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
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
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
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
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
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).
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
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
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
"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
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
"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,"
The document does not provide
examples of circumstances in which allowing early access puts FDA approval at
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
"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:
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
Kakkis, now president and CEO of Ultragenyx
Pharmaceutical Inc., led development of three Orphan drugs as CMO at BioMarin,
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
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."
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
"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."
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
"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
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
"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
"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,"
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
Adamson added: "Anyone who
says the only thing they have to focus on is meeting FDA requirements is
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
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.
Pharmaceutical Inc. (NASDAQ:BMRN), Novato, Calif.
Industry Organization (BIO), Washington, D.C.
Hospital of Philadelphia, Philadelphia, Pa.
Inc. (NASDAQ:CMRX), Durham, N.C.
Corp., Cambridge, Mass.
Inc. (NASDAQ:GLYC), Gaithersburg, Md.
v Cancer, Washington, D.C.
York University, New York, N.Y.
Research and Manufacturers of America (PhRMA), Washington, D.C.
(Euronext:SAN; NYSE:SNY), Paris, France
Pharmaceutical Inc. (NASDAQ:RARE), Novato, Calif.
Food and Drug Administration (FDA), Silver Spring, Md.