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PDUFA reauthorization creates new pathways; GAO report notes FDA’s 99% acceptance rate for expanded access
Now in place in 37 states
, so-called “right to try” laws seek to remove any federal obstacle for desperately ill patients to obtain experimental drugs that have passed Phase I (the safety step). The topic has been a legislative priority popular on the right in the US. One of its main proponents, Sen. Robert Johnson (R-WI) had threatened to hold up the Prescription Drug User Fee Act (PDUFA) legislation unless right-to-try language was included, which was done in limited form when the bill passed the Senate and then the House on Aug. 3 (at press time, the bill was awaiting President Trump’s signature). Paying for the review of branded and generic drugs, medical devices and other “UFAs” is essential to how FDA is funded; the law is expected (by a Congressional Budget Office estimate) to generate some $9 billion in fees to fund FDA’s reviews through 2022.
“Right to try” is something of a political concept; in the regulatory environment of FDA, allowing sick patients to obtain an investigational drug is known as “expanded access,” and many manufacturers now have expanded access programs (EAPs). The right-to-try measures included in the law require HHS to hold hearings and issue guidance on how clinical trial criteria might be expanded to include more patients (essentially, enabling more patients who would otherwise be forced to seek expanded access use of an investigational drug to become part of a trial); to evaluate the EAPs of manufacturers; and to assess the processes of institutional review boards that are involved in reviewing trial protocols.
The 21st Century Cures Act, one of the last laws signed by President Obama in December, included an obligation for manufacturers to publish their EAP policies, in addition to streamlining aspects of the clinical trials approval process that could make drugs available more quickly. In early July, FDA Commissioner Scott Gottlieb (who has written extensively on a risk-averse culture at FDA prior to taking its reins) issued a long list of FDA actions to be taken in light of the 21st Century Cures Act, including streamlining trial procedures.
A GAO report reviewing EAPs found that FDA continues to impose few hurdles to physicians or their patients in approving the request (or, at least, not threatening to impose sanctions on manufacturers who would provide the non-approved drug). For the fiscal years 2012–2015 inclusive, FDA allowed 5,697 of 5,753 requests to proceed. GAO’s report, “FDA has taken steps to improve the expanded access program but should further clarify how adverse events data are used,” summarizes the pharma industry’s perspective as “[some] manufacturers noted that the lack of clear information can influence their decision whether to give patients access to their drugs because of their concerns that an adverse event will result in FDA placing a clinical hold on their drug, which could delay its development.”
This dispute has been going on for years; FDA’s own policies were revamped in 2009 and again in 2016, when the current streamlined application form (FDA 3926) was issued. Since around 2014, however, the Goldwater Institute, a libertarian-leaning advocacy group, has been pushing state by state for right-to-try laws. And now it has the ear of Vice President Mike Pence, who met with the Institute early this year; President Trump is also said to be in favor of the laws. While PDUFA V was being passed this summer, Sen. Johnson was able to get a Senate commitment to also pass his bill, S.204, the Trickett Wendler Right to Try Act of 2017, which was referred to the House prior to its August recess. S.204 covers much of the same ground as state right-to-try laws.
Making a difference?
All this legislating and advocacy work, by the Goldwater Institute and other right-to-try advocates, sounds like real progress has been made to assist terminally ill patients, but the end result is still a question mark. On its website, the Goldwater Institute states that “While millions of Americans will be diagnosed with or die of terminal illnesses each year, compassionate use exceptions are only granted to about 1,000 patients a year”—which gives an indication of how overwhelming expanded access could be for companies with limited stocks of a drug that is being produced for trials.
It’s not clear, at this point, whether the right-to-try laws in place in many states have resulted in any change to patient access. None of the laws require a manufacturer to provide an investigations drug; nor is there any requirement for commercial or public insurance to pay for expanded access drugs. There is something of a track record, going back to the AIDS activist era in the 1980s, of mobilized groups essentially shaming a drug company into providing investigational drugs. Under current FDA guidance, a drug manufacturer can prepare, in a fashion, for multiple expanded access requests by including an expanded-access protocol in its FDA regulatory filings. (In this case, the manufacturer itself becomes the requester of expanded access.)
A key part of S.204 tries to clarify what FDA can do with outcomes from a patient’s EAP. The relevant clause reads:
“[HHS] Secretary may not use a clinical outcome associated with the use of an eligible investigational drug pursuant to this section to delay or adversely affect the review or approval of such drug … unless—
“(A) the Secretary makes a determination, in accordance with paragraph (2), that use of such clinical outcome is critical to determining the safety of the eligible investigational drug; or
“(B) the sponsor requests use of such outcomes.”
All of which puts the question of positive or negative outcomes from an EAP application back in the hands of FDA. Opponents of wide-open EAPs have argued that it’s bizarre not to make use of outcome data wherever it’s from in the drug-approval process; EAP proponents like the Goldwater Institute have argued that it’s immoral for the federal government to withhold a treatment from a patient who might benefit.
Jane Reese-Coulbourne, a senior consultant at MK&A, an industry consulting firm specializing in patient and healthcare stakeholder engagement strategies that include EAPs, notes that expanded access has, in the past, sometimes been very beneficial to a drug approval, citing the instance of Iressa (gefitinib), the Astra-Zeneca drug for lung cancer; an unusually broad EAP involving thousands of patients answered certain safety questions when the drug was approved in the US in 2003. “Companies now have an obligation to develop EAPs, although FDA is not enforcing this aggressively,” she says. “In any case, there is an opportunity for companies to develop these programs thoughtfully, taking into consideration issues like availability of the drug and patient selection criteria.”
And while there is earlier regulatory action on how an expanded-access drug is to be priced, economics factor into the equation. A leader in stem cell research is of the opinion that “There are scores of companies in the United States who want to sell unproven and scientifically implausible stem cell therapies to patients, some of whom are among the main supporters of right-to-try legislation.” Coming at the subject from a very different direction, at least one company, Inceptua, was recently founded to make a business from connecting patients with expanded access drugs.
Another action that FDA had taken in 2016 was to authorize the Reagan-Udall Foundation, a nonprofit public group set up by Congress to backstop a variety of FDA initiatives, to design an Expanded Access Navigator to help patients and their physicians in preparing applications. That site has already been “soft launched” according to a Foundation spokesperson. As of mid-summer, it includes a list of the 31 pharma companies who have already written (and informed FDA) of their expanded access selection criteria.
In abstract, right-to-try laws are an assault on the very essence of FDA: keeping scientifically unproven drugs off the market, to protect patients and steer healthcare dollars (no matter who pays them) to useful purposes. Shutting down FDA’s drug approval process nearly completely has been an idea kicked around in libertarian and far-right circles for years; even now, the accelerated approval mechanisms FDA currently employs are being watched for signs that the approval is being short-circuited. It could be that if Commissioner Gottlieb’s goal to speed up reviews and approvals pays off, the right-to-try movement will be mollified.