We blogged a couple of years ago about the beginnings of what has become a wave of state “Right to Try laws” – laws that purport to give terminal patients with no other medical options the right to seek investigational drugs for their conditions from manufacturers who have yet to obtain full FDA approval. Mostly, these laws are motivated by the unwieldy nature of the FDA’s “compassionate use” regulations, which are directed at the same problems. Given that these laws originated with a “states’ rights group” called the Goldwater Institute, we strongly suspect that a second motive of gratuitously poking the FDA in the eye was also at work.
Whatever their provenance, we were deeply skeptical of their practicality. Three large obstacles loomed. Number one:
For one thing, there’s the FDA. States can pass all the laws they want, but unless the FDA gives its okay to programs more expansive than its compassionate use (“expanded access”) program, nothing’s going to happen.
The reason, as is the case for so many things these days, is the threat of liability. . . . You won’t induce a manufacturer to participate in a voluntary program by painting a target on its back.
There’s no upside. These statutes are for use by very ill people, and if (as is unfortunately likely) the statutory participant died, then there’s an adverse event that must be reported to the FDA. Companies investigate drugs in the hope of obtaining approval. Adverse events definitely don’t help get approval.
Indeed, despite a couple dozen Right to Try statutes enacted over the last few years, we are unaware of even a single instance in which anybody successfully obtained treatment with an investigational drug under any of these state laws.
A couple of recent developments might favorably affect this bleak scenario, however. One is newly introduced legislation (as of May 10, 2016), called the “Trickett Wendler [an ALS victim] Right to Try Act,” and more pedantically known as S. 2912, which seeks to remove some of the obstacles identified above that hamstring the states’ efforts. S. 2912 is quite short, but it does two things. First, it grants full immunity from suit to those acting under a state Right to Try statute:
Notwithstanding any other provision of law, no liability shall lie against a producer, manufacturer, distributor, prescriber, dispenser, possessor, or user of an experimental drug, biological product, or device for the production, manufacture, distribution, prescribing, dispensing, possession, or use of an experimental drug, biological product, or device that is in compliance with subsection (a) [pertaining to Right to Try statutes].
Id. §2(b)(1). Getting the plaintiffs’ lawyers out of the way might allow lives to be saved.
Second, the statute removes the disincentives created by FDA reporting requirements for investigational drugs. S. 2912 prohibits use of adverse events involving Right to Try participants from negatively affecting possible FDA approval:
Notwithstanding any other provision of law, the outcome of any . . . use of an experimental drug, biological product, or device that was done in compliance with subsection (a) shall not be used by a Federal agency . . . to delay or otherwise adversely impact review or approval of such experimental drug, biological product, or device.
Id. §2(b)(2). Ideally, we’d like to see this protection extend to inadmissibility at trial, since some plaintiff expert could still assert such an adverse event as a supposed “red flag” in other civil litigation, but this bill would be a big step forward on the liability front. A federal-law umbrella like S. 2912 would eliminate the patchwork of liability provisions in the state statutes that we discussed at some length in our prior post.
That leaves the third piece of the puzzle – the FDA.
There’s been movement on this front as well. In what we doubt is a coincidence, the FDA released – this month – two new guidance documents that bear on the general issue of compassionate use of investigational drugs. The first, entitled “Expanded Access to Investigational Drugs for Treatment Use − Questions and Answers,” can be found here. The second, entitled “Charging for Investigational Drugs Under an IND − Questions and Answers,” is available here. These are, of course, “nonbinding recommendations,” but they do indicate that the FDA is at least responding to the dissatisfaction with the current state of affairs that has been driving the Right to Try movement over the last several years.
We learn from the first guidance that the term “compassionate use” is out, replaced by the dryer phrase “expanded access.” Expanded Access Guidance, at Q1. “Expanded access” is therapeutic, not investigational, in its purpose, and the more formal “treatment IND” is only available if the drug’s manufacturer (“sponsor”) is pursuing eventual approval of the particular use involved. Id. Not only does the guidance cover drugs for which approval is being sought, but also drugs that have “been withdrawn for safety reasons,” if they might help particular patients. Id.
Two of the processes described in the first guidance, the “expanded access protocol” and the “new treatment IND” must be initiated by the manufacturer and thus means more work for it – with no immediate benefit – not a good combination for what are, after all, for profit entities. Id. at Qs 2-5. They also require use of institutional review board review. Id. at Q6. These processes thus are not particularly relevant to what the state Right to Try statutes are seeking to accomplish, which is patient- or doctor-initiated individualized therapy. The guidance also includes information on how patients who are enrolled in a clinical trial may seek to continue treatment with the investigational drug after the trial ends or something happens that puts them outside of the study’s inclusion criteria. Id. at Qs 27-29 (discussing “open-label” studies).
More promising from this point of view is “individual patient expanded access,” in which the “sponsor/investigator” is the doctor of the patient for whom all other therapies have failed. Id. at Q9. It uses a form (FDA 3926) “created specifically for individual patient IND submissions, including those for emergency use.” Id. While this route can be used by a manufacturer, id. at Q10, it can also be initiated by a treating physician:
A physician can submit an individual patient expanded access IND for his/her patient. In this scenario, when the patient’s physician submits an expanded access IND, the physician is both the sponsor and the investigator − in other words, he or she is considered a sponsor-investigator.
Id. This method can even be used for an investigational drug where the manufacturer does not have an active IND (assuming that the manufacturer is willing to provide the drug). Id.
In individual patient expanded access, the patient’s treater “must determine that the probable risk to the patient from the investigational drug is not greater than the probable risk from the disease or condition.” Id. at Q11. In a Right to Try situation where the condition is fatal, this criterion would ordinarily be satisfied. The FDA, however, retains the final say. “FDA must determine, based on the information available to FDA, that the potential benefit justifies the potential risks.” Id. One potential reason the FDA could do so is if the expanded access would somehow “interfere” with the ongoing approval process for the drug. Id. at Q24.
Further, “individual patient expanded access is generally limited to a single course of therapy for a specified duration,” id. at Q13, although more than one investigational drug may be involved. Id. at Q31.. That effectively means one and done, except in rare instances of a “chronic disease or condition that requires extended treatment” where “the circumstances of the treatment are well defined and reasonable in light of the available evidence.” Id. at Q13. In Right to Try situations, this is unlikely to be the case. Whether expanded access is available for many investigational drugs can be determined at clinicaltrials.gov, since all sponsors who register their trials on the site are asked for their positions (not all ongoing studies are on the site, however). Id. at Q30.
Just like all of the Right to Try statutes are voluntary – no manufacturer can be ordered to supply investigational drugs – so is the FDA’s new program. Congress has not given the FDA the power to order participation. “FDA cannot compel a company to provide expanded access to its drug. When a company provides expanded access to its drug, it does so voluntarily.” Id. at Q23. The FDA’s guidance does not create, or even recommend, any form of tort immunity for participants.
Similarly, the guidance retains FDA power to use any adverse events against the manufacturer in its ultimate determination whether to approve the investigational drug. Any time a treater initiates individual patient expanded access, s/he assumes responsibility to “provide to FDA a written summary of the results of the expanded access use, including adverse effects.” Id. at Q25. Those adverse events may adversely affect FDA evaluation of the drug:
From a public health perspective, early identification of important adverse events is beneficial. For example, a relatively rare adverse event might be detected during expanded access use, or such use might contribute safety information for a population not exposed to the drug in clinical trials. There are a small number of cases in which FDA has used adverse event information from expanded access in the safety assessment of a drug.
Id. Thus, the FDA’s guidance does not address either of the two main drawbacks to manufacturer willingness to participate in expanded access – possible adverse effect on approval and exposure to litigation over investigational drugs.
Next, a bit on the FDA’s second guidance, on charging money for investigational drugs. Ordinarily manufacturers/sponsors are prohibited from “commercializing” investigational products. 21 C.F.R. §312.7(b). Since 1987, however, the FDA has allowed them to recover costs in some situations. See 21 C.F.R. §312.8. This new guidance addresses such charges are calculated, and also expands the ability to charge into expanded access situations. Charging for Investigational Drugs Guidance at Q3. Since this post is directed only to the expanded access/Right to Try situation, we’re only looking at that part of the guidance. To charge a fee for investigational drugs provided through an expanded access process, the manufacturer must:
- Provide “reasonable assurance” to the FDA that the charges will not interfere with drug development.
- Provide the FDA with “calculations” used to arrive at the amount charged that are consistent with the requirements in §312.8(d) limiting recovery to direct costs (those specifically and exclusively attributable) of making the drug available to these patients – that is, the incremental manufacturing and shipping costs, not costs of development. Such submissions consist of invoices and a accountant’s statement.
Id. at Q13. Only a years’ worth of the drug can be charged without the FDA reevaluating. Id. at Q14. Costs of drugs provided under individual patient expanded access may be recouped in this fashion, but specified “indirect” costs may not be recovered. Id. at Q17.
Finally, our take on the situation. We think that the proposal in S. 2912 is recognition of what we thought before – that individual state Right to Try statutes are unlikely to achieve their goal of broadening access to investigational drugs because they don’t (and indeed cannot) alter manufacturers’ risk/benefit ratios enough to induce them to participate in these voluntary programs. The proposed statute would eliminate two of the biggest obstacles. The FDA’s new guidance documents help somewhat, but as long as adverse events from use of investigational drugs outside clinical trials can imperil the whole point of the exercise – eventual FDA approval (or expanded approval) – voluntary participation remains unlikely. The FDA’s guidance documents also pointedly ignore even the existence of these state statutory initiatives, so it is unclear what, if any, role state law is able to play. For example, all of the state statutes include informed consent provisions, but whether they would satisfy the FDA’s informed consent requirements is not addressed. The Gordian Knot of compassionate use of investigational drugs thus remains tied around the medicine cabinet.