MARCH 5, 2015
EDITOR'S NOTE: An updated brief was published April 9, 2015.
Some states have passed legislation intended to expand access to experimental treatments for patients with serious or life-threatening conditions.
|What's the issue?
Under current federal regulations, patients with serious or life-threatening illness have two primary options to access experimental therapies that may treat their condition but that have not yet been approved by the Food and Drug Administration (FDA). The most straightforward path is to participate as a human subject in a clinical research trial. For patients who cannot be enrolled in that trial (because of their medical status or geographic location, for example), a second option is to apply to the FDA for access to the experimental drug under the expanded access (also known as compassionate use) program, which was created to allow seriously ill patients to access treatments they would not otherwise be eligible to receive.
In the past the FDA has received nearly 6,000 expanded access applications and denied just thirty-three. However, critics of the program argue that the process is too cumbersome and that it discourages many patients and physicians from applying. Since last year, have introduced laws aimed at making experimental therapies more easily accessible to patients with terminal illnesses, five of which have been signed into law. These laws are often called Right-to-Try laws. Supporters argue that patients have the right to determine what risks they are willing to undertake to save their own lives and that these laws help reduce unnecessary federal interference. Opponents argue that such laws may introduce new risks for patients while undermining laws meant to protect public safety. The ultimate effects of these state-level efforts are still unclear, and their constitutionality is open to question.
|What's the background?
Clinical testing of an experimental drug is typically a three-phase process. Phase I trials are small (20 to 80 patients) and are used primarily to evaluate safety and dosing ranges, usually in healthy volunteers. Phase II trials are larger (typically 100 to 300 patients) and are designed to show early evidence of efficacy in the patients that the drug is intended to treat. Phase III trials may include hundreds or thousands of patients and are used to demonstrate that the drug is effective compared to a control (such as a placebo or a comparator drug). Typically, a manufacturer may submit an application to the FDA for marketing approval once a drug has successfully completed Phase III trials.
The clinical research process is tightly regulated in the United States. Any drug company wishing to conduct a clinical trial must first submit an Investigational New Drug (IND) application to the FDA, which allows the company to manufacture the drug and ship it across state lines for use in the trial. The drug may be only administered to patients who are formally enrolled in that clinical trial. For some patients, however, participation in a clinical trial is not possible. The study population for that trial may be limited based on any number of factors, including specific diagnosis, age, stage of illness, or comorbidities. Patients may also be too sick (or lack the financial means) to travel to a clinical research site where the trial is taking place.
FEDERAL REGULATION OF EXPANDED ACCESS: For these patients, a second option is to apply to the FDA for access to unapproved therapies under the expanded access program. This program allows patients who meet certain eligibility requirements to receive an experimental therapy for treatment purposes rather than as part of the formal clinical research process.
An application for expanded access can be submitted by either the manufacturer or a licensed physician. The FDA currently maintains of expanded access: treatment, single patient, and intermediate. Each of these categories, described below, is further split into two subcategories. One is "expanded access INDs"--through which the manufacturer submits a separate IND for a patient or group of patients--and the other is "expanded access protocols," whereby the manufacturer amends the protocol under an existing IND to include the patient (or patients) seeking access.
Treatment INDs and protocols are the oldest form of expanded access, having been formally established in federal regulations in 1987. Under this category, a relatively large group of patients (hundreds or thousands) are permitted to access an experimental drug, provided that the sponsor is actively pursuing FDA approval and is in later stages of testing (or has already submitted trial results to the FDA for review). The formalization of this process was largely in response to activism by AIDS patients, who lobbied strongly in support of early access to the drugs being developed to treat their disease.
While individual patients were able to access experimental therapies under treatment INDs or protocols, there were no formal criteria or submission requirements governing the application process for a single person. This lack of formal criteria prompted charges that the FDA was being inconsistent in its approach, which, in turn, was leading to inequitable or preferential access for certain groups of patients. In 1997 Congress passed the FDA Modernization Act, which created the statutory basis for single patients and intermediate-size patient populations to be granted expanded access.
Single-patient expanded access is, as its name implies, used for individual patients. It may be granted on either a standard basis or, for patients who do not have time to acquire written authorization from the FDA, on an emergency basis.
Intermediate expanded access may be applied to any group of patients that is greater than one but that does not reach the threshold for expanded access under a treatment IND or protocol. Intermediate expanded access programs are sometimes used to aggregate multiple single-patient expanded access applications for the same drug. They may also be used for drugs that are not currently being developed for marketing approval or that are no longer on the market.
For , patients may be granted expanded access if under the following conditions: The patient has a serious or immediately life-threatening condition; the patient's physician has determined that no alternative comparable or satisfactory treatment is available, is willing to administer the experimental therapy, and obtains Institutional Review Board (IRB) approval for the patient to use it; the FDA determines the risks associated with the treatment do not outweigh the potential benefits to that patient; and providing the experimental therapy to the patient will not interfere with the broader clinical investigation that will ultimately support a marketing application.
Depending on the category, additional considerations may apply. For single-patient applications, the risks of taking the drug (to the extent this is known) must not outweigh the risks associated with the patient's condition, and the treatment must be limited to a single course of therapy for a specific duration, unless the FDA authorizes otherwise. The manufacturer or treating physician is also required to submit a written summary of the results of the expanded access use, including any adverse events. For intermediate applications, there must be some evidence that the drug is safe at the dose and duration proposed, and there must at least be preliminary clinical evidence of effectiveness. A in the New England Journal of Medicine provides a detailed discussion of these three categories as well as ongoing limits to expanded access.
Once an application is submitted, the FDA has thirty days to respond. Very few are denied. Of the 5,849 single-patient expanded access applications (both emergency and nonemergency) made to the FDA between 2010 and 2014, . However, the FDA cannot compel a manufacturer to provide an investigational product to a patient; it can only permit the company to do so. Manufacturers may also impose additional restrictions or requirements on patients who are applying for expanded access, and--if the FDA permits it--may charge patients (or their insurer, if it covers experimental therapies) for use of the drug.
The FDA revised its regulations on expanded access in 2009 and released draft guidance to industry on the process for expanded access and on obtaining approval to in May 2013. In February 2015 the agency released additional draft guidance including a new streamlined application form, which if implemented would greatly reduce the administrative burden of applying. However, companies may still vary significantly in terms of they will provide the drug. Manufacturers are also not required to track or report on the number of expanded access requests they approve or deny, which makes it difficult to assess how many patients are actually granted access. However, a January 2015 search of ClinicalTrials.gov found 138 ongoing studies that were available for expanded access.
CRITICISM OF THE EXPANDED ACCESS PROGRAM: Critics of the expanded access program have that the application process is unnecessarily burdensome and lengthy, which discourages doctors and manufacturers from applying. By the FDA's own , the current IND application can require about 100 hours to complete, and an IRB review adds an additional layer of paperwork and potential delay. For some, these requirements represent an unacceptable barrier for desperate patients seeking to access potentially life-saving drugs.
These criticisms of the FDA are not new. Instead, they reflect a decades-long debate about the need to balance access to new therapies against requirements that a therapy be proven safe and effective before it can be marketed. These were themselves put in place in response to highly publicized incidents of harm caused by unsafe drugs. Expanded access--which has evolved over the past thirty years in response to sustained activism by patients and other groups--represents an attempt to introduce some degree of flexibility into the regulatory process and allow patients with no other treatment options a chance to try therapies they may not otherwise be able to access.
In the past decade, there have been several attempts made at the federal and judicial levels to further relax restrictions on the administration of experimental therapies to terminally ill patients. One of the most high profile of these efforts was led by the Abigail Alliance for Better Access to Developmental Drugs, which in 2003 submitted a Citizen Petition to the FDA requesting that it make experimental therapies available to terminally ill patients, provided that the drug had passed Phase I testing. Following several years of litigation, the DC Court of Appeals ruled against the Abigail Alliance, stating that terminally ill patients have no constitutional right to access experimental therapies. The US Supreme Court subsequently declined to review the case. At the federal level, several (ultimately unsuccessful) bills have been introduced that aim to relax FDA restrictions on access to experimental therapies. The most recent of these (HR 4475, the Compassionate Freedom of Choice Act of 2014) failed to make it out of committee.
In the past year, the debate has shifted to the state level, owing in part to the efforts of the Goldwater Institute, a libertarian think tank. In February 2014 the institute released a that outlines the major critiques of the FDA's expanded access program and proposes model legislation for state governments to adopt. To date, five states (Colorado, Louisiana, Michigan, Arizona, and Missouri) have of this Right-to-Try legislation, and at least fifteen others have introduced some form of a Right-to-Try bill.
|What's in the laws?
The bills that have already been enacted share several key characteristics, largely because the Goldwater Institute's policy brief included a model legislative template. All five Right-to-Try laws seek to bypass the FDA application process and establish expanded access programs for patients meeting certain eligibility requirements.
Under all five laws, an eligible patient must have a terminal illness; have considered all other treatment options currently approved by the FDA; have received a prescription or recommendation from their physician for an experimental drug, biologic, or device; and have provided written informed consent to undertake the risks associated with the treatment.
In all five, an experimental therapy is defined as any drug, biologic, or device that is currently under investigation in a clinical trial and has successfully completed Phase I safety trials. In line with current federal regulations, none of the laws compel the manufacturers of these products to make them available. Unlike the FDA process, manufacturers would not need to obtain approval before charging for the therapy. The laws also do not compel insurers to cover the costs of these experimental therapies (which may include the cost of treating unexpected side effects). Medical licensing boards are also prohibited from taking action against a physician for recommending or prescribing the treatment.
The laws do vary in certain respects. For example, physician, and excludes controlled substances from eligibility. and included statutory language defining the minimum information that must be communicated to the patient through the informed consent procedure, and--along with Missouri--added language aimed at protecting both manufacturers and the treating physician from liability. included language that protects prescribing physicians, but not the manufacturer, from liability.excludes primary care physicians from its definition of
|What's the debate?|
Criticism of these Right-to-Try laws centers on two primary concerns. First, there are ethical concerns that patients will be exposed to significant harms with no guarantees of benefit. Phase I trials are just the first step in assessing safety. In many cases, serious side effects may not emerge until later stages of research. Although these laws do require that patients provide written informed consent to undertake the risks associated with the therapy, critics argue that in many cases, patients and physicians would have inadequate data to fully assess the . Furthermore, Phase I trials often provide little to no information on effectiveness, which makes it difficult to assess the drug's benefits. Vulnerable patients may also be particularly ill equipped to weigh the benefits and risks of participation. One , for example, found that severely ill patients had reduced ability to understand and retain information on risks when compared to healthy patients, which raises important (and much larger) questions about the adequacy of the standard informed consent process.
have also raised ethical concerns related to the fairness of these Right-to-Try laws. Because insurers are not required to reimburse for the associated costs, access may in practice be limited to patients with the resources to cover the costs, which could include the direct cost of the drug--as the manufacturer defines it--as well as the medical fees associated with its administration or the treatment of any side effects that may follow.
Second, there are concerns that broader access to experimental therapies can undermine the ongoing clinical research that might support full FDA approval. Manufacturers--particularly small companies that have limited financial resources or that are working in disease areas that affect small numbers of patients--may be ill equipped to handle the extra demands placed on their staff resources or on the limited supply of their investigational product.
Manufacturers also worry about liability related to adverse events and the chances that those adverse events might reduce the likelihood of FDA approval for their drug. Broadening expanded access programs might also deter patients from enrolling in formal clinical trials, which could further undermine the research enterprise.
Although these concerns over safety, equity, and the integrity of the research process are also present under the federal expanded access program, these state laws could, if fully implemented, intensify the problems. However, these laws are unlikely to achieve their stated goals for several reasons. As previously noted, shipping an investigational drug across state lines is illegal without an approved IND from the FDA. Companies interested in gaining full regulatory approval for their products are unlikely to ignore federal regulation. Furthermore, although the FDA has yet to issue a formal position, these laws are unlikely to withstand a legal preemption challenge. Under the Supremacy Clause of the US Constitution, federal law generally takes over state law whenever the two are in .
It is unclear whether any patients have successfully accessed an experimental therapy under the state laws, although this may be as a result of low levels of awareness. However, Right-to-Try laws have proved to be politically popular, and there are likely to be more state laws passed in the current legislative sessions. It is also unclear whether the FDA will involve itself in any legal challenges to the laws that have already passed. However, in December 2014 the agency plans to establish an expanded access working group, which will develop policies to streamline the application process.
In February 2015 the FDA redesigned its website on expanded access and released draft that introduced a new, simplified form (Form 3926) that physicians could use to apply for individual expanded access. This streamlined form is intended to address concerns that the traditional IND application is too burdensome for individual physicians to complete. The FDA estimates that the new form will take just to complete, instead of the 100 hours required to complete a traditional IND application. The form is currently available for and is expected to be finalized later this year.
At the industry level, efforts are under way to standardize and improve the way in which individual companies manage expanded access. Two major industry trade groups recently on the issue and have developed and for their respective member companies to follow when developing their expanded access policy for a particular therapy.
Legislation was also introduced at the federal level late last year (), with the goal of improving the existing expanded access program. If passed, the law would require companies to provide the FDA with more information on its process for dealing with expanded access requests. It would also direct two entities--the Government Accountability Office and a separate, multistakeholder task force--to evaluate the current program and provide recommendations for its improvement. Finally, the bill would require the FDA to finalize its current guidance on expanded access, taking these recommendations into account. The text of this legislation has since been incorporated into the House Energy and Commerce Committee's discussion draft of the , which is likely to be introduced in the next few months. It remains to be seen how these various national-level efforts will impact patient decisions to pursue expanded access under state Right-to-Try laws.
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Cite as: "Health Policy Brief: Right-to-Try Laws," Health Affairs, March 5, 2015.
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