs without involving the FDA. The institute created a model right to try bill for states to use in crafting their own right to try laws. Colorado was the first state to enact such a law, in 2014, and today 41 states have their own versions of a right to try law. At this time, it is unclear how state laws will function alongside a federal law.
CUPA members Lisa Kearns, MS, MA, and Alison Bateman-House, PhD, MPH, analyzed the variations in provisions among the first 32 state laws and found that these laws offer few tangible benefits to patients, despite their patient-centric rhetoric. The model bill contained several patient-hostile provisions that have been incorporated into many state right to try laws. For instance, of the 41 state right to try laws, 19 allow insurers to deny hospice coverage for patients using a drug obtained via right to try, 7 allow coverage for home health aides to be denied, and 4 may deny health insurance benefits altogether to patients who try an investigational drug via right to try. Although most state laws follow the model bill closely, there are differences among the laws. For example, one state doesn’t allow inpatients to request drugs under right to try, and many bills’ definitions of “terminal illness” differ.
The laws’ backers claimed that the legislation would expedite access to investigational products by removing the FDA from the process. In CUPA’s assessment, this is misleading. FDA review is quick: a decision by the agency is made within 24 hours for emergencies and a median time of 4 days for non-emergency requests. Although the FDA’s involvement adds some time between the initial request and administration of the product to the patient, the FDA does not prevent patients from getting non-trial preapproval access. The Government Accountability Office has made a similar assessment.
The primary gatekeeper of access in expanded access and right to try is the company that is developing the desired agent. Regardless of whether right to try eventually proves to be a faster pathway than expanded access, CUPA does not believe that any gain in speed is worth the loss of oversight by independent, expert third parties (the FDA and an institutional review board, or IRB).
Despite their proliferation, state right to try laws have had little impact on patient access to investigational medical products. For this reason, right to try advocates pushed for federal legislation. Another reason for pursuing a federal law was that cutting the FDA out of the picture by means of state laws was likely unconstitutional. This is speculation, but it is grounded in the fact that regulating investigational drugs is under federal, not state, jurisdiction, and legal scholars have agreed with this hypothesis.
The Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017 was signed into law on May 30, 2018. It allows patients with life-threatening diseases or conditions to request investigational drugs that have completed a phase I clinical trial if these patients have exhausted other treatment options, cannot participate in a trial involving the drug, and give informed consent. Unlike expanded access, neither FDA nor institutional review board (IRB) review is required by the law (though institutions where the investigational product would be used may choose to require IRB review). The law also requires companies to submit to the FDA annual reports on right to try usage. Finally, companies and doctors involved in a right to try effort have liability protection.
It remains unknown how the provisions of this law will be implemented and overseen. In November 2018, the FDA provided information about right to try. As with expanded access, right to try does not require companies to grant patients’ requests for their investigational products. Furthermore, companies that are willing to provide non-trial preapproval access are able to choose whether to do so via right to try, expanded access, or both.
As of September 2019, CUPA is aware of two patients who have received investigational treatments via right to try since the signing of the federal right to try law. In the first case, an investigational product was provided by the U.S. subsidiary of the Belgian company Epitopoietic Research Corporation (ERC-USA), and the patient, who has glioblastoma, first received the treatment at the University of California, Irvine, in late November 2018. UC Irvine's institutional review board (IRB) has indicated that it will follow California’s right to try as it contains more stringent reporting and informed consent requirements than the federal law. Additionally, Matthew Bellina, an advocate of the federal right to try law and one of the patients for whom the law is named, received access to an investigational agent for amyotrophic lateral sclerosis from BrainStorm Therapeutics in early 2019.
Before the enactment of the federal law, we are aware of just one instance of patients receiving an investigational product under a state law. According to the Goldwater Institute and Dr. Ebrahim Delpassand, the founder of Excel Diagnostics and Nuclear Oncology Center, between 80 and 100 patients gained access to an agent called Lu-177 Dotatate under the Texas (state) right to try law. However, because the company developing this drug (Novartis) was already making the product available via an expanded access program, we do not accept this claim as evidence of one or more patients receiving otherwise unavailable drugs because of right to try. We have no idea what happened to these 80 patients and how much, if anything, they paid to gain access to the investigational agent. Lu-177 Dotatate has since been approved by the FDA, and patients can access it with a prescription from their doctors. Learn more about Dr. Delpassand’s use of the Texas right to try law.
People in states with right to try laws who are receiving non-trial preapproval access to investigational products are most likely doing so via the expanded access pathway. For the most part, patients wouldn’t know which pathway their doctors and the supplying companies were using, as patients are not directly involved in the process.
After the federal bill was enacted in May 2018, one company, BrainStorm Therapeutics, said publicly that it hoped to provide access to a product in development under the Right to Try Act. But because the Right to Try Act placed the same restriction on charging for products as expanded access, BrainStorm decided it would be financially unfeasible to provide the product, according to several news outlets. The company agreed to give its investigational product to only one patient, Matthew Bellina, a vocal right to try advocate and one of the patients for whom the new law is named. Six months later, it was widely reported in the media that Bellina had received the BrainStorm agent via right to try.
Under right to try, physicians request products from the appropriate companies, providing information about the patients they will be treating. If the company agrees to provide a product, no FDA or institutional review board (IRB) approval is required. Right to try requires that the patient sign an informed consent document, but it does not stipulate what it must include, or what, if any process, is used to ensure that the patient is adequately informed.
Institutions where the investigational agents will be used are free to impose their own rules: for example, requiring IRB review for the use of investigational medical products obtained via right to try or banning right to try outright.
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 seeking non-trial preapproval access to an investigational drug. Burroughs did not qualify for the clinical trial that was testing the drug.
In 2013, Andrea Sloan sought compassionate use of an investigational drug. When the company initially denied the request, she appealed. Another company eventually agreed to provide its investigational product, but she died before she could use it.
In March 2014, the family of 7-year-old Josh Hardy and his supporters waged an aggressive social media campaign seeking non-trial preapproval access to an antiviral drug to try to treat an opportunistic infection that he acquired while receiving treatment for kidney cancer, which he had since infancy. Chimerix, the company developing the drug, refused to provide it to Hardy, even in the face of considerable public pressure. At the suggestion of the FDA, it created an open-label clinical trial for pediatric patients, including Hardy. (In an open-label trial, all participants know they are receiving the experimental drug; there is no randomization, nor is there blinding.) Hardy responded well to the drug and returned home. Sadly, he died several years later. (These examples were all cases of single-patient preapproval access. There are also cases of preapproval access for groups of patients.)
These stories and others caught the public’s attention, and they were used as talking points in the campaign for a federal right to try law. Despite the fact that in these cases patients did not get access to desired drugs due to company, not FDA, decisions, right to try activists depicted the FDA as the primary obstacle to patient access to investigational products. After a multiyear lobbying effort, on May 30, 2018, President Donald Trump signed into law the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017.
There are several reasons why this issue generates controversy and public debate. Access to investigational products is not a constitutional right. When companies grant access, they do not always do so in a fair or transparent manner. For example, those with financial resources or advantageous connections may seek and gain preferential access. Those who know how to utilize social media may have an advantage over those who don’t. Additionally, some doctors and patients are unaware of non-trial preapproval access and/or how to request it. Even doctors who know about non-trial preapproval access may decline to request investigational products for their patients, for such reasons as not having the time or the ability to complete and submit the paperwork, administer an investigational product, and/or perform continued monitoring. Some doctors may not believe such access is the best option for their patient. This is a complicated topic, but the takeaway is that access to investigational medicines does not operate on an even playing field. And if people know that others can get access while they are denied it, it leads to a perception of unfairness (which, unfortunately, is sometimes accurate).
Another key issue is that non-trial preapproval access can pose risks to the clinical trial process and an investigational medical product’s timeline for (possible) FDA approval. Granting individuals access to unapproved products can, if not restricted to only those unable to participate in a trial, jeopardize enrollment in the trials that are necessary to identify and approve the treatments that could help future patients. If patients have a choice between gaining access to a desired experimental product inside or outside of a clinical trial, most would likely choose non-trial access, especially if the trial involves randomization to a placebo or an existing therapy. Such decisions may be rational on an individual level, but if they were widespread, they would negatively affect clinical trial enrollment, thereby extending the drug development timeline and ultimately delaying the availability of new treatments to all other patients. Thus, there must be clear rules about who will be allowed non-trial preapproval. Both the expanded access and right to try pathways require that patients be ineligible to enroll in a clinical trial for the product being requested; however, only in expanded access is this determination verified by a third party (the FDA and sometimes the institutional review board, or IRB).
Investigational products generally are manufactured in limited quantities. Diverting a scarce experimental product from clinical trials to compassionate use may result in trials not being completed in a timely manner. Delaying the trial would, in turn, delay possible FDA approval of the new product and, ultimately, the availability of a new treatment on the market for other patients who need it. For this reason, many companies’ preapproval access policies specifically state that they prioritize clinical trials and will not offer their experimental products outside of these trials.
Experimental products may help. They may also cause further harm and suffering, or even hasten death. Or they may have no discernable effect. Investigational medical products, by definition, often do not have demonstrated effectiveness or safety. The vast majority of experimental drugs that enter clinical trials never become commercially available, either because they are not effective or because they result in more toxicity than benefit. Because the unapproved products being sought by patients have not been thoroughly tested, their efficacy and side effects are typically unknown, especially in the very sick patients who are unable to participate in clinical trials and are out of therapeutic options. These products might cause unexpected injury, shorten life, or diminish a patient’s quality of life. And although patients with no other medical options might be willing to accept these risks, a company (or doctor) may decide to not participate.
A very bad outcome in a patient who used an unapproved product via non-trial preapproval access may be blamed on the product—even if it occurred because of the patient’s illness and not as a result of the intervention. If there are concerns (justified or not) about a product in development, a company may stop developing it; or additional clinical trials may be required (adding expense and lengthening the development timeline); or those funding the company developing the product may back out. These are reasons why companies may be wary to provide investigational products to patients outside of a clinical trial, in which participants are carefully screened and will be excluded from participating if they have, for instance, comorbidities or a worrisome past medical history. However, these concerns may not be based in fact. The FDA’s Expanded Access: Information for Industry report says all severe adverse event (SAE) reports from expanded access are evaluated within the context of the patient’s treatment and that it does not use the occurrence of an SAE as a reason not to approve the product, unless it is reasonable to do so. The agency has conducted several recent audits, which it is using to assure companies that the likelihood of delaying the development of a product because of bad outcomes in the non-trial preapproval access setting is extremely unlikely. It is currently unknown whether these efforts by the FDA are assuaging companies' concerns.
If patients try these products voluntarily and with full understanding of the unknown risks and benefits, there are few reasons to argue against earlier access to experimental treatments that may help desperately ill patients. However, there are many reasons to be concerned that patients seeking preapproval access may not completely understand the associated risks. Even if an investigational product looks promising, it may not work for a particular patient; even worse, it may cause harm. It is important for patients hoping to benefit from a particular product to be informed that there are no guarantees of efficacy and that an investigational medical product’s effects may be worse than those of the patient’s medical condition. Understanding this is difficult not only for patients but also for healthcare providers, families, and friends, as we often perceive new medical options or treatments as better therapies. Thus, therapeutic misconception may color what the healthcare providers say or do not say about the investigational agent, providing patients with a biased understanding of the situation.
Therapeutic misconception and concerns about informed consent apply to both expanded access and right to try. However, right to try raises some additional concerns. The term “right to try” itself is a misnomer because it suggests that patients have a right to investigational medicines; however, it is up to the discretion of the company developing the product whether to provide it. Right to try requires informed consent but strips this of many components considered essential to informed consent in the expanded access and clinical trial contexts, raising concerns about its adequacy.
Unscrupulous medical providers and/or companies may take advantage of right to try laws to sell remedies and quack cures to desperate patients and their families. If harm were to result, purveyors of such products would likely be immune from lawsuits, due to right to try’s immunity provision. Inadequate informed consent and lack of FDA or institutional review board (IRB) review leaves patients without the benefit of additional safeguards.
Many state right to try laws stipulate that if patients use an unapproved drug obtained via right to try, then they risk losing hospice care, home healthcare, or even insurance coverage. These provisions are not well publicized, so patients may not understand what they risk under right to try.
Furthermore, right to try legislation requires only that a phase I study be completed on an investigational drug. Despite the fact that phase I studies are often called “safety studies,” the completion of a phase I study does not guarantee that an experimental drug is safe. Most phase I studies use paid, healthy volunteers to determine the appropriate dosage for future studies, without conducting long-term follow-up. There is little to no information available about how these experimental drugs may work in patients who are sick. Although patients, particularly the terminally ill, may be understandably willing to take on risk to try a new treatment, we need to ensure they understand that phase I studies are no guarantee of safety and that before the completion of phase II studies, there is no information about a drug’s efficacy. Using a drug after only phase I testing is truly a leap into the unknown.
CUPA members work to explore the many ethical issues surrounding compassionate use and other efforts to facilitate access to investigational medical products before regulatory approval. To do this, and to understand the perspectives of all of those involved in this issue, CUPA has representatives from all stakeholder communities that are involved in preapproval access: medicine, law, bioethics, government, industry, clinical trial design, and patient advocacy. CUPA works closely with patient advocacy organizations, large and small pharmaceutical and biotechnology companies, venture capitalists, medical providers, and a host of other organizations, including the FDA and various trade organizations.
The co-chairs of CUPA, Alison Bateman-House PhD, MPH, and Arthur L. Caplan, PhD, have listed their paid and unpaid professional activities and relationships via electronic long-form (ELF) disclosures.
Where it sees room for improvement, CUPA seeks to effect policy changes that will make preapproval access more realistic, more equitable, and more transparent for those seeking access to investigational medical products outside of clinical trials.
CUPA members talk with anyone who has insight or ideas about how to improve the process for those seeking preapproval access to investigational medical products. We have communicated with state and federal legislators, FDA leadership, patient advocacy organizations, and members of the pharmaceutical and biotech industries. We answer questions, share what we have learned, and provide education. Neither these conversations nor this document represents an official view of NYU Langone or any employer or other institutional affiliation of any CUPA member.
CUPA members are not precluded from speaking their own minds in an individual capacity or from writing editorial or position papers. CUPA’s positions are determined by majority, not consensus (though, to date, the group has been unified on all policy positions).
Early in its existence, CUPA stated that pharmaceutical and biotech companies should make their non-trial preapproval access policies publicly accessible and provide a telephone number, email address, or other designated point of contact to which requests for access should be directed. Also, companies should set a reasonable time frame for deciding on a request, convey this time frame to requesters, and report decisions to requesters in a timely manner. These recommendations were adopted by legislators and incorporated into the 21st Century Cures legislation that was enacted in December 2016.
In March 2018, CUPA published an updated fact sheet and recommendations about right to try laws and a list of proposals for helping those patients who wish to try unapproved medical products outside of clinical trials. This document identified key areas for legislators to address. In response to this proposal, the FDA Reauthorization Act of 2017 mandated a public meeting with the National Institutes of Health and the FDA to discuss potential barriers to clinical trial and expanded access participation. The act required that the FDA publish a report on the topics discussed at this meeting and issue new draft guidance on broadening clinical trial and expanded access eligibility.
Another component of the FDA Reauthorization Act of 2017 also stemmed from a CUPA proposal: a requirement that the FDA revise and streamline federal regulations that govern institutional review board (IRB) approval for single-patient expanded access protocols. Several months after CUPA released its proposals, the FDA announced that a single IRB member—rather than the full committee, as federal regulations previously required—may review and approve a single-patient expanded access request, as assembling a full board may cause unwarranted delay for patients.
CUPA has called for legislators to clarify the FDA’s authority over experimental drugs, as state right to try laws have unintentionally, but not unforeseeably, created confusion for stakeholders about whether to follow state or federal rules governing access to experimental drugs outside of clinical trials. These issues were discussed at a U.S. House of Representatives Energy and Commerce Committee Subcommittee on Health hearing on October 3, 2017, where CUPA members Alison Bateman-House PhD, MPH, and Kenneth I. Moch, MBA, testified on the proposed federal right to try bills.
CUPA has also advocated for legislators to explore, with the pharmaceutical and biotechnology industries, ways to make preapproval access a more appealing prospect to large and small companies. Companies are concerned that making experimental drugs available for preapproval access could cost money, threaten their drug development timeline, turn off investors, and/or get them in trouble with the FDA. These areas are actionable for legislators and have yet to be addressed, although the FDA has sought to reassure companies that it is very rare for serious adverse events in expanded access to have repercussions for a drug development program.
The FDA’s Expanded Access: Information for Industry report says that all severe adverse event (SAE) reports generated in the context of expanded access are considered within the context of the patient’s underlying medical condition and that it does not hold SAEs against the unapproved medical product unless it is reasonable to do so. The agency has recently conducted several audits and is using that data to try to assure companies that the likelihood of an experimental product’s development being slowed or derailed by bad outcomes in the compassionate use setting is extremely unlikely.
CUPA continues to evaluate new ways to increase preapproval access to investigational products, including making access a more appealing prospect for the pharmaceutical/biotechnology industry and educating healthcare providers about preapproval access.
CUPA has proposed that expanded access protocols may provide a useful source of real-world evidence (RWE). By collecting data on the patients in an expanded access program, the company developing an experimental medical product might gather evidence about how well (or poorly) a product works in patients who are sicker than those who participated in the clinical trials. This information might be useful in predicting how the product will work in the “real world,” as opposed to the cherry-picked world of a clinical trial.
CUPA members receive no compensation for their work with this group. Overhead costs and other expenses are paid by the Division of Medical Ethics at NYU Langone, which receives income from a variety of sources, including private gifts and contracted projects.
CUPA members have written and spoken extensively about preapproval access, FDA regulations, right to try laws, inclusion/exclusion criteria for clinical trials, and more.