An Examination of the Right to Try Act of 2017 and Industry’s potential Path Moving Forward
Sylvia Zaich[*]
INTRODUCTION
In 2013, a petition started to circulate the Internet, urging the CEO of BioMarin Pharmaceutical to provide its investigational drug BMN-673 to then forty-five-year-old attorney Andrea Sloan, who was undergoing treatment for late stage ovarian cancer.[1] With standard treatments no longer an option, her physicians proposed trying BMN-673, one of a new class of cancer drugs called PARP inhibitors developed by BioMarin. The advanced nature of Sloan’s cancer disqualified her from enrolling in a clinical trial, so instead she and her physicians sought access to BMN-673 through the U.S. Food & Drug Administration’s (“FDA”) expanded access program, which allows pre-approval use of drugs outside of the clinical trial setting.[2]
The FDA confirmed Sloan was a candidate for expanded access use, but that confirmation did not guarantee use. That decision was left to the discretion of the company. BioMarin declined to provide BMN-673 because the drug was still in early phase of development: “It would be unethical and reckless to provide [BMN-673 to] end-stage refractory ovarian cancer patients outside a clinical trial.”[3] This decision sparked the Change.org petition that ultimately secured more than 230,000 signatures.[4] Even with this overwhelming public support, BioMarin maintained its position. A different company, which was developing a similar drug, eventually provided Sloan with access on the condition that it remain unidentified. Sloan started the treatment, but her cancer had progressed, and she died shortly thereafter.[5]
Sloan’s expanded access experience is not unique. A number of patients, with the support of their friends and families, launched similar online campaigns, seeking access to investigational medicines after becoming frustrated with companies’ unwillingness to accommodate expanded access requests for investigational drugs.[6] Some were successful; others were not. These campaigns, including Sloan’s, increased public awareness and dialogue regarding terminally ill patients’ ability to access investigational medicine and helped spark a national legislative movement promoting such individuals’ “right to try.”[7]
In 2015, Texas was the twenty-first state to adopt right–to–try legislation.[8] The Texas bill was named in Andrea Sloan’s memory. These laws, despite often having bipartisan support, have been divisive, with supporters claiming that the right to try offers “real hope,”[9] and critics maintaining that the right to try is merely political theatrics and ultimately will do more harm than good for individual patients.[10] Forty-one states have adopted right–to–try laws since the movement first launched in 2014.[11] That success sparked a push for a federal right–to–try law.
President Donald J. Trump voiced his support for such legislation in his 2018 State of the Union address: “People who are terminally ill should not have to go from country to country to seek a cure—I want to give them a chance right here at home. It is time for the Congress to give these wonderful Americans the ‘right to try.’”[12] That endorsement was the final nudge Congress needed. On May 30, 2018, President Trump signed the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017 (“Right to Try Act”).[13]
This Note proceeds in four parts. Part I briefly looks back at the FDA’s history and the impact of two significant drug crises in establishing the agency’s current framework before explaining the current drug development process. Part II recounts previous challenges to this regulatory framework, which ultimately led to the development of the current expanded access program. Part II also examines the current expanded access program and, more specifically, the evaluation criteria applied by three of its key decisionmakers: the treating physician; the manufacturer; and the FDA.
Part III traces the beginnings of the right to try movement, examining the rationale for the laws and exploring how social media and increased direct-to-consumer advertising of approved drugs possibly created an opening for widespread support of these laws. Part III also explores why the FDA’s efforts to address criticisms of the expanded access program were unable to dissuade enactment of the Right to Try Act. Part IV provides an overview of the Right to Try Act and how the Act differs from expanded access. Part IV further explores why, in general, mainstream industry likely will not adopt the right–to–try pathway, before arguing that pharmaceutical and biotechnology companies should avoid maintaining their current positions regarding pre-approval access, and instead address some of the criticisms raised during the right-to–try movement by (1) revising their existing expanded access policies and (2) improving clinical trial access.
I. A Brief History of the FDA and the current Drug development process
To better understand the rationale for the FDA’s regulatory framework and the role it has “effectively balanc[ing] the interests of those patient populations who would benefit from having greater access to investigational drugs, with the broader interests of society in having safe and effective new therapies approved for marketing and widely available,”[14] Part I of this Note reviews how the FDA’s authority developed in response to two significant drug safety crises and provides a primer on the current drug development process.
A. The Origins of the FDA’s Regulatory Framework
The origins of the FDA can be traced back to the 1800s, but two drug safety crises prompted the development of the agency’s current regulatory framework. The deaths of more than one hundred people from an untested drug formulation led to the enactment of the Federal Food, Drug, and Cosmetic Act of 1938 (“FDCA”), which required manufacturers to show “that any new drug was safe before it could be marketed.”[15] The initial effectiveness of the FDCA was limited. If the agency did not respond to a new drug application[16] within sixty days, the drug was automatically approved for public consumption.[17] The FDCA also did not require standardized drug testing.[18] This remained the regulatory environment—despite efforts by some to address these shortcomings—until the second drug safety crisis of the twentieth century.
In 1960, the manufacturer of the then–popular sedative thalidomide submitted a marketing application for the drug in the United States.[19] The FDA refused to grant approval over concerns about inadequate and deficient safety data.[20] The manufacturer had distributed “more than two and a half million tablets . . . to approximately 20,000 patients” in the United States for clinical testing, but few, if any, of these individuals were actually monitored after receiving the drug.[21] The drug was eventually linked to an “epidemic of congenital malformations.”[22] The global thalidomide crisis motivated politicians to reconsider legislation that would have “tightened restrictions surrounding the surveillance and approval process for drugs.”[23]
Two years later, in 1962, Congress passed the Kefauver-Harris Amendment “to assure the safety, effectiveness, and reliability of drugs.”[24] This amendment eliminated the FDCA’s de facto approval loophole and extended the review period to 180 days.[25] Even more significant, the Kefauver-Harris Amendment “laid the groundwork for the [current multi-phased] system of clinical trials”[26] by requiring a manufacturer to submit “substantial evidence” of an investigational drug’s safety and efficacy with its marketing application.[27]
B. The Drug Development Process
A manufacturer or other protocol sponsor,[28] before conducting a clinical trial, must first submit an investigational new drug (“IND”) application.[29] The IND provides an overview of the biopharmaceutical company’s general investigational plan and clinical trial protocols for the drug.[30] The plan must provide:
(a) [t]he rationale for the drug or research study;
(b) the indication(s) to be studied;
(c) the general approach to be followed in evaluating the drug;
(d) the kinds of clinical trials to be conducted in the first year . . . ;
(e) the estimated number of patients . . . ; and
(f) any risks of particular severity or seriousness anticipated on the basis of the toxicological data in animals or prior studies in humans with the drug or related drugs.[31]
The IND gives the FDA the information it needs to assess the safety of the proposed phase I trials and the “scientific quality of [the proposed phase II and III trials] and the likelihood that the [trials] will yield data capable of meeting statutory standards for marketing approval.”[32]
In phase I, a manufacturer assesses the drug’s safety and determines the appropriate dosage for subsequent trials.[33] The participants are typically healthy volunteers but depending on the condition may be patient volunteers.[34] The enrollment size of these trials is small. A single phase I trial might enroll anywhere between twenty to eighty volunteers.[35] The Biotechnology Innovation Organization (“BIO”) estimates that approximately 60% of drugs advance from phase I to phase II clinical trials.[36]
In phase II, the investigational drug is tested in patient volunteers who have the disease or condition.[37] This commonly involves a randomized clinical trial in which patients are randomly assigned either the investigational drug or some other treatment—“either an inactive substance (placebo), or a different drug that is usually considered the standard of care for the disease”—without knowing which treatment they are receiving.[38] The manufacturer then compares the effectiveness of the investigational drug to the effectiveness of the alternative treatment.[39] Phase II clinical trials are also required to assess the drug’s “common short-term side effects and risks.”[40] In general, this is the stage of development with the “lowest success rate”—almost 70% of drugs fail to move beyond phase II.[41]
The pre-approval development process culminates with phase III clinical trials,[42] which are intended to produce “statistically significant data about the safety, efficacy and overall benefit-risk relationship of the investigational medicine.”[43] This data is an integral component of the new drug application a manufacturer submits to the FDA.[44] To obtain statistically significant data, these studies often require a substantial number of volunteers—sometimes upwards of 5,000 volunteers depending on the disease or condition.[45]
The recruitment process throughout clinical development can take several years and be very expensive, with manufacturers often struggling to fully enroll their clinical trials.[46] The low accrual rates can be the result of strict inclusion and exclusion criteria.[47] Still, manufacturers can be resistant to making the criteria less restrictive and more inclusive,[48] perhaps because less–standardized patients might make it harder to parse through data, extend the length or size of a clinical trial, increase the risk of adverse events potentially impacting a drug’s safety profile and potentially its approval, and make clinical development more expensive.[49]
The estimated time from discovery to FDA approval of a drug is now at least ten years. The cost of development is estimated between $10 million and $2.6 billion, with the higher estimate factoring in costs associated with investigational drugs that never advance beyond clinical development.[50] These costs are then passed on to patients, with some cancer therapies costing upwards of $375,000.[51] “The U.S. spent nearly $88 billion treating cancer in 2014, with patients paying nearly $4 billion out-of-pocket.”[52] All of that spending, however, does not necessarily translate into positive outcomes for every patient.[53]
II. ChalLenges to the regulatory framework and an overview of the Expanded access program
A. Prior Pre-Approval Access Challenges
The tension—highlighted most recently by the right-to-try movement—between ensuring patients have access to potentially groundbreaking medicines as soon as possible and ensuring that these therapies are both safe and effective is not nascent. There have been three significant pre-approval access challenges—starting with Rutherford v. United States in 1975—to the FDA’s regulatory framework since the enactment of the Kefauver-Harris Amendment.
1. 1970s: Laetrile, the FDCA, and Rutherford v. United States
In 1975, a few individuals with terminal cancer filed a lawsuit seeking to enjoin the FDA from obstructing the interstate shipment and sale of the alternative treatment laetrile because it was not approved by the FDA.[54] The district court ordered the FDA to allow patients pre-approval access.[55] On appeal, the U.S. Court of Appeals for the Tenth Circuit referred the issue to the FDA,[56] which found laetrile was a new drug within the meaning of the FDCA and could be barred from interstate sale until the necessary safety and efficacy data was submitted for FDA review and received FDA approval.[57] The district court vacated that decision on statutory and constitutional grounds,[58] and the FDA appealed.[59] The Tenth Circuit—rather than relying on the district court’s reasoning—held instead that the FDCA’s “‘safety’ and ‘effectiveness’ terms” did not apply to individuals with terminal cancer diagnoses.[60]
The case was eventually heard by the Supreme Court, which decided in favor of the agency’s FDCA interpretation.[61] The Court held the FDCA made “no special provision for drugs used to treat terminally ill patients” based on the statute’s plain language.[62] The Court also explained that it could not imply a statutory exception because the “legislative history and consistent administrative interpretation” of the FDCA did not support one.[63]
2. 1980s–1990s: The Reagan Administration and the HIV/AIDS Epidemic
After President Ronald Reagan’s election in 1980, his administration ushered in widespread deregulation efforts across all areas of government.[64] Those efforts included (1) amending the FDCA, which the administration viewed as unnecessarily delaying drug approvals, and (2) establishing a defined program for terminally patients seeking access to investigational drugs for treatment rather than research purposes.[65] The FDA, in response to the administration’s latter concern, proposed codifying the agency’s existing informal pre-approval access procedures.[66] Those efforts became even more urgent with the HIV/AIDS epidemic though the agency’s efforts and the administration’s initial concern regarding pre-approval access were not aimed directly at aiding individuals with HIV/AIDS.[67]
The FDA promulgated several significant changes not only to improve patient access outside of the clinical trial setting to drugs still in clinical development, but also to reduce the length of time between discovery and final FDA approval. The latter issue being one in which the interests of activists and manufacturers aligned, as both advocated for changes to the regulatory framework.[68] First, the FDA amended its regulations in 1987 to allow widespread access to an investigational drug outside of the clinical trial setting through a “treatment protocol.”[69] The agency continued to apply an informal standard for individual requests until the Food & Drug Administration Modernization Act of 1997 codified the expanded access program, which specifically addressed the need for a formal individual patient request process.[70] Second, the FDA created the Accelerated Approval pathway[71] and introduced a striated review framework[72] to speed up the availability of promising new drugs intended for the treatment of serious diseases or conditions. Subsequent congressional action in 1997 and 2012 armed the FDA with two additional means to further reduce the time from initial development of a drug to its approval.[73]
3. 2000s: Pre-Approval Access, a Proposal, and Abigail Alliance v. Von Eschenbach
There was not another significant challenge to the drug development and approval process until an organization, seeking to improve terminally ill patients’ abilities to obtain investigational drugs, proposed a “three-tiered approval system.”[74] The first approval tier would have allowed limited marketing of investigational drugs following completion of phase I trials.[75] The organization—the Abigail Alliance for Better Access to Developmental Drugs (the “Abigail Alliance”)[76]—claimed terminally ill patients with no other treatment options faced a “different risk-benefit tradeoff” and should have the option to try investigational drugs.[77] The FDA rejected this proposal, explaining that this approach “would upset the appropriate balance” by “giving almost total weight to the goal of early availability and giving little recognition to the importance of marketing drugs with reasonable knowledge . . . of their likely clinical benefit and their toxicity.”[78]
The Abigail Alliance, agency rejection in hand, filed an action against the FDA.[79] The organization sought to block the agency’s policy prohibiting the pre-approval sale of drugs to individuals with terminal conditions.[80] The Abigail Alliance argued that the FDA’s policy “violate[d] terminally ill patients’ constitutional privacy and liberty rights, as well as their due process rights to life.”[81] The district court found these claims legally unpersuasive.[82] But a United States Court of Appeals for the District of Columbia Circuit (“D.C. Circuit”) panel, in a 2–1 split, agreed with the group, holding that the due process clause protected the right of terminally ill patients to decide whether to use investigational drugs that the FDA had determined were safe enough for additional clinical trials after reviewing results from phase I clinical trials.[83] The panel directed the district court to determine whether the FDA’s policy was narrowly tailored to serve a compelling governmental interest.[84]
The FDA’s request for an en banc hearing was granted before a lower court could apply strict scrutiny.[85] The court en banc flatly rejected the panel’s decision.[86] The court expressed “serious doubt” about the constitutional validity of the Abigail Alliance’s articulated right: a “fundamental right of access for the terminally ill to experimental drugs.”[87] To establish its articulated right, the Abigail Alliance needed to illustrate a tradition of accessibility to drugs that were not proven to be safe or effective.[88] The en banc court found that “FDA regulation of post-phase I drugs [was] entirely consistent with [the United States’] historical tradition of prohibiting the sale of unsafe drugs.”[89] The en banc court also disputed the group’s effectiveness argument, noting the existence of “at least some drug regulation prior to [the Kefauver-Harris Amendment] address[ing] efficacy.”[90] The en banc court also dismissed the Abigail Alliance’s argument that the right to self-preservation—based on the common law doctrine of necessity, the tort of intentional interference with rescue, and the right to self-defense—created a constitutionally protected right in this context.[91] The court concluded that the Abigail Alliance’s articulated right was not fundamental.[92] The court held that “the FDA’s policy of limiting access to investigational drugs [was] rationally related to the legitimate state interest of protecting patients, including the terminally ill, from potentially unsafe drugs with unknown therapeutic effects.”[93]
Two years after the D.C. Circuit’s decision in Abigail Alliance, the FDA finally issued revised expanded access regulation clarifying the process by which an individual patient could request expanded access.[94] The current expanded access program is discussed in greater detail below.
B. The Expanded Access Program
The expanded access program, as discussed, was designed to address concern that some individuals may not have an opportunity to try a promising therapy given the sometimes ten-year path to formal regulatory approval. The expanded access program allows some patients with serious or immediately life-threatening diseases to use “an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.”[95] The program is available for individual patient use, intermediate-size patient use, and widespread patient use.[96] In addition to the patient, there are three other important decisionmakers. Section II.B.1 describes how a physician would initiate an expanded access request for an individual patient. Sections II.B.2 and II.B.3 then discuss the criteria used by biopharmaceutical companies and the FDA to determine eligibility in the individual–patient setting.
1. How a Physician Requests Expanded Access for Individual Patient Use
Prior to initiating an expanded access request for a patient, the requesting physician must first conclude that “the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition.”[97]
After this determination is made, the physician must then seek a letter of authorization (“LOA”) from the manufacturer.[98] The request must be made by a physician. The LOA allows the FDA to refer to the requested investigational drug’s IND file instead of requiring the requesting physician to obtain confidential information regarding the drug’s pharmacology, toxicology, chemistry, or manufacturing process.[99] As evidenced by Andrea Sloan’s unsuccessful request, this has been the greatest source of frustration for patients seeking expanded access use. Aside from Pfizer, most companies do not disclose how many requests they receive or grant each year.[100] This step of the process can also be lengthy as current FDA regulation does not impose a time restraint.[101] So even if a company acknowledges receipt of a request within two–to–three business days,[102] the company is not required to expediently review that request, which often involves multiple parties within a company.[103]
If the company agrees to grant use and provides a LOA, the requesting physician would then submit an application form to the FDA. The FDA asks the physician to provide an overview of the patient’s clinical history, the rationale for the expanded access request, and the proposed treatment plan.[104] The FDA has up to thirty days to review the application and provide feedback.[105] A 2017 U.S. Government Accountability Office (“GAO”) report found that the FDA’s median response time was no more than nineteen days for non-emergency situations.[106]
While the FDA reviews the application, the physician must also obtain approval from his or her institution’s or hospital’s institutional review board (“IRB”).[107] The requesting physician can also request a waiver from the FDA, which would allow the expanded access request to be reviewed by either the IRB chair or another designated member.[108] The physician must also discuss the expanded access requirements with the patient and secure the patient’s informed consent to treatment.[109]
2. How Companies Evaluate an Individual Patient Request
The expanded access regulation does not prescribe the criteria a manufacturer should use when determining whether to grant an expanded access request.[110] Industry groups Pharmaceutical Research and Manufacturers of America (“PhRMA”) and BIO, however, have each separately published guiding principles for the groups’ respective members that closely mirror the evaluation criteria used by the FDA.[111] PhRMA recommends that manufacturers consider five factors: (1) whether the individual has exhausted all available treatment options for a serious or life-threatening illness; (2) whether “[t]he investigational drug [is] under active clinical development”; (3) whether “[t]he patient is ineligible for, or otherwise unable to participate in, clinical trials”; (4) whether “[t]he potential benefit to the patient [outweighs the] potential risk”; and (5) whether approving the request would interfere with the “successful completion of the clinical trial process.”[112]
A survey of twenty biopharmaceutical companies’ eligibility criteria[113] illustrates that most large companies offering expanded access have adopted criteria modeled off either PhRMA or BIO’s guidelines, with only slight variations.[114] In general, companies include criteria limiting expanded access to patients with serious or life-threatening conditions. The extent to which a patient must have tried standard treatment options and must not have other treatment options available varies. A few companies require the patient to have tried standard treatments unsuccessfully and to not have other treatment options available. Other companies just require that the patient does not have other treatment options available. The real difference in this language, however, might be just semantics.
Of the companies surveyed, one also factored in a patient’s ability to regularly travel to a treating site for observation and follow-up while receiving the investigational drug when deciding whether to grant an expanded access request.[115] Likewise, manufacturers will not consider an expanded access request unless the drug is in active development (that is, the company cannot have discontinued the program), but some companies choose to define this criterion more narrowly than BIO or PhRMA.[116] Take for examples, Merck, Amgen, and Allergan, which will not grant requests for a specific drug unless the company is actively developing the drug in the proposed intended use.[117] The criteria used by Merck and a few other companies also requires that the company have plans to submit a marketing application.[118]
Given concerns about expanded access impacting clinical trial enrollment, companies are hesitant to grant an expanded access request unless the individual is unable to participate in a clinical trial. This criterion is generally left vague, but some companies provide specific factors that they will or will not consider.[119] For example, under Genentech’s criteria, an individual who lives too far away from a clinical trial center would not be considered ineligible for a clinical trial and therefore would not qualify for expanded access based on this factor alone.[120] In contrast, Pfizer and Teva Pharmaceutical would consider geographic limitations as a factor affecting a patient’s ability to participate in a clinical trial.[121]
All of the companies surveyed included a criterion requiring the potential benefits of the drug to outweigh the potential combined risks of the treatment and the disease to the individual patient.[122] To make this risk-benefit assessment, PhRMA explains, “there should be sufficiently robust preliminary safety and efficacy data, including dosing information, to determine that the preliminary benefit-risk balance is positive for the specific indication for which the request is made.”[123] While some companies keep this criterion vague to allow for greater discretion, a few companies’ criteria specifically mentions a dosing requirement.[124] Although most companies’ criteria did not distinguish between children and adults, one company’s guidelines specifically require sufficient pediatric data to determine the appropriate dosage before it will grant expanded access use for a child.[125]
Like the other criteria, almost all of the companies surveyed had some language in their expanded access guidelines addressing the clinical trial process and, more specifically, the need to ensure that pre-approval access use did not interfere with the clinical trial process.[126] A few companies specifically consider whether they have adequate drug supply for both their clinical trials and expanded access when making the determination.[127] While not specifically addressed, this criterion likely also considers the extent to which expanded access use might impact other aspects of clinical development, such as the FDA’s use of adverse events occurring during expanded access use, when reviewing an investigational drug’s marketing application.[128] A few companies also build in additional discretion by allowing their medical teams to establish additional criteria in light of a given drug’s current development and available data.[129]
As discussed, however, most companies do not disclose how many expanded access requests they receive or, of those, how many they grant.[130] This lack of disclosure makes it difficult for physicians, patients, or even the FDA to hypothesize how companies apply their criteria when reviewing an expanded access request. Two companies have made this type of information publicly available, but through different channels and with different levels of information. Pfizer, for example, discloses its overall expanded access approval rate on its website, but it does not explain the rationale for the small percentage of denials. By contrast, as part of a case study in the Journal of the American Medical Association (“JAMA”), Janssen released limited expanded access data regarding one investigational drug for a distinct period of time. That study reported the most common reason the company denied a request was an unfavorable risk-benefit profile.[131]
3. How the FDA Evaluates an Individual Patient Request
The FDA, as mentioned, must review all expanded access requests. When reviewing an expanded access request—whether for individual patient use, intermediate-size patient use, or widespread patient use—the FDA examines three threshold criteria: (1) patient eligibility; (2) risk-benefit analysis; and (3) impact on clinical trials.
a. Patient Eligibility
The patient or group of patients must have a “serious or immediately life-threatening disease or condition,” in which “no comparable or satisfactory alternative therapy” is available.[132] An “immediately life-threatening disease” is defined as “a stage of disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.”[133] A “serious disease” is defined as one “associated with morbidity that has substantial impact on day-to-day functioning.”[134] The FDA has previously authorized expanded access use for serious diseases like amyotrophic lateral sclerosis (“ALS”), narcolepsy, and Alzheimer’s disease.[135] In guidance from the FDA, the agency further clarifies its standard for a serious disease explaining: “short-lived and self-limiting morbidity will usually not be sufficient to qualify a condition as serious, but the morbidity need not be irreversible, provided it is persistent or recurrent.”[136] The FDA interprets no comparable or satisfactory therapy to “mean that there exists no other available therapy to treat the patient’s condition or that the patient has tried available therapies and failed to respond adequately or is intolerant to them.”[137]
b. Risk-Benefit Analysis
The second requirement is that the “potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease.”[138] This criterion acknowledges “the need for the risks and benefits of drugs to be well characterized” before the FDA will grant an expanded access request for an individual or group of patients.[139] This criterion is not intended to establish a uniform minimum approval threshold; that determination is dependent on the expanded access category and the seriousness of the disease.[140]
c. Impact on Clinical Trials
The availability of expanded access also hinges on the FDA’s determination that “providing the investigational drug . . . will not interfere with . . . clinical investigations that could support marketing approval.”[141] While it is understandable that many patients would prefer to secure an investigational drug outside of the confines of a clinical trial, especially given their randomized nature, expanded access use cannot “compromise enrollment in the trials” that would ultimately support a marketing application.[142] This criterion attempts to address concerns that expanded access would reduce individuals’ willingness to participate in clinical trials, especially given evidence that approximately 3% of adults with cancer enroll in clinical trials.[143]
* * *
The three expanded access categories each have additional category-specific criteria that the FDA must consider before granting a request (Table 1).With an individual patient expanded access request, the FDA must also conclude that “the patient cannot obtain the drug under another IND or protocol.”[144] This means that the patient is either ineligible to enroll in ongoing clinical trials based on eligibility criteria or unable to enroll for some other reason.[145]
The FDA approves most expanded access requests.[146] Between 2012 and 2015, the agency approved approximately 99% of the more than 5,000 single-patient expanded access requests it received.[147] The FDA does not just rubber-stamp these requests. The FDA made “meaningful changes in approximately 10 percent of these cases to enhance patient safety” such as adjusting dosage, increasing safety oversight, and strengthening informed consent.[148] FDA Commissioner Scott Gottlieb explained:
[t]he changes are based on the scientific and medical expertise of our staff, and informed by confidential information provided to FDA by product sponsors during the course of development. This information is often unavailable to the treating physician—and the larger medical community—and becomes available only after a drug is approved.[149]
The real question is how many expanded access requests never reach the FDA because the manufacturer declines to provide a letter of authorization.[150]
III. THE RIGHT–TO–TRY MOVEMENT
In 2014, the Goldwater Institute, a conservative and libertarian public policy think tank, launched a new initiative based on patients’ right to “some choice over their own destinies.”[151] The think tank’s initial goal was to pass state laws giving terminally ill patients the right to obtain access to investigational drugs that have completed phase I clinical trials without interference from the FDA.[152] This goal was later expanded to secure the enactment of a federal law under the same premise.
Section III.A outlines and assesses the movement’s rationale for proposing a new pre-approval access pathway before briefly discussing the movement’s success at the state level. Section III.B examines the FDA’s attempts to address the movement’s claims and why those attempts by the agency were insufficient. Section III.C discusses the efforts by Senator Ron Johnson (R-Wis.) to secure enactment of federal right to try legislation.
A. The Movement’s Rationale for Right to Try and Success at the State Level
1. The Right–to–Try Movement’s Rationale
The arguments for right to try can be distilled to three main claims: (1) the expanded access program is “so riddled with bureaucracy and delay that a patient’s chances of obtaining potentially lifesaving treatment in time are practically negligible”;[153] (2) the FDA is irreparably broken because it prevents individuals from using “potentially lifesaving medicines and treatments until those treatments receive final approval”;[154] and (3) patients with life-threatening diseases should be allowed to try an investigational drug that has already passed the FDA’s basic safety testing in phase I trials and remains within the FDA’s approval process because they are “safe.”[155]
a. The Expanded Access Program Is Overly Bureaucratic and Slow
The Goldwater Institute specifically claimed that the expanded access program burdens people’s right to try because: (1) the FDA has “unfettered authority to deny a terminal patient access . . . for a variety of reasons, including nonmedical reasons”; (2) the application is overly burdensome and complicated for requesting physicians; and (3) the IRB review requirement prolongs and prevents access for patients undergoing treatment at non-academic centers outside of major metropolitan areas.[156]
There are two problems with the first part of this claim. First, this claim completely ignores the GAO report findings, which suggest a contrary proposition.[157] Second, this claim fails to acknowledge that sign-off from the FDA is only the last step in the process.[158] Take Andrea Sloan’s story as an example. The FDA acknowledged Sloan was an appropriate candidate for expanded access, but BioMarin would not provide BMN-673.[159] While the FDA approves nearly all of the expanded access requests it receives, the perception is that the bigger obstacle is manufacturer cooperation.[160] Most companies do not publicly disclose the number of requests received or promote the number of times the company has approved an individual patient’s request.[161] Of the company policies surveyed in Section II.B.2,[162] only Pfizer publicized information on its website about the number of requests it received and how many were approved by the company.[163] The lack of collective disclosure by manufacturers––and the inability of the FDA to require manufacturers to provide this information––leaves the public and politicians with a myopic view of the expanded access program.
The FDA has since introduced Form FDA 3926 (“Individual Patient Expanded Access – Investigational New Drug Application”) and modified the IRB review requirement addressing the second and third part of this claim, which are both discussed in greater detail in Section III.B. These changes could improve accessibility to the expanded access program over time.
b. The FDA Regulatory Framework Is Broken
The Goldwater Institute argued that the current regulatory framework is broken because it can take years before the FDA approves a drug. Yet instead of offering a solution to address the clinical trial process (for example, lobbying for legislation to support the use of different clinical trial designs,[164] or to incentivize companies to reconsider their rationale for certain inclusion and exclusion criteria that could provide data that more accurately reflects real-world patients[165])––which could potentially improve access to investigational drugs more broadly––the organization decided the easier path was pre-approval access legislation that cut-out the FDA. This strategy was shortsighted and arguably based on the Goldwater Institute’s overarching goal of limiting the FDA’s oversight of drugs for all patients and not just those drugs designed for the treatment of immediately life-threatening diseases.[166]
The claim that the framework is “broken” also focuses on speed to the detriment of safety and efficacy. The need for adequate safety and effectiveness data can prolong the drug approval process,[167] however, even with these requirements, the FDA is consistently faster at approving investigational drugs than other regulatory authorities. For example,
[a]mong the 289 unique novel therapeutic agents [approved between 2001 and 2010], 190 were approved in both the United States and Europe (either by the EMA or through the mutual recognition process), of which 121 (63.7%) were first approved in the United States; similarly, 154 were approved in both the United States and Canada, of which 132 (85.7%) were first approved in the United States.[168]
The speed with which a drug is approved, however, should not be the only priority—safety and efficacy are still important concerns. Some argue the agency is now underemphasizing these two criteria in its aim to ensure patients can access novel drugs more quickly.[169] A JAMA study found that “nearly a third of [drugs] approved [by the FDA] from 2001 through 2010 had major safety issues years after they were widely available to patients.”[170] A patient with a life-threatening disease or condition may understandably be frustrated by the lengthy development timeline, especially when a drug is touted as a potential “breakthrough” early on in its development cycle. However, pre-approval access without FDA oversight does not directly fix this lag between development and approval; it could make it worse for everyone if patients attempt to seek pre-approval access instead of enrolling in clinical trials.[171]
c. Patients Should Be Allowed to Use Investigational Drugs that Have Completed Phase I Clinical Testing
Finally, the Goldwater Institute’s claim that patients should be able to try investigational drugs because completion of phase I testing renders them safe fails to acknowledge that most investigational drugs are not approved by the FDA. The “overall likelihood of [FDA] approval . . . from Phase I for all developmental candidates [between 2006 and 2015] was 9.6%.”[172] The successful completion of a phase I clinical trial also does not guarantee a drug’s safety, and in general, investigational drugs have the lowest successful transition rates at phase II.[173] Take the example of fialuridine. In 1993, five individuals enrolled in a phase II clinical trial studying the use of fialuridine in hepatitis B died, despite an earlier phase I clinical trial in which 25% of a twenty-four-patient trial were cured after receiving fialuridine for twenty-eight days.[174] This example might seem extreme, but it still illustrates the risks associated with equating successful completion of a phase I trial with a broad endorsement of safety. As discussed, an approved drug’s safety profile is also not fully understood until sometimes years after it is approved. The potential harm of an investigational drug, even to someone “facing imminent death,” still needs to be considered before allowing an individual with a serious or life-threatening disease to use the investigational drug merely on the basis of completion of phase I testing.[175]
In conclusion, the movement’s rationales for these laws were misplaced and ill-guided. There is no doubt, however, that despite these claims, the Goldwater Institute was successful in securing the support necessary to pass both state and federal legislation.
2. The Movement’s Success at the State Level
Post-Abigail Alliance, efforts were made to enact legislation to amend the expanded access program. While these federal bills failed to make it beyond congressional committee,[176] the state right–to–try bills, from the outset, gained more support. There are several possible reasons for this increased support. First, information regarding investigational drugs, especially data from medical meetings, has become more accessible with the Internet and social media.[177] This increased accessibility is good, but it also can lead to increased interest in investigational drugs—especially when a drug is deemed “revolutionary” by the medical community, even with limited safety and efficacy data.[178] Timothy Turnham, the former executive director at the Melanoma Research Foundation, explains: “There is a disconnect between what researchers think is statistically significant and what is really significant for patients . . . . Patients hear ‘progress,’ and they think that means they’re going to be cured.”[179]
Second, there has been an increase in direct-to-consumer advertising of approved specialty drugs for the treatment of conditions such as cancer and autoimmune disorders by pharmaceutical companies[180] and of specific practices areas such as oncology and organ transplantation by cancer hospitals.[181] The United States is one of only a small number of countries which allows drug company advertising to not only mention an approved drug and its intended use, but also claims about its safety and efficacy.[182] These advertisements—though meant to be scientifically accurate—can also sometimes have misleading effects on people’s perceptions of their individual health outcomes.[183] If patients’ perceptions are skewed when they see a television advertisement claiming an FDA-approved drug will give them “a chance to live longer,” it is reasonable to think that patients’ perceptions could be equally skewed about investigational drugs given that investigational drugs are often touted as “revolutionary” at medical meetings by the manufacturers, tweeted as “ground-breaking” by physicians, and reported as “life-saving” by media, as compared to the currently available treatment option.
Third, with social media, individual patients like Andrea Sloan have a more accessible, widely-used platform by which to raise awareness of their struggle to obtain these investigational drugs through expanded access.[184] In the past, publicized efforts to pressure manufacturers for expanded access were generally a coordinated effort led by advocacy groups, aimed at obtaining an investigational drug for more widespread use.[185] Individual patients were often left to phone calls and letter writing with slim chance of successfully obtaining an experimental treatment without a connection.[186] This changed with social media. The news media found these campaigns and latched onto Sloan’s and other patients’ stories with headlines like “Company Denies Drug to Dying Child” and “Merck Expands Cancer Drug Access but too Late for Denver Dad,” which only amplified the public’s frustration with expanded access.[187] The social media campaigns and media attention, in turn, increased pressure on politicians to fix the system and allow individuals access to investigational drugs.[188]
The Goldwater Institute initially targeted more conservative states like Colorado, Arizona, and Texas,[189] but the movement also gained traction and success in more liberal states like California and Oregon.[190] The state bills also often had little political opposition and were supported by members on both sides of the aisle.[191] In total, forty states adopted right–to–try laws prior to the enactment of the federal Right to Try Act. With Alaska’s enactment of its own right–to–try law in July 2018, that total is now forty-one states.[192]
The goal of these state-level right–to–try laws, as discussed, is to enable terminally ill patients to bypass the FDA expanded access program and request pre-approval use directly from manufacturers, but there are variations in these laws’ provisions regarding, among other things, cost recovery,[193] insurance coverage,[194] and informed consent.[195] The extent to which those variations now matter given the enactment of the Right to Try Act of 2017 is still not fully clear, but as discussed below, at least some are likely still applicable.
B. The FDA’s Response
In response to the right–to–try advocates’ criticisms, the FDA further clarified and modified aspects of the expanded access program to address its perceived shortcomings. The FDA also stepped up efforts to increase awareness and understanding of the expanded access program.
1. Clarifying the FDA’s Use of Clinical Outcomes
A major issue for manufacturers—which face external pressure from investors, physicians, and patient groups to bring new drugs to market—concerns the potential impact an adverse event during expanded access use could have on an investigational drug’s development and subsequent agency review.[196] This concern was likely overstated, particularly given that “clinical safety data from expanded access treatment” has only been considered in a “small number of cases” when determining an approved drug’s label,[197] and that such a criterion has never been used to deny approval.[198] Still, the potential for an adverse event was often cited as an obstacle for patients seeking expanded access use.[199]
The FDA attempted to address these concerns, even if arguably overstated, by clarifying its policy. The treating physician needs to report only “suspected [serious or unexpected] adverse reactions . . . if there is evidence to suggest a causal relationship between the drug and the adverse event.”[200] The agency also noted that given the nature of expanded access use (in other words, an investigational drug administered outside of a controlled clinical trial to a terminally ill patient with multiple comorbidities), it would be difficult to often establish the necessary causal relationship.[201]
This modification, however, did not address the other major concern raised by manufacturers: the lack of a readily available supply of the drug sought for expanded access.[202] The FDA cannot directly tackle this issue, but it could affect the drug supply indirectly through clinical trial policies promoting diversity and inclusion.[203] This, in turn, could help some patients, who are willing to participate in a clinical trial but are instead driven to seek expanded access due to their failure to satisfy clinical eligibility requirements given age or certain comorbidities.[204]
2. Demystifying Manufacturers’ Eligibility Criteria
A long-standing frustration for patients and their physicians was biopharmaceutical companies’ lack of transparency regarding how they evaluated expanded access requests. Before the enactment of the 21st Century Cures Act (“Cures Act”), manufacturers were not required to disclose their evaluation processes.[205] A few biopharmaceutical companies released their criteria after either coming under pressure from patients’ social media campaigns, which requested expanded access, or observing the impact that such campaigns had on other, similar companies.[206] Generally, however, this information was not easily available to patients or physicians.[207]
The Cures Act now requires manufacturers to disclose how they evaluate and respond to individual patient requests for access to investigational drugs.[208] The following information must be included on a manufacturer’s website: (1) contact information; (2) expanded access request procedures; (3) individual patient eligibility criteria; (4) anticipated response time; and (5) a link or other reference to information about the clinical trials of the drug for which expanded access is sought, available on ClinicalTrials.gov.[209]
Three primary issues have impacted the Cures Act’s effectiveness. First, not all companies are in compliance with its provisions.[210] The Cures Act does not contain an enforcement mechanism to give the FDA the ability to penalize companies that do not publish policies. Second, the Cures Act does not require participation in expanded access—just that a company post its policies. Though most companies have guidelines similar to the ones previously detailed in Section II.B.2, a company is still allowed under the Cures Act to have a policy against providing expanded access, so long as that policy is available on the company’s website.[211] And even if a company’s criteria mirrors that of PhRMA’s criteria, they are still subject to interpretation by that company’s employees. This could make it difficult to determine whether a physician’s request on behalf of a patient will be approved. Third, the Cures Act does not ensure timely response—just that a company post an anticipated response time. In general, that time frame represents the estimated time to an acknowledgment rather than an estimated time to a decision.[212] The FDA seems posed to address this final issue but has not announced definite plans to institute a timing requirement.[213]
3. Increasing Awareness of Expanded Access
The FDA has also attempted to dispel many of the misconceptions regarding expanded access and clarify the application process for physicians and patients, especially those outside of major academic medical centers. The Reagan-Udall Foundation for the FDA, for example, created the “Expanded Access Navigator.”[214] This website provides an overview of the application process from both a physician and patient perspective. The physician-specific section includes contact information for independent IRB committees should a physician’s institution not have its own IRB committee,[215] and a manufacturer directory listing companies’ expanded access criteria and their anticipated response time.
4. Streamlining the Individual Patient Request Process
a. Form FDA 3926
Prior to the release of Form FDA 3926, a physician could spend up to one hundred hours in his or her attempt to secure expanded access use for a single patient.[216] Although a significant portion of that estimate likely included time spent negotiating with the manufacturer to obtain a LOA and coordinating with the IRB, physicians complained the application, comprised of Form FDA 1571 (“Investigational New Drug Application”) and Form FDA 1572 (“Statement of the Investigator”),[217] was unnecessarily complex and took upwards of eight hours to complete.[218]
In 2016 the FDA rolled out a streamlined application, Form FDA 3926, to ease the application process.[219] This change was meant not only to reduce the burden on physicians already familiar with requesting expanded access, but also, more importantly, to encourage doctors less familiar with the regulatory process who may have been previously dissuaded from submitting an expanded access request for their patients because of the forms’ complexities.[220] Form FDA 3926 only requires the physician to provide: (1) the patient’s initials; (2) the date of submission; (3) the type of submission; (4) clinical information; (5) treatment information; (6) a LOA; (7) the physician’s qualification statement; and (8) the physician’s name, address, and contact information.[221] The new two-page form takes forty-five minutes to complete—a time savings of more than 90%.[222] The total application process is now estimated to take thirty hours with this new estimate likely factoring in the FDA’s simplified IRB requirement.[223]
b. IRB Review
In October 2017, the FDA announced another change to the single-patient expanded access process. A requesting physician can now seek approval from a specifically assigned IRB or the IRB chairperson, rather than waiting for a full IRB review (in other words, a committee meeting where “a majority of the members are present”).[224] This change was intended to reduce the time between when the patient and treating physician determine an investigational drug might be appropriate and when the treating physician’s IRB approves that request, as well as to remove another potential hurdle for physicians outside of major academic centers.[225]
This modification attempts to strike the appropriate balance between oversight and timeliness as it recognizes the continued need for independent confirmatory review, while also acknowledging that full IRB review may be unnecessary in the individual patient expanded access setting, given that it could cause undue delays and potentially deter some community-based physicians from using the expanded access pathway. Yet this change also has at least one limitation and two potential drawbacks. With respect to the limitation, it is difficult to know whether hospitals will adopt this modification as it is permissive not mandatory. At least a few major centers appear to be utilizing it, though further research is necessary to determine the full extent of its adoption.[226] To facilitate more widespread adoption, the FDA or the Reagan-Udall Foundation should work with those institutions effectively utilizing the less-stringent IRB review process to develop recommended criteria that other institutions could utilize.
With respect to potential concerns, first, the modification to the IRB requirement potentially reduces the amount of independent oversight. The average IRB is composed of fourteen members, so before the change, an average of seven members would need to be present to constitute a full IRB review.[227] This change places that decision in the hands of one chairperson or another designated member; this type of reduced oversight is typically reserved for research that poses “minimal risk” to the individual.[228] Second, the FDA did not establish specific eligibility criteria for this waiver. Instead, the FDA has said “such a waiver is appropriate for individual patient expanded access INDs when the physician obtains concurrence by the IRB chairperson or another designated IRB member before treatment use begins.”[229] This standard again places that decision in the hands of one person; the same person who also decides whether expanded access treatment is appropriate. To address these concerns, the FDA should closely monitor incoming expanded access requests to determine if reducing the number of IRB reviewers increases the number of denied FDA requests based on patients not meeting the eligibility criteria. As an initial step, the FDA could refer institutions incorrectly utilizing the waiver to other hospitals that are correctly applying the waiver criteria, and if that appears to not resolve this potential problem, the FDA should consider changing its policy to require at least two or three IRB members or one designated IRB member and a consulting physician specializing in the patient’s disease or condition.[230]
* * *
There were arguably three reasons that these modifications did not quell the right–to–try movement and those ultimately pushing for a federal law. First, the legislation—both at the state and federal level—was not aimed at improving pre-approval access for patients, but was instead meant “to weaken” the FDA.[231] Congress did not even wait to assess the impact of the modifications before voting on the Right to Try Act, even though it had authorized the agency to release a report assessing the impact of some of these modifications in 2017.[232] That report, published after the enactment of the Right to Try Act, suggests that all of the key stakeholders, patients, physicians, manufacturers, and payers, have a positive perception of the program and the FDA’s role in pre-approval access decisions.[233] The efforts to reduce some of the administrative burdens associated with expanded access appear to be well-received.[234] In 2017 (the first full year Form FDA 3926 was available and the year the Expanded Access Navigator was launched), there were 1,151 single-patient expanded access requests, which was a 12% increase from 2016 (1,025 requests).[235] Moreover, Congress did not thoroughly assess the effectiveness of the state right–to–try laws before moving forward with the federal law.
Second, the slow implementation of the FDA’s modifications likely further validated for some the right–to–try advocates’ argument that the FDA is too rigid and unresponsive. For example, the modifications to the application process were introduced more than two years after the right–to–try movement started.[236]
Third, the modifications, aside from the clarification regarding use of clinical outcomes, also did not address the other weakness of the expanded access program—uneven manufacturer participation.[237] The movement’s supporters argued a federal right–to–try law would improve manufacturer participation in pre-approval access.[238]
C. The Push for a Federal Right to Try
Capitalizing on the success at the state level, proponents pushed for federal legislation,[239] even though (1) there was little evidence to suggest that existing state laws had a real impact on patients’ ability to secure pre-approval access,[240] and (2) the effects of the FDA’s modifications to the expanded access program were not fully evaluated.
The first proposed bill never made it out of committee,[241] but in 2016 Senator Ron Johnson (R-Wis.) started strategically laying the groundwork. As Chair of the U.S. Senate Committee on Homeland Security and Governmental Affairs, he convened a hearing to discuss how Congress could reform the regulatory framework to provide “more patients a chance to save their lives.”[242] He introduced a right–to–try bill later that year,[243] but this bill was blocked by Senate Minority Leader Harry Reid (D-Nev.) who objected over the bill’s lack of bipartisan support and nonexistent review through a formal hearing process.[244] In January 2017, Senator Johnson reintroduced a federal right–to–try bill—the Trickett Wendler Right to Try Act of 2017 (“S. 204”).[245] On August 3, 2017, the Senate passed the bill with no opposition, thus moving the debate over right to try to the U.S. House of Representatives.[246]
The fate of S. 204 remained in limbo for several months after an October hearing before the House Committee on Energy and Commerce.[247] The momentum shifted in favor of the right–to–try movement, however, after President Trump singled out the proposed right–to–try law in his 2018 State of the Union address.[248] This mention was enough to reenergize efforts in the House. In March 2018, the House Committee on Energy and Commerce introduced H.R. 5247, Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2018, a narrower right–to–try bill incorporating feedback from the FDA.[249] H.R. 5247 failed an initial vote on March 13, but a week later, on March 21, 2018, the bill passed by a vote of 267–149, mostly along partisan lines.[250]
H.R. 5247 never reached the Senate floor.[251] With the Senate at a standstill, the House renewed discussions over S. 204.[252] In spite of ongoing criticism from industry, patient groups, and physicians,[253] on May 22, 2018, the House passed S. 204 by a vote of 250–169, again on partisan lines.[254] On May 31, 2018, President Trump signed the Right to Try Act and declared the law a victory for patients.[255]
IV. the Right to Try Act of 2017
A. The Law
The Right to Try Act creates “national standards and rules by which investigational drugs may be provided to terminally ill patients.”[256] The federal law—like its predecessor state laws—is permissive and not mandatory. A manufacturer is not required and cannot be compelled to provide access to an investigational drug after receiving a right–to–try request pursuant to the federal Right to Try Act.[257]
1. Who is Eligible?
First, a patient may pursue a right-to-try request if they have a “life-threatening disease or condition.”[258] Senator Johnson chose this disease threshold, rather than the “immediately life-threatening disease” standard previously used in the expanded access program “because [he thought that the ‘immediately life-threating disease’ definition] would exclude patients with Duchenne muscular dystrophy, an illness [he] explicitly intended to be covered.”[259] Second, the patient must have “exhausted approved treatment options” and be “unable to participate in a clinical trial involving the eligible investigational drug.”[260] A physician—but not necessarily the requesting physician—must certify the patient cannot participate in a clinical trial.[261] The physician who certifies that a patient is unable to participate in the clinical trial must be in “good standing” and cannot receive compensation from the manufacturer in direct response to the certification.[262] Third, the patient must provide “written informed consent”––a term that is undefined under the law, rather than using the existing federal regulation defining informed consent.[263]
2. When Would an Investigational Drug Qualify?
To qualify for right to try, an investigational drug must satisfy four requirements. First, it must have completed a phase I clinical trial.[264] The Act does not specify whether the investigational drug must have completed a phase I clinical trial in the requested indication. The Act also does not preclude requests for investigational drugs that have only been tested in healthy volunteers. Second, the drug must not be approved for any other use.[265] Third, the manufacturer must either (1) have already filed a marketing application for the investigational drug with the FDA, or (2) be investigating the drug in a clinical trial that is “intended to form the primary basis of a claim of effectiveness in support of approval” and is the subject of an active IND.[266] This language is broad because, as Senator Johnson explains, the Act was “not intended to enable the FDA to exclude any clinical trial as a basis for precluding access to treatments under right to try.”[267] Fourth, the drug must be in active development (that is, not discontinued) and not subject to a clinical hold.[268]
An investigational drug that meets these requirements is then exempt from certain statutory and regulatory requirements[269] as long as the providing company also complies with sections 312.6 (labeling of investigational new drugs), 312.7 (promoting investigational drugs), and 312.8 (charging for investigational new drugs) of the Code of Federal Regulations.[270]
3. What are the Reporting Obligations?
a. Companies ’ Reporting Obligations
The Right to Try Act requires a company to file a yearly report of right-to-try use with Health and Human Services (“HHS”). This yearly report to HHS must include “the number of doses supplied, the number of patients treated, [and] the uses for which the drug was made available”; the manufacturer must also report “any known serious adverse events.”[271]
b. FDA’s Reporting Obligations
The Right to Try Act also requires the publication of a yearly report summarizing right-to-try use on the FDA’s website. This yearly report must disclose how often the FDA determines a clinical outcome to be critical to deciding safety, how often a manufacturer asks the FDA to consider such outcomes, and how often the FDA does not consider clinical outcomes when reviewing the investigational drug’s marketing application.[272]
4. When Can the FDA Use Clinical Outcomes?
The Right to Try Act bars the FDA from considering a “clinical outcome” related to a patient’s use of an investigational drug “to delay or adversely affect the review or approval” of that drug––except in two situations.[273] The FDA is allowed to use a clinical outcome if it is (1) critical to the assessment of the investigational drug’s safety, and (2) the company that provided the investigational drug can also ask for a clinical outcome to be considered.[274] The Act does not define “critical.”
* * *
B. Industry’s Potential Path Moving Forward
This Section proceeds as follows. Section IV.B.1 explains why regardless of future FDA guidance, most companies are unlikely to adopt a two-pathway approach or even a single-pathway approach using just right to try, favoring continued use of the expanded access program instead. Section IV.B.2 argues that the status quo, however, is insufficient and that companies need to address some of the criticisms raised during the right-to-try movement by (1) revising their existing expanded access policies, and (2) improving clinical trial access.
1. Even with the Right to Try Act, Most Companies Will Continue to Use Expanded Access
All along, right-to-try advocates have contended that the Right to Try Act’s provisions limiting liability and limiting the FDA’s use of outcome data would incentivize manufacturers to utilize this new pre-approval pathway.[275] Yet, as this Note explains below, these two provisions are not enough for most companies to utilize the Right to Try Act.[276]
Lack of Support from Key Stakeholders. The Right to Try Act lacks support from industry, advocacy groups, physician organizations, and the FDA. Companies, including Janssen and Bristol-Myers Squibb, have already stated that right-to-try requests will be funneled through the expanded access pathway.[277] Janssen announced prior to the enactment of the federal Right to Try Act that it would not “evaluate right-to-try requests because [the state] laws don’t allow for FDA input, which is ‘critical for ensuring patient safety.’”[278] Patient advocacy groups and physician organizations have not significantly changed their position on the Right to Try Act since its adoption.[279] The FDA has also since voiced its continued preference for use of the expanded access program in November 2018,[280] and announced in December 2018 a new program, “Project Facilitate,” which aims to further alleviate the criticisms of the expanded access program. Project Facilitate will establish a department within the FDA that (1) will field calls from physicians requesting expanded access on behalf of a patient and patients seeking single-patient expanded access for themselves; (2) complete Form FDA 3926, and if necessary forward the completed form to a patient’s treating physician for sign-off if the initial request was made by the patient; (3) forward the request to an IRB; and (4) ultimately submit the request to the company developing the requested drug, which must make a determination “within a specified time period . . . yet [to be] determined” by the FDA.[281] With industry generally reticent to act without agency guidance,[282] the November 2018 announcement and the forthcoming Project Facilitate arguably send strong signals to keep using the expanded access program.
Insufficient Incentives. The Right to Try Act’s provisions limiting a company’s liability and limiting the FDA’s use of outcome data are insufficient incentives. First, the Right to Try Act does limit a company’s potential liability but does not protect a manufacturer against any and all liability claims. As attorney James M. Beck notes, the Act still allows claims of reckless or willful misconduct, gross negligence, or intentional tort.[283] The Right to Try Act also does not foreclose claims under state or federal product liability, tort, consumer protection, or warranty law.[284] A company would also be trading more liability protection for less FDA input when it is not clear further liability protection is even necessary. As others have pointed out, there are no examples of patients suing manufacturers of investigational drugs for “treatment-related harm[s]” stemming from expanded-access use.[285] Therefore, companies––at least within the context of expanded access––should have minimal concern over potential tort claims.
Second, although the Right to Try Act limits the FDA’s use of outcome data to when it is “critical” to determining safety, in practice the FDA rarely uses expanded access data when reviewing an investigational drug unless there is evidence to suggest a causal relationship.[286] Even though the FDA’s use of outcomes is often a concern for manufacturers, the FDA has assured companies it rarely uses expanded access data, so it is unclear how the Right to Try Act’s provision further limits the FDA’s use. Furthermore, as the Act does not define “critical,” without some guidance from the FDA it is unclear whether this is the same standard as used in expanded access, a more relaxed standard, or a heightened standard given that the FDA is not involved in reviewing the right–to–try request and determining proper usage, such as dosage. Finally, even if the FDA is limited in its ability to assess reported events, manufacturers may still be concerned about whether any adverse events associated with right–to–try use would impact regulatory approval in other countries.[287]
Third, the Right to Try Act does not contain a significant financial incentive for industry. The Act requires companies to comply with the existing regulation, which limits cost recovery to direct costs, except under specific circumstances.[288] A two-pathway approach would require companies to allocate additional money, personnel, and drug supply to another program that is outside the drug development process. With the cost of developing a new drug estimated to be around $2.6 billion,[289] it seems unlikely that manufacturers would be willing to expend any additional resources to only recoup direct costs.[290] A publicly traded company, like Pfizer or Janssen, might have the necessary financial resources and employees but will still answer to shareholders and still have concerns about maintaining adequate supply of the drug for its clinical trials.[291] A small, private company under pressure from investors is likely to have even less motivation to redirect limited resources to a two-pathway pre-approval program, or even a single-pathway program without some financial upside.[292] Take, for example, BrainStorm Therapeutics, which announced plans to offer its therapy through right to try and would have charged patients seeking the right to try its drug potentially $300,000. The company’s now–retracted plan likely did not comply with federal regulation given that it was positioned as a “semicommercial enterprise with modest profits.”[293]
Unanswered Implementation Questions. The Right to Try Act is meant to be a parallel pathway to expanded access and not a replacement, but it would be difficult for a company to implement a pre-approval access program in which both of these programs co-exist. The Right to Try Act does not provide companies considering utilizing right to try as a parallel pathway guidance to the threshold issue: when it should use right to try and when it should use expanded access. The FDA is working to develop guidance,[294] but for now it has said that companies are in the best position to make that determination.[295] While this Note identifies two potential options, each is not without their own drawbacks and complexities. A company could (1) use right to try when an investigational drug will be used by a single patient and use expanded access when an investigational drug will be used by a larger patient population, or (2) use right to try under certain pre-defined circumstances (for example, pediatric patients or patients with exceptional safety risks) and use expanded access in all other circumstances.
The first option—use of right to try in the single-patient setting—would be administratively easier. A company would not need to develop new policies delineating between the two pathways for individual patients. That said, this approach does have potential challenges. First, individuals with certain types of serious diseases would not qualify for the right–to–try pathway, therefore limiting their pre-approval access options until the drug has sufficient evidence to support expanded access for intermediate-size or widespread treatment.[296] Take, for example, the conditions narcolepsy or rheumatoid arthritis, which the FDA has said would independently qualify as a serious disease; these conditions would not be considered “life–threatening” because both are considered chronic diseases and are alone not fatal.[297] Therefore, adoption of this approach would likely be dependent on a company’s investigational drug pipeline. A company with a single drug in development might be less concerned about this issue, but a company with a large disease pipeline that targets multiple different disease areas might be.
Second, it is not clear what the patient limit should be for right to try (that is, at what point should a company stop providing pre-approval access through right to try and transition over to expanded access for intermediate–size and widespread treatment). The Right to Try Act does not provide any guidance. A company should not be able to provide five, ten, or fifteen patients at a single hospital with an investigational drug through the right to try pathway. That starts looking more like an intermediate-size expanded access protocol[298] and arguably should have FDA oversight. Without specific right-to-try guidance, a manufacturer would need to rely on expanded access guidance as a benchmark for when a company should transition from the right–to–try pathway to intermediate-size or widespread use through expanded access, but even then the existing FDA guidance does not address other concerns regarding the potential applicability of the Right to Try Act’s provisions limiting liability and use of outcome data once a certain patient threshold is crossed.
The second option—use of right to try under certain pre-defined settings—would be administratively more complicated, given that it would require companies to determine those pre-defined circumstances and ensure that the criteria for those standards is clear and easy to apply. That said, some companies might consider this approach in order to allow some patients who might otherwise not be eligible for expanded access to receive the drug through right to try, given the Act’s provisions limiting liability and use of outcome data. Two such settings that a company might reasonably consider are (1) patients who have exceptional safety risks[299] and (2) patients who are children.[300] The former group is frequently ineligible for a clinical trial and likely to be denied expanded access use because of manufacturers’ concerns about potential liability or adverse events impacting clinical development.[301] The latter group—often the face of the right–to–try movement[302]—is also frequently ineligible for industry-sponsored clinical trials and may be denied expanded access use because of manufacturers’ concerns about inadequate clinical data to determine an adequate dosage in the pediatric setting, potential liability, or adverse events impacting clinical development.[303]
This second approach is also not without its drawbacks. First, the pre-defined settings would need to be unambiguous. Though pediatric patients can be more clearly defined by age, the term “exceptional safety risks” is not susceptible to one definition, so companies allowing pre-approval access in this setting would need to establish a specific standard and make sure it is clearly communicated internally and externally. Second, with pediatric patients[304] and patients who are terminally ill,[305] there are also ethical considerations requiring companies to adopt more rigorous informed consent requirements and procedures. Take pediatric patients, for example, cases in which “[p]arents or other surrogates technically provide ‘informed permission’ for diagnosis and treatment, with the assent of the child whenever appropriate.”[306] Third, companies would also still need to refer back to the state right–to–try laws to ensure their pre-defined settings are compliant. Oregon, for example, limits the right to try pathway to individuals who are at least eighteen years old.[307] This could increase the complexities of implementation. Fourth, the drawbacks relating to the first option likely would also impact the second option.
The practical complexities of operating a two-pathway approach, stemming from presently unanswered legal questions regarding the Right to Try Act and concerns that might arise from utilizing Right to Try in specific patient settings, make companies unlikely to use right to try even if the FDA provides guidance.
State Right-to-Try Laws. The applicability of state right–to–try laws is also still uncertain.[308] While the Right to Try Act creates a national standard,[309] it does not explicitly preempt these state laws.[310] Senator Ron Johnson has previously stated that the Right to Try Act was meant to be the “federal counterpart” to the state right–to–try laws.[311] With forty-one state–level right–to–try laws, implementation and compliance would be complicated. A company would likely need to comply with at least some of the provisions of the state right–to–try laws in addition to the Right to Try Act’s provisions.
Take, for example, the California state statute’s criteria for patient eligibility, which requires a person to have: (1) “an immediately life-threatening disease or condition”; (2) “considered all other treatment options currently approved”; (3) “not been accepted to participate in the nearest clinical trial to his or her home . . . within one week of completion of the clinical trial application process, or, in the treating physician’s medical judgment, it is unreasonable for the patient to participate in that clinical trial”; (4) “received a recommendation from his or her primary physician and a consulting physician”; (5) “given written informed consent”; (6) “documentation . . . attesting that the patient has met the requirements . . . .”[312]
The first requirement limiting patient eligibility is narrower than the Right to Try Act.[313] The second requirement is arguably broader, because it would allow a patient to rely on the pathway after considering, but not exhausting, all treatment options. The first part of the third requirement could possibly supplement the Right to Try Act’s clinical trial requirement if it was interpreted as requiring proof of non-acceptance, but it is likely more accurately interpreted as allowing a patient to make a request within one week of not receiving a response, which is broader than the Right to Try Act. The second part of that requirement is clearly broader, however, than the federal law, as the Right to Try Act requires a physician to certify that a patient cannot participate in a clinical trial, and not just that it would be unreasonable for a patient to participate in a clinical trial; the California law uses a different standard. The fourth requirement supplements the Right to Try Act because it requires confirmation from a second physician.[314] The fifth requirement also supplements the federal law because, whereas the federal law leaves “informed consent” undefined, California defines “informed consent” in another part of the statute.[315] The sixth requirement mirrors the federal law.[316]
Although a company could theoretically challenge state right to try laws as preempted by the federal provision, this is not an issue that an individual company, or companies collectively, are likely to challenge, particularly given the high costs of litigation and limited financial incentive of success on the merits.[317] This issue could also impact patient’s actual interest[318] and healthcare providers’ willingness to offer such treatments.[319]
External Regulatory Challenges. The adoption of the Right to Try Act by industry seems less likely given that companies already face “challenges particularly related to . .
