Now that the family of seven-year-old Josh Hardy has successfully obtained access to an experimental drug, aided by an explosion of social media support, lawmakers, industry and patients still are left grappling with the fundamental inequities and flaws of the U.S. system for granting compassionate access to investigational therapies.

The problems have existed for years, including the idiosyncrasies of who gets access to investigational drugs outside of clinical trials and the criteria companies use to make decisions that are often life-and-death.

The fact that individual companies have been left to make these decisions on an ad hoc basis inevitably fuels suspicions among patients, family members and the public about the motives for denying access.

The difference in perspectives between companies focused on gaining regulatory approval and individuals trying to save desperately ill loved ones can make mutual suspicion curdle into antagonism.

The rise of social media as an advocacy tool now raises the prospect that medical and regulatory decisions will be tipped by a public outcry.

As the Hardy case illustrates, patients or their relatives can generate hundreds of thousands of supporters virtually overnight, along with a wave of attention on television. In the heat of a media feeding frenzy, it is impossible for a CEO to communicate the complexities of drug development and why the integrity of the regulatory approval pathway must be protected to get a drug to as many patients as possible.

And a CEO who says "no" is no match for 100,000 angry Twitter messages and death threats from angry individuals who jump on the bandwagon. The threat of demonization has led companies to be wary of individuals and groups seeking to obtain compassionate use access to their products.

While the Hardy case reflects old problems, it also may be a game-changer. The almost immediate and apparently extraordinary effectiveness of Chimerix Inc.'s brincidofovir for Josh Hardy, coupled with the power of social media to push the company to find a way to provide access, have already led other families to pursue similar campaigns (see "The Josh Hardy Chronicles," A7).

The Hardy case also has prompted members of Congress, industry trade associations, patient advocacy groups and individual companies to reassess the need for new principles to guide compassionate access decision-making in the era of social media and patient empowerment.

Biotech industry leaders are suggesting it may be time to shift some decisions about compassionate access off the shoulders of CEOs and onto new institutions to help adjudicate requests for pre-approval access to medicines.

All of this points to the need for public consensus on a transparent pathway for making decisions about compassionate access (see "Commentary," A9 & "Decision Tree for Compassionate Use," A11).

FDA procedures

The medical, ethical, business and logistical aspects of providing access to investigational drugs can be complex and contentious, but the regulatory pathway is straightforward.

While companies, patients and the media sometimes accuse FDA of preventing compassionate access to an investigational drug, data show the agency virtually never denies requests.

This does not mean patients always get access to unapproved drugs. Requests for access must be submitted by drug sponsors or with their permission. Patients cannot apply directly to FDA, and the agency will not process an application from a physician unless a sponsor is willing to provide access to its product.

That does not mean FDA always plays a passive role. Agency officials sometimes reach out to companies to encourage them to provide access to investigational drugs, according to Richard Klein, director of FDA's Patient Liaison Program.

The agency has initiated expanded access discussions with companies based on requests from patients, media coverage and other triggers.

Biotech executives report they've received calls from FDA relaying requests from members of Congress for family members or constituents to receive access to investigational drugs.

FDA has used the term "compassionate access" in the past, but now it uses "expanded access to investigational drugs for treatment use." According to guidance released in 2013, expanded access is intended "for patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives."

The guidance lists criteria FDA applies to review expanded access applications, including a determination that the "potential benefit justifies the potential risks of the treatment use with the drug and that those risks are not unreasonable in the context of the disease or condition to be treated."

FDA must determine that providing expanded access "will not interfere with development of the drug for the expanded access use, and that the patient cannot obtain the drug under another IND or protocol."

To reduce impediments to expanded access, FDA does not require reporting of outcomes data.

"Expanded access is designed for regular doctors - treating physicians as opposed to research doctors - so reporting requirements are minimized," Klein told BioCentury. FDA requires reports only about basic safety information, such as "serious and unexpected adverse events that may be related to the drug, for example liver failure," he added.

As a result, Klein noted, FDA only has anecdotal information about the efficacy of drugs provided under expanded access.

In some cases, as with Chimerix's brincidofovir, the agency works with companies to create a clinical trial that could lead to a new approval or expanded indication.

But while Josh Hardy's response to brincidofovir may have been dramatic, Klein noted the feedback FDA receives suggests that patients and physicians seeking expanded access are often over-confident about the potential for experimental treatments to provide dramatic cures.

"Every now and then people will call back and say, 'We really appreciate the help, but my mom has died'," he said. "No one has ever called up and said, 'I really appreciate the help, and my mom's great.' You would think they would be more likely to call if that happened."

There are, however, numerous reports in the medical literature of positive responses to compassionate use treatments. For example, in 2009 German researchers reported in Blood that compassionate use of Nexavar sorafenib in five patients with acute myelogenous leukemia (AML) produced "sustained regression before and after allogeneic stem cell transplantation."

And the first published report about the efficacy of brincidofovir recounted the dramatic rescue of a pediatric transplant patient with a life-threatening adenovirus infection.

Tip of the iceberg

Despite the extensive list of criteria FDA staff apply to expanded access applications, "for the most part it is not a very intense review; they are not looking for reasons not to give" expanded access, Klein said.

FDA reports that it approved 99.4% of expanded access applications submitted from October 2009 to September 2013 (see "Expanded Access Scorecard").

Neither FDA nor any other entity keeps track of how many requests from patients and physicians for access to experimental treatments are turned down by companies.

Arthur Caplan, a bioethicist who often provides advice to hospitals and life sciences companies about compassionate use and other ethical issues, says it is likely that only a small fraction of refusals make it into the media.

"From my own experience getting calls from companies for input, the cases we see in the media are the tip of an iceberg," he told BioCentury.

Caplan is director of the Division of Medical Ethics in the Department of Population Health at New York University's Langone Medical Center.

Clinicians report that companies routinely deny their requests for compassionate access.

Peter Adamson, chief of the division of clinical pharmacology and therapeutics at the Children's Hospital of Philadelphia, told BioCentury he limits compassionate use requests to instances in which there is good evidence that an investigational drug will help a child and the potential benefits clearly outweigh risks from the underlying disease.

Adamson said he has applied for compassionate use about 10 times in the last 20 years and cannot recall a time that a request was denied.

Reasons for refusal

There are two sets of reasons for companies to deny compassionate access requests: reasons the industry publicly acknowledges and reasons executives discuss only off the record.

BIO published its views in 2010 in a document titled "Early Access Programs: Points to Consider."

BIO starts from the premise that "a patient's right to treatment based on his or her autonomous decision-making ability does not supersede a company's ethical responsibility to develop and market safe and effective products as fast as possible."

The document warns that allowing early access can risk market approval of the product in in some circumstances.

"Thus, the question often confronting companies is whether to put an entire project at risk and therefore jeopardize availability of a drug for a larger patient population - in order to provide early access to a product for an individual or small group of patients," said BIO.

The document does not provide examples of circumstances in which allowing early access puts FDA approval at risk.

Biotech executives who did not want to be identified told BioCentury their biggest concern is that a serious safety issue will be identified in a population that would not have been included in clinical trials. Even if it is impossible to definitively attribute the adverse event to the investigational drug, a safety incident could lead FDA to deny approval, they said.

Caplan recounted similar worries, telling BioCentury companies have told him they are concerned that adverse events in patients who receive an investigational drug outside a trial will delay or prevent drug approval.

Adamson of Children's Hospital does not buy those arguments. He argued the fear of adverse events leads companies to inappropriately reject compassionate use requests for pediatric cancer patients.

"There is a mythology that if FDA sees a serious adverse event in children it will derail development of a drug. That's nonsense," he said.

Moreover, Adamson said, "There is no data I am aware of that a company with a compassionate access program has experienced a delay in approval."

Nancy Goodman, founder of patient advocacy organization Kids v Cancer, also rejects the adverse event fears.

"Companies are often too quick to reject requests for compassionate use from kids because they have an exaggerated fear of negative attention from the death of a child on their drug," she told BioCentury.

Goodman said regulators, families and the public understand experimental drugs may not always be effective, and that safety hasn't been fully characterized, especially in the case of cancer treatments.

FDA officials "cannot think of an example of a drug that was not approved because it was provided through compassionate use/expanded access," agency spokesperson Stephanie Yao told BioCentury.

There is at least one example where a death in an expanded access program did not prevent approval: Aldurazyme laronidase.

According to briefing documents prepared by BioMarin Pharmaceutical Inc. and partner Genzyme Corp. for a January 2003 advisory committee meeting, Aldurazyme was provided to four patients with mucopolysaccharidosis I (MPS I) who were seriously ill and did not meet the selection criteria for participation in ongoing trials. A 10-year-old patient who was treated under a single-patient special access protocol died.

"With Aldurazyme, we did do an expanded access patient outside of the study, and the patient did die, and we included it in the safety data that was submitted in the package. And it had no apparent impact on the approval pathway," Emil Kakkis told BioCentury.

Kakkis, now president and CEO of Ultragenyx Pharmaceutical Inc., led development of three Orphan drugs as CMO at BioMarin, including Aldurazyme.

While FDA's briefing documents for the advisory committee meeting discuss deaths in the formal clinical program in some detail, they mention the death in the special access protocol only in a table.

"FDA was very rational and asked for the safety information, and we did the right thing," Kakkis said.

Aldurazyme was approved to treat MPS I in April 2003. The product is marketed by BioMarin and Genzyme (now part of Sanofi).

Whether the fear is justified or not, Congress could make the issue disappear.

"The American people could say, 'We don't want you holding bad outcomes against the drug,'" said NYU's Caplan. "If we want companies to be more liberal about compassionate use, we should minimize the risk exposure when a company becomes compassionate."

Moral challenge

Companies also must consider the possibility that implementing early access could divert scarce resources from development and approval, thus delaying broader availability of a drug.

According to BIO's Points to Consider, companies have an ethical obligation to bring drugs to market as fast as possible.

"While the case of each individual patient may be moving and compelling, very difficult decisions must be often made to ensure fair and optimal use of limited resources in order to achieve full evaluation of a drug's safety and effectiveness as quickly as possible," BIO elaborated in a statement released March 18.

BIO said it is essential for companies to consider whether the development and administration of a compassionate use program "will draw the attention of key company personnel and other resources away from the crucial task of getting the drug approved for a wider population."

The competing priorities put companies between a rock and a hard place.

"The moral challenge is you have two goals that are fundamentally incompatible," Caplan noted. "One is trying to do the best you can for an individual in desperate need. The other is to try and ensure that drugs, vaccines and medical devices appear for the public that are safe and known to be efficacious. To achieve the latter you can't always do the former."

The media oversimplify compassionate access stories by failing to note the trade-offs, according to Caplan. "It would be nice to explain to the public that many compassionate access requests involve slowing the approval process," he said.

In an email to BioCentury, BIO EVP for Health Sara Radcliffe described the practicalities of administering a compassionate use program.

"People must be found to design the expanded access program (including some algorithm for determining who gets the product, and possibly learning about a whole new therapeutic area), communicate with FDA and other stakeholders in order to set that program up, and then administer it," she said.

Radcliffe added: "All these steps require substantial work. In a small company, these folks are likely already wearing a couple of hats and working more than full time on the jobs for which they were hired, and may not be able to put their regular work on hold to sustain an expanded access program."

Chimerix President and CEO Kenneth Moch, who has been at the center of the Josh Hardy story, said the compliance burdens are especially high for a small company with few employees and limited financial resources.

When a patient received access to a drug under an expanded access protocol, Moch noted, a sponsor is required to collect data on safety. "That collection has significant costs associated with it," he said.

Moch noted the costs are not primarily financial. Rather, they relate to the time and expertise that have to be devoted to a compassionate use program - which is then not available to move a drug development program forward.

"Compassionate use is not drug development," Moch told BioCentury. "That is the really important point that gets lost."

Limited resources

In some cases, compassionate access decisions are further complicated because companies have limited quantities of an investigational drug. This is more likely to occur with biologics, and in the earliest stages of clinical development of small molecules.

"Companies often have to address the challenge of equitable distribution of limited drug supply to a large number of patients in need," according to BIO's March 18 statement. "These decisions are particularly difficult and heart-wrenching when we know the personal stories of the individual patients."

Companies also have an ethical obligation to ensure that compassionate access is granted fairly, according to BIO.

Patient advocates argue that supply and resource limitations are not acceptable reasons to deny all compassionate access requests.

"Just because you can't help everyone doesn't mean you shouldn't help someone," Goodman told BioCentury.

"Drug development is a public good that our society has elected to distribute through the private sector. Drug companies are profit maximizing while doing something that is good for the world," she said.

Goodman argues this social contract confers obligations on companies to make their products widely available.

"When we give monopolies there have to be really good reasons for limiting access. These companies want a monopoly right for the purpose of providing more supply, not less. They have to defend why it is appropriate to supply less, even if it is before approval," she said.

Adamson feels that compassionate access should be built into the development programs for drugs with the potential to provide substantial therapeutic advances, certainly in Phase III and often in Phase II.

"No one is telling the company to put all your resources into compassionate access, but a well-managed compassionate access program should not consume many resources," he said. "Investors are looking for a return, but they have to realize that you have to be a responsible corporation, and part of that responsibility is providing compassionate access."

Adamson added: "Anyone who says the only thing they have to focus on is meeting FDA requirements is irresponsible."

Next steps

Beyond these arguments, the success of social media campaigns for expanded access raises questions about fairness. The questions aren't about the motives or actions of people who turn to social media, but rather about the fairness of a system that gives preference to individuals who succeed in gaining Twitter followers and Facebook "likes" as opposed to patients and families that lack the resources and sophistication to attract media attention.

And there is a darker side to social media. Campaigns to get Josh Hardy access to brincidofovir, and a failed attempt last year to persuade BioMarin to provide ovarian cancer patient Andrea Sloan access to the company's BMN-673 PARP inhibitor, quickly went viral. In both cases, death threats were sent to corporate executives.

FDA's Klein is concerned that taking disputes with companies over compassionate access to the media will become the norm.

"I worry - are cases like Josh's going to set a new standard for how patients pursue this? This is already happening; other people are doing the same thing," he said.

Some consensus on an ethical framework for compassionate access is needed, according to Adamson. "We can't leave it to social media."

The Hardy and Sloan cases have prompted Congress and industry to consider whether new compassionate access policies are needed that account for the realities of social media and the movement for patient empowerment.

One of the options they should consider, according to Caplan, is creation of a third party that could make recommendations about requests for compassionate access.

Goodman would go further, arguing that a third party might be given some power over decisions.

"If we as a society think there are certain instances in which patients should have access to unapproved drugs, then the decision-maker as to who gets the drugs should be one with society's goals as its own goals, not a company that has a fiduciary responsibility to its investors."

Meanwhile, some biotech CEOs are considering ways to shift the decision-making off their shoulders.

"Having the company on the hook for making these very difficult decisions is not the right thing for the company, patients or regulators," Rachel King, CEO of GlycoMimetics Inc., told BioCentury.

"If you got everyone in a room to discuss making allocations of scarce resources, they wouldn't say leave it to the biotech CEO or whoever gets the most signatures or has the best connections to a powerful member of Congress," said King, who also is chair of BIO's board of directors.

"Congress is beginning to acknowledge that compassionate use has its shortcomings," Rep. Michael McCaul (R-Texas), told BioCentury. "We recognize the importance of starting a conversation with patient advocates, industry and other stakeholders about how expanded access could be improved."

McCaul, founder and co-chair of the Congressional Childhood Cancer Caucus, tried to help Andrea Sloan, a constituent, get access to BMN-673.

"I'm convinced there is a better way to make treatments more widely available to terminally ill patients, including experimental drugs that hold lifesaving potential when all other options have been exhausted," McCaul said. "We also need to recognize these drugs would not exist if not for the companies that develop them, so our first priority is to do no harm to industry and to educate ourselves about industry's concerns while we work with them to explore options."

Meanwhile, BIO and PhRMA say they will renew their attention to compassionate access issues.

"BIO plans to expand our dialogue with FDA, patient groups and our member companies to see if improvements to the compassionate use process can be made," Radcliffe said.

PhRMA has similar plans, according to Sascha Haverfield, VP of scientific and regulatory affairs.

"PhRMA is in the process of creating a workgroup consisting of policy, regulatory, clinical, and legal subject matter experts from member companies to improve the clarity of the expanded access process and to further educate patients and physicians about the importance of clinical trials and the appropriate role for expanded access programs," he told BioCentury.


BioMarin Pharmaceutical Inc. (NASDAQ:BMRN), Novato, Calif.

Biotechnology Industry Organization (BIO), Washington, D.C.

Children's Hospital of Philadelphia, Philadelphia, Pa.

Chimerix Inc. (NASDAQ:CMRX), Durham, N.C.

Genzyme Corp., Cambridge, Mass.

GlycoMimetics Inc. (NASDAQ:GLYC), Gaithersburg, Md.

Kids v Cancer, Washington, D.C.

New York University, New York, N.Y.

Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, D.C.

Sanofi (Euronext:SAN; NYSE:SNY), Paris, France

Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE), Novato, Calif.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.