Recommendations to Facilitate Expanded Access to Investigational Therapies for Seriously Ill Patients

Abstract

When clinical trial enrollment is not an option for seriously ill patients whose illnesses have not responded to approved treatment options, those patients and their physicians may consider gaining access to investigational therapies through a pathway established by the Food and Drug Administration (FDA) called expanded access. However, recent events have highlighted the challenging dynamics involved in accessing investigational therapies through expanded access that include a complex interplay of factors involving the patient, physician, drug company, FDA, and, increasingly, social media.

The authors offer several potential strategies to streamline what is otherwise an arduous process for all involved. (1) The drug company should prospectively determine whether it will establish an expanded access program for specific drugs. (2) A central clearinghouse for companies should support registration of expanded access drugs for suitable patients. (3) The determination of whether a patient fits criteria would be made by an independent review board of clinicians. (4) An independent coordinating center is needed; academic health centers are ideally suited for that role. (5) Adequate financing of the costs of therapy need to be in place to make expanded access a reality, given frequent lack of payor coverage for therapies. (6) Further enhancement of regulatory pathways, approaches, or rules would promote expanded access. (7) Patients should explicitly acknowledge the limited data available. (8) There should be a shared, secure, technical platform to facilitate expanded access.

All the authors’ strategies present important prospects for improving treatment options for the most seriously ill patients.

Despite tremendous advances in disease therapies, the U.S. health care system includes significant subpopulations of patients with serious conditions who have exhausted treatments approved by the U.S. Food and Drug Administration (FDA). Often these are our sickest patients in greatest need: various cancers, idiopathic pulmonary fibrosis, and ultra-rare diseases are just a few examples for which existing treatments may fail to arrest disease progression. The current drug development landscape includes a rich array of investigational (non-FDA-approved) options that may target an afflicting condition and offer at least hope of improvement. Although clinical trials provide an option for some patients to access these therapies, many others fall through the gaps by not meeting rigid (albeit necessary) inclusion criteria.

Consider, for example, the patient with ovarian cancer whose disease has progressed despite treatment with the FDA-approved therapies. She and her physician explore trials of therapies that could be appropriate for her next stage of care via the Web site ClinicalTrials.gov (www.clinicaltrials.gov), scanning for novel therapies. However, when they review the criteria for trials of promising therapies relevant to her characteristics, they find that she fails to meet the tight eligibility criteria for these trials. Most worrying, the presence of distant metastases is often an exclusion criterion, but this can be the very sign that approved therapies have failed. Life expectancy estimates and adverse effects during previous therapies can also limit applicability to interested patients.

Such patients and their physicians, feeling the lack of viable options in the face of worsening disease, may turn to options for accessing investigational drugs outside of trials. While recent media attention has focused on the roles of drug companies and the FDA in accessing investigational drugs outside of trials, in this article, we offer potential solutions, including roles for academic health centers, to streamline what is otherwise an arduous process for all involved.

Regulatory Context

Fortunately, the FDA has a longstanding program to enable use of investigational agents outside of a clinical trial, a special circumstance known as expanded access or compassionate use. This regulatory process focuses on patients with serious or immediately life-threatening diseases without “comparable or satisfactory alterative treatment options” (see List 1), and includes both single patients and intermediate-sized groups of similar patients (usually fewer than 100 individuals).^1–4 In practice, the FDA appears agreeable to these requests; between October 1, 2009 and September 30, 2014, the FDA granted 5,996 of 6,029 requests (99.5%)⁵ and noted recent increases in such requests.⁶

List 1.

Patient Characteristics Necessary for an Expanded Access Request to Use an Investigational Therapy^a

The patient has a serious or immediately life-threatening disease. Alternative treatment options have been exhausted and the patient is not a candidate for appropriate clinical trials. A promising investigational therapy is in the pipeline. The patient’s physician must determine that the probable risk with the investigational agent is not greater than the probable risk from the disease.

^aWhen clinical trial enrollment is not an option, patients and their physicians may consider gaining access to investigational therapies through a pathway established by the Food and Drug Administration called expanded access, or commonly called compassionate use.

Challenging Dynamics

Despite the well-defined FDA pathway, in reality, seeking expanded access may involve a complex, labyrinthine process, even before obtaining FDA approval. The FDA does not mandate cooperation from a drug company, but rather focuses on reviewing the rationale and protocol for expanded access after a physician has determined that use is appropriate and a drug company has agreed to provide the drug.

Drug companies may cite valid concerns⁷ that expanded access may hinder active registration trials. There is an underlying fear that data from expanded access patients may have an impact on the FDA’s ultimate decision on drug approval, as these patients may be at greater risk of adverse events, given the stage of their diseases. Unease regarding liability can similarly affect decision making.⁸ The company may also have legitimate manufacturing issues; investigational agents may be expensive and difficult to produce, and existing stores of a drug may be earmarked for trials or depleted. Processing expanded access requests also requires time from legal, regulatory, and scientific personnel that may conflict with commercial goals.

The treating physician may find the pursuit of expanded access burdensome, with responsibilities for many tasks: securing the drug company’s approval to provide the investigational agent, obtaining approval from an institutional review board (IRB), and submitting the expanded access request to the FDA, all of which are time-consuming. An additional complexity is the FDA requirement that a request for expanded access undergoes full committee review by an IRB (of note, a subset of requests meeting FDA criteria for emergency use of an investigational therapy follow different requirements). IRB submissions can involve considerable time and effort for people unfamiliar with expanded access, and can add significantly to the timeline.⁹ Physicians practicing at institutions not affiliated with an IRB must seek out an IRB to provide the review, potentially at additional cost to the patient. IRBs are then faced with fitting these nuanced and challenging reviews into already over-burdened schedules. Certainly, there is need for ethical oversight for the potentially vulnerable patients seeking expanded access; however, full IRB review adds a significant layer of complication.

Patients seeking expanded access face intimately personal challenges. These patients work with the physician to weigh options and make difficult decisions in the face of worsening disease, having exhausted standard treatments. Cost for expanded access to an investigational agent can be an issue; although some companies agree to provide an agent at no cost, charging is allowable per FDA regulations³ and may be necessary depending upon a company’s resources. Such expenses are not usually covered by a patient’s insurance. Informed consent also poses unique challenges. Assessing the risk–benefit ratio often is difficult due to the small body of data regarding potential adverse events for investigational agents.⁶ Cognitive biases such as underestimation of risk and overestimation of benefit are vital pitfalls to overcome to aid the patient in framing reasonable expectations.

Integration of these issues creates a distressing conundrum for our society. Dynamics between stakeholders may fail to align, leading to a breakdown in the process before it has really begun, as well as frustrated physicians and angry, desperate patients and families.

A Backdrop of Increasing Public Attention

The ubiquitous use of social media has increased the complex interplay of constituents. There have been several prominent social media firestorms in recent years, with patients who were denied access to investigational agents starting grassroots campaigns to lobby on their behalf, resulting in a barrage of phone calls and e-mails to drug company leadership. A recent CNN piece discussing expanded access, “Dying patients denied drugs,” ¹⁰ describes widely varying outcomes, including the case of Christian Barker, a boy whose family unsuccessfully sought use of an experimental drug for treating his eventually fatal graft-versus-host disease, and the case of Josh Hardy, another child, who survived after receiving expanded access to an investigational antiviral agent after a significant grassroots campaign. Expanded access to novel therapies has produced significant debate during the Ebola epidemic.¹¹ Recent films have also generated awareness, framed in the groundbreaking events surrounding access to investigational drugs in the early days of the AIDS epidemic, including 2013’s Dallas Buyers Club and the 2012 documentary describing the tremendously influential HIV advocacy group ACT UP, How to Survive a Plague.

Further signifying current relevance, several groups have focused thoughtful debate and recommendations on improving the path to expanded access.^12–15 The issue has also caught the attention of some state legislators, who have passed new “right to try” laws in several states,¹⁶ though it remains uncertain how such laws might be applied, given their conflict with the FDA’s federal mandate. Congress has also considered amending the process for expanded access, including legislation currently being considered.^17–19 The regulatory process has also been challenged by lawsuits; in one of the more recent cases (Abigail Alliance v. von Eschenbach), the U.S. Court of Appeals for the District of Columbia judged that there was no Constitutional right to unapproved drugs for seriously ill patients.²⁰

Proposed Solutions for Improved Patient Care

Given the issues surrounding expanded access, the small volume of requests received by the FDA is not surprising. The number of requests is paltry when compared to the unmet medical need; although it is difficult to arrive at a confident quantitative assessment of the volume of patients affected by lack of options, studies in serious diseases such as chronic obstructive pulmonary disease and various cancers indicate that anywhere from 30% to over 80% of patients may be ineligible for trial participation.^21–23 While some patients do and will continue to receive expanded access with current approaches, we suggest that there is a significant need for more effective routes to novel therapies for seriously ill patients who do not have other options. We offer some ideas below to catalyze discussion of strategies for improving the path to expanded access.

The drug company should prospectively determine whether it will establish an expanded access program for specific drugs

As part of the planning involved in the drug development pipeline, a drug company can assess the utility of expanded access for a given investigational agent. As an agent begins to show promise in early-phase studies involving patients with serious or life-threatening conditions, there lies a clear opportunity for the drug company to proactively consider whether an explicit expanded access plan is appropriate. Criteria to be uniformly applied in identifying the affected patients can be determined at the front end, allowing for subsequent inception of a program if the agent’s development meets a threshold of interest, such as promising entry into Phase III work. The plan could then be submitted by the drug company to the FDA through the existing pathway for expanded access approval of an intermediate sized population when the predetermined threshold is reached. Even making this information known would help manage expectations and eliminate false hope.

A central clearinghouse for companies should support registration of expanded access drugs for suitable patients

A neutral third party, such as an academic health center or a group of such centers, could maintain a Web-based registry of investigational agents available through expanded access, including the pre-established inclusion and exclusion criteria. Patients and their doctors who have exhausted other options could search for potential therapies. An expanded access portal could include application templates to aid in the physician’s initial assessment of a patient’s eligibility, including structured formats for reporting disease characteristics, previous treatment approaches, and documentation of inability to qualify for relevant trials, which would remain the primary path to an investigational agent whenever possible, in accordance with the important premise that expanded access should not interfere with trial enrollment.

The determination of whether a patient fits criteria would be made by an independent review board of clinicians

Combining the clearinghouse and application templates with establishment of a dedicated independent review process would further streamline this process. The review board would function independently from the drug company and comprise a group of appropriate clinician specialists assembled for this specific purpose.

The board would review expanded access applications submitted by the treating physician, including assessment of a risk–benefit ratio for each patient. Many models exist to incorporate risk and benefit variables, along with their uncertainties, to produce estimates of net benefit under specific assumptions. In the context of expanded access, however, we propose that when prospects for a patient are relatively dismal, such as when the probability of death within the next 6 months is exceedingly high, risk–benefit assessment for a single individual becomes far less complicated. Further, as outcomes are increasingly informed by patient input,²⁴ the purely psychological value of hope may be included; indeed, published reports of expanded access cases include both clinical variables such as tumor response and less tangible metrics such as quality of life.^25,26 Though detailed discussion of this concept is outside our scope, the proposed framework would naturally contribute to evolving thought on these issues.

After thorough evaluation of risk and benefit for the patient, the board would arrive at a decision about eligibility, and notification of this decision and supporting rationale would include the treating physician, patient, FDA, and drug company, making the decision-making process transparent to all key constituents. One recent academic/industry partnership has begun to explore the utility of a review panel in making expanded access decisions, suggesting that independent stakeholders can collaborate to find new solutions to historical challenges.²⁷

An independent coordinating center is needed

Organizations such as academic health centers have scientific infrastructure, intellectual capital, and track records of high-quality clinical care and research. We posit that such institutions are ideally positioned to adapt the coordinating center model, successfully implemented in clinical research, to the development and administration of expanded access programs. Although for-profit entities such as contract research organizations have also show interest in these programs, we believe the independence, objectivity, and non-profit focus of academic health centers would help minimize perceived or real conflicts of interest and biases.

These centers could facilitate procedural steps in an expanded access case, such as searching for clinical trials and documenting lack of trial options when appropriate. When expanded access is a valid strategy for a particular case, a coordinating center could facilitate FDA and IRB submissions (in 2012, 62 major academic health centers have regulatory experts through their Clinical and Translational Science Awards).²⁸ Cases could then move through either the local IRB, or, alternatively, through a central IRB²⁹ or shared IRB model such as IRBshare³⁰ if needed. The coordinating center could also facilitate interaction between the drug company and treating physician; templates for required reports on the case as well as guidelines and form templates for adverse event reporting to the FDA would also be incorporated into this process. With an established review process and coordinating body, expanded access would become more streamlined, minimizing burdens on other parties.

Adequate financing of the costs of therapy need to be in place to make expanded access a reality, given frequent lack of payor coverage for therapies

The cost of the investigational agent is a potential insurmountable barrier in the expanded access process. As described above, the drug company, in an expanded access situation, may elect to provide the investigational agent for free to the patient, or to charge for use of the drug, an expense that is usually not covered by insurance. Of note, current Internal Revenue Service guidelines allow for larger deductions by a corporation when inventory is donated to a non-profit organization for care of the ill³¹; it is worth exploring this and other avenues, such as funding opportunities with relevant foundations and other granting entities, for making an expanded access case more financially benign to the drug company and the patient.

Further enhancement of regulatory pathways, approaches, or rules would promote expanded access

The FDA acknowledges concerns that requiring full IRB review may deter expanded access and notes that it is currently considering other options for ethical oversight⁴; although alternatives have not yet been proposed, streamlined approaches could be drawn from existing medical device requirements, such as requiring approval by an IRB chair and an independent physician, or through the expedited review process. Recent draft guidance released by the FDA also proposes to significantly simplify the application form for single-patient expanded access.³²

It is also possible that new guidance would include provisions that safety data for expanded access use not be collected beyond what would be captured in the course of routine clinical interactions. These provisions would minimize the risk of interference with an agent’s approval pathway. Given the negligible statistical power of a single case—particularly a case that by definition is unlike one involving a trial participant—to contribute to the body of knowledge on a particular agent, it might make sense to exclude these data from the FDA’s evaluation of the new drug application. Further, data could always be reviewed if the drug company elects to pursue marketing approval for a broader population that would include cases similar to the expanded access case.

Other FDA incentives for drug companies are also worth consideration. Recently, steps to increase applicability of drug development to the health care of children included new provisions for adding six months of market exclusivity when pediatric studies are completed. This incentive has been tremendously successful in strengthening our national evidence base for safety and efficacy of drugs in children,³³ and a parallel incentive in expanded access may have similar attractiveness.

Patients should explicitly acknowledge the limited data available

As noted above, the smaller body of data on risk and benefit for an investigational agent may generate liability concerns and challenges in effective informed consent. Expanding on the model for informed consent used in clinical trials, it seems reasonable to adapt that model in expanded access, whereby the patient is explicitly informed of the possibility of unknown side effects and communicates awareness and acceptance of the possibility of gaps in relevant safety or efficacy data. Many patients will opt not to seek expanded access; others may be willing to assume such risk and uncertainty if their personal narrative focuses on continuing the battle against their serious disease.³⁴

There should be a shared, secure, technical platform to facilitate expanded access

Last, expanded access could receive significant facilitation by combining several of the above options in a neutral, independent technical system in support of a clearinghouse of information to be accessible by patients, companies, and doctors. This secure, technical platform should serve to:

• promote awareness of companies with specific drugs available for expanded access;

• assist physicians and patients with the determination of whether expanded access is applicable;

• provide an intake mechanism for individuals wishing to participate in an expanded access program;

• provide pre-assessment of patient characteristics and human-assisted communication tools for those not deemed to be strong candidates;

• provide quasi-automated selection, enrollment, and feedback from a dynamically assembled review board of independent clinicians in cases where the physician–patient combination makes a strong case for expanded access;

• facilitate a template-based collection of structured data from physicians and patients regarding pre-established efficacy and safety measures; and

• automatically collect metrics related to process, regulatory documentation requirements, and all other data necessary to evaluate whether the new system is adding value.

The informatics infrastructure must be secure and user friendly to all stakeholders to achieve the goal of a more transparent and usable approach.

Seeking to Create a Better Future for Expanded Access

The current system for expanded access is, at best, misleading for all but a few patients. When physicians and patients try to obtain a promising and novel therapy for a serious and life-threatening disease, the likelihood of obtaining the therapy should not be so impossible to predict. Although approval channels exist, for practical purposes, drivers for decision making are often almost completely misaligned. We have sought to reinvigorate the dialogue on this challenge by offering the possible strategies for improvement stated above.

Strategies like those would help mitigate drug company concerns that have led to expanded access refusal, and make the entire decision-making process more transparent to physicians and patients. An effective expanded access cohort could further yield a benefit to the drug company as a clear, positive implementation of humanitarian objectives. Compliance with FDA regulations also would ensure that such programs avoid perceptions of “off-label” use, though an ethical expanded access approach could also naturally have the unintended side effect of increasing pre-marketing visibility of a promising agent.

In addition to streamlining the expanded access process and lessening stakeholder burdens, the solutions would provide opportunities for collaboratively developing ideas for handling expanded access safety and efficacy data. This could be especially important, as there does not appear to be a single standard for how expanded access data should be used in the review process across divisions of the FDA. It is also likely that implementation of these solutions would illuminate additional strategies for improving the attractiveness of expanded access to drug companies and for refining the regulatory path.

Too many lives are lost without access to investigational drugs that could prolong life or improve quality of life; all of us engaged with expanded access issues must work to effect change within the system that exists. Academic health centers are well-positioned to partner with drug companies, patients, physicians, and the FDA as independent coordinating centers, as described earlier. At best, we can create a better future for expanded access; at least, we can inform patients of their options, so that precious time is not wasted at the end of life on truly useless efforts to gain access to inaccessible drugs.