Federal 'Right to Try' Legislation - perpetuating a misguided skepticism towards the FDA [From CRITical Thinking]

George Consortium member Jeanie Kim, with the Collaboration for Research Integrity and Transparency (CRIT) at Yale Law School, has written a detailed look at the proposed federal "right to try" legislation.  Wendy Parmet and Elisabeth Ryan wrote about the Senate bill on PHLW a few months ago; Jeanie's commentary serves as a great companion piece, emphasizing the potential dangers of making an end run around the FDA.

____________________________________________________________________

Federal “Right to Try” Legislation – perpetuating a misguided skepticism towards the FDA

September 8, 2017

By Jeanie Kim

This blogpost provides a commentary on the federal “right-to-try” bills. For a succinct primer on “right-to-try,” see this article in Vox.

The “right to try” (RTT) movement presents a narrative that pits patients against the FDA. Supporters of RTT, powered by the libertarian Goldwater Institute, have pushed for laws that let terminally ill patients bypass regulators to access unapproved treatments.

As of September 2017, 37 states have enacted RTT laws. Earlier this year, the Senate and the House introduced federal RTT bills, and on August 3, 2017, the Senate unanimously passed an amended RTT bill without an opportunity for debate. There is pressure on the House to follow suit, but it is unclear whether the House will consider the originally introduced RTT bill(1) (“RTT 1.0”) or the Senate’s amended version(2)(“RTT 2.0”), or even take up the legislation at all.

Despite the recent legislative backing, RTT is not a new concept.(3) It is a variation on an age-old skepticism towards the FDA that has been around as long as the agency’s inception. At the core of RTT is the previously rejected, yet persistent argument that the FDA’s approval standards for safety and efficacy should not matter for terminally ill patients who have nothing to lose.(4)

The RTT bills are the latest tactic to undermine the FDA by suggesting that regulators are standing in the way of terminally ill patients. RTT 1.0 prohibits the FDA from interfering with “the production, manufacture, distribution, prescribing, or dispensing of an experimental [treatment]” that has passed initial safety testing on healthy volunteers and is intended for terminally ill patients who have exhausted medical options.

By adopting the premise that the FDA is a bureaucratic bottleneck, RTT misplaces the problem. The FDA has an efficient expanded access (EA) program for patients with life threatening conditions. Patients, in consultation with their physicians, can request access to experimental medicines from pharmaceutical companies. Once the company approves, patients can submit their applications to the FDA.

According to a recent report by the Government Accountability Office, of the nearly 5,800 EA requests received by the FDA from 2012 to 2015, the FDA allowed 99% to proceed, and for emergency single-patient requests, the agency typically responds within hours.(5) (In many cases, the FDA provides feedback on dosage and other safety issues.)

These numbers show that the FDA is hardly a barrier.

RTT overlooks these facts and undermines a broader principle. Congress empowered the FDA with the scientific authority to evaluate clinical trial evidence and the regulatory authority to approve drugs for marketing. This dual grant of authority is based on the policy that companies should not be able to profit from medicines before proving that the medicines are safe and effective. Even the EA program operates within this framework – early access to unapproved drugs is carefully balanced against the need for information about a drug’s safety and efficacy.

RTT 1.0 contains provisions that could destabilize this system.

First, RTT 1.0 prohibits the FDA from using any clinical outcomes from RTT uses to negatively impact its review of a drug. This absolute bar removes the flexibility that the FDA needs to evaluate safety information. Under the current EA program, agency reviewers generally give little weight to adverse events that occur from EA uses but still have the scientific discretion to consider whether certain outcomes – such as unexpected organ failures – could be useful for future patients in similar situations.(6)

Second, because the bill prohibits the FDA from interfering with the “distribution” of experimental treatments for terminally ill patients, RTT 1.0 leaves open the possibility of permitting companies to market unapproved drugs. The term “distribution,” which has various meanings,(7) is not defined in the bill and thus, could be a camel’s nose for deregulatory efforts to loosen the FDA’s prohibition on selling unapproved treatments.

Together, these two aspects of RTT 1.0 not only remove basic safeguards for current patients seeking access to experimental treatments but also undermine the research process that ensures that future patients will have access to drugs that are proven to be safe and effective. The removal of regulatory oversight is all the more problematic because RTT 1.0 also shields companies from all liability associated with RTT uses.

The Senate made attempts to address these concerns in its amended bill. First, while RTT 2.0 still prohibits the FDA from using clinical outcomes from RTT uses, the amended bill makes an exception for cases where it would be “critical” to determining the safety profile of a drug.

Second, RTT 2.0 requires manufacturers to adhere to FDA regulations concerning experimental treatments – specifically, regulations that prohibit companies from commercially distributing and promoting experimental drugs(8) and from charging more than "direct costs" for experimental drugs.(9)

The amended bill also does not release companies from liability if there was reckless or willful conduct or gross negligence.

A side-by-side comparison of the two RTT bills shows that RTT 2.0 includes several provisions intended to protect patients and maintain some regulatory oversight.  See chart here.

The comparison also reveals just how detrimental RTT 1.0 could be, particularly for patient safety, as the original RTT bill would leave patients vulnerable to opportunistic behaviors by companies and physicians.

However, despite these improvements, RTT 2.0 is still based on the same misguided premise of RTT 1.0 – that the FDA is a barrier – and the same skepticism towards the FDA. Under RTT 2.0, RTT is intended to act as “an alternative pathway alongside [the EA program]” such that both pathways are available for patients with “life-threatening diseases or conditions.” The only difference is that the EA pathway preserves the FDA’s role and the RTT pathway minimizes it. While RTT 1.0 is a swift blow to the FDA, RTT 2.0 sets the stage for a gradual weakening of the agency’s scientific and regulatory authority.

For an example, RTT 2.0 does not expressly prohibit companies from selling unapproved drugs but cites FDA regulations for experimental drugs. This presents a loophole where the FDA can be pressured into loosening its regulations on experimental drugs in the same way as under RTT 1.0. Given the current antiregulatory climate, this is not far-fetched. In fact, a former president of Goldwater Institute has suggested that allowing companies to profit from experimental treatments is aligned with the end goals of the RTT movement.(10)

Finally, adding to the point that RTT is merely a shell for antiregulatory sentiments, neither RTT bill would actually improve patient access to experimental drugs. Many of the patient-centered additions in RTT 2.0—such as the transparency and reporting requirements for companies and the FDA—could easily be incorporated into the EA program without legislative action and without removing the FDA’s oversight.

Unsurprisingly, the RTT bills fail to deliver on its promise to streamline patient access to experimental treatments because they remove a “hurdle” that is not much of a hurdle for patients in the first place, but a critical component of the drug development process.

Other barriers for patients exist. Companies, who are the initial decision makers, are generally reluctant to grant access to unapproved treatments. And even after getting EA approval, patients must be able to afford the costs as payers typically do not cover unapproved treatments. 

These issues are multifaceted and much more complex than the “solution” that RTT offers. Patient access to experimental treatments can be improved under the current EA program while maintaining the overall regulatory structure that balances access with safety and efficacy. In fact, there are already efforts to increase the transparency of companies’ EA policies and address other legitimate barriers. True solutions will require collaboration from regulators, manufacturers, and patients, and the FDA is best suited to facilitate improvements that will benefit both present and future patients.

Jeanie Kim is a research fellow at Yale Law School and the Collaboration for Research Integrity and Transparency (CRIT).

1 House RTT bill (H.R.878) (as of September 8, 2017).

2 Senate RTT bill (S.204) (as of September 8, 2017).

3 Joshua Sharfstein, Déjà Vu at the FDA, 95 The Milbank Quarterly (2017), available at https://www.milbank.org/quarterly/articles/deja-vu-fda/.

4 The Supreme Court rejected the argument that terminally patients have the right to access unapproved treatments. U.S v. Rutherford, 442 U.S. 544 (1979); see also Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach, 495 F.3d 695 (D.C. Cir. 2007), cert denied 552 U.S. 1159 (2008). Contrary to the optimism of the RTT movement, 90% of drugs that enter the first phase of clinical testing do not receive approval because of unexpected toxicity or lack of effectiveness, and even drugs that show promise in Phase 2 clinical trials are often not confirmed by Phase 3 trials. Katarzyna Smietana et al., Trends in clinical success rates, 15 Nature Reviews Drug Discovery 379 (2016), doi: 10.1038/nrd.2016.85; U.S. Food and Drug Admin, 22 Case Studies where Phase 2 and Phase 3 Trials has Divergent Results, January 2017, available at link (accessed September 8, 2017).

5 U.S. Government Accountability Office (GAO), Investigational New Drugs – FDA Has Taken Steps to Improve Expanded Access Program but Should Further Clarify How Adverse Events Data Are Used, GAO 17-564, at 17 (July 11, 2017), available at http://www.gao.gov/assets/690/685729.pdf.

6 U.S. Food and Drug Admin., Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers, at 18 (June 2016).

7 Under current FDA regulations, “distribution” is defined as "to sell, offer to sell, deliver, or offer to deliver a drug to a recipient." 21 C.F.R. § 203.3(h).

8 21 C.F.R. § 312.7.

9 21 C.F.R. § 312.8(d)(1).

10 Darcy Olsen, The Right to Try: How the Federal Government Prevents Americans from Getting the Lifesaving Treatments They Need 205-206 (2015) (then-president of Goldwater Institute stated that “[a]llowing companies to charge for investigational drugs would make compassionate use instantly more attractive [for companies]”).

FDA Reboots Tobacco Regulation with Harm Reduction

By the Public Health Advocacy Institute

On Friday, July 28, 2017, U.S. Food and Drug Administration (“FDA”) Commissioner Scott Gottlieb unveiled a revamped approach to tobacco product regulation in an announcement that surprised tobacco companies, investors, and the public health community in equal measure.  The goal, as articulated by Gottlieb, will be to regulate products so as to encourage migrating existing consumers from the most lethal combustible tobacco products (i.e., cigarettes) to non-combustible products lower on the continuum of risk. This approach is known as “harm reduction.”  The keystone will be to promulgate product standards so that cigarettes deliver insufficient nicotine to users to create or sustain addiction so that current nonsmokers never start and current smokers either quit or switch to non-combustible tobacco product that present a lower health risk.

This idea, while somewhat radical, is not new.  It had been a topic of discussion at the American Medical Association in the mid-1990s. Congress gave the FDA regulatory authority over tobacco in 2009 with the Family Smoking Prevention and Tobacco Control Act of 2009 (“Tobacco Control Act”).  It prohibited the agency from banning cigarettes or from banning nicotine.  The law does, however, explicitly allow for the potential reduction of nicotine in cigarettes to any level above zero.  The Public Health Advocacy Institute at Northeastern University School of Law produced a white paper on this approach in 2009 and proposed further research on the policy, but enthusiasm at the agency and the Executive Branch was lacking. Northeastern University Distinguished Professor, Richard A. Daynard, characterized non-addictive cigarettes in the New York Times as one of two important strategies that could end the cycle of addiction, disease, and death from tobacco products.

Research to date, including a $50 million research project funded by the National Institute on Drug Abuse, have produced preliminary results supporting the notion that very low nicotine cigarettes will lead to fewer cigarettes smoked and reduced toxic exposure to consumers.  So long as the nicotine levels are very low, compensatory smoking behaviors such as inhaling more deeply and smoking greater numbers of cigarettes do not seem to generally occur.  Some of these preliminary results were presented at Northeastern University School of Law in 2014 by a Principal Investigator of the grant, Dorothy Hatsukami, at PHAI’s conference, “Accelerating Tobacco Endgame Strategies in the United States.”

Another important tool that the FDA can use is to issue rules pertaining to the use of flavors in tobacco products.  While the Tobacco Control Act banned the use of characterizing flavors other than mint or menthol in cigarettes, concerns around the role of flavors in tobacco initiation have intensified in recent years.  “Little cigars,” which closely resemble cigarettes, are available in a range of child-friendly flavors.  E-cigarettes, likewise, have been criticized for offering fruit and candy flavors that would seem to appeal to children.

The question of exempting menthol flavored cigarettes from the flavor ban has been extremely controversial.  The Tobacco Control Act, it was thought, would not have garnered the votes needed to pass Congress were a menthol cigarette ban included.  Rather, the law specified that an expert committee must be convened by FDA to study the issue and issue a report on the health impact of menthol as a characterizing flavor in tobacco products. 

The resulting reports concluded that although menthol itself did not contribute to the toxicity of tobacco products, it tended to anesthetize the lungs in a way that facilitates smoking initiation by youth and frustrated cessation efforts.  Further, mentholated cigarettes have been historically marketed in a way that targets African Americans.  Almost 90% of African American smokers prefer menthol cigarettes, which is the most robust sector of the cigarette industry in the United States.  The company that produces the menthol market leader, Newport, was recently acquired by R.J. Reynolds which, in turn, was acquired by British American Tobacco this year. Reportedly, much of the value sought in these acquisitions derived from the Newport brand and the value of menthol cigarettes.

To date, the FDA has taken no action on mentholated tobacco products.  Chicago and San Francisco have passed ordinances restricting sales of menthol tobacco products.  San Francisco’s ordinance, which passed in July of 2017, is a total ban on all flavored tobacco product sales, including menthol.

The FDA announced that it will soon release three Preliminary Notice of Proposed Rulemakings seeking public and stakeholder comment on: 1) pros and cons of nicotine reduction strategies; 2) role of characterizing flavors, including menthol, in youth initiation and as a means to attract smokers to non-combustible tobacco products with less risk; and 3) potential health risks and use patterns of premium cigars. 

Non-combustible products such as electronic nicotine delivery systems including e-cigarettes and emerging “heat-not-burn” products would be likely alternatives to non-addictive cigarettes as would nicotine replacement therapies such as the gum and patch.  While this harm reduction approach has many supporters in the public health community, it would have the likely effect of perpetuating the commercialized recreational use of nicotine long into the future. 

Since the FDA began regulating tobacco products in 2009, almost every substantive regulatory effort has been met with litigation. This includes 2 lawsuits challenging a host of the law’s provisions; challenges to the legal legitimacy of the report FDA issued about menthol; a successful First Amendment challenge to regulations for graphic cigarette warning labels; and a dozen or so lawsuits challenging the agency’s regulation of e-cigarettes and cigars. 

This litany of litigation has, to this point, slowed or partially derailed the agency’s regulatory agenda and has drawn the criticism of many in the public health community. The FDA’s announcement marks a new and more aggressive regulatory vision for tobacco. Many questions remain. Is the scientific evidence base sufficient to justify this new approach?  What will be the effect of inevitable legal challenges from manufacturers and smokers? What are the health impact of non-combustible tobacco products to users and non-users?  How did the political environment in the Executive Branch change to allow for this new strategy to emerge and will it last?

With so many questions remaining and so many potential rules to enact, the timeline for the FDA to implement its new regulatory approach is uncertain.  Based on past experience, it would be reasonable to expect that it may be a decade or more until cigarettes are non-addictive.  Until then, there will be an effort by the tobacco industry to attract millions of consumers to new, less dangerous, but still addictive tobacco products.