Currently, patients have two main options to access experimental therapies that may treat their conditions but that have not yet been approved by the Food and Drug Administration (FDA): enrolling in a clinical trial or applying to FDA’s expanded access (also known as compassionate use) program. But because FDA’s expanded access program has been viewed as cumbersome and overly restrictive, 31 states have passed “Right-To-Try” laws in the past two years. Based on model legislation created by the Goldwater Institute, a public policy think tank, right-to-try laws are intended to authorize use of experimental, not-yet-approved treatments for patients with advanced illness; prohibit sanctions of health care providers for providing experimental treatment; and clarify health insurers’ roles. In May, the Trickett Wendler Right to Try Act of 2016, a companion to a House bill introduced in 2015, was introduced in the Senate.
But right-to-try laws, while currently popular, are controversial. In California, Governor Jerry Brown recently vetoed a right-to-try law, saying the FDA’s revised expanded access program should be given a chance to work. A 2015 article in The New England Journal of Medicine provides a legal and ethical critique of expanded access and use of investigational drugs, noting that right-to-try laws “will have limited effect” because “they do not compel manufacturers and insurers to supply and pay for experimental therapies.”
I am a survivor of advanced metastatic melanoma. As I wrote in my Narrative Matters essay in the July issue of Health Affairs, I was excluded from extremely promising clinical trials three different times and the delays in access almost killed me. “Faced with imminent death, informed patients have the right to risk their lives by taking a promising but unproven drug, just as they have the right to decide when to terminate further treatment,” I concluded in my essay. “Withholding drugs in such situations is unethical and paternalistic, even if it may violate the physician’s Hippocratic oath to ‘first, do no harm.’”
A day after my article appeared, a representative of The Goldwater Institute contacted me, asking if I would be interested in possibly testifying on behalf of right-to-try legislation. After reading the model legislation and the proposed Senate bill, and doing some digging, I decided that while the right-to-try movement has a goal I could approve of in theory, I think it will be counter-productive in the end.
Concerns With Right-To-Try Laws
To date, I know of no publicized cases where a right-to-try law has enabled access to drugs by the critically ill. There are a number of problems with right-to-try legislation that may explain why.
Will pharma participate?
There is nothing in any right-to-try legislation, including the proposed federal bill, that compels drug companies to provide their experimental drugs to critically ill patients. This is likely to be the major sticking point. There are many reasons a drug company would not want to provide experimental and unproven drugs, including burdensome costs (especially if the company is small) and potential poor health outcomes when the drug is used in a less controlled situation with sicker patients (leading to liability or bad publicity).
Who pays?
There is nothing in the proposed Senate bill concerning payment, and the model legislation merely notes that a health plan may, but is not required to, cover experimental therapies. In some states, insurance companies are likely to cover costs, and in others it remains unclear who is responsible.
Under compassionate use, the FDA prohibits drug companies from charging more than their manufacturing costs for a yet-unapproved drug, which should prevent profiteering at the patient’s expense. Still, my fear is that the right-to-try laws will likely favor the wealthy and best informed.
What drugs and how promising?
The model legislation and proposed federal legislation specify that any drug deemed safe by the FDA (that is, experimental drugs that have completed Phase 1 trials, which establish dosage levels) should be acceptable for use under right-to-try provisions. However, some level of evidence indicating a drug’s efficacy as compared to its risks should be a requirement, even for the most desperately ill. This is where FDA’s expert judgment would still be necessary.
What doctors will use this?
Many right-to-try laws state only that “a physician” will be able to prescribe drugs, while others say there must be Institutional Review Board approval in order to prescribe experimental drugs, presumably with specialists prescribing. Without safeguards, less scrupulous providers will take advantage.
Which patients?
Some state right-to-try laws specify that only terminally ill patients (as defined by their physician or physicians) can have access to unapproved experimental drugs. Proper informed consent is also crucial — and difficult to achieve. Critically ill patients, and their caregivers, have varying degrees of ability to comprehend the benefits and risks of an experimental drug. True informed consent in these situations requires considerable background preparation on the patient’s part, as well as good communication on the physician’s.
Only those patients who are critically ill, who have exhausted all other treatment options, and who have been excluded from participation in promising clinical trials, should be allowed access to promising, safe, but not yet approved drugs. In addition, the greater good, in this case clinical trial recruitment and integrity, must not be affected.
The Alternative To Right-To-Try Laws
So, what needs fixing? My own history illustrates the problem.
After participation in some early clinical trials (all of which failed) and four surgeries, I progressed to stage 4 melanoma, with a median estimated survival of nine months. I was then treated, to no discernable effect, with alpha-interferon and interleukin-2, both FDA-approved immunotherapy treatments with very low response rates. I tried to join more clinical trials, including some for the promising new immunotherapies, but was excluded three different times. Ipilimumab took a decade to be approved, and the approval of an anti-PD-1 drug was delayed unnecessarily by two years as the company tried to establish an optimal dose level. I finally obtained both drugs in expanded access programs, a few months prior to their FDA approvals. I had an excellent response to anti-PD-1, but only in the very nick of time.
I and others in the same circumstances should have been allowed access to these promising immunotherapy drugs years earlier. It was clear that the drugs had enormous advantages over other approved treatments for advanced melanoma, even in early phase 1 studies. With my oncologist’s support, I wrote letters of appeal to the drug company involved (Bristol-Myers Squibb), the head of the National Cancer Institute, and the FDA — to absolutely no effect. Many melanoma patients I’d befriended died waiting for the new drugs to be approved.
There have been burdensome bureaucratic barriers and financial costs to compassionate use applications, which physicians file on behalf of their patients. A potential flood of applicants for experimental drugs could theoretically overwhelm, or at least divert, the energies of small companies and research institutions involved in drug evaluations. And as mentioned, the threat of compromising clinical trials by providing drugs to critically ill patients remains a concern.
Is the FDA to blame? In the past, the FDA was very slow to approve provision of experimental drugs to the desperately ill. One thinks immediately of the HIV/AIDS crisis. However, this has changed remarkably in recent years. The drug evaluation process has been accelerated in a number of ways (such as through the breakthrough therapy designation). FDA drug approval times for novel drugs are now often faster than in any other country, and the number of approvals per year has increased.
In addition, the expanded access application for individual patients was streamlined in June. If a doctor can obtain a letter of authorization from the relevant drug company, FDA approval for an experimental drug for a critically ill patient is now simpler, and very rarely denied. These changes should be communicated to physicians and their critically ill patients — and should satisfy many of my stated concerns.
However, the underlying problem of unlikely drug company participation remains. Neither right-to-try laws nor the streamlining of FDA expanded access procedures will solve this issue. Right-to-try legislation points fingers of blame in the wrong direction. The FDA has responded to calls for reform in this area. Will the pharmaceutical industry also respond in kind? Since there appears to be no profit incentive, given the restrictions on experimental drug pricing, I fear not.
from Health Affairs BlogHealth Affairs Blog http://ift.tt/2cSJu0c
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