P&T Journal - October 2014 - for a PDF copy of the published version go
HERE.
Time, Expense, and Quality of Results Are at Issue, As Is the Relationship to Drug Pricing
The storm seeded by the pricing of Sovaldi has led payers, patients,
and the federal government to seek cover from what some view as
problematic pharmaceutical industry practices, including a few partly
outside of the industry’s control.
Sovaldi’s $84,000 list price for a course of treatment has raised
questions about how a company such as Gilead Sciences, Inc., decides on a
price tag. The answer may hinge—in small or large part, depending on
who’s talking—on the length and complexity of the clinical trials a
company must conduct in order to win approval from the Food and Drug
Administration (FDA) for the new drug. Sundeep Khosla, MD, Dean for
Clinical and Translational Science at the Mayo Clinic, says clinical
trials are subject to the “Valley of Death.” He explains, “This refers
to the fact that the average length of time from target discovery to
approval of a new drug currently averages approximately 14 years, the
failure rate exceeds 95%, and the cost per successful drug exceeds $2
billion, after adjusting for all of the failures.”
According to Robert J. Meyer, Director of the Virginia Center for
Translational and Regulatory Sciences at the University of Virginia
School of Medicine, “It is well documented that one of the major
categories of expenditure in developing a new therapeutic is the expense
of conducting randomized, phase 3 clinical trials, which are intended
to address the regulatory expectations in the U.S. and beyond.” However,
Meyer doesn’t think the clinical trial costs for Sovaldi are
substantially higher than those for similar drugs, much less those with a
list price of $84,000 for a 12-week regimen. “I think pricing is driven
by what the market will bear, including the value of the drug’s ability
to forestall later disease,” he states. “But I can’t say clinical trial
costs have no relationship to the price of drugs. The company must
amortize those costs, especially the costs of the 50% of drugs that fail
in phase 3 trials.”
Gilead has declined to provide data on the cost of clinical trials
for Sovaldi. On March 20, 2014, U.S. Rep. Henry Waxman (D-Calif.) and
colleagues sent a letter to John Martin, PhD, Chief Executive Officer of
Gilead, asking for information about the methodology Gilead used to
establish Sovaldi’s pricing.
1
One of the things Waxman wanted to know was “the value to the company
of the expedited review provided under the priority review and
breakthrough therapy designation and how any savings provided by the
expedited review factored into pricing decisions for the drug.” The
priority review and breakthrough therapy designations are new tools that
Congress has given the FDA in the past few years that enable the agency
to approve a drug faster based on abbreviated clinical trials.
Cara Miller, a Gilead spokeswoman, says the company met with Waxman’s
staff to “share our perspective on the scientific and medical evidence
for treating a disease that causes significant morbidity and mortality
in the U.S. and the benefits of Sovaldi.” But that perspective is not
public, nor has Waxman himself published anything that Sovaldi may have
shown his staff. Miller declines to discuss the costs of Sovaldi
clinical trials or the relationship of those costs to Sovaldi pricing.
A Waxman spokeswoman says Gilead was “not able to answer all our
questions, and [was] not able to provide us with information that
adequately justified the cost of the drug.”
It is not just the cost of conventional clinical trials that is at
issue, but also their inclusiveness. In an interview with the
Wall Street Journal
on August 4, 2014, Arvind Goyal, MD, Medical Director of the Illinois
Department of Health Care and Family Services, raised questions about
the population enrolled in the Sovaldi clinical trials.
2
He complained that Gilead did not include people with alcohol and drug
problems, which are prevalent among his state’s Medicaid population. “If
someone is using a street drug such as heroin,” he said, “I can’t be
sure they are compliant taking Sovaldi. It is a total waste.”
Miller, the Gilead spokeswoman, says: “Patients with ongoing illicit
drug use such as cocaine and heroin were excluded from the clinical
trials. Patients who were actively abusing alcohol were excluded from
the clinical trials. However, a history of alcohol abuse or ongoing
alcohol use was not exclusionary; approximately 5–10% of patients in the
phase 3 studies self-reported this medical history.”
Congress Looks at Possible Reforms
Because of the many structural imperfections that prevent faster,
cheaper, more accurate clinical trials, Democrats and Republicans in
Congress are considering what they can do to inject doses of modernity
into a dusty system. The House Energy and Commerce Committee, as part of
its year-long “21st Century Cures” hearings, has been exploring
varieties of unconventional clinical trials—often grouped under the
rubric of “adaptive” clinical trials—and looking at ways useful
flexibility can be injected into FDA requirements. At hearings in July,
Jay Siegel, MD, Chief Biotechnology Officer and Head of Scientific
Strategy and Policy at Johnson & Johnson, said, “I believe that we
now face an extraordinary opportunity to reinvent our approach to
clinical trials and, as a result, to greatly increase the quality of
medical care and the quality of life itself.”
The President’s Council of Advisors on Science and Technology
succinctly stated the problem in its 2012 report on drug innovation:
3
Unfortunately, there is broad agreement that our current clinical
trials system is inefficient. Currently, each clinical trial to test a
new drug candidate is typically organized de novo, requiring
substantial effort, cost, and time. … Navigating all of these
requirements is challenging even for large pharmaceutical companies, and
can be daunting for small biotechnology firms.
U.S. Rep. Joe Pitts (R-Pa.), Chairman of the House Health
Subcommittee, detailed the shortcomings of the clinical trial system
when he welcomed Janet Woodcock, MD, Director of the FDA Center for Drug
Evaluation and Research, to a hearing on July 11, 2014. “Widespread
duplication of effort and cost also occurs because research is
fragmented across hundreds of clinical research organizations, sites,
and trials, and information regarding both the successes and failures of
clinical trials is rarely shared among researchers,” Pitts said. “It is
often difficult to identify potential participants due to a shortage of
centralized registries, low awareness of the opportunity to participate
in clinical trials, low patient retention, and lack of engagement among
community doctors and volunteers.”
Dr. Woodcock said the FDA has been doing what it can to reduce
clinical trial requirements, consistent with maintaining patient safety,
but “some of these challenges need to be addressed by those outside of
FDA.” The FDA issued guidance in December 2012 on clinical trial
enrichment strategies. She pointed to Novartis’ Zykadia (ceritinib), a
new drug for patients with a certain type of late-stage, non–small-cell
lung cancer, which the FDA approved in April 2014 via a breakthrough
therapy designation. “It took less than four years—versus the roughly 10
years it used to take—from the initial study of the drug to FDA
approval,” she stated.
The FDA granted Zykadia a conditional approval based on a phase 1,
single-arm study of 163 people that investigated the maximum tolerated
dose, safety, pharmacokinetics, and preliminary antitumor activity of
Zykadia. Dana Cooper, a Novartis spokeswoman, declined to provide
details on what the company has spent so far on clinical trials for the
drug. “As we manage our research investment across a portfolio of
medicine in development, we do not provide estimates of research costs
for individual molecules,” she says. The company is continuing phase 2
and 3 trials as a condition of FDA conditional approval. The average
wholesale price for a 30-day supply of Zykadia at the recommended daily
dose is $16,197, according to Red Book.
Recent FDA Efforts to Cut Approval Times
The cost of clinical trials and their required length to completion
have been the subject of criticism within the pharmaceutical industry
for some time. Over the past decade or so, Congress has provided the FDA
with authority to approve new drugs more quickly in certain
circumstances, sometimes on the basis of shortened clinical trials.
4
With Sovaldi, for example, Gilead asked for and received a priority
review, which reduces the FDA review goal date from 10 to six months.
The FDA also awarded Sovaldi a breakthrough therapy designation, which
allows a company to submit a new drug for approval based on preliminary
clinical evidence “that the drug may have substantial improvement on at
least one clinically significant endpoint over available therapy.” In
addition, the FDA offers drug developers accelerated approval, which can
be granted on the basis of studies establishing that the drug or
biologic “has an effect on a surrogate endpoint that is reasonably
likely to predict a clinical benefit, or on a clinical endpoint that can
be measured earlier than irreversible morbidity or mortality, that is
reasonably likely to predict an effect on irreversible morbidity or
mortality or other clinical benefit, taking into account the severity,
rarity, or prevalence of the condition and the availability or lack of
alternative treatments.”
Some drugs the FDA has approved with its new authorities, based on
truncated trials, have turned out to be problematic in the
post-marketing period. Avandia and Avastin are two examples. “The recent
history of drug misadventures provides numerous examples of rare but
catastrophic side effects overlooked at current levels of testing in
broader patient populations,” says Thomas J. Moore, Senior Scientist at
the Institute for Safe Medication Practices and Lecturer in the
Department of Epidemiology and Biostatistics at The George Washington
University School of Public Health and Health Services.
Moore is skeptical about the FDA’s efforts to establish a new
“alternative approval pathway for certain drugs intended to address
unmet medical needs.” Congress directed the FDA to do so in the Food and
Drug Administration Safety and Innovation Act (FDASIA) of 2012,
5
the law that established the breakthrough therapy designation. The 2012
law also included language expanding the types of evidence the FDA can
use to assess whether a surrogate endpoint is likely to predict clinical
benefit and encouraged usage of a broader variety of endpoints for
accelerated approval. Moore says the alternative approval pathway “could
compromise patient safety, is unnecessary given seven existing
expedited approval programs, has no clear public health justification
for exposing patients to increased risks, and is insufficiently
researched and documented to permit a clear evaluation.”
The FDA held a hearing in February 2013 to seek input from industry
and the public on the viability of a new alternative pathway. Paul
Huckle, Chief Regulatory Officer for GlaxoSmithKline PLC, stated, “We
believe that the proposed pathway should be considered in parallel, and
in addition to, already existing regulatory pathways such as accelerated
approval, fast track, priority review, and breakthrough therapy
designation, and if implemented should be applied at the sponsor’s
request.” The FDA has not published any draft, much less final,
guidelines offering a new alternative pathway.
Need for More Flexibility and Infrastructure
Speeding up the FDA review process, though, is essentially nibbling
around the edges of an antiquated system, where one drug is tested in a
large population of people suffering from one disease, be that lung
cancer, hepatitis C, or any of the conditions that afflict much smaller
populations. There is broad agreement that this “one drug, one
condition” methodology must change. Winds of change—actually, they are
more like light breezes—are blowing through the hallways of contract
research organizations and academic medical centers, which do the
majority of clinical testing. The reforms include use of biomarkers to
select participants, use of “adaptive” clinical trials sponsored jointly
by drug companies, and establishment of nationwide academic networks
with access to electronic medical records. Study participants are chosen
because they have a specific genotype that is thought to be responsive
to a specific agent. Large groups of patients across numerous academic
centers are recruited because those genes are found in a very small
percentage of those volunteers. Often new patients are recruited on a
rolling basis, under a master protocol that test sites adhere to across
the country. A number of agents are tested at the same time, each one in
a separate small group consisting of patients who all have the same
target gene.
Lung-MAP, which is testing five lung cancer agents, is a clinical
trial now getting under way that uses many of the new clinical trial
techniques. It is expected to screen as many as 1,250 patients each year
for more than 200 cancer-related genomic alterations. Participants will
eventually be divided into five “baskets,” each including patients with
an identical genotype thought to be responsive to a single agent. Five
agents are being tested by five companies, all of them cooperating. None
of the five companies, on their own, could recruit that many patients.
That kind of large population is important because each of the five
biomarkers will be found in a very small percentage of people, so it is
necessary to recruit large numbers in order to have enough participants
in each of the five baskets.
Moving Straight From Phase 2 to Phase 3
“Another distinctive feature of Lung-MAP is the ability for a drug
that is found to be effective in phase 2 to move directly into the phase
3 registration components, incorporating the patients from phase 2,”
explains Roy S. Herbst, MD, PhD, Ensign Professor of Medicine, Chief of
Medical Oncology, and Associate Director for Translational Research at
Yale Cancer Center. “This unique statistical approach can save both time
and the number of patients that would be needed to program compared to
conducting separate phase 2 and phase 3 studies.”
As its endpoint, the trial is using “median progression-free
survival,” which Dr. Herbst concedes is a surrogate endpoint. He
explains that any of the five agents could show a positive effect as
early as the first year. But clearly nothing is certain: the efficacy of
the agents, the viability of the trial’s structure, or the cost savings
to the five companies compared with what they would have spent had they
embarked on singular, conventional trials.
Not everyone thinks the potentially fast transition from phase 2 to
phase 3 is a blessing. “While this sounds attractive, this kind of
adaptive trial raises many significant issues—not the least of which is
the loss of the ability to conduct a true ‘learn and confirm’
development paradigm, which is the very heart of cogent drug
development,” explains the University of Virginia’s Meyer. “If there is
any message in the rising failure rate of phase 3 trials, I think it is
that the increasingly parallel drug trials paradigm, rather than the
serial learn-and-confirm model, does not allow for enough careful
thought of past results to properly inform future designs.”
That kind of skepticism may explain why the FDA has not opened the
door very wide to adaptive studies. The agency published draft guidance
in March 2010,
6
but final guidance has never appeared. Industry generally applauded the
FDA’s draft, but felt it was too restrictive. The draft talked about
“familiar” and “less familiar” approaches, and seemed to bestow approval
on the former and skepticism on the later. “The less familiar design
methods incorporate methodological features with which there is little
experience in drug development at this time,” the draft stated.
Industry and Academia Slow to Help
To some extent, the fact that clinical trials take as long and cost
as much as they do is partly the fault of the companies that conduct
them, according to Meyer. He calls some of the steps in phase 3 trials
“self-inflicted.” A recent Tufts University study
7
showed the number of endpoints and procedures in clinical trials went
up more than 60% from 2002 to 2012. At the same time, this study showed
that a minority of the procedures, endpoints, and related trial costs in
phase 3 trials were driven by regulatory requirements. This study
estimated that non-core elements of these trials cost $4 billion to $6
billion in aggregate spending across the industry.
A significant portion of those “self-inflicted” costs come from
companies reinventing the wheel every time they conduct a clinical
trial. Those costs include setting up a network and developing and
implementing a protocol. Some of those costs disappear when companies
and academic centers avail themselves of clinical trial networks. But
these networks are few and far between.
The National Institutes of Health inaugurated a Clinical and Translational Science Awards (CTSA) program in 2006.
8
It is active at 62 sites, mostly academic medical centers, and is
funded at a level of nearly $500 million. The hope was for those centers
to work together on specific clinical trial projects. A 2013 report
from the Institute of Medicine (IOM)
9
said the program is “contributing significantly” to clinical research.
But based on the number of recommendations made to improve the program,
that praise seemed
pro forma. The report described the program as
being in an infant stage, with little cross-center or center-public
collaboration, and hamstrung by a bureaucratic structure. It said: “The
IOM committee envisions a transformation of the CTSA program from its
current, loosely organized structure into a more tightly integrated
network that works collectively to enhance the transit of therapeutics,
diagnostics, and preventive interventions along the developmental
pipeline; disseminate innovative translational research methods and best
practices; and provide leadership in informatics standards and policy
development to promote shared resources.”
Even for a clinical trial network such as the one being developed by
Lung-MAP, one can see what a huge task it is to assemble 5,000 patients,
obtain and massage their personal health data, and de-identify that
data. Paula Brown Stafford, MPH, President of Clinical Development at
Quintiles, a major contract research organization, thinks Congress
should create a central repository of accessible, securely de-identified
patient-level data and make it available for research use through
appropriate licensing. “And just think about the amount of time that
would be cut out of the trial,” she says, “from four years [for] finding
patients down to 14 days because we have the data that gives us access
to identify the patients.” Dr. Herbst says, for example, that Lung-MAP
registered 10 patients in the first two months the trial was in
progress.
No one would argue the merits of a more national clinical trial
infrastructure, backed by national disease registries and fueled by
electronic medical records. The use of biomarkers to select trial
participants is a bit more dicey, given its reliance on diagnostic tests
that may or may not have received FDA approval.
Congress is likely to include clinical trial reforms in the next
reauthorization of the Prescription Drug User Fee Act (PDUFA). In past
reauthorizations, the emphasis has been on speeding FDA approval, not
clinical trials. Helping companies get to the FDA with a new drug
application more quickly and more cheaply, in a way consistent with
protecting safety and efficacy, should be the focus this time. Given the
importance of this objective, it shouldn’t be necessary to wait until
2017, when PDUFA is scheduled to be reauthorized for the sixth time.
Author bio:
Mr. Barlas, a freelance writer based in Washington, D.C., covers topics inside the Beltway.
