By R. Bert Wilkins, JD, MHA, CIP, executive chair, Western IRB
There is a constant struggle between giving people, particularly the terminally ill, access to new treatments quickly, while also ensuring that those treatments are as safe and effective as possible. The debate continues with the proposal and passage of state “Right to Try” laws, which would give terminally ill people access to investigational drugs that have completed Phase I studies.
What are Right to Try laws?
Currently, four states — Arizona, Colorado, Louisiana, and Missouri — have passed Right to Try laws, and Michigan has a proposed statute that is fairly similar to the other four. While there are differences between these statutes, they all appear to be based on the model drafted by the Goldwater Institute. (The institute’s model can be found at http://goldwaterinstitute.org/sites/default/files/Proposed%20Statutory%20Language.pdf.)
The laws in all four states say that a manufacturer may provide experimental drugs to patients:
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who have a terminal illness;
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do not have comparable or satisfactory alternatives;
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when the probable risk to the individual from the investigational drug is not greater than the probable risk from the disease or condition;
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the individual receives a prescription or recommendation from a licensed physician.
There is also a proposed bill in the U.S. House of Representatives, entitled The Compassionate Freedom of Choice Act of 2014, which would amend the Food, Drug, and Cosmetic Act (FDCA) to prohibit the U.S. Food and Drug Administration (FDA) from implementing or enforcing any provision of any law preventing or restricting the manufacture, importation, distribution, or sale of an investigational drug or device intended for use by terminally ill patients. This proposed bill differs from the state Right to Try laws in that the federal law requires that there be no drug or device that is lawfully marketed in the U.S. that is likely to cure the illness, and that the drug or device has to be the subject of one or more clinical trials. (Text of the bill can be viewed at http://www.gpo.gov/fdsys/pkg/BILLS-113hr4475ih/html/BILLS-113hr4475ih.htm.)
Currently, terminally ill patients have access to investigational drugs only through clinical trials or the FDA’s expanded access program. In order to be treated under expanded access, the following criteria need to be met:
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The patient or patients to be treated have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition.
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The potential patient benefit justifies the potential risks of the expanded access and those potential risks are not unreasonable in the context of the disease or condition to be treated.
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Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.1
There are three different levels of expanded access: single patient treatment use, intermediate population treatment use, and treatment use. As the names imply, these programs are designed to get investigational drugs to various groups of people. Single patient and intermediate population treatment use protocols are designed to give small numbers of people access to the investigational drug while there are ongoing studies. Treatment use protocols are designed to give whole populations access to the investigational drug, either because the drug is not available in the U.S., or the protocols have all been completed and the drug is waiting for final approval. For more information, please see 21 C.F.R.§ 312.305-320.
Expanded access vs. Right to Try
The first major difference between the Right to Try laws and expanded access goes to the heart of why these laws were enacted or proposed in the first place: The Right to Try laws do not require that there be a comparable or satisfactory alternative. The FDA has indicated that FDA-approved drugs should be the first option pursued before trying to set up an expanded access protocol. This means that, unless they qualify for a clinical trial, many people will not qualify for expanded access until they have tried and failed all other approved treatments. For many people, by this time, their disease may have progressed to the point where it is too late for any treatment to work. In contrast, the Right to Try laws require only that an individual, in consultation with his or her physician, consider all of the alternatives. If the physician believes that an investigational product provides the best option, the physician can prescribe or recommend the product.
To compound the problem, the FDA takes different approaches when defining an available alternative. For example, the FDA guidance document, titled “Physician Request for an Individual Patient IND under Expanded Access for Non-emergency or Emergency Use,” requires as part of the application for a single patient treatment use protocol the rationale for requesting the proposed treatment, including a list of available therapeutic options that would ordinarily be tried before the investigational drug or an explanation of why use of the investigational drug is preferable to use of available therapeutic options.2 This implies that for single patient treatment use, the comparable alternatives are not limited to FDA-approved treatments so long as there is adequate justification for using the investigational drug.
In contrast, other expanded access protocols require that there be no comparable or satisfactory therapeutic alternative. This means that FDA-approved treatments should be used first; specifically, patients may have access to investigational drugs only if they do not respond to or are intolerant of approved therapy. (For more information, see http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM202331.pdf..)
Will Right to Try laws be effective?
There are a number of things that may prevent the Right to Try laws from being successful. The first is that these laws cannot bypass the FDA and they provide little additional value. The FDA has sole jurisdiction in regulating the approval of new drugs, and it is unlikely that the FDA will allow the use of an investigational drug unless it meets the requirements under expanded access. If the intent of these laws is to give individuals access to investigational drugs, these laws will have little impact, because for single patient treatment use protocols the FDA already approves 99% of the requests.
The second reason the Right to Try laws may not be effective is that drug companies are often asked to balance providing treatment to individuals and getting the drug approved for everyone. The Right to Try laws are permissive and do not require the drug companies to provide an investigational drug. Given their limited resources, drug companies have been reluctant to provide investigational drugs under the existing FDA expanded access regulations. There have been several high-profile cases recently highlighting the fact that many people do not get access to investigational drugs through expanded access until journalists, congresspeople, and advocacy groups step in and apply pressure to drug companies to provide the treatment.3 The Right to Try laws do not offer any additional incentives for drug companies to provide investigational drugs, and, given the choice, drug companies will likely prefer to use limited resources to obtain approval of the drug.
There is also the major underlying issue that as investigational drugs move through the various phases of testing, fewer drugs move out of the phase than enter it. According to CenterWatch, only about 70% of drugs go from Phase I to Phase II, and only about 33% of drugs that start Phase I studies complete Phase I and Phase II. Between 10% and 30% of drugs that enter Phase III do not get approved.4 This means that only about 25% of drugs that start Phase I studies ultimately get approved. In recent years, this quantity has been shown to be much smaller, and only about 10% of drugs that enter Phase I ultimately get approved.
Drugs may not progress from one phase to another for a variety of reasons; however, the most common reasons are the drug is found to have greater side effects or risks than previously determined, or the drug is not effective. A new drug may look promising in early testing, but as more people take the drug, the initial promising results often do not hold up. All studies are well controlled and subjects who have comorbid conditions or who would otherwise confound the data are excluded from the studies. Even if patients are able to get access to investigational drugs through Right to Try laws, the overwhelming odds are that the drug is not safe and/or not effective. The patients who would be able to access investigational drugs may, in fact, have worse outcomes if they eschew approved treatments for an investigational drug. New does not always mean better.
Intent vs. effect
The Right to Try laws are intended to give terminally ill patients more options and help them direct their own care. While the intent is laudable, it is unlikely that these laws will have the intended effect. The intent appears to be to provide a mechanism for terminally ill patients to get access outside of the FDA expanded access regulations, but these laws will not be able to bypass the FDA requirements, and there are no additional incentives for drug companies to provide investigational drugs.
R. Bert Wilkins is the Executive Institutional Review Board Chair for the Western IRB in Puyallup, WA.
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Access to Investigational Drugs. U.S. Food and Drug Administration. http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM202331.pdf
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Physician Request for an Individual Patient IND under Expanded Access for Non-emergency or Emergency Use. U.S. Food and Drug Administration. http://1.usa.gov/14sNsbm
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Caplan A, Moch K. Rescue Me: The Challenge of Compassionate Use In The Social Media Era. Health Affairs blog, 27 Aug 2014. http://healthaffairs.org/blog/2014/08/27/rescue-me-the-challenge-of-compassionate-use-in-the-social-media-era/.
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CenterWatch. Overview of clinical trials. www.centerwatch.com/clinical-trials/overview.aspx.
