Alison Bateman-House

Should patients in need be given access to experimental drugs

Patient access to experimental drugs outside of clinical trials is called compassionate use or expanded access. Compassionate use/expanded access presents a powerful ethical dilemma in that it involves competing claims that both have moral weight: specifically, an individual patient’s very understandable desire to try to extend his or her life versus the orderly and efficient functioning of a drug development and clinical trial system that benefits much larger numbers of patients. Patient advocates, the FDA, pharmaceutical trade groups, and state and national legislators in the US are all currently weighing in on patient access to experimental drugs, and new guidelines and rules are being introduced. In this editorial, we discuss the impulse to rescue individual patients facing dire diseases and underscore the ethical questions that such rescue efforts raise.

The Federal Right to Try Act of 2017—A Wrong Turn for Access to Investigational Drugs and the Path Forward

In 2017, President Trump said that “one thing that’s always disturbed”1 him is that the US Food and Drug Administration (FDA) denies access to experimental drugs even “for a patient who’s terminal...[who] is not going to live more than four weeks [anyway.]”1 Fueled by emotionally charged anecdotes recirculated by libertarian political activists, 38 states have passed Right to Try laws. In 2017, the US Senate approved a bill that would create a national law (Box).2 As of December 2017, the US House of Representatives was considering the bill. Although the FDA has an expanded access option for utilizing experimental drugs outside of clinical trials, Right to Try laws create an alternative pathway that bypasses the agency. Moreover, the term “Right to Try” is a misnomer: the legislation creates a right for a patient to ask a company to provide a product, the same right that currently exists.3 As is the case with the FDA program, companies are not obligated to provide access. The proposed federal Right to Try legislation2 sets the threshold for patients to access investigational drugs at the completion of phase I (dosage-determination) trials, grants companies and physicians broad immunity from liability, and largely blinds the FDA to safety or efficacy data from these therapeutic attempts. Such changes would upend the agency’s expanded access program, which has worked successfully for decades to provide patients who are seriously ill and without therapeutic options access to investigational drugs and still assure the safety and efficacy of new drugs before these products gain marketing approval. The legislation does not solve actual concerns, such as lack of knowledge that the program exists and the very limited supply of many investigational products. A 2016 review4 of 10 years of FDA records found that the Center for Drug Evaluation and Research receives over 1000 expanded access applications per year. The FDA reviews such requests in days—or hours when an emergency so requires—and approves over 99%.5 This is no mere rubber stamp of proposals: unlike individual physicians, the FDA has access to proprietary data about the risks and benefits of the investigational product or others in the same class. In some instances, the agency can improve the proposed treatment via modifications of drug dosage, dosing schedule, or other aspects.6 Eliminating the FDA’s review of expanded access requests is perilous, because most of the drugs that succeed in phase 1 trials turn out to be too unsafe or ineffective for clinical use. Phase 1 trials are intended to find a reasonable dosage of a drug in a small number of subjects, who may not even have the disease in question. About two-thirds of successful phase 1 drugs will fail as they proceed to phase 2,7 and even more will fail at phase 3. Given the low odds that an investigational drug will succeed, patients benefit from the agency’s review. Under expanded access, the FDA does not set a threshold for when patients may access investigational drugs: the agency has permitted access to products that are in phase 1 testing, and well as in preclinical (nonhuman) testing. Such a case-by-case approach is appropriate and should be retained. The federal Right to Try legislation2 creates immunity for physicians who prescribe investigational agents and companies that dispense them even if they act negligently in certain circumstances or if their actions may have been influenced by financial conflicts of interest. In our view, such broad liability protection is not needed. If Congress, nonetheless, seeks to provide immunity, it should be premised on FDA review of the protocol and the patient having received independent advice from a physician who has no economic or reputational stake in the investigational drug. Under the expanded access option, pharmaceutical companies can only charge shipping and manufacturing costs for their investigational products. The Senate bill2 has no such restrictions, opening the door for companies to profit from selling unproven drugs. The FDA policy of limiting what companies can charge for their investigational products provides an important incentive for companies to complete clinical trials. In addition, the bill includes no mechanisms or incentives for insurance coverage, which would be essential if companies were to charge, as private and government health insurance plans generally exclude coverage for experimental treatments. Instead, the Senate bill creates a very real opportunity for vulnerable patients to be taken advantage of financially. Furthermore, 19 state Right to Try laws specifically allow insurers to deny hospice coverage to patients who try investigational products via the Right to Try pathway: 5 of those laws also allow denial of coverage for home health care (as does the law of an additional, sixth state, which does not have the hospice provision). Three of the 19 state laws allow, in addition to denial of both hospice and home health care coverage, denial of insurance coverage altogether for up to 6 months after treatment with the investigational product ends. One state law allows denial of home health care and insurance coverage without mention of hospice coverage.8 If investigational products are to be treatment options—as advocates of Right to Try laws intend—then federal law should prohibit insurers from VIEWPOINT

Compassion for Each Individual's Own Sake

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Fair, just and compassionate: A pilot for making allocation decisions for patients requesting experimental drugs outside of clinical trials

Patients have received experimental pharmaceuticals outside of clinical trials for decades. There are no industry-wide best practices, and many companies that have granted compassionate use, or ‘preapproval’, access to their investigational products have done so without fanfare and without divulging the process or grounds on which decisions were made. The number of compassionate use requests has increased over time. Driving the demand are new treatments for serious unmet medical needs; patient advocacy groups pressing for access to emerging treatments; internet platforms enabling broad awareness of compelling cases or novel drugs and a lack of trust among some that the pharmaceutical industry and/or the FDA have patients’ best interests in mind. High-profile cases in the media have highlighted the gap between patient expectations for compassionate use and company utilisation of fair processes to adjudicate requests. With many pharmaceutical manufacturers, patient groups, healthcare providers and policy analysts unhappy with the inequities of the status quo, fairer and more ethical management of compassionate use requests was needed. This paper reports on a novel collaboration between a pharmaceutical company and an academic medical ethics department that led to the formation of the Compassionate Use Advisory Committee (CompAC). Comprising medical experts, bioethicists and patient representatives, CompAC established an ethical framework for the allocation of a scarce investigational oncology agent to single patients requesting non-trial access. This is the first account of how the committee was formed and how it built an ethical framework and put it into practice.

Institutional Review Boards as Arbiters of Expanded Access to Unapproved Drugs Time for a Change

Institutional review boards (IRBs) are one of the bodies charged with prospectively reviewing compassionate use, the hopefully therapeutic use of an unapproved drug in a seriously ill or dying patient who has no other treatment options. However, there are ethical issues in assigning this role to a body whose primary purpose is to review research proposals. The role of IRBs with regard to compassionate use must be examined and potentially revised.

Compassionate Use: A Modest Proposal.

Editor’s Note: The following article is based on the 2016 ASCO Annual Meeting Education Session “Expanded Access and the Right to Try: Navigating the Intersection of Drug Development and Patient Ac...

Improving Expanded Access in the United States: The Role of the Institutional Review Board

Background: The FDA allows patients with a serious or immediately life-threatening illness to use investigational medical products outside of clinical trials through its “expanded access” program. In response to criticism that the process to apply for expanded access is too onerous, numerous changes have been made over the last few years. These have been largely focused on the FDA and the pharmaceutical industry, while institutional review boards (IRBs)—which must approve expanded access protocols, except in emergencies when there is not time to do so—have remained relatively unstudied. We conducted a pilot study to review a sample of publicly available IRB policies from the United States to investigate how these entities handle expanded access. Methods: We performed an online search to find publicly available policies for IRBs operating in the United States, utilizing a convenience sampling strategy, selecting the first 100 eligible policies we identified. Results: Of the 95 policies reviewed, the majority (92.6%, n = 88) contained language referencing nonemergency expanded access and/or expanded access for emergency requests for a single patient. Of these 88 policies, 11.4% (n = 19) did not explicitly specify detailed procedures for handling nonemergency single-patient expanded access requests. Of the 88 policies that mentioned expanded access in nonemergency situations, 11.5% did not explicitly specify whether full IRB review was required, as was the rule at that time. There was considerable variation in other aspects of these policies, including charging patients for use of investigational products and the use of data from expanded access. Conclusions: Based on the findings of our pilot, IRB policies on expanded access vary considerably. It is often difficult to find, interpret, and understand IRB policies on expanded access. Further research is needed to determine if and to what extent this negatively impacts patient access to investigational products outside of clinical trials.

A Pilot Experiment in Responding to Individual Patient Requests for Compassionate Use of an Unapproved Drug: The Compassionate Use Advisory Committee (CompAC)

Background: Janssen Research & Development, LLC, part of the Janssen pharmaceutical companies of Johnson & Johnson, and NYU School of Medicine partnered to establish the Compassionate Use Advisory Committee (CompAC) to evaluate the use of an independent, external, expert committee in ensuring transparent, fair, beneficent, evidence-based, and patient-focused compassionate access to investigational medicines, a public health challenge that has been an ongoing issue for over 3 decades. Methods: To this end, NYU School of Medicine was responsible for the formation, member selection, and operation of CompAC, consisting of physicians, ethicists, and patient advocates, under Johnson & Johnson’s sponsorship. Results: A pilot was successfully run using CompAC to provide recommendations on compassionate use access to a Johnson & Johnson oncology investigational asset called daratumumab. Conclusion: This innovative model provides a framework that can be emulated by the industry globally.

Pre-approval Access Terminology: A Cause for Confusion and a Danger to Patients

Background: Patients who are seriously ill and have run out of available treatment options may seek access to investigational agents that have not yet been fully vetted by regulatory agencies for safety and efficacy and approved for use in human subjects. Over time, a variety of terms have evolved internationally to denote mechanisms for providing access to such unapproved investigational agents. The lack of consistency in terminology used to describe this process is confusing at best and, at worst, possibly even detrimental to patients. Methods: To highlight variation around the globe in terminology denoting pre-approval access to investigational agents, we conducted extensive Internet searches to locate specific legislation, guidance, or policy documents describing access mechanisms in numerous countries. We created a table of results intended to convey a sampling of international terminological diversity. Results: The profusion of terms used internationally to indicate pre-approval access to investigational agents is evident. We recommend a shift toward the use of “pre-approval access” as an umbrella term encompassing all forms of access to unapproved agents. We also recommend use of the phrases “individual/named patient regulatory routes for pre-approval access” and “group/cohort regulatory routes for pre-approval access” to differentiate between pre-approval access programs designed for single patients, versus those designed for groups of patients. Conclusions: There is a pressing need to revisit and better align pre-approval access terminology at the international level. Adopting the umbrella term “pre-approval access” may be a useful strategy for initiating and promoting harmonization of terms to reduce potential confusion by patients and health care decision makers regarding experimental treatment options.

Ensuring Justice in Access to Investigational Neurological Drugs

Abstract Patients who suffer from life‐threatening illnesses or are stricken with conditions that could result in serious morbidity who have exhausted all appropriate treatments may choose to try, through the Food and Drug Administrations expanded access program, an investigational drug or device in development. The program has succeeded for decades in allowing patients to access potentially helpful but still experimental agents. Nevertheless, the administration of investigational drugs outside of clinical trials raises several ethical issues. Of particular concern are the validity of informed consent and the absence of a framework to ensure that experimental drugs are allocated justly and transparently. Although there are some safeguards to help protect the soundness of consent, little work to date has been done to guarantee that investigational medical products are allocated justly and transparently. We introduce a novel pilot project that seeks to address this issue.