In 2007 FDA once again broadened its policy for expanded access to new drugs when it amended the Food and Drug Administration Modernization Act (FDAMA) to include criteria for approved drugs with risk evaluation and mitigation strategies (REMS).(Fed Reg 2009;74(155)) This marks the 3rd major revision in 3 decades to regulations that grant seriously ill patients increasingly open access to investigational drugs.
Access to investigational drugs via treatment Investigational New Drug (IND) applications was first formalized in 1987 following intense pressure from AIDS activists. Supporters applaud each move towards easier access to unapproved drugs, but the regulation, in essence, reverses elements of the Food, Drug, and Cosmetic Act (FD&C) which were put in place to protect all patients from unsafe medications and charlatanism. This nullifies the attempts to protect the best interests of patients, including those who are terminally ill.
In the context of this paper I define “best interests” as: meeting one’s fundamental rights to self-preservation, ensuring one’s safety, ensuring no person or persons has fewer or more rights than others, and ensuring benefits are equitably distributed. This definition corresponds to the criteria listed in the “Rule” below.
ISSUE:
Does FDA’s expanded access program serve the best interests of terminally ill patients?
RULE:
FDA’s expanded access program serves the best interests of terminally ill patients if all of the following are true:
- Expanded access meets a fundamental right of access to investigational drugs
- The benefits of using an investigational drug outweigh the risks and the patient is not exposed to unreasonable and significant additional risk of illness or injury, even if the patient is already terminally ill.
- Terminally ill patients do not need the same protection against unsafe or ineffective drugs as patients with less serious or non-life-threatening illness.
- All terminally ill patients have equal access to the drugs in question.
- Expanded access does not interfere with development of new drugs and thereby negatively affect future access to other patients.
ANALYSIS:
CRITERIUM 1: Expanded access meets a fundamental right to access investigational drugs
The current laws do not support fundamental right to access investigational drugs. According to the FD&C Act, “no person shall introduce or deliver for introduction into interstate commerce any new drug” unless it has been approved for marketing by FDA. Approval requires that the new drug has been proven both safe and effective in humans based on at least 3 phases of “adequate and well-controlled” clinical studies. [See 21 CFR 312.21 Phases of an investigation and 21 USC 355 Section (d)] Drug sponsors are permitted to submit treatment INDs to provide Phase 3 or, less commonly, Phase 2 drugs to patients with “a serious or immediately life-threatening disease condition in patients for whom no comparable or satisfactory alternative drug or other therapy is available.” [See 21 CFR 312.34] However, FDA reserves the right to deny access if there is “insufficient evidence of safety and effectiveness to support such use” or there is an “unreasonably and significant additional risk of illness or injury,” even if the patient’s illness is immediately life-threatening. [See 21 CFR 312.34] Furthermore, no one can compel the drug sponsor to provide investigational drugs to patients not enrolled in clinical studies, or make such a request on their behalf; participation in a treatment IND is voluntary. So the current laws do not support the existence of a fundamental right.
This argument is supported by the 2007 ruling in a recent case: Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach. The Abigail Alliance was formed by Frank Burroughs after his daughter, Abigail, died of head and neck cancer in 2001. She had been denied access to then-investigational treatments cetuximab (Erbitux) and gefitinib (Iressa), both of which went on to win FDA approval after her death. Convinced the denial of access (and possibly Abigail’s premature death) was caused by unnecessary regulation and bureaucracy, the Abigail Alliance sued FDA (Andrew von Eschenbach was Commissioner at the time) in an attempt to change the existing regulations and permit terminally ill patients to access new drugs as soon as they have completed Phase 1 trials.
In its argument the Abigail Alliance claimed “the concepts of self-defense, necessity, and interference with rescue are broad enough to demonstrate the existence of the fundamental right they seek—a right for ‘persons in mortal peril’ to ‘try to save their own lives, even if the chosen means would otherwise be illegal or involve enormous risks.’” In support of its argument, the Alliance cited Washington v Glucksberg saying FDA’s regulations violated the Constitutional concept of Due Process and the right to self-protection. But the US Court of Appeals for the District of Columbia dismissed the argument by saying, “The Alliance’s effort to focus on efficacy regulation ignores one simple fact: it is unlawful for the Alliance to procure experimental drugs not only because they have not been proven effective, but because they have not been proven safe.” The Court disagreed with the Abigail Alliance’s interpretation of Washington v Glucksberg stating, “A tradition of protection does not alone establish a fundamental right."
In addition, the US Court of Appeals for the District of Columbia asserted, “There is no fundamental right ‘deeply rooted in this nation's history and tradition’ of access to experimental drugs for the terminally ill.” The Abigail Alliance took its appeal to the US Supreme Court, but they were denied certiorari in 2008 and the District Court decision stood.
I feel it is also important to add here that a fundamental right should not, and could not, apply to only to a segment of the population (terminally ill people). If the right is truly fundamental, all persons should have the same access to investigational drugs even if their illness is mild and non-life-threatening. Current laws and the Constitution include no such fundamental right, and so this first criterium is not met.
CRITERIUM 2: The benefits of taking investigational drugs outweigh the risks
The FD&C Act was enacted in 1938 after 100 Americans died as a result of taking an unregulated formulation of elixir sulfanilamide. The drug had been given successfully in tablet form to treat streptococcal infections, but when it was dissolved in diethylene glycol to create a liquid form the results were lethal. FD&C therefore required sponsors to demonstrate the safety of their drugs before being able to sell them. The subsequent 1962 Kefauver-Harris Amendments to FD&C required sponsors to demonstrate that new drugs were also effective by completing 3 phases of clinical trials and gaining approval on a New Drug Application (NDA). The Amendments were meant to protect patients against charlatans who made false promises to cure ill people, including patients with terminal diseases.
Phase 1 clinical trials are conducted in a handful of healthy volunteers to “determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses.” Phase 2 clinical trials are conducted in no more than a few hundred patients with the disease under study to “determine the common short-term side effects and risks associated with the drug.” It isn’t until Phase 3 that trials are conducted in a wider population (several hundred to several thousand patients with the disease under study) that the sponsor is able to “gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling.” [See 21 CFR 312.21]
The expanded access program violates the protection afforded by FD&C by exposing patients to drugs that do not have proven safety or efficacy profiles. Medical and physiological responses of healthy Phase 1 volunteers are not representative of the effects of a drug in sick patients who may suffer from concomitant illnesses, have compromised abilities to metabolize drugs or manage side effects, and may be taking other medications. Even Phase 2 and 3 trials may not be representative of the larger population afflicted with a given disease because the number of trial participants is small compared to the total population, and the controlled conditions of clinical trials differ from the “real world” experience of patients.
Furthermore, only 11% of drugs that enter clinical trials are ever approved for marketing. For cancer drugs the approval rate is 6%. (Okie 2006, Society for Clinical Trials Board of Directors 2006) Researchers have been surprised in the past when drugs that appeared to be effective and safe in Phase 1 or 2 trials turned out to be ineffective, dangerous or both once the drug was used to treat a larger population in Phase 3. [Society for Clinical Trials Board of Directors 2006, Cortez 2011, Ray 2011] Of course, some drugs are recalled or have additional warnings added to their labels after they are approved for marketing. [eg, Vioxx, Meridia, Avastin, Avandia, Darvon & Darvocet, Depo-Provera, Plavix] This demonstrates the limitations of even Phase 3 trials in establishing safety and efficacy in the broader population.
Investigational drugs have, by definition, an incomplete safety and efficacy profile. So the expanded access program cannot predict whether the benefits of taking investigational drugs outweigh the risks. Therefore this second criterium is not met.
CRITERIUM 3: Seriously or terminally ill patients do not need the same protections as people with less serious disease
There is no legal precedent indicating seriously ill people, even those with terminal disease, have less need for protection than people with less serious diseases. In United States v Rutherford cancer patients argued that they had a right to Laetrile, an investigational drug that was said to be useful in treating cancer. Laetrile was never shown to be effective and was never approved by FDA, but in their arguments the plaintiffs claimed that denying them access was an infringement on their Constitutional privacy rights to benefit their personal health. They also claimed that the safety and efficacy standards outlined in FD&C are not reasonable applicable to terminally ill cancer patients.
A District Court sided with the plaintiffs and a Court of Appeals approved the District Court’s decision, but on certiorari the US Supreme Court reversed the decision. In the unanimous opinion Justice Thurgood Marshall wrote: “Nothing in the history of the 1938 Food, Drug, and Cosmetic Act, which first established procedures for review of drug safety, or of the 1962 Amendments, which added the current safety and effectiveness standards in § 201(p)(1) suggests that Congress intended protection only for persons suffering from curable diseases. To the contrary, in deliberations preceding the 1938 Act, Congress expressed concern that individuals with fatal illnesses, such as cancer, should be shielded from fraudulent cures...For the terminally ill, as for anyone else, a drug is unsafe if its potential for inflicting death or physical injury is not offset by the possibility of therapeutic benefit.”
I would also add that terminally ill people are more at risk for being manipulated because they are making decisions under duress. They are more likely to believe a treatment will be helpful because it provides them with hope, whereas if their illnesses were not life-threatening they may be more wary and skeptical of the same investigational drugs.
Just as the Declaration of Helsinki protects vulnerable populations (prisoners, children, pregnant women) those who are desperately ill need protection, even if they don’t always perceive regulations to be protective. The expanded access program fails to protect terminally ill people in the same way as people with non-life-threatening diseases, because it allows them to be exposed to unknown risks that are otherwise considered unacceptable for the rest of the population.
The program also falsely raises the hopes of the terminally ill simply because by granting early access FDA implies the drugs are acceptable for use. Due to these failures of protection, the third criterium is not met.
CRITERIUM 4: All terminally ill patients have equal access to the drugs in question
Expanded access was meant to make treatments available to terminally ill patients who do not qualify for clinical trials and who have no alternative approved treatments. However, this access is not equal.
First, to apply for the drug an individual patient (as opposed to a population represented by a drug sponsor) needs a physician who is dedicated and willing to complete the treatment IND. Not all treating physicians are willing or able to commit their time to this work and some physicians may be uneducated on the process or even the availability of a treatment IND. So a patient may be denied access based on their choice of physician (if they had a choice).
Second, sponsors are permitted to charge for investigational drugs so long as they are only recouping their costs to manufacture the drug. Insurance companies generally do not cover investigational drugs so the cost, which can be considerable, may fall to the patient. This favors patients with more financial resources. (Sponsors can choose to waive costs, but they are not required to do so.)
Third, even if drug sponsors are willing to take on treatment INDs their eligibility criteria can exclude some patients. Drug sponsors want to get the best results possible and so they are prone to recruiting patients who are most likely to respond well. This bias will always prevent some portion of the population from equal access to investigational drugs.
Fourth, investigational drugs are typically manufactured in small quantities. Even if the sponsor is willing to provide the treatment free of charge, there simply may not be enough medication available for all patients who apply for it through the expanded access program. And the sponsor cannot be compelled to make enough of the drug to meet all possible demand.
Fifth, patients can be disadvantaged by their geographical location. If a condition of treatment is proximity to a location where the drug can be administered, patients who are unable to travel (for financial, health, or any other reasons) are excluded.
For these reasons the fourth criterium is not met.
CRITERIUM 5: Expanded access does not interfere with development of new drugs (and therefore decrease access to the wider population of patients)
Drug sponsors have legitimate reasons not to want to participate in expanded access. For example, expanded access can decrease enrollment in clinical trials. Patients who are terminally ill generally do not want to risk being randomized to placebo or existing treatment arm if they think the investigational drug offers more hope. So they opt out of the clinical trial and apply instead for expanded access. Each time FDA loosens restrictions around investigational drugs the demand for access outside of clinical trials grows. This makes it more difficult for sponsors to recruit participants for controlled studies.
Additionally, unfavorable side effects, injuries, or deaths resulting from the use of investigational drugs outside of clinical trials results must be reported to FDA and can put post-approval marketing efforts at risk. Sponsors are understandably skittish about potential negative impacts on revenue.
Finally, expanded access exposes drug sponsors to potential lawsuits. In several recent cases patients have also sued sponsors for not making investigational drugs available to them indefinitely. [See Abney v Amgen and Suthers v Amgen] This legal and financial exposure is a deterrent to sponsors.
The potential for negative impact on clinical trials and safety data threatens profitability and can drive sponsors to curb research and development (R&D) investments in new drugs that are targets for expanded access (eg, serious but relatively uncommon diseases). This interferes with the development of new treatments and can unfairly prevent future patients from access to life-saving drugs.
For these reasons, the fifth criterium is not met.
CONCLUSION:
While terminally ill patients can sometimes benefit from getting investigational treatments, the expanded access program does not serve the best interests of terminally ill patients.
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