Preapproval Access and Right-to-Try Initiatives

FDA Expanded Access

FDA has a long history of facilitating expanded access to investigational drugs for treatment use for patients with serious or immediately life-threatening diseases when there are no viable therapeutic alternatives. Since 2009, FDA regulations ² have allowed patients to request “expanded access” to investigational drugs outside of clinical trials, providing treatment use under an investigational new drug (IND) application. More recently (as of June 2, 2016), FDA has greatly simplified the paperwork required to submit such a request in developing Form FDA 3926 (Individual Patient Expanded Access – IND). The form may be used by licensed physicians to simplify the application process to request FDA approval for expanded access to investigational drugs for treatment use for individual patients. ³ The patient-specific IND application can now be completed in approximately 45 minutes. The agency also issued 2 additional final guidance documents to further clarify the implementation of expanded access regulations. ^4,5

Since 2009, applications for expanded access have primarily been IND submissions for individual patients. FDA receives more than 1000 compassionate-use requests per year (although it was nearly 2000 in 2014). In the past 5 years, fewer than 1% of the applications have been denied to proceed by the FDA, usually for safety reasons (Figure 1). These included requests for access where there was no human experience and very little animal data upon which to judge toxicity, as well as requests for agents that were on clinical hold due to deaths or to manufacturing issues related to the agent (R. Klein, FDA, email communication, September 2, 2016).

OPEN IN VIEWER

Figure 1.

Expanded-access investigational new drug (IND) submissions and protocols at FDA’s Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER), fiscal years (FY) 2010-2015. *For FY 2010 and 2011, the reporting period was October 13 through October 12 of the following year.

It should be noted that there have been requests that have been granted for preclinical access to drugs based solely on existing animal data. In fact, when I approached FDA with a request for potentially granting preapproval access for a patient with methicillin-resistant Staphylococcus aureus (MRSA), they were receptive, even though the only data available for the investigational product were from preclinical studies. Each single-patient request is decided on a case-by-case basis based on the patient’s condition and available data about the requested investigational agent (R. Klein, BS; FDA, personal communication; September 2, 2016).

Approvals are usually granted within a few days.

Right-to-Try Initiatives

While there have been precedent attempts to increase preapproval access outside of the FDA processes (eg, Abigail Alliance; http://www.abigail-alliance.org/mission.php), right-to-try legislative efforts were initiated by the Goldwater Institute—a libertarian think tank—which developed a template for language for use as a model by state legislatures. ¹ The Goldwater Institute has aggressively lobbied for these laws, resulting in the first passage in Colorado in May 2014. To date, right-to-try legislation has been signed into law in 31 states.

The justification for right-to-try bills is a belief by the Goldwater Institute that there were too many barriers to allow extremely sick people to use treatments that are not currently allowed to them under federal regulations. They felt that the FDA application processes to gain such access were too cumbersome and time consuming. ⁶

A recent article by Alison Bateman-House, Kenneth Moch, Arthur Caplan, and Lisa Kearns summarizes the key elements of typical right to-try laws ⁷ :

The Model Legislation typically addresses several concerns about patients’ use of experimental drugs:

It would allow access only to medications that have passed manufacturers’ Phase I clinical trials.

A similar bill, the Access to Medical Treatments (Innovation) Bill (also known as the Saatchi Bill) recently passed in the British House of Commons. ⁸ The bill is presented as offering patients with terminal disease potentially curative options.

Choices

Overlaying this discussion is the principle of individual agency—the capacity for human beings to make choices and to impose those choices on the world. In this, it is subtly distinct from the concept of free will, the philosophical doctrine that our choices are not the product of causal chains, but are significantly free or undetermined.

Human agency invests a moral component into a given situation. If a situation is the consequence of human decision making, persons may be under a duty to apply value judgments to the consequences of their decisions, and held to be responsible for those decisions. It is here that I take issue with unencumbered agency. I hold that the right-to-try legislation, in fact, encourages a selfish course of action that violates a social contract between the individual and the society at large. Too often, potential “collateral damage” is not considered in the decision-making algorithm. This oversight may be a result of naiveté, misinformation, or, most likely, an unwillingness to consider the consequences of one’s own actions.

The foundations of the FDA were established in order to protect patients and clinical trial subjects from potential undue harm. The principles embodied in FDA regulations and guidance represent the obligations of institutions to protect the well-being of US citizens in accessing medicines and, as it pertains to this particular discussion, in the context of clinical trials.

I maintain that there is an obligation of the protected citizen to allow medical community access to data acquired during the course of voluntary participation in clinical research so as to contribute to the advance of medical science that may benefit their fellow citizens in the near term and into the future. The potential value of such information is decreased when it is not collected in an empirically controlled manner; however, even a single patient’s experience can be informative if data are collected in a meaningful way that adds to the collective database. The collection of data pertaining to safety and, when available, efficacy, should be a condition of granting access to preapproved medicines. This principle should be applied universally, whether access is considered via federal (FDA) or state-specific right-to-try laws. It is important to note that while there is no prohibition under right-to-try to provide to the patient protections similar to FDA pre-approval access, there is no obligation to do so.

Juxtaposing the rights and obligations of the individual against those of Society brings to light significant dynamic tensions. These should be evaluated in the course of deciding whether or not to follow one of the limited options. In doing so, should universal decision-making standard(s) be applied, or should they be developed de novo on a case-by-case basis?

Obligation to Protect Versus Obligation to Rescue

FDA acts as public health protector by ensuring that all drugs on the market are safe and effective. Authority to do this comes from the 1938 Federal Food, Drug, and Cosmetic Act and the 1962 Kefauver-Harris Amendment, which require drug firms to prove safety and effectiveness in the intended use. In the establishment of the FDA charter, the guiding principle is to protect patients from harmful products and from products that do not deliver on their promise of therapeutic benefit. These protections prevent commercialization of drugs that, based on controlled clinical trials, fail to achieve these standards of evidence. When a drug is in the midst of the development process, there may be data available that anticipate positive outcomes; however, until the full testing regimen is complete, there is an element of speculation and associated risk.

In the case of a desperately ill patient, do desperate circumstances warrant desperate measures? Consideration must be given as to whether the protections afforded under FDA law should be waived in these circumstances, and whether there is an obligation on the part of a government agency to provide unrestrained “rescue.” Of course, the hitch here is that in order to provide any promise of “rescue” there should be a legitimate and valid body of evidence to ensure that there is a reasonable therapeutic index in-play (eg, that the potential benefits outweigh the risks of harm). Even then, there are well-warranted cautions about implying any degree of certainty that the patient will be “cured” upon administration of the drug. How does one convey the degree of uncertainty associated with early-stage clinical data? How are the probability of harm and possibility of benefit adequately conveyed in a valid informed consent process?

The assessment of the weight of evidence is critical, yet there is much subjectivity, particularly given that interventions of interest are usually still in early stages of clinical development. Can one, with reasonable assurance, make value-based decisions if a drug has completed phase I testing in normal, healthy volunteers—often limited to collecting information on pharmacokinetics, pharmacodynamics, and systemic toxicity? The attrition rate of compounds in development remains astonishingly high, with a large number falling out of the pipeline in later-stage development.

Practice Versus Research

There are very clear distinctions between medical practice and medical research. These are articulated in the Belmont Report. ⁹ Practice consists of “interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide: diagnosis, preventive treatment or therapy to particular individuals.” Research is an “activity designed to: test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge. Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective.”

If right-to-try is not considered to be research, is it exempt from protections embodied in “research-based” standards, as articulated in FDA guidance, International Council for Harmonization (ICH) Good Clinical Practices, ^10,11 Declaration of Helsinki, ¹² European Union Regulation No. 536/2014, ¹³ and other policies that govern human behavior? In other words, are we as a society willing to remove protections already in place for individuals involved in research? This would require creation of one-off ethical standards. As noted in the Belmont Report, ⁹

When a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is “experimental,” in the sense of new, untested or different, does not automatically place it in the category of research. Radically new procedures of this description should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Thus, it is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research project.

Protections also include specific rules for stopping studies should certain types or incidences of associated adverse events occur or if there is evidence of futility in achieving therapeutic success in a patient population. As there are no protocols required under right-to-try initiatives, those “canaries in a coal mine” are not built into the process.

Access to aggregate data across patients and sites, as well as information provided by monitoring concurrent literature, would not necessarily be conveyed to physicians treating patients under right-to-try initiatives. There are no provisions in right-to-try that address the need for the provider of the investigational product to ensure that insights gained from this information are communicated to others outside of the IND-based clinical study community. In the latter context, principal investigators and the FDA are advised of meaningful information through amendments to the investigator’s brochure, annual IND reports, and formal letters to investigators.

An online editorial in The Lancet Oncology ¹⁴ stated that “there are many ways in which physicians can access drugs that are in early-stage clinical trials but not yet widely available. However, provision of these agents on a desperate whim, in an unmonitored environment, could lead to patient harm. For example, the maximum tolerated dose may be unknown, leading to the dose being sub-therapeutic, or causing unexpected adverse events.” From the physician’s perspective, does the greater degree of uncertainty of doing harm, as compared with the more controlled context of a study under protective standards, come into conflict with the Hippocratic oath of “above all, do no harm”?

Individual Versus Society

A fundamental dynamic tension is that between the individual and society. There are necessarily trade-offs between potential value to be gained by each of these entities, and one must consider if, as an individual member of society, one has an obligation to the greater good of the greater number of that group to which one belongs. This concept applies to both personal obligations and to personal liberties. We obey laws and societal conventions, not because they necessarily have great potential benefit to us (not robbing the local bank, for example) but because they form the underpinnings of a functioning society. We also have protective laws in place that constrain unwarranted actions by Society (eg, laws against illegal search-and-seizure). These precepts also apply to corporations (setting aside recent US Supreme Court decisions such as Citizens United v Federal Elections Commission, ¹⁵ which in many respects grants the rights of persons to corporations).

We must assess the location of the tipping point of tradeoffs of individual liberties for the benefit of the whole and ensure, to the best of our ability, that the point is determined on preapproval access to optimally balance the needs of the one versus the needs of the many.

If there are costs to be borne by Society in making available early-stage preapproval drugs, are there quid pro quo obligations on the part of the individual patient to compensate for these costs? Right-to-try laws offer no direction on financial assistance to offset attendant costs, and a petitioned company has the option to charge, on a cost-of-goods basis, for their investigational product. Examples of costs would be the withholding of that patient’s data from a database for future analysis; diversion from participation in a controlled clinical trial; cost of procedures, drugs administered during the course of treatment; and cost of addressing sequelae emerging as a result of treatment with the preapproval drug. The right-to-try model states the written informed consent must include a “statement that the patient understands that he or she is liable for all expenses consequent to the use of the investigational drug, biological product, or device and that this liability extends to the patient’s estate, unless a contract between the patient and the manufacturer of the drug, biological product, or device states otherwise.” ⁸ Third-party insurance may or may not reimburse some of these costs. Thus, a patient’s offsetting obligations might include making available data obtained in the course of drug administration—scheduled measurements, assessments, and observations in accordance with predefined criteria. At the very least, there should be an obligation to report deaths and serious adverse events considered by the physician to be causally related to the investigational product. While anecdotes may have value as guides to further empirical investigation, they do not equal data. One might consider a hierarchy of “admissible evidence”:

Anecdote

↓

Data

↓

Evidence

↓

Admissible Evidence

Additionally, one must consider the needs of the current patient in the context of what it might mean to therapeutic options for future patients. This is important because ultimately, individual patients benefit by advances resulting from empirically sound data contributed by other individuals. These, in turn, result in therapeutic benefit to the broader population, both in terms of improved or novel therapeutic interventions (thus made available earlier to individual patients) and, in many cases, by reducing costs for care associated with chronic disease—costs borne by the society at large. By removing prospective patients from the structured clinical trial population, there may be a delay in recruiting adequate numbers into the study. This is particularly true for rare and orphan diseases, with many fewer representative patients in the general population. Is there not an element of altruism that should be expected of anyone who wishes to avail oneself of an institutionally provided benefit?

Another consideration is the diversion of resources. Is the right to be offered rescue affected by efficient use of resources? Often, particularly at the beginning of the clinical research cycle, investigational product is in short supply. Quantities barely cover amounts required for the conduct of the studies and, in some cases are made on an as-needed basis. If these supplies are diverted to nonstructured clinical studies, the manufacturer is not gaining value (measured in valid, usable data) from the provision of the drug. Human resources are also required to consider requests; as well as prepare, administer, and oversee the processes involved with the provision of an investigational product.

Responsibility Versus Accountability in the Context of Individual Choice (Agency)

In a litigious society where no one accepts blame for unanticipated negative consequences, is there room for a process that may lead to “blameless harm”? This scenario is compounded by the proliferation of social media, providing an unvetted “bully pulpit” to anyone with access to a computer. This allows someone who might feel that they, or a loved one, have been unduly harmed in the course of being treated (or not) with a drug in early-stage development, to “rage against the machine.” This could result in significant damage to drug developers (in either a case where the patient is granted access to the developmental drug or, conversely, if they are refused access). These may include threats of physical harm to executives of companies that would not provide access, discouragement of funding from potential investors, and much negative publicity that could damage future sales.

Are patients who access preapproval drugs, particularly at the early stages (eg, phase I) allowed by most of the state-based right-to-try legislative initiatives, willing to accept the potential hazards of such access? Or, should something go wrong, will they or their families seek to place blame on those who provide the access at the patient’s request? Despite the fact that under the model legislation, there are limits to the legal exposure of the manufacturer of the drug, there are other avenues of retribution (see above).

Certainly both the FDA and right-to-try programs provide limited assurances of a robust therapeutic index to patients. These are, after all, products under investigation and, depending upon how early in the cycle they are and how similar they are to other therapies, there will be a significant degree of uncertainty. Informed consent will, by necessity, be limited in terms of how well the product profile can be understood. This is inescapable in both programs.

A Price Too High?

In considering the topics addressed above, I maintain that the costs of circumventing a system of structured and monitored preapproval access, such as that embodied in the FDA’s Individual Patient Expanded Access Application, are too high to bear. Perceived administrative impediments that imposed delays on patients and their physicians requesting access to drugs in development have been, for the most part, removed. The safeguards provided in the context of accessing drugs in development through the FDA are too important to give up, particularly since there are few, if any, advantages to a right-to-try process that adds to an already risky scenario by removing requirements that bring to bear vital information and insights provided by investigators, regulators, and pharmaceutical company sponsors. Further, there is no obligation to gather or report structured data, thereby potentially depriving current and future patients of the benefit of information on therapeutic responses and safety profiles of experimental drugs based on experiences of surrogates in their cohort. Under the recently issued Department of Health and Human Services final rule on clinical trial reporting on ClinicalTrials.gov, ¹⁷ it appears that one-off right-to-try cases would not be considered as “applicable clinical trials,” thus exempting them from registration and results posting requirements mandated under the rule.

Juxtaposing the rights and obligations of the individual against those of society brings to light significant dynamic tensions. These should be evaluated in the course of deciding whether or not to follow one of the limited options.

It is important to be compassionate; however, we cannot allow this to cloud the lens through which we view unintended consequences. Emotion and personal experience will always affect our decisions, and this is a positive essence of our humanity. However, when considering formulation of social policy, these emotions may cloud the assessment of consequences of those decisions. If we objectively consider costs and benefits, not just for ourselves—as patients—but for our fellow patients, now and in the future, we will reach a point of clarity that will better inform the way we provide the best possible options to those in desperate need.