Some patients facing death take drastic, or even desperate measures in order to prolong their lives. Such actions often include taking unapproved, investigational drugs. In the U.S., a program known as Compassionate Use, or Expanded Access, allows terminally ill patients who meet certain medical criteria to apply (through their physicians) to the Food and Drug Administration (FDA) and the drug manufacturers for access to drugs that are undergoing FDA clinical trials. At first blush, it may appear that there should be no legal, political, or ethical controversies surrounding the concept of expanded access. How can one possibly deny a dying patient even the slightest chance of prolonged life or recovery? Is there a side effect worse than certain death?
Beneath its seemingly altruistic and uncontroversial veneer, the Compassionate Use program has been a lightning rod for intense legal, legislative, and public policy controversies, many of which have been framed as “libertarian vs. regulatory” battles between those who wish to allow patients freer, even unrestricted, access to experimental drugs (often by changing or limiting the role of the FDA), and those who prefer a more measured, rigorous approach to dispensing unproven and potentially dangerous therapies.
One of the most highly publicized manifestations of this controversy has been the passage of Right-To-Try Laws in 33 U.S. states (as well as current bills before the U.S. House of Representatives and Senate), which seek to expedite patient accessibility to experimental drugs by allowing patients to appeal solely to drug manufacturers for access to their experimental therapies, thereby eliminating the FDA from the Compassionate Use application process. Vice President Mike Pence recently voiced his support for the national legislation, telling supporters in a closed-door meeting that “he and President Trump have had multiple conversations about this and it’s something the president is very passionate about.”
Passion aside, removing the FDA from the Expanded Access equation will in no way result in more patients receiving access to experimental drugs, because it is each drug manufacturer, and not the FDA, that possesses the ultimate authority to dispense its product, and Right-To-Try laws place no requirements on pharmaceutical companies to grant pre-approval access to their investigational therapies. Statistical evidence of how often companies fulfill compassionate use requests is not public knowledge, because drug companies are not required to submit data on appeals they receive, nor their outcomes. There is no published evidence on whether Right-To-Try laws have actually resulted in more patients applying for, or receiving, experimental drugs.
The legal status of state Right-To-Try Laws is under scrutiny although, to date, no action has been taken against them by the FDA or other federal authority. Opponents assert that state Right-To-Try Laws are unconstitutional because they are preempted by the FDA’s exclusive federal authority over drug regulation. Proponents of the state laws contend that constitutionally, individual states may provide additional and greater protections of individual rights—including medical rights—often citing the example of Right-to-Die legislation, which falls under state jurisdiction. This debate will be rendered moot if federal Right-To-Try legislation currently before the House and Senate passes, thereby amending the federal jurisdiction of the FDA over Compassionate Use requests.
It is unclear whether patients and physicians within the 33 states with Right-To-Try laws have availed themselves of the laws and disregarded the FDA in their Compassionate Use requests. As one recent article notes, “to date, there is no evidence that anyone in a state with a Right-To-Try law has obtained anything under that law that would have been unattainable under pre-existing federal regulations.”
We believe these Right-To-Try Laws represent a populist, anti-government, anti-regulatory movement, which may be a dangerous, not to mention ineffective, policy trend. The FDA provides meaningful supervision over the use of experimental therapies, and marginalizing the agency may place patients at risk while neither insuring nor improving their access to such therapies. We believe that any policies that strive to improve patient access to investigational drugs must balance the well-intentioned desire to provide hope to terminally ill patients with the necessity to protect patient safety and the integrity of the drug development and approval processes.
How Does Compassionate Use Work?
Compassionate Use, or Expanded Access, as it currently exists in the U.S. does not simply guarantee access to an experimental drug to any terminally ill patient who requests it. Only a physician, on behalf of his/her patient, may apply for compassionate use access, and strict rules require that the patient must be suffering from an illness for which “there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment,” must have exhausted all other treatment options, and is ineligible to participate in this (or a similar) drug’s clinical trial. There are additional safeguards (or roadblocks, depending one’s position) to ensure proper dispensing, application, and oversight of the drugs. The following is a brief description of how the Compassionate Use application process operates in the U.S.:
- A patient and/or physician will learn about an ongoing clinical trial for a drug that applies to the patient’s terminal condition. Such information is available through news and publications, as well as the National Institutes of Health’s (NIH) website, clinicaltrial.gov, a registry and database of worldwide clinical studies.
- The patient’s physician usually first contacts the pharmaceutical company to ascertain whether the investigational drug is available on a compassionate use basis, and if the patient is eligible to receive it. Many pharmaceutical companies (for example, Pfizer and Janssen Pharmaceuticals) publish their eligibility requirements, which nearly universally include the following:
- The patient must have a serious or life-threatening illness or condition.
- The investigational drug should be under active clinical development, meaning it is being tested on human subjects.
- The patient must be ineligible or unable to participate in a clinical trial of the requested drug.
- The companies providing the investigational medicine for the requested use must not interfere with the initiation, conduct, or completion of clinical trials.
- If the pharmaceutical company agrees to dispense the investigational drug, and the patient lives in a state in which Right-To-Try legislation has not been enacted, the physician must submit an Investigational New Drug (IND) application to the FDA’s Office of Health and Constituent Affairs. The FDA’s requirements for pre-approval access are similar to those of the pharmaceutical companies:
- The patient’s condition has reached a stage in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.
- The patient must have exhausted all reasonable alternative treatments.
- Both the patient’s physician and the FDA must determine that the probable risks from taking the investigational drug (such as greater pain and suffering or an accelerated death) is not greater than the probable risk from his/her disease or condition. The patients must also acknowledge the experimental drug’s risks and unknown effectiveness, usually by signing an informed consent.
- Patient must be ineligible to participate in a clinical trial for this or a related, potentially-= appropriate drug.
- Expanded Access will not impede the clinical trial process.
- The physician agrees to manage the patient’s care and follow all necessary protocols. These requirements include discussing risks and benefits, obtaining all required informed consent and Institutional Review Board (IRB) approval, reporting adverse events and outcomes, and submitting the necessary paperwork to the FDA. The FDA website states that “treatment may begin 30 days after FDA receives the IND, or earlier if FDA notifies the treating physician that the expanded access use may begin.”
- Following both drug company and FDA approval (if necessary), an Institutional Review Board (IRB) at or near the medical institution where patient will be treated must approve the investigative drug protocol and confirm that the patient has given informed consent to the experimental treatment.
The FDA Is A Vital Partner In The Compassionate Use Framework
Advocates of Right-To-Try Laws contend that removing the FDA from the Compassionate Use application process will ensure greater and faster access by patients to experimental therapies. This is not the case. Since 2010, the FDA has approved nearly 99 percentof Compassionate Use applications, and in 2015, in response to criticisms that the process was too slow and cumbersome, the FDA streamlined the application and even implemented an 24-Hour Emergency Expanded Access program, through which a physician may request and the FDA may authorize—by telephone or other rapid means of communication—compassionate use of unapproved drugs.
We believe that circumventing the FDA to gain compassionate use can prove detrimental to patient care and the overall drug approval process in the U.S. For all compassionate use treatments that it approves, the FDA requires that each patient’s physician provide the agency with a written summary of the patient’s response to the drug, including adverse effects and death. Such data, although not directly applicable to the specific drug’s clinical trials, can prove vital to understanding the efficacy and side effects of the drug. Under a Right-to-Try regime, this important aspect of FDA oversight is severely compromised, potentially putting future patients at risk.
Pharmaceutical Companies: The Pivotal Player In Compassionate Use
It is the pharmaceutical companies themselves, and not the FDA (nor the IRBs) that decide whether or not to dispense their investigational products to those who request them. The FDA may give its blessing and approval, but in cannot compel the company to dispense its drug. If advocates wish to enhance and accelerate the rate at which terminally ill patients receive experimental drugs, they must develop and promote policies that incentivize pharmaceutical companies to accede to requests. Drug companies are under no obligation to dispense their investigational drugs, and if they do, they are legally indemnified from any harm that may result from their use. Unlike the FDA, drug companies do not publish data on the number of Expanded Access requests they receive or fulfill, the patients they serve, or patient outcomes.
One may naturally ask, “why would a drug company refuse to give (or even sell) its experimental product away on a compassionate use basis, especially if there is no risk to the company?” First and foremost, Compassionate Use considerations must not interfere with a drug’s clinical trial. Drug companies must not only make certain that Compassionate Use applicants are not eligible to participate in clinical trials, but also must weigh a number of difficult, inter-related medical, financial, administrative, and ethical considerations for each request, including the following:
Does the company possess enough of the investigational drug to both conduct clinical trials and dispense through Compassionate Use? Some investigational drugs require enormous time and expense to produce, and many companies (especially those with limited financial resources) stockpile only enough inventories required for development and clinical trial purposes.
Can the company afford to give away its investigational drugs? Insurance companies are not required to reimburse patients for non-approved drugs, and although drug companies are permitted to charge patients for their experimental products, many companies, in their desire to equitably dispense compassionate use drugs, do not charge patients for them. The cost of the drug itself, however, is only one expense. Other expenditures include employee salaries and overhead necessary to produce additional drug supplies, manage the program, and collect, report, and analyze data on patients receiving the drugs.
Impacts on Clinical Trials and the FDA
Even though the clinical results of patients receiving an experimental drug via expanded access are not factored into clinical trial data, drug companies nevertheless may be concerned about the consequences of poor patient outcomes. Pre-approval access is usually requested as a “last ditch” effort, and eligible patients are generally sicker than clinical trial participants (in that they have been classified as terminally ill, have not responded to other therapies, and are ineligible to participate in further clinical drug trials), which places them at higher risk for negative outcomes. Drug companies may worry that any news of negative results may hurt a drug’s chance of approval, lead to additional label warnings, or create negative publicity.
Ethics of the Decision-Making Process
Who at the drug companies should take on the awesome responsibility of determining which patients should receive their scarce resources, and what is the most ethical and just way to carry out these duties? There are no regulations regarding how companies evaluate Compassionate Use requests, and each company may have different employees and team members who evaluate them and weigh in on the decision-making process. For example, Genentech’s website states that “Decisions regarding potential access to investigational or unapproved medicines can only be made, in certain circumstances, after in-depth discussions between Genentech’s clinical teams and the patient’s qualified treating doctor.” Smaller companies, however, may not have the resources for such in-depth, widespread consultations, and decisions are often left up to the senior management. To quote one biotech executive, “These ethical decisions should not rest solely on corporate leadership. Instead, there needs to be a focused effort to create a more equitable approach to expanded access.”
It is in the best interest of all parties to try to speed compassionate use access in the U.S., and we believe that the most effective means for doing so is to help drug companies better assess and respond to compassionate use requests. The pharmaceutical companies, not the FDA, are the true, justified gatekeepers to their proprietary products. Therefore, if lawmakers and others wish to facilitate wider, faster, fairer, and safer access to experimental therapies, then they must devise policies that take this fact into account and incentivize pharmaceutical companies to provide for greater access to their products in development. Patients deserve fair, appropriate, timely, and safe access to experimental drugs. However, legislation such as Right-To-Try laws and policies that focus solely on the FDA’s practices are unproductive and futile.