eBriefing

Pre-Approval Access: Can Compassion, Business, and Medicine Coexist?

Pre-Approval Access
Reported by
Hallie Kapner

Posted January 25, 2016

Presented By

NYU School of Medicine

The New York Academy of Sciences

Overview

On October 28–29, 2015, the New York Academy of Sciences and NYU School of Medicine convened a multidisciplinary conference on pre-approval access to medicines outside a clinical trial, or what is often referred to as compassionate use. The process by which critically ill patients may request access to experimental therapies prior to regulatory approval poses complex ethical, legal, and social challenges that often leave patient advocacy groups, physicians, pharmaceutical companies, regulators, and patients at odds in the struggle to determine how far an individual can go to try to save his or her own life, and at what—and whose—cost.

The 2-day conference consisted of panel discussions designed to probe different aspects of compassionate use. Stakeholders came together to put the system under the microscope, examining how heightened public awareness of compassionate use, advances in drug development, the advent of social media, and the costliness of safely bringing a drug to market affect decisions about whether—and how—to provide experimental therapies on a compassionate-use basis.

Through spirited debates and networking opportunities, conference attendees worked to lay the foundation for better, more collaborative decision making regarding compassionate use policies and programs, and to answer the title question—Pre-Approval Access: Can Compassion, Business, and Medicine Coexist?

Use the tabs above to find a meeting report and multimedia from this event.

Panel discussions moderated by:
Alison Bateman-House, MA, MPH, PhD (NYU School of Medicine)
Arthur Caplan, PhD (NYU School of Medicine)
Nancy Neveloff Dubler, LLB (New York City Health and Hospitals Corporation; NYU School of Medicine)
Brooke Gladstone (WNYC Studios, On the Media)
Fred Guterl (Scientific American)

The portion of the eBriefing that pertains to Matthew Hepburn's remarks in Session 7 is a work of the U.S. Government, and the copyright protection under 17 U.S.C § 105 is not available for any work of the U.S. Government.


This symposium was made possible with support from


Presented by

  • NYU School of Medicine

How to cite this eBriefing

The New York Academy of Sciences. Pre-Approval Access: Can Compassion, Business, and Medicine Coexist? Academy eBriefings. 2016. Available at: www.nyas.org/CompassionateUse-eB

Setting the Stage: Current Challenges and Complexities of Compassionate Use


Arthur Caplan (NYU School of Medicine)
  • 00:01
    1. Opening thanks and agenda setting
  • 03:21
    2. Colloquium background
  • 10:16
    3. Terms and terminology; The ethical challenge
  • 13:38
    4. Information availability; Impediments to access; Exploitation
  • 20:05
    5. Cost and budget; Drug management during humanitarian emergencies; Conclusio

Patient Perspectives on Compassionate Use and Expanded Access


Moderator: Arthur Caplan (NYU School of Medicine)
  • 00:01
    1. Introduction and panelists' opening remarks
  • 23:00
    2. Negotiating access obstacles; Learning what's available
  • 36:53
    3. Exposure to placebo; Trial design
  • 52:13
    4. Patient advocacy
  • 72:43
    5. A compromise in trial design; Patient prioritization; Standardization of information
  • 85:34
    6. Wild type data; Unfettered access; Conclusio

The Case of Josh Hardy: Social Media and Compassionate Use


Moderator: Brooke Gladstone (WNYC Studios, On the Media)
  • 00:01
    1. Introduction
  • 04:20
    2. Remarks by Kenneth Moch
  • 19:50
    3. Remarks by Richard Plotkin
  • 25:15
    4. Remarks by Meg Tirrell and Nancy Goodman
  • 32:50
    5. Remarks by Debra Birnkrant
  • 41:14
    6. The media, narrative arcs, and what was learned
  • 58:30
    7. Regarding social media
  • 67:33
    8. Audience Q and A session; Conclusio

Ebola: Compassionate Use in a Public Health Crisis


Moderator: Arthur Caplan (NYU School of Medicine)
  • 00:01
    1. Introduction and panelists' opening remarks
  • 31:45
    2. Informed consent
  • 50:04
    3. Research vs. saving lives
  • 63:19
    4. Do we need a rapid deployment/research agency?
  • 66:08
    5. Audience Q and A session; Conclusio

Future Vision and New Directions at Johnson & Johnson


Joanne Waldstreicher (Johnson & Johnson)

Can Legislative or Regulatory Changes Ease the Challenges of Expanded Access?


Moderator: Alison Bateman-House (NYU School of Medicine)
  • 00:01
    1. Introduction; Remarks by Carla Mann Woods
  • 11:05
    2. Remarks by Christina Sandefur
  • 19:19
    3. Remarks by Linda Rosenthal
  • 27:29
    4. Remarks by Fritz Bittenbender
  • 35:39
    5. Remarks by Peter Adamson
  • 46:30
    6. Primary responsibility for expanded access
  • 57:18
    7. Provisional approval; Right to try
  • 70:03
    8. Audience Q and A session; Conclusio

International Perspectives on Compassionate Use


Moderator: Arthur Caplan (NYU School of Medicine)
  • 00:01
    1. Introduction
  • 04:50
    2. Remarks by Barbara von Tigerstrom
  • 10:16
    3. Remarks by Marcela Simoes
  • 14:10
    4. Remarks by Rob Camp
  • 21:51
    5. Remarks by Tom Watson
  • 27:30
    6. Early access approaches in other countries
  • 45:55
    7. The fallout from adverse events
  • 48:10
    8. Audience Q and A session; Conclusio

Future Vision: Ethics and Policy Lens


Moderator: Alison Bateman-House (NYU School of Medicine)
  • 00:01
    1. Introduction
  • 07:49
    2. Remarks by Jerry Menikoff
  • 09:48
    3. Remarks by Daniel McIntyre
  • 14:30
    4. Remarks by Luann Van Campen
  • 19:54
    5. Remarks by Beth Roxland
  • 22:22
    6. Remarks by Franklin Miller
  • 24:48
    7. Remarks by Nancy Neveloff Dubler
  • 28:11
    8. Thoughts on pre-approval
  • 37:30
    9. Risk and benefit; Care and research
  • 47:35
    10. Time devoted to bioethical concerns
  • 53:31
    11. Audience Q and A session; Conclusio

Stakeholder Perspectives on Compassionate Use


Moderator: Nancy Neveloff Dubler (New York City Health and Hospitals Corporation; NYU School of Medicine)
  • 00:01
    1. Introduction
  • 06:42
    2. Remarks by Richard Klein
  • 17:24
    3. Remarks by Steve Usdin
  • 32:13
    4. Remarks by Ronald Krall
  • 40:18
    5. Remarks by Sandy Macrae
  • 48:56
    6. Remarks by Jane Reese-Coulbourne
  • 57:44
    7. Considering an industry/advocacy/patient collaborative
  • 69:10
    8. Audience Q and A session; Conclusio

New Directions for Pre-Approval Access


Moderator: Fred Guterl (Scientific American)
  • 00:01
    1. Introduction; Remarks by David Scheer
  • 10:48
    2. Remarks by Tanya Scharton-Kersten
  • 17:18
    3. Remarks by Amrit Ray
  • 26:12
    4. Remarks by Matthew Hepburn
  • 32:55
    5. Remarks by Martha Donoghue; Accessing compassionate use data
  • 42:33
    6. Audience Q and A session; Conclusio

Resources

NYU Langone Medical Center Working Group on Compassionate Use and Pre-Approval Access
Resources from the NYU Langone Medical Center Working Group on Compassionate Use and Pre-Approval Access include links to publications and interviews as well as other information and FAQs.

Perspectives on pre-approval access and compassionate use

Bedell E. Global access to medicinal products: compassionate use procedures. Regulatory Focus. 2010.

Bromwich D, Rid A. Can informed consent to research be adapted to risk? J Med Ethics. 2015;41(7):521-8.

Buhles WC. Compassionate use: a story of ethics and science in the development of a new drug. Perspect Biol Med. 2011;54(3):304-15.

Caplan A, Bateman-House A. Compassion for each individual's own sake. Am J Bioeth. 2014;14(11):16-7.

Caplan AL, Bateman-House A. Should patients in need be given access to experimental drugs? Expert Opin Pharmacother. 2015;16(9):1275-9.

Darrow JJ, Sarpatwari A, Avorn J, Kesselheim AS. Practical, legal and ethical issues in expanded access to investigational drugs. N Engl J Med. 2015;372(3):279-86.

Danis M, Wendler D, Kim S. Acceptable approaches to enrolling adults who cannot consent in more than minimal risk research. Am J Bioeth. 2015;15(10):70-1.

Johnson & Johnson News. Johnson & Johnson announces NYU School of Medicine partnership to evaluate compassionate use of investigational medicines. May 2 2015.

Klopfenstein M, Van Campen LE, Garnett T. Expanded access programs: ethical and practical considerations for biopharmaceutical sponsors. Ther Innov Regul Sci. 2015;49(3):352-8.

Mayer M. From access to evidence: an advocate's journey. J Clin Oncol. 2003;21(20):3881-4.

Rahbari M, Rahbari NN. Compassionate use of medicinal products in Europe: current status and perspectives. Bulletin of the World Health Organization. 2011;89:163-163.

Rid A. How should we regulate risk in biomedical research? An ethical analysis of recent policy proposals and initiatives. Health Policy. 2014;117(3):409-20.

Rid A, Saxena A, Baqui AH, et al. Placebo use in vaccine trials: recommendations of a WHO expert panel. Vaccine. 2014;32(37):4708-12.

Van Campen LE, Therasse DG, Klopfenstein M, Levine RJ. Development, implementation and critique of a bioethics framework for pharmaceutical sponsors of human biomedical research. Curr Med Res Opin. 2015;31(11):2071-80.

Van Campen LE, Therasse DG, Klopfenstein M, Levine RJ. Eli Lilly and Company's bioethics framework for human biomedical research. Curr Med Res Opin. 2015;31(11):2081-93.

The case of Josh Hardy: social media and compassionate use

Caplan A, Moch K. Rescue me: the challenge of compassionate use in the social media era. Health Affairs. August 27 2014.

Tirrell M. When unapproved drugs are the only hope. CNBC. August 5 2014.

Kids v Cancer
Kids v Cancer promotes pediatric cancer research by identifying structural impediments in the research process—new drugs, tissue donation, and access to funding—and developing strategies to redress them.

Max Cure Foundation
The foundation was created in 2008, inspired by one child's brave fight against a rare B-cell lymphoma. The Max Cure Fund is held at Memorial Sloan-Kettering Cancer Center and earmarked for underwriting an immune cell therapy lab at MSKCC.

Ebola: compassionate use in a public health crisis

Adebamowo C, Bah-Sow O, Binka F, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet. 2014;384(9952):1423-4.

Caplan AL, Plunkett C, Levin B. Selecting the right tool for the job. Am J Bioeth. 2015;15(4):4-10.

Caplan AL. Morality in a time of Ebola. Lancet. 2015;385(9971):e16-7.

Cooper BS, Boni MF, Pan-ngum W, et al. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med. 2015;12(4):e1001815.

Heymann DL, Chen L, Takemi K, et al. Global health security: the wider lessons from the west African Ebola virus disease epidemic. Lancet. 2015;385(9980):1884-901. Review.

Horby PW, Endzt H, Muyembe-Tamfum JJ, et al. Ebola: Europe-Africa research collaborations. Lancet Infect Dis. 2015;15(11):1258-9.

Mobula LM. Courage is not the absence of fear: responding to the Ebola outbreak in Liberia. Glob Health Sci Pract. 2014;2(4):487-9.

Mobula LM. When potentially lifesaving drugs are both experimental and in very short supply: a clinician's story from the front lines of the battle against Ebola. Am J Trop Med Hyg. 2015;93(2):210-1.

Rid A. Setting risk thresholds in biomedical research: lessons from the debate about minimal risk. Monash Bioeth Rev. 2014;32(1-2):63-85.

Rid A. The goals of research during an epidemic. Am J Bioeth. 2015;15(4):47-50.

Rid A, Emanuel EJ. Ethical considerations of experimental interventions in the Ebola outbreak. Lancet. 2014;384(9957):1896-9.

Shah SK, Wendler D, Danis M. Examining the ethics of clinical use of unproven interventions outside of clinical trials during the Ebola epidemic. Am J Bioeth. 2015;15(4):11-6.

Whitehead J, Olliaro P, Lang T, Horby P. Trial design for evaluating novel treatments during an outbreak of an infectious disease. Clin Trials. 2016. [Epub ahead of print]

World Health Organization. Ethical issues related to study design for trials on therapeutics for Ebola virus disease. WHO Ethics Working Group meeting. 2014.

Ethics, legislation, and regulations

Adamson PC, Houghton PJ, Perilongo G, Pritchard-Jones K. Drug discovery in paediatric oncology: roadblocks to progress. Nat Rev Clin Oncol. 2014;11(12):732-9.

Altman K, Sandefur C. Right to try laws fulfill the Constitution's promise of individual liberty. Health Affairs. July 14 2015.

Anderson ML, Califf RM, Sugarman J; participants in the NIH Health Care Systems Research Collaboratory Cluster Randomized Trial Workshop. Ethical and regulatory issues of pragmatic cluster randomized trials in contemporary health systems. Clin Trials. 2015;12(3):276-86.

Bateman-House A, Kimberly L, Redman B, et al. Right-to-try laws: hope, hype, and unintended consequences. Ann Intern Med. 2015;163(10):796-7.

Berlin JA, Morris S, Rockhold F, et al. Bumps and bridges on the road to responsible sharing of clinical trial data. Clin Trials. 2014;11(1):7-12.

Biotechnology Innovation Organization. BIO statement on compassionate use. 2014.

Chan-Tack KM, Kim C, Moruf A, Birnkrant DB. Clinical experience with intravenous zanamivir under an Emergency IND program in the United States (2011–2014). Antivir Ther. 2015;20(5):561-4.

Goldwater Institute. The Right to Try. January 20 2015.

Mello MM, Brennan TA. The controversy over high-dose chemotherapy with autologous bone marrow transplant for breast cancer. Health Aff (Millwood). 2001;20(5):101-17.

Mishra P, Murray J, Birnkrant D. Direct-acting antiviral drug approvals for treatment of chronic hepatitis C virus infection: Scientific and regulatory approaches to clinical trial designs. Hepatology. 2015;62(4):1298-303.

Sharp RR, Taylor HA, Brinich MA, et al. Research ethics consultation: ethical and professional practice challenges and recommendations. Acad Med. 2015;90(5):615-20. Review.

Sullivan R, Kowalczyk JR, Agarwal B, Ladenstein R, et al. New policies to address the global burden of childhood cancers. Lancet Oncol. 2013;14(3):e125-35. Review.

Welch MJ, Lally R, Miller JE, et al. The ethics and regulatory landscape of including vulnerable populations in pragmatic clinical trials. Clin Trials. 2015;12(5):503-10.

Websites

Abigail Alliance for Better Access to Developmental Drugs
The Abigail Alliance seeks to increase expanded access and compassionate use programs for cancer drugs and other drugs for serious life-threatening illnesses that are in development.

AdvancedBC.org
An organization that offers support and resources on advanced breast cancer issues.

EURORDIS
EURORDIS is a non-governmental alliance of patient organizations, representing 695 rare disease patient organizations in 63 countries in Europe and beyond.

Interfarma, Brazil
Interfarma is an industry group and non-profit organization representing companies and national and foreign researchers responsible for health innovation in Brazil.

National Breast Cancer Coalition
NBCC lobbies Congress and other decision-makers for public policies concerning breast cancer research, diagnosis, and treatment.

National Health Council
NHC seeks is to provide a united voice for people with chronic diseases and disabilities and their family caregivers.

Parent Project Muscular Dystrophy
The Parent Project Muscular Dystrophy is an advocacy organization for Duchenne muscular dystophy.

St. Baldrick's Foundation
The St. Baldrick's Foundation is a volunteer-based charity that seeks to fund promising research for childhood cancers.

Scientific Organizing Committee

Alison Bateman-House, PhD, MPH, MA

NYU School of Medicine
website | publications

Melanie Brickman Stynes, MSc, PhD

The New York Academy of Sciences

Arthur Caplan, PhD

NYU School of Medicine
website

Brooke Grindlinger, PhD

The New York Academy of Sciences

Erick T. Tatro, PhD

The New York Academy of Sciences


Speakers

Peter C. Adamson, MD

The Children's Hospital of Philadelphia; University of Pennsylvania
website | publications

Debra Birnkrant, MD

U.S. Food and Drug Administration
website | publications

Fritz Bittenbender, MPA

Biotechnology Industry Organization (BIO)
website

Marc Boutin, JD

National Health Council
website | publications

Rob Camp

European Organization for Rare Diseases (EURORDIS), Spain
website | publications

Valerie Cwik, MD

Muscular Dystrophy Association
website

Marion Danis, MD

U.S. National Institutes of Health
website | publications

Martha Donoghue, MD

U.S. Food and Drug Administration

Nancy Neveloff Dubler, LLB

New York City Health and Hospitals Corporation; NYU School of Medicine
website | publications

Pat Furlong

Parent Project Muscular Dystrophy
website

Brooke Gladstone

WNYC Studios, On the Media
website

Nancy Goodman, JD

Kids v Cancer
website

Fred Guterl

Scientific American
website

Matthew Hepburn, MD

Defense Advanced Research Projects Agency
website | publications

Richard Klein

U.S. Food and Drug Administration
website | publications

Ronald Krall, MD

University of Pittsburgh
website

Danielle Leach, MPA

St. Baldrick's Foundation
website

Sandy Macrae, MD, PhD

Takeda Pharmaceuticals

Carla Mann Woods

Mann Healthcare Partners

Musa Mayer, MS, MFA

AdvancedBC.org; National Breast Cancer Coalition
website

Daniel McIntyre, MPA

Biogen
website

Jerry Menikoff, MD, JD

U.S. Department of Health and Human Services
website | publications

Franklin Miller, PhD

Weill Cornell Medical College
website | publications

Jennifer E. Miller, PhD

NYU School of Medicine
website | publications

Linda M. Mobula, MD, MPH

Johns Hopkins University
publications

Kenneth I. Moch, MBA

Chimerix (2009–2014); Euclidean Life Science Advisors

Piero Olliaro, MD, PhD

Special Programme for Research & Training in Tropical Diseases (TDR), World Health Organization
publications

Richard Plotkin, JD

Max Cure Foundation Inc.
website

Amrit Ray, MD

Janssen Pharmaceutical Companies of Johnson & Johnson

Jane Reese-Coulbourne, MS, ChE

Reagan-Udall Foundation for the U.S. Food and Drug Administration
website

Annette Rid, MD

King's College London, UK
website | publications

The Honorable Linda Rosenthal

New York State Assembly
website

Beth Roxland, JD, MBioethics

Johnson & Johnson; NYU School of Medicine
website | publications

Christina Sandefur, JD

Goldwater Institute
website

Tanya Scharton-Kersten, PhD

International AIDS Vaccine Initiative
website

David I. Scheer, MS

Scheer and Company Inc.

Marcela Simões, MBA

Interfarma, Brazil
website

Paul Stoffels, MD

Johnson & Johnson
website | publications

Meg Tirrell, MSJ

NBC Universal, CNBC
website

Steve Usdin

BioCentury
website | publications

Luann Van Campen, MA, MS, PhD

Eli Lilly and Company
website | publications

Barbara von Tigerstrom, MA, LLB, PhD

University of Saskatchewan, Canada
website | publications

Joanne Waldstreicher, MD

Johnson & Johnson

Steven T. Walker, MS, PG

Abigail Alliance for Better Access to Developmental Drugs
website

Tom Watson

Idis Managed Access, part of the Clinigen Group, UK
website


Hallie Kapner

Hallie Kapner is a science writer based in Chappaqua, NY. She works with research universities and scientific organizations in the New York area, and has been writing about science for lay audiences and the media for more than 15 years. She has also written for the New York Academy of Sciences Magazine.

Sponsors

This symposium was made possible with support from


Presented by

  • NYU School of Medicine

Speakers

Paul Stoffels

Johnson & Johnson

Arthur Caplan

NYU School of Medicine

Highlights

Use of experimental therapies outside clinical trials is a high-stakes activity, for both patients and pharmaceutical companies.

Patients with life-threatening or serious diseases and no other treatment options may be willing to accept risks that would be unacceptable to most people.

Pharmaceutical companies, particularly small ones, may need to choose between granting compassionate use requests and continuing clinical trials; diverting supply to compassionate use may delay the trials required to seek FDA approval.

All stakeholder groups—patients, advocates, companies, and regulators—acknowledge that the current framework for compassionate use needs improvement.

Introduction

Few topics in modern health care are as ethically complex, emotionally wrenching, and financially fraught as compassionate use, or pre-approval access. To enter the world of compassionate use is to meet the sickest patients, to witness last-grasp efforts to save the terminally ill. It is the desperate process of pleading for access to experimental therapies not yet approved by the Food and Drug Administration (FDA)—compounds that may or may not be safe or effective. For patients, the stakes—life and death—could not be higher; for companies and regulators, the financial, ethical, and social costs are very high as well. The general population also has a stake in these decisions that affect which drugs come to market, and when.

The cost of bringing a single new drug to market can well exceed $1 billion, and the process can take up to 10 years. Safety and efficacy trials demand that patients meet strict eligibility requirements, and in some efficacy trials one group of patients may receive a placebo compound. Pre-approval access exists outside these clinical trials and often involves patients who are too sick to enroll, who live too far from testing sites, or who are otherwise unable to participate. Patients appeal directly to the company developing the compound, and requests are subject to FDA approval. Companies that agree to provide an investigational medicine on a compassionate-use basis often do so at their own cost. Sometimes, particularly at small companies, this cost means diverting supply and financial resources from the clinical trials that could make the drug widely available for future patients. Most large, and many small, pharmaceutical companies operate compassionate use programs, and the results are sometimes remarkable.

However, the system leaves much to be desired. For patients, finding information about experimental therapies can be challenging, and the process of making a request to a company and seeking the required approvals (company, FDA, and institutional review board) is so time- and labor-intensive that some die awaiting an answer. Pharmaceutical companies may be inundated with compassionate use requests, and may find themselves in the unenviable position of denying all requests for lack of resources or because of inability to meet requests equitably. Over the past 2 years, several high-profile bids for compassionate use have hit the mainstream press, with huge social media campaigns mounted in support of a single patient's plight.

These cases often divide parties with the same interests in patient care, treatment and eradication of disease, safety, and financial solubility into opposing camps. Whether the various stakeholders can collaborate in the service of patients was the central question of this conference. Can compassion, business, and medicine coexist?

Paul Stoffels of Johnson & Johnson, who gave opening remarks, is "absolutely convinced the answer is yes, and we have to practice it every day." He encouraged conference attendees to use the meeting to fuel dialogue and forge new, creative approaches to pre-approval access policies and programs.

Stoffels reflected on the early days of pre-approval access—it was the mid-1980s, and the spread of a newly discovered virus, HIV, left communities of suffering patients desperate to try anything. Speaking from his own experience at that time, he credited the determination of patients and their physicians, along with the willingness of pharmaceutical companies and the FDA, with helping create a new paradigm for offering experimental therapies and accelerating regulatory approval.

Today, expanded access requests come from around the world—for chronic diseases such as cancer, amyotrophic lateral sclerosis, and others, and during epidemics, such as the recent Ebola virus disease outbreak in West Africa, which posed new ethical issues for the use of investigational medicines. Stoffels stressed the urgency of setting new standards to serve the most desperately ill patients and their families, recalling the words of Dr. Paul Janssen—"the patients are waiting."

Arthur Caplan of NYU gave an overview of the practical and ethical complexities of expanded access programs. Balancing the needs of all parties involved is "tricky, interesting, difficult, and vitally important," he said. There is neither a single system governing compassionate use nor a consistent language to describe it: compassionate use, pre-approval access, expanded access, and early access are largely used interchangeably.

Absent a formal system, stakeholders often grapple in silos, leading to frustration and anger. Patients and patient advocates struggle to learn about experimental therapies and lament the long, confusing process of applying for expanded access; companies face financial and social pressure to attend to the requests of desperate patients while moving the regulatory approval process forward; and regulators fight misconceptions about the processes that govern their work.

At the center of pre-approval access debates lies this ethical question: how to design and conduct clinical trials that provide the rigorous safety data needed for FDA approval, while still showing concern for patients who are ineligible for trials and have little time left.

"From the point of view of someone who is very sick right now, they don't have time for proof of safety to be established, or they may accept less evidence about safety and efficacy as others might," Caplan said.

Resolving this conflict means undertaking large-scale, cooperative changes to pre-approval access systems: making information about clinical trials and eligibility more readily available, streamlining the processes for requesting investigational medicines via both pharmaceutical companies and the FDA, and revising the protocols used to review compassionate use requests to increase equitability. Caplan cited the explosion of "right to try" laws as evidence of public demand to meet the needs of terminally ill patients.

The matter of who bears the cost of providing investigational medicines is another hurdle for expanded access programs. Today, U.S. pharmaceutical companies that agree to provide pre-approval access must offer the investigational medicine at very low or no charge, but patients cover their own medical, travel, and other expenses to obtain it. The costs can be staggering, and for many families and smaller companies, unsustainable. "It's clear that the public wants something done," Caplan said. "Morally, most of us believe in a right to be rescued—if someone is trapped in a mine or on top of a mountain, we'll rescue them, even if it's not an efficient use of resources. But where do we draw the line?"

Panelists

Arthur Caplan

Moderator

NYU School of Medicine

Steven Walker

Abigail Alliance for Better Access to Developmental Drugs

Marc Boutin

National Health Council

Danielle Leach

St. Baldrick's Foundation

Musa Mayer

AdvancedBC.org; National Breast Cancer Coalition

Pat Furlong

Parent Project Muscular Dystrophy

Highlights

Cost of treatment is a major concern for patients with serious diseases, whether seeking approved or experimental therapies.

Clinical trials have strict eligibility criteria, especially for rare diseases, and patients often have no choice but to seek treatment outside the trial system.

Physicians and patients need better information about the efficacy of approved and experimental therapies.

Novel clinical trial designs could provide more options for critically ill patients and decrease the need for expanded access.

Access and education

The conversation began with a discussion of how to achieve equitable access to all therapies, approved and investigational. Marc Boutin of the National Health Council explained that accessing even approved medical services is difficult for people with chronic conditions, even under the recently implemented Patient Protection and Affordable Care Act of 2010. "Meaningful access to medical care should include both approved therapies and compassionate use," he said.

Several panelists mentioned cost as the primary concern for patients. "When I was a patient navigator, my number one phone call from patients was related to payment—and this was for approved therapies, not even compassionate use," said Danielle Leach of St. Baldrick's Foundation. Steven Walker of the Abigail Alliance described how the business model of insurance providers makes equitable access to care impossible unless those who can afford higher health care premiums contribute even more to the system than they already do.

Patients with serious illnesses also struggle to learn about experimental treatment options; Leach cited a 60% participation rate in clinical trials among pediatric cancer patients. "When you run out of options, that's where it becomes more challenging—that's when you're scouring the Internet late at night to try to find out what's out there," she said. A lack of options is also how Pat Furlong, founder of Parent Project Muscular Dystrophy, characterizes the plight of families in search of therapies for children with Duchenne muscular dystrophy, a fatal, degenerative disease that affected both of Furlong's sons. For less common diseases, clinical trials offer little in the way of access; the criteria for entry are often so strict that parents must seek therapies outside the trial system. Furlong explained that families with a child close to the eligibility criteria are often told to come back when the child is sicker. "Progression of the disease is a slide toward death," she said.

Improved access also means better education for patients and physicians about existing and experimental therapies. Musa Mayer, a breast cancer survivor and longtime advocate, asserted that misinformation can have deadly consequences for patients. Tens of thousands of women requested and received then-experimental stem cell transplants as a treatment for metastatic breast cancer in the 1990s, despite significant risk and no evidence of improved longevity. Many died, not from their cancers, but from the transplants. Today, about 40% of women being treated with adjuvant aromatase inhibitors and tamoxifen for early breast cancer—a regimen with proven results—do not take the full course of drugs as prescribed. "I've become less and less convinced that the latest is the greatest—the most expensive isn't always the best," Mayer said. "We could save so many more lives if we were making full use of the treatments we know work now."

A new model for clinical trials

Overhauling the clinical trial process is a high priority for patient advocates, and most attention is paid to the subject of randomization to a placebo group. Following phase I trials to test safety and dosing in a small cohort, standard protocol dictates a phase II randomized trial, in which one group of patients may receive a placebo compound. (Not all phase II trials involve placebos, but patients may avoid even trials that do not use placebos for fear of receiving one.) Walker and Furlong called this convention inappropriate for drugs that show both safety and strong signs of efficacy in phase I trials. They argued that randomization to placebo in phase II or phase III trials wastes time, and that there are better approaches to testing than delivering a placebo to patients whose disease has a known outcome. "We already have a prognosis ... so more time without whatever intervention it is means more of the prognosis that's going to occur," Furlong said.

Precision medicine is changing how physicians and researchers view clinical endpoints, with advances in genomics and proteomics paving the way for drugs designed to hit targets for specific subsets of disease. The panelists advocated innovation in clinical trial design to keep pace with this progress. Mayer pointed out that in cancer studies, placebos are used less frequently. The National Cancer Institute has begun a basket trial—a new design that tests certain molecular markers' responses to targeted compounds and assigns patients to trial groups on the basis of their tumor types. Walker supported this approach, as well as recent moves by the FDA to consider data from subsets of patients in the approval process. "When we know there's a better way, we should never do something because of convention," he said.

The role of advocacy

To close the panel, Caplan asked panelists to weigh in on the strengths and potential drawbacks of patient advocacy groups. These organizations are seen as key allies for patients, helping families navigate the health care system as it pertains to a specific disease, as well as providing social and emotional support. "They play a terrific role, but one role they cannot play is to tell you what's going on in the rest of your life and how care and treatment may impact you," Furlong said.

The panel closed on a strongly optimistic note about the degree to which patients themselves are transforming advocacy, and the ways in which advocacy organizations are beginning to collaborate in the service of increasingly vocal patient communities.

Panelists

Brooke Gladstone

Moderator

WNYC Studios, On the Media

Kenneth Moch

Chimerix (2009–2014); Euclidean Life Sciences Advisors

Debra Birnkrant

U.S. Food and Drug Administration

Nancy Goodman

Kids v Cancer

Richard Plotkin

Max Cure Foundation Inc.

Meg Tirrell

NBC Universal, CNBC

Highlights

Use of social media to gain access to experimental therapies has changed the landscape of compassionate use and raised ethical questions about influence and decision making in pre-approval access cases.

Pre-approval access decisions are complex and the different factors influencing them can be difficult to convey fully in a social media campaign; the medium also poses challenges to balanced reporting.

The FDA does not regularly communicate with companies about the number of pre-approval access requests it receives, and it can use regulatory flexibility to make access possible in some cases.

The case

Kenneth Moch, former chief executive officer of Chimerix, described the Josh Hardy case and the ethical and moral dilemmas surrounding pre-approval access decisions. In 2014, Josh Hardy was a 7-year-old cancer patient at St. Jude Children's Research Hospital fighting a life-threatening adenovirus infection following a bone marrow transplant.

Josh's physicians requested an experimental antiviral, brincidofovir, which had shown evidence of activity against adenovirus and had been provided in over 400 expanded access cases. Chimerix, the small biotech company developing the drug, had closed its expanded access program more than a year earlier to focus its resources on completing the trials necessary for FDA approval. The company had subsequently turned down over 300 expanded access requests for brincidofovir, and it denied the request by Josh's physicians as it had the others.

The Hardy family, supported by pediatric cancer advocates, mounted a social media campaign to pressure Chimerix into providing the drug. Almost overnight, the campaign amassed over a million followers and captured the attention of news outlets worldwide. Chimerix executives and board members received thousands of angry calls and emails, as well as death threats credible enough to force the company to hire private security. Five days after the social media campaign began, Chimerix announced it had worked with the FDA to create an open-label pilot trial of brincidofovir that would lead directly into a phase III trial. Josh Hardy was the first patient enrolled. He survived.

The Hardy case changed the stakes for compassionate use requests. Through freely available social media channels, the Hardy family and hundreds of thousands of supporters forced the hands of Chimerix and the FDA, saving one child's life but raising a slew of ethical questions about access to investigational medicines. Who decides who receives these medicines? Should the decision-making process ever be open to influence, be it from social media, politics, or other forces? Does this case create an unfair precedent for patients who have no way to marshal public support?

A firestorm, and a solution

Richard Plotkin of the Max Cure Foundation explained how he was introduced to the Hardy case.

The former trial lawyer turned pediatric cancer advocate summed up his approach as, "If this boy didn't get the drug, I was going to destroy Chimerix and destroy Ken Moch. As far as I was concerned, there was a 7-year-old boy who was going to die." Plotkin was instrumental in creating the public relations and social media campaign to help Josh Hardy gain access to brincidofovir. Nancy Goodman, founder of Kids v Cancer, joined the media effort.

Debra Birnkrant of the FDA's Center for Drug Evaluation and Research first learned of the case through the media, and she described the coverage as "something I have never seen, and I've been in this division for 26 years." She was familiar with brincidofovir, as it was in her review division. But the FDA was not aware that the company had discontinued its expanded access program.

Compassionate use programs for individual patients often produce very little data that a sponsor company can use to bolster its case for FDA approval, and Chimerix had decided not to make a single-patient exception. "We wanted success for this little boy, success for the company, and a chance to collect more data to move the drug toward approval," Birnkrant said. "The solution was a win-win."

Waking the giant

Moderator Brooke Gladstone described the tenor of the media campaign as understandably negative and lacking nuance. "Whenever one of the main characters in a news story is a grieving or terrified parent, there isn't a person in the world who doesn't feel a strong identification," she said. Meg Tirrell, who reported on the Hardy case and has continued to write about compassionate use, commented about the one-sided nature of the news coverage, and noted that it was not until Hardy received brincidofovir that the complex back-story came to light.

The panel ended with a request for each speaker to share lessons learned from the Hardy case. For Birnkrant, the case highlighted the need for improved communication between the FDA and pharmaceutical companies receiving large numbers of requests for compassionate use.

Plotkin revealed that the experience was a powerful lesson. "As a lawyer, your obligation is to one client. But as an advocate, my obligation is to all children," he said. "If Josh had received the drug and died as a result, FDA may have slowed the clinical trial process or caused destruction of this incredible drug. How many kids would have died in the future?" He does not regret the social media storm that saved Josh’s life but admitted that if he knew then what he knows now, he would have made the same decision that Moch made initially in denying Josh the drug.

Goodman believes the social media effort was justified and cited the positive outcomes—nearly 200 children were enrolled in a pilot trial, many of whom survived because of it. This result would have been impossible without the social media effort, which she described as a democratic, acceptable tool for shining light on an issue. "If we had more pediatric trials with experimental therapies, we wouldn't need to rely on compassionate use or social media strategies," she said.

Moch, who lost his job in the wake of the Hardy case, argued that one of the main problems with the use of social media in situations like Josh Hardy’s is that the crowd often ignores ethical factors influencing compassionate use decisions, such as an effort to consider the needs of the individual alongside those of future patents. Recounting the week he spent with armed security guards, Moch also took the position that those who use social media cannot distance themselves from the negative outcomes of the approach. Citing the potential for social media campaigns to become "a public temper tantrum," he said: "You cannot wake the giant and then disclaim responsibility for what the giant did. If you start a social media campaign, and somebody says, 'If you don't do what I want, I will kill you,' can you deny responsibility for that?"

As the panel ended, all participants agreed that the system for accessing and communicating about compassionate use—within industry and with patients and the public—must be improved. The onus to resolve the competing needs of the few who are currently sick against the future patients a medicine might benefit should not rest on life sciences companies. "As a CEO, I have to choose the many, unless there's a better path for the few," Moch said.

Panelists

Arthur Caplan

Moderator

NYU School of Medicine

Piero Olliaro

Special Programme for Research & Training in Tropical Diseases (TDR), WHO

Marion Danis

U.S. National Institutes of Health

Linda Mobula

Johns Hopkins University

Annette Rid

King's College London, UK

Highlights

In a public health crisis, the standard procedures of trial design, data collection, and informed consent are pushed to new limits and may be compromised.

The only drugs being tested to treat Ebola virus disease had never been tested on humans at the time of the 2014 outbreak in West Africa.

Low literacy, language barriers, and local customs can complicate the already difficult process of obtaining informed consent from a very ill patient.

It is hard but vitally important to collect data when investigational medicines are used in an epidemic.

Higher stakes

The high stakes in compassionate use cases escalate in a public health crisis such as the Ebola virus disease (EVD) outbreak that killed 11 000 people in West Africa in 2014–15. Marion Danis of the NIH opened a panel on compassionate use during an epidemic with the suggestion that the usual terminology may not apply in times of crisis. Tens of thousands of people were sick and dying, including health care workers from the region and from aid organizations around the world. Perhaps 30 doses of investigational medicines that had only been tested on animals existed. "Compassionate use is a misnomer here," Danis said, explaining the frantic decision making that takes place when many people are critically ill, time is short, and difficult choices to prioritize individuals come into play.

Linda Mobula had to make just such a decision in July 2015, when she and other physicians treating patients in Guinea were faced with helping one of their own. Dr. Kent Brantly, an American physician working in Liberia, contracted EVD and was given the option to receive ZMapp, an experimental monoclonal antibody that "may have caused adverse effects—it had never been tested in a human—or potentially save his life," Mobula said. Brantly survived. Mobula described the choices facing crisis responders when it comes to delivering investigational therapies that are scarce. In this case, the fact that ZMapp was untested in humans governed the choice to try it on a health care worker. "If it had been administered to a Liberian and had an adverse effect that would have caused more harm than good in the long run," Mobula explained.

In 2014, the World Health Organization convened a working group to discuss the ethical issues that arise when testing experimental EVD therapies. Piero Olliaro of the WHO reported that the group recommended that a new term, monitored emergency use of unregistered and experimental interventions (MEURI), replace the term compassionate use in public health crises. Olliaro, who participated in the design and conduct of trials sponsored by the University of Oxford, UK, explained that in circumstances where mortality is high, experimental therapies are scarce, and conducting standard trials is very difficult, two priorities emerge. The first priority is saving lives, and in that case, as long as requirements for human research ethics are met, various types of trial designs are acceptable. The second priority is collecting information to further research and drug development for future patients. More than 100 therapies were considered as potential candidate treatments for EVD during the recent epidemic—some of them were experimental, others combinations of existing drugs—but only few could be tested in clinical trials. And, Olliaro asserted, while data are still forthcoming and no standout treatment emerged, the ability of various groups to conduct trials even in extraordinarily challenging circumstances is a positive outcome.

Research ethics in a crisis

Annette Rid of King's College London offered three broad reflections from a research ethics perspective. First, with a disease transmitted through bodily fluid, as opposed to an airborne disease, the public health benefit of pre-approval access to medicines is limited because prevention is the most effective method to stop the disease. Rid noted that EVD cases began dropping before experimental interventions were introduced, largely as a result of grassroots efforts to reduce transmission.

Next, in a crisis, perceptions of risk change dramatically, shifting our perspectives on what is an acceptable risk. With EVD, public perception of the standard of care was widely pessimistic, and messages about the risk of experimental therapies were downplayed amid the optimism about their efficacy. "If you combine these—a lot of pessimism and then a lot of optimism vis-à-vis the experimental treatments—the case for pre-approval access looks much more compelling than it actually is," she said.

Finally, ethical questions about the design of the trials for experimental therapies created considerable tension, with some groups saying that all agents needed to be tested in randomized control trials and others insisting that withholding treatment during an epidemic is unethical. None of the experimental agents were available on a large scale, and Rid advocated flexibility in trial design in such a crisis situation.

Is informed consent possible?

Caplan queried the panelists on the subject of informed consent in a crisis, asking whether they believed that health care workers and local citizens who were treated with experimental agents were truly able to consent. Mobula commented that Brantly was aware of the risks of receiving ZMapp. "But only one patient had survived of all of those he had treated, so he also knew the disease pretty well," Mobula said.

She agreed that gaining informed consent from a local Liberian or Guinean was nearly impossible, both because of her protective gear, which made conversations difficult, and because of the low literacy level of most patients. "This is a setting where you just try to do the next best thing," Danis added. "Our usual approaches were stretched to the limit."

Olliaro emphasized that despite these difficulties, every effort was made to obtain informed consent from participants in the two University of Oxford–sponsored trials conducted in Africa during the epidemic. The discussion underscored the importance of ethical trial design and institutional review processes to ensure that the risks to patients who may be unable to fully consent are as reasonable as possible.

Learning for the future

The dialogue turned to the need to collect treatment outcome data for experimental therapies and supportive care–only interventions. "It's morally obligatory to learn something from this for the sake of future patients who will encounter this infection," Danis said. With so little known about which treatments are effective, every data point counts. The array of symptoms known as "post-Ebola syndrome" is also poorly understood.

In closing, the panelists debated the merits of a hypothetical rapid-deployment research unit that could be dispatched to the site of future outbreaks. The panelists noted that most of the research in EVD took place toward the end of the epidemic—if a flexible research unit had existed, it may have helped accelerate the process. Conducting research on-site during a health crisis requires intense social mobilization efforts to assuage concerns among patients about being "experimented on" and to boost community support, which was indeed critical in combating the EVD epidemic.

Panelists

Nancy Neveloff Dubler, Moderator

New York City Health and Hospitals Corporation; NYU School of Medicine

Jane Reese-Coulbourne

Reagan-Udall Foundation for the U.S. Food and Drug Administration

Richard Klein

U.S. Food and Drug Administration

Ronald Krall

University of Pittsburgh

Sandy Macrae

Takeda Pharmaceuticals

Steve Usdin

BioCentury

Highlights

Compassionate use regulations, codified in 1987, were overhauled in 2009 to add greater flexibility and expand the rules to cover more diseases.

The FDA approves 99% of compassionate use requests it receives, but the vast majority of requests never make it to this stage.

A sponsor company is obligated to make its expanded access policy clear to the public.

Sponsor companies should plan for expanded access early in the drug development process.

Major systemic changes are needed to bridge the divides between regulators, industry, and patients when it comes to compassionate use.

The regulations

The final session of the first day turned from the perspective of patients and clinicians to that of regulatory and pharmaceutical stakeholders. The topic was the decision-making process for allocating scarce resources in compassionate use cases. Richard Klein of the FDA explained the regulatory framework behind compassionate use. While limited use of experimental compounds for therapeutic purposes, rather than research, began in the 1970s, the practice was not codified in FDA regulations until 1987.

As originally written, compassionate use regulations encompassed both large-scale investigational new drug applications (INDs) and individual INDs making a drug available to a single patient. The regulations were overhauled in 2009 to encompass unexpected circumstances and more diseases. Now there are three tiers of access: single-patient or individual access INDs; intermediate population INDs, which include more than one but fewer than 100 people; and large-scale treatment INDs for more than 100 people.

The FDA receives about 1200 requests for compassionate use each year, and approves 99% of them. Klein reminded the audience that these requests do not represent everyone seeking an investigational medicine for compassionate use—that number is far higher. This is the number of requests coming to the FDA with agreement from a sponsor company to provide the compound. "The product doesn't belong to FDA, it doesn't belong to the American people—it belongs to the sponsor, and they make the decision about whether the drug is made available," he said.

Hurdles for sponsor companies

Steve Usdin of BioCentury noted that while most pharmaceutical companies claim to be patient-centered, it is not possible to be genuinely invested in the needs of patients without discussing compassionate use. Indeed, when a product is granted "breakthrough" designation by the U.S. FDA, the company has an obligation to publicly state its compassionate use policy, even if that policy is not to provide the compound for compassionate use purposes. A company can apply to have a product in its pipeline given this designation, allowing it to expedite certain processes and use the term "breakthrough" in clinical trial recruitment materials. Usdin acknowledged that compassionate use decisions are difficult for sponsor companies. "We learned from the Josh Hardy case and others that CEOs should not be making life-and-death decisions," Usdin said. He suggested that a third-party group similar to data safety monitoring boards used in clinical trials be considered for reviewing compassionate use requests.

The financial burden of providing access falls harder on small companies, a hurdle Usdin believes may be surmountable through public funding. Companies may also be concerned about compassionate use programs slowing the approval process (diverting financial resources or supply), or about encountering, and needing to respond to, adverse events.

The hardest choices

Klein described the compassionate use process as often unsatisfying; it is never comfortable to decline early access requests, even when that is the medically correct choice. He outlined how expanded access trials could run in parallel to the drug development process and include specific planning and provisions and novel trial protocols for the subset of patients most likely to want a compound immediately. "I would like to see us in a situation where we've done a thorough job of thinking about these questions and preparing for them right at the beginning of drug development," he said.

Sandy Macrae outlined the framework for evaluating compassionate use requests at Takeda Pharmaceuticals. Clinical trial entry is always prioritized—if there is a trial that a patient can enter, that course of action is preferable, not least because data collection is a guarantee. Each request is reviewed for scientific plausibility and undergoes risk/benefit analysis to assess whether there is a reason to think an investigational medicine may help the patient, and at what risk. "We're looking for benefits accrued and risks avoided," Macrae said. Some cases fall into a rare category where only a specific agent has a hope of helping a patient, and in those cases, it is more acceptable to release the medicine with less evidence about risk.

The compassionate use framework needs to allow for all these factors, but Macrae acknowledged that there is no one right approach. "There's always someone with an opinion about how to do compassionate use, and the voices within the company are as diverse as the voices in this room," he said.

Fighting on the same side

Jane Reese-Coulbourne is a veteran of expanded access, both professionally and as a late-stage breast cancer patient who joined a clinical trial 25 years ago and emerged cancer-free. She commented that compassionate use cases tend to create unnecessary divisions between like-minded groups. "Most people will do the best thing they can given the situation, and I think that's what we're dealing with now. It's the systems that are screwed up—they don't bring people together," she said. Systemic change that would promote collaboration instead of conflict would make expanded access smarter and more equitable.

Reese-Coulbourne believes helpful approaches could be learned from the Federal Emergency Management Agency, which mobilizes quickly and follows up with data collection to aid in future crises. "These are complicated situations and they require help from a lot of people," she said. "But what if we could create systems that would get us all fighting on the same side?"

Forming a multi-stakeholder group or conference could advance collaboration. Ronald Krall of the University of Pittsburgh noted that the pharmaceutical industry has a precedent of collaborating pre-competitively, and mentioned the Biomarkers Consortium, the Advanced Medical Partnership, and other innovative public–private partnerships that have conducted clinical trials. "There have been a lot of efforts to bring the industry together to create opportunities which advance development of medicines.... I can easily imagine a similar kind of effort to examine a structure and a funding mechanism for expanded access," he said. Any partnership should be operational, "a group that can actually do something, not just study it," Reese-Coulbourne added.

Macrae and Usdin agreed that what will ultimately drive change in compassionate use strategies is not celebrity cases or anything involving social media. It will be a major biomedical advance, such as the development of PDCD1 (PD1)–inhibitor drugs, which are likely to be in such high demand that compassionate use will be front and center.

Panelists

Alison Bateman-House, Moderator

NYU School of Medicine

Peter Adamson

The Children's Hospital of Philadelphia; University of Pennsylvania

Fritz Bittenbender

Biotechnology Industry Organization (BIO)

Carla Mann Woods

Mann Healthcare Partners

The Honorable Linda Rosenthal

New York State Assembly

Christina Sandefur

Goldwater Institute

Highlights

Several new legislative approaches seek to advance patient access to investigational medicines, whether by fast-tracking FDA approval for compounds to be used in deadly diseases or by circumventing FDA approval of patient requests.

Twenty-four states have enacted "right to try" laws, which are designed to give patients and their physicians the right to circumvent regulatory approval for pre-approval access.

There is considerable hype about new therapeutics even without much data on efficacy. Physicians must manage patient expectations and ensure that the risks of trying a new medicine are reasonable.

Efforts to improve the system require the involvement of all stakeholders, but legislative action may play a leading role in bringing about change.

Provisional approval and "right to try"

Carla Mann Woods of Mann Healthcare Partners highlighted the gap between the number of compassionate use requests coming into the FDA each year—about 1200—and the tens of millions of Americans fighting deadly diseases.

She argued that the gap exists because the compassionate use system is part of an "economically futile" regulatory process where only the largest pharmaceutical companies can survive the decade-long process of bringing a drug to market or bear the six-figure-per-patient costs of providing early access. One idea is to allow for provisional approval of fast-track compounds in cases of deadly disease, as detailed in the proposed Patient Choice Act of 2015. This type of approval would allow compounds granted "fast-track" designation by the FDA to be marketed to patients with specific, deadly illnesses prior to formal FDA approval. Fast-track medicines are those deemed "adequately safe" by the FDA and designed to treat serious diseases, and these are often candidates for accelerated approval, allowing wide access as quickly as possible.

Christina Sandefur of the Goldwater Institute described the legal efforts to provide greater access to investigational medicines. Twenty-four states have passed "right to try" laws that are written to allow patients to request access to compounds that have passed phase I safety trials, and are still being tested in clinical trials, without FDA approval. "Right-to-try is about medical autonomy—about your right to make your own choices ... terminal patients should not have to beg the government for permission," Sandefur said.

New York State Assemblymember Linda Rosenthal has introduced right-to-try legislation in New York. Opponents of the bill argue that it undermines the FDA or paves the way for medical misconduct. Rosenthal supports the right of patients to access unapproved agents under the right-to-try framework. "We're not talking about healthy people suffering with a medical condition and letting them try a drug that may make them sicker. We're talking about people with no options," Rosenthal said. "Who am I to tell them that they can't try, or that I know better?"

Realism and hope

Fritz Bittenbender from the Biotechnology Industry Organization (BIO) shared the concerns of industry regarding right-to-try laws. The current regulatory environment hinges on the clinical trial process, and pharmaceutical companies prioritize getting approval as quickly as possible.

While many companies ideologically support compassionate use, anything that may compromise the clinical trial process is viewed with caution. "When we look at right-to-try and some of the other legislation, our concern is how to have an expanded access program that tries to give every patient access to a medicine ... and do it in a way that assures we can still enroll patients in clinical trials," he said.

There is also concern about how data from compassionate use cases may be used. If patients who are ineligible for a clinical trial receive a therapy through compassionate use and experience adverse events, these outcomes may put the continuation of trials in question.

Pediatric oncologist Peter Adamson sees pitfalls in some of the legislative efforts to increase pre-approval access. "We should never underestimate hope, but there is danger to false hope, and it's our job to guide that hope," he said, explaining that pre-approval access needs to be balanced with realistic expectations. Having a mechanism to gain early access is crucial, but the process must be steered by research and trial data to the greatest degree possible. Adamson asserted that the high hopes of early access are a mess of our own making; compounds may be publicly hailed as "promising" after a test on a single animal model. "We don't present balanced views of what the data shows, and what it doesn't," he said. "There is far too much hype and far too little data."

Digging deeper

Moderator Alison Bateman-House asked the panel who should lead the charge in making the compassionate use process more patient-friendly and transparent, and less risky for pharmaceutical companies. The consensus was that all stakeholders are important, but legislation that improves the framework needs to lead.

The panel dug deeper into the legislative solutions proposed, starting with provisional approval. Mann Woods explained that provisional approval is on the surface similar to right-to-try, but it has the bonus of providing an incentive for outside investment in a company. "A company can't wait for a revenue stream 15 years out," she said. "We can enable companies to survive the approval process ... and provide benefit not just for the few who need investigational access, but for everyone."

Adamson added that it is not unusual to consider a therapy with limited safety data under certain circumstances, especially because some compounds and pathways are better understood than others. If an investigational compound acts on a pathway that is well researched, clinicians are likelier to feel comfortable offering it to patients who have exhausted other options. He pointed to the need for more realistic clinical trials with looser eligibility requirements, because these requirements are often motivated by fear of outcomes that could negatively affect the trial, and there are valuable data to be collected from a more diverse patient population. "There is no such thing as an ideal patient," he said.

The debate about right-to-try laws centers on whether these laws prioritize the individual over the many. Sandefur suggested that rather than thinking of right-to-try as a silver bullet, we should consider it a first step to create more access for people who cannot enter clinical trials. She reiterated the point that companies may hesitate to allow compassionate use for fear of adverse events being reported to the FDA, and questioned the FDA's assertion that such events in compassionate use cases would not derail drug development. Prior panelist and FDA representative Richard Klein responded that such occurrences are rare, and stated that the right-to-try laws may unintentionally make early access harder, because the laws vary among states and are more restrictive than the FDA's requirements for pre-approval access.

Panelists

Arthur Caplan

Moderator

NYU School of Medicine

Rob Camp

European Organization for Rare Diseases (EURORDIS), Spain

Barbara von Tigerstrom

University of Saskatchewan, Canada

Tom Watson

Idis Managed Access, part of the Clinigen Group, UK

Marcela Simões

Interfarma, Brazil

Highlights

Compassionate use procedures in the U.S. differ greatly from those in other countries.

Globally, there is a move toward creating more consistent systems for pre-approval access to ease the path for patients and allow companies to recoup costs.

The costs of compassionate use in countries with national health care can be crippling, and cases are often decided in the court system.

Little common ground

Barbara von Tigerstrom of the University of Saskatchewan opened a panel examining how compassionate use policies differ in various countries, with an eye toward strategies that may help forge new directions in the U.S. An analysis comparing compassionate use regulations in the U.S., Canada, and Australia shows greater differences than similarities—one of the only areas of common ground is the reporting requirements, which are fairly weak across the board.

The U.S. is the only one among these countries to require ethical approval of compassionate use requests by an institutional review board (IRB). In Canada and Australia, there is less involvement by federal regulators; for example, Australians with a terminal condition can seek any experimental treatment with only the assistance of a physician, and in Canada, patients may seek investigational devices even without a life-threatening condition.

The 28 countries of the European Union each have their own regulatory scheme for compassionate use, as Rob Camp and Tom Watson explained. These schemes fall into three categories: some countries prohibit access to unapproved therapies; some permit early access but insist on treating a group of patients, free of charge, within a compassionate use protocol; and some have no protocols but permit early access and allow pharmaceutical companies to charge for medications.

Amid the confusion created by dozens of different interpretations of compassionate use, EURORDIS is spearheading efforts to create a unified set of patient-centered best practices. Much like in the U.S., however, there is no one group in Europe officially tasked with leading the movement. "It's slow moving, it's almost a Sisyphus-like process, because no one is really in charge," Camp said.

Marcela Simões of Interfarma characterized Brazil as a country in flux when it comes to pre-approval access. Brazil's health care system is government funded, and health care has become increasingly judicialized. Pleas for specific medical services, including compassionate use, often end up in the court system. The financial costs are unsustainable.

The panel discussed the contrast between the U.S., where some groups argue that there is too much federal regulation, and Europe, which lacks regulatory continuity. Von Tigerstrom mentioned that an advantage to the kind of federal oversight provided by the FDA is that there is a unified system; in Australia and Canada, states' and institutions' criteria for compassionate use vary. "I don't think we can assume that taking away the need for federal approval lessens barriers—in some cases, it may be the opposite," she said.

Who pays?

Some biotech companies based outside the U.S. recoup some of the costs of pre-approval access through outside funding or by charging patients for medication and associated services. "Maybe that increases the inequity across the world—there are always pros and cons," Watson commented while discussing these financial disparities. His company works with patients and pharmaceutical companies to facilitate pre-approval access, and 60%–70% of the compassionate use requests it receives each month come from the top five European markets. These numbers are reflective not of the degree of medical need but of where compassionate use programs exist to facilitate requests.

The question of who pays for compassionate use requests is more straightforward in countries with public health systems. "It's the government, but the question is, can the budget handle it?" Camp said. Simões noted that Brazil's system is struggling to meet compassionate use requests in rare disease much as it once struggled to providing early access to medicines for HIV. "We have good examples of compassionate use and bad examples, and HIV is a good one—now we are struggling to figure out how to give rare disease patients access and good care," she said.

Not the Wild West

The discussion turned to outcome data from countries with different regulations for compassionate use. Von Tigerstrom reported that what little data exist for the Australian system show that "some physicians are testing the limits on what is a life-threatening condition, raising concerns about what happens if this option is being used inappropriately." The equivalent of the FDA must be notified of outcomes in many cases, and a physician's professional obligations still apply. "This is not the Wild West," Watson added, debunking the perception that absent federal regulation, access to unapproved therapies is unfettered and uncontrolled. "There are different controls in place, but there are controls," he said.

Panelists

Fred Guterl, Moderator

Scientific American

Martha Donoghue

U.S. Food and Drug Administration

Matthew Hepburn

Defense Advanced Research Projects Agency (DARPA)

Amrit Ray

Janssen Pharmaceutical Companies of Johnson & Johnson

Tanya Scharton-Kersten

International AIDS Vaccine Initiative (IAVI)

David Scheer

Scheer and Company Inc.

Highlights

There is room to create meaningful change within the current regulatory framework for pre-approval access.

Granting pre-approval access should not be a financial breaking point for companies.

Sponsor companies need to improve transparency and objectivity when it comes to compassionate use decision-making.

Compassionate use trials can contribute meaningful data that enhance the clinical trial process, not harm it.

Recasting the mold

David Scheer, who heads a venture capital and strategic advisory firm for life sciences companies, began by stating that requests for pre-approval access to medications are not only an unavoidable reality but also "an opportunity to do the right thing—and the right thing isn't always adverse to the interests of a sponsor company." Within this reality, companies both large and small need to be prepared for these requests, creating best-practice guidelines and mechanisms to facilitate access when appropriate. Scheer suggested that enacting systems that allow sponsor companies to recoup some of the costs of compassionate use would lower barriers in the U.S. and make "doing the right thing" more feasible.

Tanya Scharton-Kersten facilitates public–private partnerships in AIDS vaccine development, with a focus on helping academic investigators begin human trials and understand what constitutes a successful phase I trial. When it comes to early access, she asked, "Should we break the mold or just recast what we're doing?"

The level of protection the FDA provides when it comes to safety testing and trial ethics is something that many other countries strive to enact, but Scharton-Kersten believes there is room for improvement within the current U.S. regulatory framework. "Expanded access should not only be viewed in terms of morbidity or survival," she said. "We need to fund more early-stage research to look at success and failure" of medicines in development, including when they are provided in early access protocols, looking at biomarkers and other data points that can help researchers understand how a compound or vaccine works in the body and whether it is likely to be effective in a broader population. Improving the application and data-collection processes for expanded access would provide a snapshot of the demand for a compound, allowing stakeholders to collaboratively assess these needs.

Taking action

"If Josh Hardy's family were to come to us today with the same request, what exactly would change?" asked Amrit Ray of Janssen Pharmaceutical Companies of Johnson & Johnson. He argued that that rather than just talking about new ideas for pre-approval access, stakeholders must have "a bias toward action."

Ray detailed three points of action, starting with the simple but crucial idea that all sponsor companies should have a transparent, public policy for compassionate use. The policy should be easy to find on the company's website and be written in language the public can understand. Janssen took this concept one step further—"We put together a 2-minute YouTube video to explain what patients need to know, and the one phone number patients can call," Ray said.

Ray's second recommendation is to use independent, external experts to review each request to ensure objectivity. The third is to make outstanding operational follow-through on compassionate use requests a mandate; patients should have a seamless experience from the initial contact through a timely decision-making process to delivery of the medication.

Thinking differently

Matthew Hepburn of DARPA discussed how a more creative approach to drug development and testing could rapidly advance therapeutics. For example, in the case of infectious disease, rather than identifying a pathogen and developing an antibiotic or antiviral, it may be possible to modify a host's response so that the pathogen is no longer deadly. "My job is to think about problems completely differently, and to try something high risk," he said. Hepburn suggested that computer modeling and simulation could make the laborious clinical trial process easier by providing predictive information about safety and efficacy before a compound is tested on humans.

Martha Donoghue of the FDA pushed for a different view of expanded access, one in which an expanded access trial can advance the main clinical trial process rather than hamper it. As breakthrough oncology therapies target ever-smaller subsets of patients, there is less clinical trial data available. Patients accessing these medicines for compassionate use can contribute meaningful data to bolster the case for approval. In some cases, the FDA has used data from expanded access use of investigational medicines to support drug approval. "We can use regulatory flexibility to help propel development further," she said.

Panelists

Alison Bateman-House, Moderator

NYU School of Medicine

Nancy Neveloff Dubler

New York City Health and Hospitals Corporation; NYU School of Medicine

Jerry Menikoff

U.S. Department of Health and Human Services

Franklin Miller

Weill Cornell Medical College

Beth Roxland

Johnson & Johnson; NYU School of Medicine

Luann Van Campen

Eli Lilly and Company

Daniel McIntyre

Biogen

Closing Speaker

Valerie Cwik

Muscular Dystrophy Association

Highlights

Compassionate use is one of the most complex bioethical issues, and it is a constant struggle to balance the needs of current patients with the needs of many more future patients.

Patient autonomy is important, but companies must consider pre-approval access in the greater context of drug development.

Pre-approval access could be viewed not as a part of evidence-based medicine but instead as a part of research, with a communitarian ethic governing decision-making.

There is only consensus on a need for change, not a clear path forward.

Patient autonomy and the bigger picture

In the final session, a panel of ethicists reflected on the outstanding issues raised by the conference. Comments and suggestions centered on three themes: the need to consider patient autonomy and patient rights within the current regulatory framework; the need to reconsider the lens through which we view pre-approval access to allow for better data collection and clearer risk/benefit propositions; and the need to improve communication among groups.

Luann Van Campen of Lilly described bioethicists as playing the role of walking alongside patients who are suffering. "But in a company of 40 000 people, how do we do that?" she asked. Her question points to the overall difficulty of bridging the gap between patients, researchers, and industry, particularly in an area as emotional as compassionate use. Jerry Menikoff of the Department of Health and Human Services commented that this gap is even harder to manage amid the push for patient autonomy when it comes to life-threatening illnesses. "We're blurring the lines between what happens in a trial and what happens outside the trial ... and this isn't going to go away," he said.

"Right-to-try" laws have opened a new avenue for individuals requesting access to investigational medicines. Nancy Neveloff Dubler believes these laws may in fact degrade patient autonomy. "Right-to-try is a sham," she said. "It's an empty promise which delivers nothing, and patients who want to try a substance that's in the middle of a phase I trial have no basis on which to choose that [substance] and the company has no basis on which to grant it," she said. One of the core ethical principles of compassionate use must be a scientifically valid basis for believing a treatment will benefit a patient, and "right-to-try" circumvents some of the protections that ensure that validity.

Van Campen added that patient requests for early access weigh heavily on companies, even those that have the resources to provide access. "Risk is the argument for patient autonomy, with patients saying 'I will take that on myself,' but we have to ask if we're providing fair access, and if it's safe for the patient," she said. Additional ethical quandaries arise when patients request an investigational medicine "off indication"—for a condition different than what is being tested in clinical trials. "We may have absolutely no data and no indication of benefit, so it's much harder to review these requests," she said.

To ease the burden for sponsor companies, Dubler suggested that an external group similar to a data safety monitoring board could review available data about a compound before expanded access is considered. "I'm looking for fixed points in the process that might help companies decide as a threshold matter whether they want to go forward," she said.

A new lens for pre-approval access

Several panelists raised the need to change the way we view pre-approval access. "We can't look at pre-approval access through the lens of evidence-based medicine," said Franklin Miller of Weill Cornell Medical College, noting that compassionate use is an option when there is little or no evidence. "We need to look at it as part of research, and those who go into it as research participants—and that's all the more reason we should collect systematic data on these patients," he said.

Dubler offered the view that a less individualized, communitarian ethic should govern the process. Within that context, "giving people pre-approval access will not destroy the scientific structure of the study ... the risks are not only to the individual, the risks are to the other members of the class and to science," she said.

Daniel McIntyre of Biogen relayed the story of planning for a 5000-patient expanded access trial for an amyotrophic lateral sclerosis medicine, only to abort the program when phase III trials showed the compound had no efficacy. "If you've seen one compassionate use program, you've seen one compassionate use program," he said, urging participants to consider the unique factors in each case—there is no monolithic solution.

Collaboration and coexistence

"Every stakeholder that spoke over the past two days said that we could do better, and nobody came here without some openness," said Beth Roxland of Johnson & Johnson. Like many prior panelists, Roxland commented on the value of bringing different groups together to discuss solutions and new directions.

In closing remarks, Valerie Cwik from the Muscular Dystrophy Association called the symposium "a tremendous start for an open dialogue" on pre-approval access. The greatest points of agreement related to the push for systemic change to allow patients' needs to be met equitably, while preserving financial solubility for sponsors and the safety regulations crucial to drug development. "There is consensus for improvement, but there is no agreement on what the paths forward should be," Cwik said. Reiterating the need to go beyond conversation and take action, she closed with a reminder that "patients, who may include anyone in this room, deserve no less."

Should compassionate use requests be reviewed by external review boards to increase objectivity and promote equitable distribution? If so, should this replace the current requirements for FDA and IRB review, or be added to them?

How can stakeholders balance the needs of patients who are critically ill now with the needs of future patients?

Are there mechanisms that should be enacted to help sponsor companies recoup some of the costs associated with compassionate use?

Is it ethical to charge patients for access to experimental therapies?

How can clinical trials and compassionate use protocols be redesigned to run in parallel, and without conflict or compromise?

Is it ethical to use investigational agents in a public health crisis, when informed consent and data collection opportunities are difficult or impossible?

How can the FDA improve communication with pharmaceutical companies to become more aware of compassionate use requests?

Can meaningful change that will lower the barriers to pre-approval access best be accomplished legislatively, by regulation, by industry initiative, or by something else?