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Health Policy Brief u p d a t e d a p r i l 9 , 2 0 1 5

signed into law. These laws are often called Right-to-Try laws. Supporters argue that pa- tients have the right to determine what risks they are willing to undertake to save their own lives and that these laws help reduce unnec- essary federal interference. Opponents argue that such laws may introduce new risks for pa- tients while undermining laws meant to pro- tect public safety. The ultimate effects of these state-level efforts are still unclear, and their constitutionality is open to question.

w hat ’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 pri- marily 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 effica- cy in the patients that the drug is intended to treat. Phase III trials may include hundreds or thousands of patients and are used to demon- strate 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 ap- proval once a drug has successfully completed Phase III trials.

w hat ’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 hu- man subject in a clinical research trial. For patients who cannot be enrolled in that trial (because of their medical status or geograph- ic location, for example), a second option is to apply to the FDA for access to the experi- mental 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 four years 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 pa- tients and physicians from applying. Since last year, more than twenty states have introduced laws aimed at making experimental therapies more easily accessible to patients with ter- minal illnesses, thirteen of which have been

Right-to-Try Laws. Some states have passed legislation intended to expand access to experimental treatments for patients with serious or life-threatening conditions.

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The clinical research process is tightly regu- lated in the United States. Any drug company wishing to conduct a clinical trial must first submit an Investigational New Drug (IND) ap- plication to the FDA, which allows the compa- ny 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 for- mally 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.

feder a l regul ation of e xpa nded 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 eli- gibility requirements to receive an experimen- tal 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 main- tains three general categories of expanded access: treatment, single patient, and inter- mediate. 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 pa- tients) seeking access.

Treatment INDs and protocols are the oldest form of expanded access, having been formal- ly established in federal regulations in 1987. Under this category, a relatively large group of patients (hundreds or thousands) are permit- ted to access an experimental drug, provided that the sponsor is actively pursuing FDA ap- proval 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 appli- cation 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 prefer- ential access for certain groups of patients. In 1997 Congress passed the FDA Moderniza- tion 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 ap- plied to any group of patients that is greater than one but that does not reach the thresh- old for expanded access under a treatment IND or protocol. Intermediate expanded ac- cess programs are sometimes used to aggre- gate 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 all three categories, patients may be granted expanded access if under the follow- ing conditions: The patient has a serious or immediately life-threatening condition; the patient’s physician has determined that no alternative comparable or satisfactory treat- ment is available, is willing to administer the experimental therapy, and obtains Institu- tional 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 pro- viding the experimental therapy to the patient will not interfere with the broader clinical in- vestigation that will ultimately support a mar- keting application.

Depending on the category, additional con- siderations may apply. For single-patient ap- plications, 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, un- less the FDA authorizes otherwise. The manu- facturer or treating physician is also required to submit a written summary of the results of the expanded access use, including any ad- verse events. For intermediate applications, there must be some evidence that the drug is

“Supporters argue that patients have the right to determine what risks they are willing to undertake to save their own lives.”

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safe at the dose and duration proposed, and there must at least be preliminary clinical evi- dence of effectiveness. A January 2015 article by Jonathan J. Darrow and colleagues 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. Ver y few are de- nied. Of the 5,849 single-patient expanded access applications ( both emergenc y and nonemergency) made to the FDA bet ween 2010 and 2014, just thirty-three were rejected. However, the FDA cannot compel a manufac- turer 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 expand- ed access in 2009 and released draft guidance to industry on the process for implementing expanded access and on obtaining approval to charge for it 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. How- ever, companies may still var y significantly in terms of whether and under what circum- stances they will provide the drug. Manufac- turers 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 grant- ed access. However, a January 2015 search of ClinicalTrials.gov found 138 ongoing studies that were available for expanded access.

c r i t i c i s m o f t h e e x pa n d e d a c c e s s p r o - gr a m : Critics of the expanded access program have argued that the application process is un- necessarily burdensome and lengthy, which discourages doctors and manufacturers from applying. By the FDA’s own estimate, the cur- rent 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. In- stead, 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 federal requirements 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—repre- sents an attempt to introduce some degree of f lexibility into the regulatory process and al- low patients with no other treatment options a chance to try therapies they may not other- wise 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 adminis- tration of experimental therapies to terminal- ly 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 test- ing. 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 experi- mental therapies. The US Supreme Court sub- sequently 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 pol- icy paper that outlines the major critiques of the FDA’s expanded access program and pro- poses model legislation for state governments to adopt. To date, thirteen states have enacted a version of this Right-to-Try legislation, and at least twent y-one others have introduced some form of a Right-to-Try bill.

w hat ’s in the l aws? T he bills that have already been enacted share several key characteristics, largely be- cause the Goldwater Institute’s policy brief included a model legislative template. All thir- teen laws seek to bypass the FDA application process and establish expanded access pro- grams for patients meeting certain eligibility requirements.

6,000 In t h e pas t fo u r yea r s t h e FDA has received n ea r ly 6,000 e x pa nded access a pplic a tio ns.

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Under the 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 rec- ommendation from their physician for an ex- perimental drug, biologic, or device; and have provided written informed consent to under- take the risks associated with the treatment.

An experimental therapy is defined as any drug, biologic, or device that is currently un- der 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 thera- pies (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 pre- scribing the treatment.

The laws do var y in certain respects. For example, A r izona excludes pr imar y care physicians from its definition of physician, and Missouri excludes controlled substances from eligibility. Most of the states (with the exceptions of Arizona, Arkansas, Louisiana, Missouri, and Wyoming) include statutor y language defining the minimum information that must be communicated to the patient through the informed consent procedure, and all but two (Louisiana and Arizona) added lan- guage aimed at protecting both manufactur- ers and the treating physician from liability. Louisiana included language that protects prescribing physicians, but not the manufac- turer, from liability. Although none of the bills require insurers to cover the costs associated with the prescription or administration of these drugs, Maine specifically allows insur- ers to deny coverage for services provided to a given patient for up to six months from the time that the patient stops receiving the ex- perimental treatment. However, in line with federal regulations, insurers may not deny coverage for ser vices related to preexisting conditions or for treatments that began prior to the use of the investigational product.

w hat ’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 sig- nificant harms with no guarantees of benefit.

Phase I trials are just the first step in assess- ing 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 under- take the risks associated with the therapy, critics argue that in many cases, patients and physicians would have inadequate data to fully assess the risks of a given therapy. Further- more, Phase I trials often provide little to no information on effectiveness, which makes it difficult to assess the drug’s benefits. Vul- nerable patients may also be particularly ill equipped to weigh the benefits and risks of participation. One survey, 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.

Some have also raised ethical concerns related to the fairness of these Right-to-Tr y laws. Because insurers are not required to re- imburse for the associated costs, access may in practice be limited to patients with the re- sources to cover the costs, which could include the direct cost of the drug—as the manufac- turer defines it—as well as the medical fees associated with its administration or the treat- ment of any side effects that may follow.

Second, there are concerns that broader ac- cess to experimental therapies can undermine the ongoing clinical research that might sup- port full FDA approval. Manufacturers—par- ticularly small companies that have limited financial resources or that are working in disease areas that affect small numbers of pa- tients—may be ill equipped to handle the ex- tra demands placed on their staff resources or on the limited supply of their investigational product.

Manufacturers also worr y about liabilit y related to adverse events and the chances that those adverse events might reduce the likeli- hood of FDA approval for their drug. Broad- ening expanded access programs might also deter patients from enrolling in formal clini- cal 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 ac- cess program, these state laws could, if fully implemented, intensify the problems. How- ever, these laws are unlikely to achieve their

“Efforts are under way to standardize and improve the way in which individual companies manage expanded access.”

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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 gain- ing full regulatory approval for their products are unlikely to ignore federal regulation. Fur- thermore, although the FDA has yet to issue a formal position, these laws are unlikely to withstand a legal preemption challenge. Un- der the Supremacy Clause of the US Constitu- tion, federal law generally takes precedence over state law whenever the two are in conflict.

w hat ’s ne x t? It is unclear whether any patients have suc- cessfully 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 announced plans to establish an expanded access working group, which will develop policies to streamline the application process.

In Februar y 2015 the FDA redesigned its website on expanded access and released draft guidance that introduced a new, simpli- fied 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 forty-five minutes to com- plete, instead of the 100 hours required to complete a traditional IND application. The form is currently available for public comment 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 ac- cess. Two major industry trade groups recent- ly delivered statements on the issue and have developed standards and principles for their respective member companies to follow when developing their expanded access policy for a particular therapy.

Legislation was also introduced at the fed- eral level late last year (HR 5805), with the goal of improving the existing expanded ac- cess program. If passed, the law would require companies to provide the FDA with more in- formation on its process for dealing with ex- panded 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 improve- ment. 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 21st Century Cures Act, which is likely to be introduced in the next few months. It re- mains to be seen how these various national- level efforts will impact patient decisions to pursue expanded access under state Right-to- Try laws. n

resources

Christina Corieri, Ever yone Deser ves the Right to Try: Empowering the Terminally Ill to Take Control of Their Treatment (Phoenix, AZ: Goldwater Insti- tute, Policy Report No. 266, February 2014).

Jonathan J. Darrow, Ameet Sarpatwari, Jerry Avorn, and Aaron S. Kesselheim, “Practical, Legal, and Ethical Issues in Expanded Access to Investigational Drugs,” New England Journal of Medicine 372, no. 3 (2015): 279–86.

Food and Drug Administration, Expanded Access: Information for Patients (Silver Spring, MD: FDA, February 10, 2015).

Food and Drug Administration, Guidance for Indus- tr y: Charging for Investigational Dr ugs under an IND—Qs & As (Silver Spring, MD: FDA, May 2013).

Food and Drug Administration, Guidance for Indus- tr y: Expanded Access to Investigational Drugs for Treatment Use—Qs & As (Silver Spring, MD: FDA, May 2013).

Food and Drug Administration, Individual Patient Expanded Access Applications: Form FDA 3926: Guidance for Industry (Silver Spring, MD: FDA, Feb- ruary 2015).

Darsha k Sanghav i, Meaghan George, and Sara Bencic, “Individual Patient Expanded Access: De- veloping Principles for a Structural and Regulatory Framework,” Health Affairs Blog, July 31, 2014.

A b o u t H e a lt h P o li c y B r i e f s

Written by E li z a b e t h R i c h a r d s o n Research Associate Engelberg Center for Health Care Reform Brookings Institution

Editorial review by J o a n H . K ra u s e Associate Dean for Facult y Development Universit y of Nor th Carolina School of Law

J o r d a n P a ra d i s e Associate Professor of Law Seton Hall Universit y School of Law

R o b L o t t Deput y Editor Health Affairs

Tra c y G n a d i n g e r Assistant Editor Health Affairs

Health Policy Briefs are produced under a par tnership of Health Affairs and the Rober t Wood Johnson Foundation.

Cite as: “Health Policy Brief: Right-to-Tr y Laws,” Health Affairs, Updated April 9, 2015.

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