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

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.

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.

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.

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.

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.

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.

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.

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."