Remarks by Scott Gottlieb, MD

Resident Fellow at the

American Enterprise Institute

Before the 21st Annual International Meeting of the

International Society for Pharmacoeconomics and Outcomes Research (ISPOR)
Opening Plenary Session, Monday May 23, 2016, Washington, DC

Accelerating Cures: Addressing Unmet

Patient Need or Putting Patients at Risk

Im sometimes invited to these point and counterpoint discussions about the FDA review
process, and especially how that process addresses drugs aimed at unmet medical needs,
because Ive historically been a critic of how FDA approached these challenges. Im sure
thats, in part, why I find myself here today, with the opportunity to discuss these issues with
the esteemed Jerry Avorn, and in particular, debate the merits of FDAs Breakthrough
Therapies designation and, as the title of todays plenary session asks, whether these policies
are addressing unmet patient needs or putting patients at risk?
With that introduction you can probably guess that Im here to argue that were addressing
genuine patient needs. Risk, where it exists and may be amplified as a result of the policy
concessions weve made, can be acceptable relative to the benefits we seek through earlier
access to breakthrough drugs and less costly development programs. But the conditions
where we make certain concessions must be carefully described. Any risks must be properly
defined in a way that allows patients and providers to be fully aware of the uncertainties.
Its important that I note at the outset that much of my past criticism of FDAs handling of
these issues was lodged in relation to the agencys cancer drug approval process. And the last
time that I could find myself prominently on the record, raising critical issues about FDAs
handling of potential breakthrough drugs, was in a 2010 editorial titled FDA is Evading the
Law that I published in the Wall Street Journal. This is not to suggest that Ive moved on
from these topics -- or that I believe that FDAs challenges are all fully resolved.
A New Mindset in Cancer
Its just that I see FDAs oncology group making great strides in recent years to adjust its
regulatory process to the scope of the opportunities being enabled by scientific discoveries,
advances if medicine, and drug development. These include the greater degree of biological
understanding of the basis of disease, and how these insights are translating into entirely new
ways of developing drugs, and targeting them to patients. Also, how these insights, and the
more targeted drugs that result, enable us to learn more about a new medicines risks and
benefits through more efficient drug development programs. We have earlier access to many
transformative medicines to show for this, and many lives that have been saved as a result.
We shouldnt fall into the trap of reflexively concluding that just because weve made certain
concessions, in terms of trial size or the endpoints used to assess effectiveness, that it
inevitably follows that the process is somehow less complete or riskier. As the science of
drug development improves, we should be able to find ways to make the same
determinations, and develop even more confidence, on complements of data that are
different than historical standards, and may comprise smaller, more focused packages.
I believe better science and better drugs, at least as it relates to the oncology division,
instigated a lot of FDAs regulatory adjustment. But also, to some degree, it was enabled by
implementation of the Breakthrough process. And I believe that no FDA division has
more fully embraced these methods and the spirit of that law than FDAs cancer group. But
as Ill point out today, there are regrettably parts of FDA that I believe are well behind the
curve in making these same accommodations. Not only when it comes to their regulatory
policy, but also their adoption of better scientific methods as part of their decision making.

So with that backdrop, I want to do three things here today. First I want to provide some
policy context around the Breakthrough process -- some background on the programs
aim, and its implementation. Second, I want to give you a view of where I believe were still
falling short in achieving the programs goals. Third and finally, I want to close with some
thoughts on how we can extend the policy advances like those made in FDAs cancer drug
review process, more broadly. This is especially important as medical science evolve in ways
that create more opportunities for transformative medicines across many indications, while
enabling us to get more certainty through far more efficient drug development programs.
Why Expediting Development Matters
Why are these goals important? For one thing, expediting the development of promising
drugs means they can get to patients sooner. This is especially critical in areas of medicine
involving serious and deadly disorders, where there isnt adequate available therapy.
Making drug development more efficient can also reduce the capital to undertake these
efforts, which will allow more drugs to be pursued, and can ultimately lower the costs that
need to be recouped after a drug is approved. Drugs are priced, in part, off the cost of
capital needed to underwrite the investment, time and risk of developing a new medicine. If
these elements can be reduced, so can the cost return needed to underwrite these efforts.
Another compelling reason to make development more efficient is that it simply makes good
scientific sense. If the science allows us to be more effective, because we know more about
the biological basis of a disease and how drugs target it, we ought to leverage this knowledge.
With that backdrop, I want to relate some history on the Breakthrough program. The
pathway was established in 2012 with passage of the FDA Safety and Innovation Act
(FDASIA). The law allowed FDA to grant Breakthrough Therapy designation to a drug
that treats a serious or life threatening disease, and where preliminary clinical evidence
suggests that the drug may provide a substantial improvement over existing therapies.
This designation provided the sponsor with some tangible benefits designed to expedite drug
development. Principally was the opportunity for closer and more frequent communication
with FDA, as well as the opportunity to apply for expedited approval, through programs like
accelerated approval, that have long existed as part of FDAs review process, but were being
less commonly and consistently applied by FDA prior to FDASIA.
In addition, there are also certain intangible benefits offered by Breakthrough designation.
First are more frequent meetings with the FDA review team. This is no trivial opportunity. It
allows sponsors to better adjust development programs to meet FDAs eventual
requirements and prevents the sort of costly guessing that so frequently plagues
development programs. Another benefit offered by Breakthrough designation is the
assignment of a cross-disciplinary lead to the review. This is another key opportunity, in
large measure because of the sometimes-byzantine structure of FDAs internal organization.
Key FDA review functions are housed in organizational silos that dont readily communicate
with one another. The FDAs professional silos can pose an obstacle to the timely resolution
of disagreements between different FDA units over matters of science and policy.

As I noted, I believe the Breakthrough Therapies Program was born of a frustration that
FDA wasnt robustly and consistently applying programs like Fast Track and Accelerated
Approval. In many respects, the Breakthrough Program was largely a nudge from Congress
albeit a forceful one -- that policymakers wanted FDA to revive these programs.
That was the thrust of my criticism in that 2010 Op Ed I mentioned, titled FDA is evading
the Law. I was arguing that FDA was ignoring statute that instructed it to enable
accelerated approval in these types of settings. The Breakthrough Therapies Program, in my
view, said the same. It offered FDA a revised and more modern scientific framework under
which Congress believed that the agency should be applying these regulatory programs.
To these ends, there were many similarities between how Congress framed the application of
Breakthrough designation, and when it said that Accelerated Approval and Priority Review
should also apply. The statutory framework for Breakthroughs was also similar to the
framework created by Congress in legislation passed in 1997 in section 115 of FDAMA.
Heres where we stand today: Since the inception of the Breakthrough Therapies Program,
there have been 415 requests for the designation1, with 130 granted and 212 denied. It
probably comes as little suprise that the bulk of these designations have been granted by
FDAs cancer division for drugs targeting cancer. In fact, of the 10 drugs approved in 2015
that had previously earned Breakthrough designation, half were oncology drugs.

Breakthrough Therapy Designations

Since the inception of the program, there have been 415 requests for BT
designation, with 130 designations granted and 212 requests denied
Breakdown!by!Center!
Fiscal'Year!

CDER'BT'Requests!

Granted!

Denied!

Withdrawn!

2016'

59'(16'under'review)'

16'

21'

6'

2015'

93'

32''

43''

18''

2014'

96''

31''

51''

14''

2013'

92''

31''

52''

9''

2012'

2''

1''

1''

0''

Fiscal'Year!

CBER'BT'Requests!

Granted!

Denied!

Withdrawn!

2016'

15'(5'under'review)'

3'

6'

1'

2015'

20

8'

9'

3'

2014'

26''

7''

19''

0''

2013'

12''

1''

10''

1''

2012'

0''

0'

0'

0''

FDA (5/4/16): http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm

This is, at least in part, a reflection of where drug makers are making the most substantial
investments. It also reflects where the scientific opportunity to develop the sort of targeted
and transformative drugs envisioned by the Breakthrough Program, are being found.
But its not the only place these opportunities arise. Were seeing an equal if not greater
effort being made to develop drugs for ultra rare and inherited disorders. Id argue that, in
many of these cases, when it comes to these ultra-orphan and especially inherited disorders,
the biology of these diseases -- and the mechanism of many candidate drugs -- are even more
clearly defined than is the general experience in cancer right now. So why havent these
progressive regulatory constructs been as readily embraced outside the setting of oncology?
The problem, as I see it, is that these rare diseases cut across many different clinical divisions
inside FDA. And the willingness to substitute a stronger biological basis as a way to make
certain regulatory accommodations in the setting of terrible and largely untreatable diseases
is not as consistently recognized across every part of FDA, or embraced with the same vigor.

Breakthrough Therapy Designations by Indication

BT Designations Granted*

Other'
19%'

* Only available for

designations that have
been made public

Rare'Inherited'
Disorders'
17%'
'
Infec5ous''
Disease'
14%'

Cancer'
47%'

Cardiovascular'
3%'
Source: Friends of Cancer Research: http://www.focr.org/breakthrough-therapies

These observations are reflected in FDAs approval statistics. As of last week, there have
been 41 drugs with Breakthrough Designation approved by FDA since the inception of the
program. As I noted, the bulk of these approvals have been drugs targeted to cancer. A
disappointingly small number have been for ultra rare, inherited disorders despite the
opportunities were seeing in these fields. And the embrace of these same regulatory
approaches by FDAs biologics center has been, by any objective view, almost foreclosed.

The Case of Ultra-Rare Diseases

Let me expand on the issues related to rare and ultra-rare and inherited disorders. Ill then
want to conclude with some policy prescriptions that, I believe, can enable a more robust
and consistent application of the regulatory approach offered by Breakthrough designation.
Like the increased investment in oncology drug research, were seeing a commensurate
increase in investment in the development of drugs targeting rare, inherited diseases. In part,
this is because the genomic, proteomic, and now gene and cell based approaches to drug
development are especially amenable toward targeting inherited, genetically driven disorders.
This is especially true when it comes to modalities such as gene editing.
Many of these inherited disorders are inborn errors of metabolism. Some of these diseases
affect so few patients, that I remember a time when it was said that many of these diseases
would never be drugged because the cost of development could never be recouped over
such a small number of patients, or it would require trials could never be recruited.

Approved Products with Breakthrough Therapy Designation

As of May 15, 2016, there have been 41 BT designated

indications approved by FDA since programs inception
(Note: Not all BT designations are made public)
!
Breakdown by disease category:
Cancer: 21 approvals
Infectious Disease: 7 approvals
Rare Inherited Disorders: 5 approvals
Cardiovascular: No approvals
Other: 8 approvals

!
Source: Friends of Cancer Research: http://www.focr.org/breakthrough-therapies

Yet were starting to see these diseases chased by drug developers for a whole host of
reasons, not least is a belief that regulatory constructs make it more feasible to conduct
reasonably sized registration studies. I am not as optimistic on this last point, once you get

away from oncology. I am not sure that FDAs evolving culture is reaching all of these ultraorphan settings. To see why, one only has to look at drugs aimed at the MPS diseases.
Take, for example, the regulatory history of Aldurazyme, a drug targeted to Hurler
Syndrome, or MPS 1. This is a genetic disorder affecting 2,000 people worldwide, only 500
of whom live in the U.S. Its an older FDA approval. But I fear that the regulatory approach
to Aldurazyme, and the policies that shaped its development, largely persist inside FDA.
The disease results in the buildup of glycosaminoglycans (formerly known as
mucopolysaccharides) due to a deficiency of an enzyme responsible for the degradation of
mucopolysaccharides in lysosomes. In December of 1997, Dr. Emil Kakkis at UCLA first
developed the enzyme replacement therapy and a human clinical trial was begun.
In September of 1998, the biotech companies BioMarin Pharmaceutical, Inc. and Genzyme
Corporation came together to form a joint venture to develop and commercialize
Aldurazyme. The drug companies obtained Orphan Drug designation from the FDA and a
similar designation from European regulators. In January 2001, the results of the first clinical
trial of Aldurazyme were published in the New England Journal of Medicine.
The study showed that in ten patients with MPS 1, Aldurazyme given intravenously once a
week for 52 weeks resulted in substantial improvement in organ size and urinary
glycosaminoglycan levels, two widely accepted surrogate markers for the diseases activity.
Patients also showed improvement in their joint-range-of-motion and symptoms of sleep
apnea, two indications that the drugs benefits were have a clinical impact on their health.
But FDA wouldnt approve the drug on the basis of these results. The agency wanted to wait
for completion of a much larger study, that was had already begun, before it would make the
drug available. So in November, almost a year after the initial results were first published;
findings from a much larger, pivotal trial of the drug were unveiled.
You might say that a 10 patient, open-label trial isnt large enough to form the basis for
approval. Yet previous drugs targeting these MPS diseases werent evaluated in randomized
trials, where patients were obligated to placebo. In part it was because the diseases were so
damaging to their young patients. FDA didnt want to obligate some of the children to
placebo. FDA had allowed the first of the drugs targeting MPS diseases to be approved on
the basis of small, open label studies, where everyone got the drug, and FDA compared their
improvement to matched control patients drawn from historical records on how patients
would have declined if the drug were not conferring some kind of benefit. Keep in mind
these are all distinct diseases, so a drug for one MPS diseases wont work in another MPS
diseases. Yet the basic principles are the same. If a certain kind of enzyme replacement
works in one MPS diseases, there is a pretty good chance that the same approach is going to
work in other MPS diseases, so long as you can manufacture the specific enzyme thats
missing. In other words, as more MPS disease got drugged, FDA should have developed
confidence in the basic construct that replacing an enzyme in a disease where the
mechanism of the malady was driven by the absence of the enzyme, should work.
But the opposite happened. As more drugs targeting different (and rarer) MPS diseases were
developed, and the basis for understanding how these drugs provided relief in these settings

firmed, the FDAs requirements didnt become more streamlined. Instead they increased
substantially. In other words, as the theoretical rationale for these drugs firmed, the agencys
regulatory requirements moved in the exact opposite direction. Instead of streamlining its
regulatory requirements based on this learning, FDA substantially increased the burdens.
In the case of Aldurazyme, the pivotal trial that FDA required included 45 patients in a
randomized, double blind, placebo-controlled study. The results showed that patients treated
with Aldurazyme demonstrated meaningful improvement in pulmonary function and in
walking ability. Improvements were also seen in urinary glycosaminoglycan levels.
FDA finally approved the drug more than 15 months later, On April 30, 2003. Yet could the
drug have been confidently approved in 2000, when results of that first study were available?
The drug Ceredase, the first drug to treat an MPS disease (in this case Gauchers diseases)
was approved by FDA in 1991 on the basis of a trial that looked very much like that initial
study of Aldurazyme. The Ceredase trial was a single arm, open label study involving 13
patients. Among other things, the Ceredase showed that it could shrink organ size. FDA
accepted this as a valid surrogate for a drug targeted to an MPS disease. Moreover, Ceredase
had some speculative risks associated with it. The drug was derived from human placentas,
and there was at least a theoretical reason to worry that it could transmit human disease.
Aldurazyme would hardly be a watershed moment. It was just another upward march in a
long line of incrementally more difficult reviews that FDA subjected these drugs to.
As each of the subsequent and different enzyme replacement therapies targeting distinct
MPS diseases sought FDA approval, the clinical trial requirements increased substantially.
In other words, as FDA got smarter about the mechanism of these treatments, instead of
using that knowledge to streamline development, the hurdles grew substantially.
To these ends, when an experimental enzyme-replacement drug for another MPS disease,
Hunter syndrome, came along later, in an effort to satisfy it increasing requirements for data,
FDA required a trail with 96 patients with Hunter syndrome some 20% of all Americans
afflicted with the disease. The unprecedented trial involved the randomization of patients to
placebo for a full year. FDA also wouldnt rely on surrogate measures for response to
treatment. Instead, the agency required the use of two clinical endpoints as measures of
benefit for the trial. These endpoints were the children to walk and breath.
FDA finally approved the drug for Hunters in 2006. By the time the trial was finished, many
of the children obligated to the placebo had permanent and crippling affects from the
disease. A year is a long time for these patients to continue to decline. By comparison, the
advance of the disease was substantially mitigated in those who had received the new drug.2
If FDA maintained confidence in well-established surrogate markers of disease activity in
these settings, and relying on the well established historical data on how patients with these
conditions decline in the absence of an effective treatment, all of the subsequent approvals
could have and should have mirrored the agencys approach to Ceredase.

Expanding on Promising Reforms

So why is the application of these constructs so inconsistent across FDA? Why are patients
with ultra rare disorders forced to enroll on placebo arms, only to deteriorate and suffer
permanent disability? Why would FDA obligate patients to receive a placebo in settings
where they shouldnt have to? Why is this sort of experimentation still necessary for FDA to
gain the certainty it needs to make a policy decision to approve a drug in these settings?
I would point to four regulatory and policy observations that still challenge parts of FDA.
Each offers an opportunity to build on the Breakthrough policy framework.
First, we need a more systematic and inclusive process for qualifying biomarkers and
measures of disease activity that can form the basis of regulatory approvals. Many
biomarkers and measures of disease activity are readily incorporated into clinical practice
years and sometimes decades before FDA is willing to accept them as objective endpoints in
trials. This is true in cases where these surrogates would only be relied on for approvals
contingent on confirmatory studies, and even true in cases of severe and very rare diseases.
Second, its often the case that the issues related to a particular type of platform or approach
to drug development is a more prominent and challenging feature of the drug review versus
the clinical issues. Yet FDA organizes its review process almost solely around the clinical
aspects of a product. The problem is that not all clinical review divisions have the same
degree of familiarity with different approaches to trial design, statistical analysis, and the
product issues related to new platforms for pursuing biological targets. Greater expertise
with these areas of the critical path might allow FDA to have more creativity in how it
approaches development programs and applies concepts like Breakthrough designation.
We should consider organizing more aspects of the regulatory review process on the basis of
these other aspects of the review. For example, perhaps all drugs for ultra orphan diseases
should be reviewed by a separate division just focused on these products a sort of skunk
works for ultra orphan products -- where there is more expertise in statistical approaches to
clinical trial design that involve open label or single arm studies that are sometimes the only
feasible approach in these disease settings. Consultants from the relevant clinical review
division could inform the clinical aspects of the review. Right now, its the clinical review
division that drives the process, with the experts in the product and trial design issues who
serve as consultants to the process. This can enable these other considerations to become
marginalized, even in cases where they are the more critical and challenging features.
Third, we need to pursue a more modern statistical orthodoxy in certain settings and not try
and retrofit the frequentist approach to clinical areas where its hard to accommodate and
policy settings where it is at odds with our public health goals. This includes more
incorporation of Bayesian approaches to statistical design of trials. We need to more
carefully define those settings of significant clinical need where we can enable market entry
based on these different statistical constructs. We also need to come to terms with those
areas of clinical need where the frequentist approach is always going to be far less feasible,
like a disease affecting on a few dozen or just hundreds of patients. In such a setting, the
requirement for randomization can put inappropriate burdens on patients and providers.

We sometimes behave as though such accommodations are an inappropriate conciliation.

Yet weve made such modifications in the past -- with good results. The only thing that has
changed is our level of adherence to a single statistical orthodoxy and methodology - and our
unwillingness to acknowledge when we make deliberate deviations from this norm.
FDA adheres rigidly to a view that theres a single standard for drug approval. Conceptually,
that serves as an important management principle. But in practice, FDAs statistical and
policy standards fluctuate depending on the clinical circumstance. This bureaucratic
adherence to a false construct (that theres one single standard, when in practice the
agencys data requirements and prerequisite for different levels of statistical certainty already
fluctuate depending on clinical circumstance) is an obstacle to providing more uniformity
around when FDA is willing to adjust its requirements, and when its not.
The result is that there are pockets of FDA that adhere to a rigid conceptualization of the
agencys standard and other parts that are willing to make modifications to that statistical
abstract based on clinical challenges. But the standard is defined by FDAs policy decision
to reach a particular conclusion, and not necessarily by the data package, which rightly
fluctuates depending on clinical indication, statistical practicality, and medical circumstance.
Because of the FDAs occasional reluctance to acknowledge that varying its pre-market data
requirements isnt the same thing as changing its standard, it becomes hard to reach a
systematic approach to these considerations and to when FDA is willing to embrace more
uncertainty and those circumstances where it rightly maintains a very high bar. Keep in
mind, in many cases, side effects are fairly well established in these areas of significant unmet
medical need. The uncertainty turns on issues of efficacy and how much sureness FDA
requires that the magnitude of the observed benefit is real and not a statistical artifact. In
other words, the risk isnt a question of side effects. Its a question of over the magnitude of
the observed benefit, and how much statistical certainty FDA wants around these results.
Toward these same ends, Congress could also provide a firmer guidance to FDA by more
clearly defining when certain accommodations should apply, and limiting some of FDAs
historic flexibility around when the agency invokes constructs like accelerated approval,
single arm trial designs, or other approaches that dont require randomization. For those
areas of extreme clinical need, instead of directing that FDA may approve products based
on surrogate measures of benefit for example, FDA could direct that the agency shall
employ one or more of these approaches in its approval standard in these narrow settings.
Fourth and finally, more of the circumstances that enable us to make some accommodation
to our traditional requirements involve clinical settings where the biology of the disease and
the drugs mechanism is very clearly established. Where only patients who posses a certain
biology thats likely to correlate with robust response actually receive the treatment. In some
cases, this involves pre-specification based on characteristics of disease. In a growing
number of cases it involves the use of diagnostic tests to screen apart such patients.
I believe its time we reconsider the old governmental structures at FDA that place the
regulation of drugs and diagnostics in separate Centers. There are some diagnostic systems
that are very clearly devices. But more of these tests are closely coupled to the delivery of
treatments. We should think about organizing more of FDAs review process along the lines

10

of medical programs that recognize that many drugs are components of a medical treatment
system that incorporates and is dependent on other products like a diagnostic test.
These are just some of the ideas for expanding on what I believe has been the successful
implementation of the Breakthrough Pathway, at least as it relates to oncology. The CURES
Act already pursues policies that address some of these concepts.3 For example, CURES
would nudge FDA to establish a firmer framework for the elevation and use of drug
development tools, including biomarkers. Among other things, it would instruct FDA to
reaffirm the agencys commitment to a process it has already begun for the qualification of
biomarkers. This process, in my view, should be broadened to include a larger body of
stakeholders. The establishment of a biomarker as a tool for diagnosis is a key element of the
practice of medicine. The broader medical community needs to share this process.
A confluence of scientific advances has exposed the biological basis of more diseases. These
advances have enabled new approaches to drug development. Its allowing us to target
diseases in highly novel ways. Weve been able to expose more maladies to targeted drug
development. These methods are changing the contours of medical practice and the scope of
human suffering. Regulatory policies are adapting to these opportunities, but slowly, and
unevenly. Were still allowing too many chances for big gains in human health to languish.

Notes:

As of May 16, 2016. Source: FDA

http://www.nationalaffairs.com/publications/detail/changing-the-fdas-culture
3 https://www.congress.gov/bill/114th-congress/house-bill/6
1
2

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