The Development of Brincidofovir And Its Possible Use To Treat Josh Hardy

Last March 4, seven-year old Josh Hardy lay critically ill in the intensive care unit at St Jude Children’s Hospital in Memphis, Tennessee with a life-threatening adenovirus infection. His weakened immune system was unable to control the infection, a complication of a bone marrow stem cell transplant he needed as a result of treatments for several different cancers since he was 9 months old.

His physicians tried to treat the adenovirus with an anti-viral agent, Vistide (IV cidofovir), but had to stop due to dialysis-dependent renal failure. They were aware of another anti-viral in Phase 3 clinical development, brincidofovir, an oral compound chemically related to Vistide. In earlier clinical testing brincidofovir had shown the potential for enhanced antiviral potency and a more favorable safety profile.

Chimerix (where one of us, Moch, was CEO), a 55 person North Carolina-based biopharmaceutical company, had previously made brincidofovir available to more than 430 critically ill patients in an expanded access program for the treatment of serious or life-threatening DNA viral infections, including adenovirus as well as herpes viruses (such as cytomegalovirus) and polyomaviruses.  This program started in 2009 as a series of individual physician-sponsored emergency INDs — investigational new drug exemptions issued in physician-certified compassionate use situations.

The program evolved via word of mouth to the extent that brincidofovir was made available under emergency INDs for more than 215 patients. During 2011, Chimerix received funding from Health and Human Service’s Biomedical Advanced Research and Development Authority (BARDA) to provide brincidofovir to an additional 215 critically ill patients for the purpose of gaining insights into the potential use of brincidofovir as a medical countermeasure against smallpox. (Department of Health and Human Services Contract No. HHSO100201100013C.  For further information on brincidofovir Study CMX001-350, see Identifier NCT01143181.)

When BARDA funding ended in 2012, Chimerix stopped accepting new requests for compassionate use under its expanded access program. Although requests continued from physicians around the world, the company decided that it was in the best interests of the greatest number of patients to devote its limited human and financial resources to the clinical development pathway necessary for FDA approval of brincidofovir.

This post examines the implications of the ultimately successful campaign waged by Josh Hardy’s family to obtain access to brincidofovir for their son. We discuss several issues raised by the Hardy case, including the overarching question of whether it is fair for social media or influence of any form to play a role in determining which patients get access to experimental treatments; whether rescuing individual patients in need can be reconciled with an evidence-based regulatory approval process for new therapies; and whether there is a duty to “rescue” terminally ill patients by paying for access to experimental therapies.

Finally, we propose a new framework for regulating access to experimental treatments.

Josh Hardy’s Case Continued

After completing its initial public offering in April 2013, Chimerix started a Phase 3 clinical trial of brincidofovir for the prevention of reactivation of CMV infections in adult hematopoietic stem cell transplant recipients.  The company anticipated results in 2015 which, if positive, would support FDA approval and thus the broad availability of brincidofovir.

By early 2014, a number of case reports and abstracts had been published or presented reporting positive results from the earlier expanded access use of brincidofovir. For example, in February 2011, an article appeared in the Journal of Clinical Virology regarding a 12-year-old severely immunocompromised pediatric stem cell transplant recipient who had developed a life-threatening adenovirus infection, the same kind of complication as Josh Hardy. This paper reported that treatment with brincidofovir resulted in “successful eradication of disseminated adenovirus” with no serious adverse events.

On February 12, 2014, doctors at St. Jude requested that Chimerix provide brincidofovir for Josh Hardy. Consistent with Chimerix’s policy to focus its full resources toward completing the ongoing Phase 3 clinical trial, this request, as with others, was denied. On March 5, after Josh developed renal failure, the St. Jude’s Vice President, Clinical Trials Administration sent a letter containing a second request to Chimerix stating that “it is likely that after having fought against childhood cancer for so long, he may succumb to this infection without a non-nephrotoxic medication with superior efficacy proven in clinical trials.”  The second request was also denied.

On Thursday evening, March 6, Josh Hardy’s mother, Aimee, posted a letter on her Facebook page seeking to identify someone who could influence Chimerix to change its stance. Within hours people began to contact Chimerix management and Board members. Later that night, Josh Hardy’s uncle launched both a Facebook page and a Twitter site called #SaveJosh. His first post on the Facebook page was the letter from St. Jude’s Vice President to Chimerix containing the second request for brincidofovir.

Overnight, and intensifying the next morning, the company received hundreds of phone calls and emails pleading for access for Josh. By Friday morning, March 7, several state and national politicians contacted Chimerix’s CEO. By Saturday morning, March 8, local and national TV networks were calling Chimerix to set up interviews to include in their coverage of the #SaveJosh story.

Around noon on Saturday, the uncle posted on Facebook the text of a letter from Chimerix’s CEO explaining the company’s compassion for Josh and its ethical rationale for not making brincidofovir available. Rather than mitigating the growing social media pressure, the uncle’s commentary on the letter further inflamed supporters, who then posted the personal contact information of Chimerix’s CEO and board of directors.

On Sunday evening, March 9, CNN featured an eight minute segment on the Josh Hardy story, followed on Monday by other national TV and print media stories from around the world. On March 10 the #SaveJosh Twitter feed trended in the top five national stories and the Facebook page reached over one million views. Chimerix’s CEO, management and Board members were deluged with thousands of phone calls and emails, some of which included death threats. The company hired security for corporate leadership.

While the very public and highly negative social and traditional media frenzy pleading for access for Josh was ongoing, discussions had started on Monday, March 10 between the FDA and Chimerix about how to give access to Josh and others without compromising the effort to complete the clinical trials that could lead to approval of brincidofovir.  On Tuesday evening, March 11, 120 hours after the first Facebook post by Aimee Hardy, Chimerix announced it would make brincidofovir available to Josh as part of a 20-patient open-label pilot trial that would lead to a pivotal Phase 3 trial for the treatment of adenovirus infections.

Josh received brincidofovir on Wednesday, March 12 and, according to his family, responded very well to the drug.  He left the ICU on March 25 nearly virus-free.

After the announcement that Josh Hardy would receive brincidofovir, the “tone” of the social media reversed course from criticism to praise. Chimerix stock rose almost 50 percent throughout the course of the social media campaign.  On April 9, the Chimerix Board replaced the CEO with the chief medical officer of the company. On April 10, Josh Hardy was allowed to leave St. Jude Hospital, although he was required to remain in Memphis to be near his physicians. On July 17, he was allowed to return to his home in Virginia.

Access To Unapproved Drugs, Devices And Vaccines

The Hardy case illustrates the growing power of social media to influence the decision-making process regarding access to health care interventions in the United States. It also shows the ethical concern that patients, families, treating clinicians, and the American people have about roadblocks to providing rapid access to potentially beneficial experimental drugs for those who are terminally ill.  The question of whether to pay for and attempt rescue, which in the media is primarily focused on the provision of drugs to terminally ill persons, also arises with respect to those facing permanent serious disability such as blindness, dementia, and paralysis.  Requests for access are not confined to drugs — they exist for medical devices, vaccines, and other biologic therapeutic modalities such as stem cells.

The question of whether there is a duty to pay for the use of unproven and experimental therapies to attempt to rescue individuals in dire medical straits, even those with poor odds of success, is one that health policy makers have not acknowledged as part of ongoing national health care debates in the United States and in other nations.

In the case of many experimental therapies, there is a clear and growing moral dilemma which society will ultimately need to address: Do attempts to help individuals in immediate need place at risk the pursuit of evidence-based regulatory approval that will make a product available as quickly as possible to the largest number of affected and soon-to-be affected individuals?  This dilemma is often more difficult for smaller companies, which have limited human and financial resources and are ill-positioned to address the conflicting choice of trying to rescue needy individuals versus advancing the interests of large numbers of future patients.

A separate but equally powerful question is how to choose and how to be fair with respect to providing access to an unapproved treatment.  Should an experimental product be made available to an individual patient who is more vocal, more sophisticated in the use of media, more knowledgeable about the system, more adept at electronic searches?  What about those individuals in equal medical need who do not have these tools at their disposal or do not know how to find or use them?  In other words, while it is extraordinarily difficult to say “no,” it is equally difficult to say “yes” and be sure that the “yes” applies fairly to all patients in extreme need.

More broadly, should social media or any form of influence — be it political, monetary, or social — play any role in decision-making about access? If so, what role? Given that a key ethical principle in this country is that access should be based on need, and should be equally available to all with the same level of need, is the use of intense social media or other forms of influence be used to gain such access, potentially detrimental to those without such influence? As social media increases its presence, this question must be thoroughly considered.

As for the current availability of compassionate use for the critically ill, many put the blame for lack of rapid access on the Food and Drug Administration. Over the past decade, efforts have been launched at the state level to minimize the involvement of the FDA in allowing access to experimental products by the terminally ill.  In 2003 a lawsuit brought by the Abigail Alliance to force the FDA to permit access to any post Phase I drug failed in Federal Court, and the U.S. Supreme Court declined to consider an appeal.

Many of those involved with that lawsuit are now promoting so-called ‘right to try’ laws which permit terminally ill persons who have exhausted all treatment options to use investigational drugs, biological products, or devices without seeking permission from the FDA. Several states have recently enacted this legislation and a number of other states are evaluating whether to do so.

Yet FDA statistics show that few requests for expanded access are rejected by the Agency; since 2009, over 99 percent of expanded access requests submitted to FDA have been approved. Additionally, in response to patient and public demand, over the past 20 years the FDA has created programs designed to speed availability of novel therapies, including accelerated approval, priority review, breakthrough therapy, and fast track status. While none of these programs allows for individual access to experimental drugs during the development program, they do help define and hasten the path to approval of medicines with unmet medical needs.

In the current environment, there are certainly many impediments for those seeking access to experimental drugs. Many still have concerns with the FDA process, which is generally not well known to patients, patient advocacy groups or their doctors, and can be time-consuming.  While resources are needed to standardize FDA application procedures and promulgate information about the steps would-be patients and families can take, more could be done to facilitate access.

However, merely taking the FDA out of the picture, as ‘right to try’ laws do, does nothing to allay company or investor concerns that negative outcomes will be held against a drug or other intervention provided outside of the rigorously controlled parameters of a clinical trial; provides no resources to pay for drugs or travel to gain access; leaves those who are not terminally ill with no pathway to pursue; and opens the door to quacks, charlatans, and others who may seek to exploit desperately ill patients by offering interventions that cost a great deal but offer no realistic hope of benefit.

The Ethical Challenge Of Rescue Versus Treatment

The duty to seek to rescue those in very dire straits is a powerful norm in American society and in major religious traditions around the world.  Whether it is coal miners trapped in a mine, mountaineers stranded on a peak or a child fallen into a long-abandoned well, it is very clear that, despite difficulty and cost, society wants strenuous rescue efforts to be made. Health policy discussions often fail to reflect this deep moral concern as shown in the absence of attention to the issue of ‘rescue’ and in the lack of funding in public and private insurance for attempting to do so.

Moreover, there has been little effort to address the fact that regulation and public policy in the development of new drugs, devices, biologics and vaccines focus on assuring that what is made available to the public attains a very high threshold of safety and efficacy. Companies, their investors and boards strive mightily to pursue product development pathways that meet this threshold in the most efficient timeline and at the most rational cost.

The moral tension between efforts to rescue the (usually) small number of desperately ill individuals and the desire to do good for the (usually) large number of the afflicted or yet to be afflicted has for the most part not been a development criterion.  This complexity is often further exacerbated by the societal bias towards saving the lives of children over older individuals and identified persons over statistical lives.

Since completion of trials aimed at making a new therapeutic option available to the broadest number of people is the primary goal sought in the current system, individual rescue does not have a formal place in the structure, budget or compliance aspect of many company sponsors.  A system that relies solely on the discretion of the sponsor, be it a large or small pharmaceutical, biotech, biologics or device company, to make humanitarian decisions with conflicting pressures from investors, variable resources within companies, limited or no funds to reimburse costs, the risk of diversion of efforts away from formal clinical development programs and no legal or regulatory relief from adverse events, all while in the glare of social and traditional media, is not a system that is fair, just, thoughtful or efficient.

It is simply putting the weight of resolving the needs of the few against the needs of the many on an entity — the sponsor — that often lacks resources, skills, and the neutrality requisite to make the best decision.

What Is Needed To Rescue Compassion?

A new system must be created to bring fairness, equality, and appropriate oversight to the availability of experimental treatments. The weight of such decisions should not and cannot rest solely on sponsoring companies. Consideration should be given to the creation of a national “Expanded Access Institutional Review Board,” which would be able to weight factors including the proximate needs of the few versus the longer term needs of the many, the availability and cost of the experimental treatment, risks and benefits to the individuals, and equitable access.

Additionally, to make this possible, regulators must address sponsors’ concerns regarding the potential for unintended consequences that could negatively impact a product’s development program, pathway, or timeline, such as unanticipated adverse events or the reluctance of patients to enter placebo controlled trials.  Finally, the issue of who will pay for these compassionate uses must be addressed.  If society desires access to unapproved medicines, should the government or some other funding agency bear some if not all of the financial burden?

Without a new system and clarity within the regulatory process, medical decision-making will be left to those individuals and mechanisms — to social media, newscasters and print reporters, and politicians — least appropriate to decide complex medical facts. Demands and threats will supersede science and logic, creating a system that promotes unfairness rather than equality and potentially destructive logjams rather than speedy development. If rescue is an important value of a humane society, then that society must insure that rescue is truly fair, transparent, and affordable by those in need.