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**TABLE OF CONTENTS**

[[EXECUTIVE
SUMMARY]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#execsummary%23execsummary)

[[INTRODUCTION]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#intro%23intro)

[[INNOVATION OR
STAGNATION?]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#innovation%23innovation)

[[NEGOTIATING THE CRITICAL
PATH]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#negotiating%23negotiating)

[[SCIENTIFIC AND TECHNICAL DIMENSIONS ALONG THE CRITICAL
PATH]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#dimensions%23dimensions)

[[A BETTER PRODUCT DEVELOPMENT TOOLKIT IS URGENTLY
NEEDED]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#toolkit%23toolkit)

[[TOOLS FOR ASSESSING
SAFETY]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#assessing%23assessing)

[[Towards a Better Safety
Toolkit]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#safety%23safety)

[[Getting to the Right Safety
Standards]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#standards%23standards)

[[TOOLS FOR DEMONSTRATING MEDICAL
UTILITY]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#utility%23utility)

[[Towards a Better Effectiveness
Toolkit]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#effective%23effective)

[[Getting to the Right Effectiveness
Standards]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#effectiveness%23effectiveness)

[[TOOLS FOR CHARACTERIZATION AND
MANUFACTURING]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#char%23char)

[[Towards a Better Manufacturing
Toolkit]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#manu%23manu)

[[Getting to the Right Manufacturing
Standards]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#get%23get)

[[A PATH
FORWARD]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#path%23path)

[[The Orphan Products Grant
Program]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#orphan%23orphan)

[[The Next
Steps]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#next%23next)

LIST OF TABLES AND FIGURES

[[Figure 1: 10-Year Trends in Biomedical Research
Spending]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig1%23fig1)\
[[Figure 2: 10-Year Trends in Major Drug and Biological Product
Submissions to
FDA]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig2%23fig2)\
[[Figure 3: Investment Escalation per Successful
Compound]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig3%23fig3)\
[[Figure 4: The Critical Path for Medical Product
Development]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig4%23fig4)\
[[Figure 5: Research Support for Product
Development]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig5%23fig5)\
[[Figure 6: Working in Three Dimensions on the Critical
Path]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig6%23fig6)\
[[Figure 7: Industry - FDA Interactions During Drug
Development]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig7%23fig7)\
[[Figure 8: Problem Identification and Resolution During the FDA Review
Process]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig8%23fig8)\
[[Table 1: Three Dimensions of the Critical
Path]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#table1%23table1)

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**Executive Summary**

This report provides the Food and Drug Administration\'s (FDA\'s)
analysis of the pipeline problem \-- the recent slowdown, instead of the
expected acceleration, in innovative medical therapies reaching
patients.

Today\'s revolution in biomedical science has raised new hope for the
prevention, treatment, and cure of serious illnesses. However, there is
growing concern that many of the new basic science discoveries made in
recent years may not quickly yield more effective, more affordable, and
safe medical products for patients. This is because the current medical
product[^[1]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f1%23f1)
development path is becoming increasingly challenging, inefficient, and
costly. During the last several years, the number of new drug and
biologic applications submitted to FDA has declined significantly; the
number of innovative medical device applications has also decreased. In
contrast, the costs of product development have soared over the last
decade. Because of rising costs, innovators often concentrate their
efforts on products with potentially high market return. Developing
products targeted for important public health needs (e.g.,
counterterrorism), less common diseases, prevalent third world diseases,
prevention indications, or individualized therapy is becoming
increasingly challenging. In fact, with rising health care costs, there
is now concern about how the nation can continue to pay even for
existing therapies. If the costs and difficulties of medical product
development continue to grow, innovation will continue to stagnate or
decline, and the biomedical revolution may not deliver on its promise of
better health.

What is the problem? In FDA\'s view, the applied sciences needed for
medical product development have not kept pace with the tremendous
advances in the basic sciences. The new science is not being used to
guide the technology development process in the same way that it is
accelerating the technology discovery process. For medical technology,
performance is measured in terms of product safety and effectiveness.
Not enough applied scientific work has been done to create new tools to
get fundamentally better answers about how the safety and effectiveness
of new products can be demonstrated, in faster time frames, with more
certainty, and at lower costs. In many cases, developers have no choice
but to use the tools and concepts of the last century to assess this
century\'s candidates. As a result, the vast majority of investigational
products that enter clinical trials fail. Often, product development
programs must be abandoned after extensive investment of time and
resources. This high failure rate drives up costs, and developers are
forced to use the profits from a decreasing number of successful
products to subsidize a growing number of expensive failures. Finally,
the path to market even for successful candidates is long, costly, and
inefficient, due in large part to the current reliance on cumbersome
assessment methods.

A new product development toolkit \-- containing powerful new scientific
and technical methods such as animal or computer-based predictive
models, biomarkers for safety and effectiveness, and new clinical
evaluation techniques \-- is urgently needed to improve predictability
and efficiency along the critical path from laboratory concept to
commercial product. We need superior product development science to
address these challenges \-- to ensure that basic discoveries turn into
new and better medical treatments. We need to make the effort required
to create better tools for developing medical technologies. And we need
a knowledge base built not just on ideas from biomedical research, but
on reliable insights into the pathway to patients.

The medical product development process is no longer able to keep pace
with basic scientific innovation. Only a concerted effort to apply the
new biomedical science to medical product development will succeed in
modernizing the critical path.

Many accomplished scientists in academia, government, and industry are
working on these challenges, and there has been much success in recent
years. But the fact remains that the pace of this development work has
not kept up with the rapid advances in product discovery. The result is
a technological disconnect between discovery and the product development
process \-- the steps involved in turning new laboratory discoveries
into treatments that are safe and effective.

Although the FDA is just one participant in advancing development
science, we have an important role to play. Because FDA\'s standards are
often used to guide development programs, we need to make sure that our
standard-setting process is informed by the best science, with the goal
of promoting efficient development of safe and effective new medical
treatments.

Because FDA is uniquely positioned to help identify the challenges to
development, we need to work with the larger scientific community on
developing solutions. Directed by Congress to promote and protect the
public health, FDA is responsible for ensuring that safe and effective
medical innovations are available to
patients.[^[2]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f2%23f2)
As part of its regulatory role, FDA must use available scientific
knowledge to set product standards. During clinical testing, FDA
scientists conduct ongoing reviews of emerging data on safety, efficacy,
and product quality. Agency reviewers see the complete spectrum of
successes and best practices during clinical trials, as well as the
failures, slowdowns, barriers, and missed opportunities that occur
during product development. When serious problems emerge in the
development process or common problems continue to recur, FDA scientists
attempt to address them by bringing them to the attention of the
scientific community, or by conducting or collaborating on relevant
research. As an example of such work, the Agency often makes guidance
documents publicly available that summarize best practices in a
development area and share FDA insights into specific issues or topics.
Sponsors report that the availability of guidance documents has been
shown to foster development and innovation in areas of therapeutic need,
to improve the chances of initial success of a marketing application,
and to shorten the time it takes to get safe and effective treatments to
patients. But much more needs to be done.

The product development problems we are seeing today can be addressed,
in part, through an aggressive, collaborative effort to create a new
generation of performance standards and predictive tools. The new tools
will match and move forward new scientific innovations and will build on
knowledge delivered by recent advances in science, such as
bioinformatics, genomics, imaging technologies, and materials science.

FDA is planning an initiative that will identify and prioritize (1) the
most pressing development problems and (2) the areas that provide the
greatest opportunities for rapid improvement and public health benefits.
This will be done for all three dimensions along the critical path \--
safety assessment, evaluation of medical utility, and product
industrialization. It is critical that we enlist all relevant
stakeholders in this effort. We will work together to identify the most
important challenges by creating a Critical Path Opportunity List.
Concurrently, FDA will refocus its internal efforts to ensure that we
are working on the most important problems and intensify our support of
key projects.

Through scientific research focused on these challenges, we can improve
the process for getting new and better treatments to patients. Directing
research not only to new medical breakthroughs, but also to breakthrough
tools for developing new treatments, is an essential step in providing
patients with more timely, affordable, and predictable access to new
therapies. We are confident that, with effective collaboration among
government, academia, and the private sector, these goals can be
achieved.

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**Introduction**

The mission of the U.S. Food and Drug Administration (FDA) is, in part,
to protect the public health by assuring the safety, efficacy, and
security of human and veterinary drugs, biological products, and medical
devices. The FDA is also responsible for advancing the public health by
helping to speed innovations that make medicines more effective, safer,
and more affordable; and helping the public get the accurate,
science-based information they need to use medicines to improve their
health.

In keeping with its mission, FDA is issuing this report to address the
growing crisis in moving basic discoveries to the market where they can
be made available to patients. The report evaluates how the crisis came
about and offers a way forward. It highlights examples of Agency efforts
that have improved the critical path and discusses opportunities for
future efforts. Finally, the report calls for a joint effort of
industry, academia, and the FDA to identify key problems and develop
targeted solutions.

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height="8.333333333333333e-3in"}

**Innovation or Stagnation? Challenge and Opportunity on the Critical
Path to New Medical Products**

The sequencing of the human genome four years ago raised widespread hope
for a new era in the prevention and treatment of disease created by the
ongoing investment in biomedical research ([[Figure
1]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig1%23fig1)).
But that new era has not yet arrived. Instead, 2000 marked the start of
a slowdown in
new[^[3]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f3%23f3)
drug and biologic submissions to regulatory agencies worldwide ([[Figure
2]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig2%23fig2)).
The submission of innovative medical device applications has also slowed
recently.[^[4]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f4%23f4)
This means fewer new products can be approved and made available to
patients. At a time when basic biomedical knowledge is increasing
exponentially, the gap between bench discovery and bedside application
appears to be expanding. There is great concern about the ability to
bring the hoped-for outcomes of basic research advances \-- much awaited
new treatments \-- to patients. There is concern that hoped-for advances
in medicine and new treatments for diseases may never materialize.

Current costs of bringing a new medicine to market, estimated by some to
be as high as \$0.8 to 1.7
billion,[^[5]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f5%23f5)
are a major barrier to investment in innovative, higher risk drugs or in
therapies for uncommon diseases or diseases that predominantly afflict
the poor. Product development in areas crucial to public health goals,
such as antibiotics, has slowed significantly during the past decade.
Inventors of candidate artificial organs, bioengineered tissues, and
other novel devices face serious challenges and uncertainties. A viable
path for developing many preventive therapies (e.g., some types of
cancer chemoprevention) has not been elucidated.

Recent basic science achievements promise significant payoffs in human
health, but these potential benefits are threatened by low productivity
\-- measured by the high costs and high risks of failure in the current
development processes and the declining number of successful products
reaching patients. Often, developers are forced to rely on the tools of
the last century to evaluate this century\'s advances. And the situation
does not appear to be improving. Recent data suggest that the investment
required to launch a new drug has risen 55 percent during the last five
years ([[Figure
3]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig3%23fig3)).
Pharmaceutical, biotechnology, and medical device productivity appears
to be declining at the same time that the costs to develop a small
number of treatments are rising.

If biomedical science is to deliver on its promise, scientific
creativity and effort must also focus on improving the medical product
development process itself, with the explicit goal of robust development
pathways that are efficient and predictable and result in products that
are safe, effective, and available to patients. We must modernize the
critical development path that leads from scientific discovery to the
patient ([[Figure
4]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig4%23fig4)).

In response to the widening gap between basic biomedical knowledge and
clinical application, governments and the academic community have
undertaken a range of initiatives. After decades of investment in basic
biomedical research, the focus is widening to include translational
research \-- multidisciplinary scientific efforts directed at
\"accelerating therapy development\" (i.e., moving basic discoveries
into the clinic more
efficiently).[^[6]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f6%23f6)
Notable are:

-   National Institutes of Health (NIH) Roadmap, announced in
    September 2003. This is a series of initiatives intended to \"speed
    the movement of research discoveries from the bench to the bed
    side\"[^[7]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f7%23f7)

-   National Cancer Institute\'s (NCI) Specialized Programs of Research
    Excellence
    (SPOREs)[^[8]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f8%23f8)

-   MdBIO, a private nonprofit corporation that supports the growth of
    bioscience in
    Maryland[^[9]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f9%23f9)

-   The European Organization for the Treatment of Cancer (EORTC) is
    committed to making translational research a part of all cancer
    clinical
    trials[^[10]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f10%23f10)

-   The British government announced the National Translational Cancer
    Research Network to facilitate and enhance translational research in
    the United
    Kingdom[^[11]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f11%23f11)

Although necessary for product development, these translational research
efforts will not yield the hoped-for results without an analogous focus
on downstream development concerns. As one group has observed, \"Massive
investments in one part of the network are likely to be at least partly
wasted unless the other links are strengthened as
well.\"[^[12]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f12%23f12)
A third type of scientific research is urgently needed, one that is
complementary to basic and translational research, but focuses on
providing new tools and concepts for the medical product development
process \-- the steps that must be taken to get from selection of a
laboratory prototype to delivery of an effective treatment to patients.
We call this highly targeted and pragmatic research critical path
research because it directly supports the critical path for product
development success ([[Figure
5]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig5%23fig5)).

**Negotiating the Critical Path**

To get medical advances to patients, product developers must
successfully progress along a multidimensional critical path that leads
from discovery or design concept to commercial marketing.

Currently, a striking feature of this path is the difficulty, at any
point, of predicting ultimate success with a novel candidate. For
example, a new medicinal compound entering Phase 1 testing, often
representing the culmination of upwards of a decade of preclinical
screening and evaluation, is estimated to have only an 8 percent chance
of reaching the market. This reflects a worsening outlook from the
historical success rate of about 14
percent.[^[13]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f13%23f13)
In other words, a drug entering Phase 1 trials in 2000 was not more
likely to reach the market than one entering Phase 1 trials in
1985.[^[14]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f14%23f14)
Recent biomedical research breakthroughs have not improved the ability
to identify successful candidates.

The main causes of failure in the clinic include safety problems and
lack of effectiveness: inability to predict these failures before human
testing or early in clinical trials dramatically escalates costs. For
example, for a pharmaceutical, a 10-percent improvement in predicting
failures before clinical trials could save \$100 million in development
costs per
drug.[^[15]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f15%23f15)
In the case of medical devices, current capacity for technological
innovation has outstripped the ability to assess performance in
patients, resulting in prolonged delays between design and use. For very
innovative and unproven technologies, the probability of an individual
product\'s success is highly uncertain, and risks are perceived as
extremely high. Whole fields may stagnate as a result of the failure of
early products. The goal of critical path research is to develop new,
publicly available scientific and technical tools \-- including assays,
standards, computer modeling techniques, biomarkers, and clinical trial
endpoints \-- that make the development process itself more efficient
and effective and more likely to result in safe products that benefit
patients. Such tools will make it easier to identify earlier in the
process those products that do not hold promise, thus reducing time and
resource investments, and facilitating the process for development of
medical products that hold the most promise for patients.

**Scientific and Technical Dimensions Along the Critical Path**

Whether working with devices, drugs, or biologicals \-- medical product
developers must negotiate three crucial scientific/technical dimensions
on the critical path from scientific innovation to commercial product
(see [[Table
1]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#table1%23table1)).
These three dimensions are interdependent, and in none is success
assured. The vast majority of development costs are attributable to
these three dimensions.

![](media/image3.png){width="6.1875in" height="6.197916666666667in"}

Developers must manage the interplay between each dimension from the
earliest phases of development. For example, the first dimension \--
ensuring product safety \-- is crucial to consider when designing a drug
molecule, choosing production cell lines or reference strains for
biological production, or selecting biomaterials for an implanted
medical device ([[Figure
6]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig6%23fig6)).
The traditional tools used to assess product safety \-- animal
toxicology and outcomes from human studies \-- have changed little over
many decades and have largely not benefited from recent gains in
scientific knowledge. The inability to better assess and predict product
safety leads to failures during clinical development and, occasionally,
after marketing.

The second dimension, demonstrating the medical utility of a new product
\-- showing that it will actually benefit people \-- is the source of
innumerable failures late in product development. Better tools are
needed to identify successful products and eliminate impending failures
more efficiently and earlier in the development process. This will
protect subjects, improve return on R&D investment, and bring needed
treatments to patients sooner.

A number of authors have raised the concern that the current drug
discovery process, based as it is on in vitro screening techniques and
animal models of (often) poorly understood clinical relevance, is
fundamentally unable to identify candidates with a high probability of
effectiveness.[^[16]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f16%23f16)
[^[17]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f17%23f17)The
current scientific understanding of both physiology and pathophysiologic
processes is of necessity reductionistic (e.g., is knowledge at the
gene, gene expression or pathway level) and does not constitute
knowledge at the level of the systems biology of the cell, organ, or
whole organism, and certainly does not reach a systems understanding of
the pathophysiology of particular diseases. Reaching a more systemic and
dynamic understanding of human disease will require major additional
scientific efforts as well as significant advances in bioinformatics.
Nevertheless, progress in discovery will
continue,[^[18]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f18%23f18)
and as candidates emerge, the best tools available should be used for
their evaluation. This will require strengthening and rebuilding the
relevant disciplines (e.g., physiology, pharmacology, clinical
pharmacology) and working to identify ways to bridge between the
laboratory and the whole organism and correlate early markers of safety
and benefit with actual outcomes in patients.

In addition, it is likely that more interest will develop in earlier
\"proof-of-concept\" trials that seek to confirm activity in humans
before a commitment to full-scale development is made. The FDA is
working to facilitate such studies.

The final dimension on the critical path can be described as the
industrialization process \-- turning a laboratory concept into a
consistent and well-characterized medical product that can be mass
produced. The challenges involved in successful industrialization are
complex, though highly underrated in the scientific community. Problems
in physical design, characterization, manufacturing scale-up and quality
control routinely derail or delay development programs and keep needed
treatments from patients. These problems are often rate-limiting for new
technologies, which are frequently more complex than traditional
products and lack standard assessment tools.

**A Better Product Development Toolkit Is Urgently Needed**

It is clear to FDA scientists, who have a unique vantage point and
experience base, that a better product development toolkit is urgently
needed. The Agency oversees all U.S. human trials and development
programs for investigational medical products. As part of its regulatory
role, FDA works with the scientific community to set the clinical and
technical standards used in development. During the clinical phases of
product development, Agency scientists conduct ongoing reviews of
product safety, efficacy, and quality data. At the marketing application
stage, data submitted by medical product sponsors are evaluated against
the established scientific standards. FDA scientists are in frequent
communication with industry and academic scientists over development
issues ([[Figure
7]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig7%23fig7)).
Agency reviewers see the successes and associated best practices as well
as the failures, slowdowns, barriers, and missed opportunities that
occur during the course of product development. In addition, data on
product testing, safety evaluation, and clinical trials are stored in
the millions of pages of FDA files. FDA reviewers oversee the totality
of the preapproval development process. Because of this perspective, FDA
reviewers are in a unique position to help identify common themes and
systematic weaknesses across similar products and can draw important
lessons from what they see.

Few other groups of physicians and scientists are positioned to see so
much of the broad picture. Of course, industry scientists encounter
these problems in terms of their own product portfolios, but often lack
cross-cutting information about an entire product area, or complete
information about techniques that may be used in areas other than
theirs. Academic programs focused on the medical product development
process are rare and, at present, cannot be informed by FDA\'s broad
experience with often confidential information. In fact, since the
details of most failed programs cannot possibly be shared publicly or
for applied research purposes, FDA holds the only broad, cross-cutting
knowledge about how certain investigational products fail, why certain
therapeutic areas remain underdeveloped, and when certain development
hurdles persist despite advances in technology that could mitigate them.
Indeed, these failures may trigger regulatory actions such as putting
clinical holds on human trials, or turning down applications. In the
course of such an action, FDA identifies problems and offers advice on
how to overcome them. Advice given to product developers is based on
FDA\'s experience with the totality of other applications and FDA\'s
efforts to keep up with the latest science; it does not reflect specific
proprietary information from individual applications. Despite these
efforts, the ability of product developers and FDA scientists to
overcome development challenges is often confounded by the limitations
of current tools to address development challenges.

When the tools and concepts fall short, FDA works proactively with
product developers and the scientific community to identify and resolve
critical development problems and stimulate research, encouraging the
development of solutions. The Agency often makes this information
available to the public through guidance documents that synthesize
current knowledge on approaches to development problems, or, as
appropriate, through workshops, or peer reviewed publications ([[Figure
8]{.underline}](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#fig8%23fig8)).
Guidance documents can also help ensure that FDA\'s safety and
effectiveness standards in a particular area of product development are
up to date.

Sponsors report that the availability of FDA guidance
documents[^[19]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f19%23f19)
often substantially decreases uncertainties associated with product
development. Our own research has confirmed this. For example, compared
to device development lacking FDA guidance, medical devices developed in
areas with extant FDA guidance documents are almost twice as likely to
be approved after the initial review process and are approved in a third
less
time.[^[20]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f20%23f20)
FDA has undertaken efforts to develop such guidances in some of the most
crucial public health issues.

There is currently an urgent need for additional public-private
collaborative work on applying technologies such as genomics,
proteomics, bioinformatics systems, and new imaging technologies to the
science of medical product development. Properly applied, these new
technologies could provide tools to detect safety problems early,
identify patients likely to respond to therapy, and lead to new clinical
endpoints. New medical technologies, including bioengineered tissues,
cellular and gene therapies, nanotechnology applications, novel
biomaterials, and individualized drug therapies, will all need new
product development tools and standards, as discussed below, to be able
to move from the laboratory to the market quickly and safely.

There is also an urgent need to improve the efficiency and effectiveness
of the clinical trial process, including trial design, endpoints, and
analyses. The NIH is addressing very important clinical research
infrastructure problems in its Roadmap initiative, and FDA is
collaborating in the Roadmap efforts. In addition, much more attention
and creativity need to be applied to disease-specific trial design and
endpoints intended to evaluate the effects of medical products.

**Tools for Assessing Safety**

For effective development, safety issues should be detected as early as
possible, and ways to distinguish potential from actual safety problems
should be available. Unfortunately, in part because of limitations of
current methods, safety problems are often uncovered only during
clinical trials or, occasionally, after marketing. One pharmaceutical
company estimates that clinical failures based on liver toxicity alone
have cost them more than \$2 billion in the last decade \-- dollars that
could potentially be directed toward successful new product
development.[^[21]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f21%23f21)
Sometimes, early tests suggest the possibility of safety problems that
never materialize, potentially eliminating candidates unnecessarily.
Many of FDA\'s targeted efforts to date have involved defining more
reliable methods for early prediction and detection of significant
safety problems. The Agency seeks to prevent harm to patients during
clinical development as well as potentially devastating setbacks to a
new technology\'s progress and to public confidence.

Tools for safety assessments include product testing (e.g., for
contamination), as well as in vitro and animal toxicology studies, and
human exposure. Despite some efforts to develop better methods, most of
the tools used for toxicology and human safety testing are decades old.
Although traditional animal toxicology has a good track record for
ensuring the safety of clinical trial volunteers, it is laborious,
time-consuming, requires large quantities of product, and may fail to
predict the specific safety problem that ultimately halts development.
Clinical testing, even if extensive, often fails to detect important
safety problems, either because they are uncommon or because the tested
population was not representative of eventual recipients. Conversely,
some models create worrisome signals that may, in fact, not be
predictive of a human safety problem.

Many of FDA\'s recent targeted efforts have involved working with the
scientific community to define more reliable methods to predict and
detect significant safety problems. For example, in the past, failure to
predict unfavorable human metabolism of candidate drugs has led to
costly failures in the clinic as well as multiple drug market
withdrawals. FDA recommendations on the use of human cell lines to
characterize drug metabolic pathways provide a straightforward in vitro
method for prediction of human metabolism, allowing developers to
eliminate early on compounds with unfavorable metabolic profiles (e.g.,
drug-drug interaction potential). Failures in the clinic due to drug
interaction problems are now far less likely.

In another effort, FDA developed and standardized methods for
documenting clearance of retrovirus-like particles from tissue culture
fluids. This effort successfully addressed potential safety concerns
that surrounded the early use of monoclonal antibodies and paved the way
for the development of many important medical treatments. Through its
own laboratory efforts, FDA has continued to refine these methods, share
them publicly, and reduce their cost.

Additional examples of FDA efforts are listed under Highlights.

**Highlight: Tools for Assessing Safety**

1.  The need to ensure the safety of biological products by preventing
    contamination has resulted in numerous Agency research programs and
    resulting animal models, test methods, and technical standards.

    -   A reference standard for evaluating gene therapy vector
        contamination by retroviruses has been developed with FDA input
        and is being distributed by the American Type Tissue Collection
        (ATTC).

    -   In the wake of concern over the safety of gene therapies for
        genetic diseases, FDA developed an animal model for assessing
        the safety of adenovirus vectors.

    -   FDA developed several rodent toxicity models to assess the
        neurovirulence of live virus vaccines, an approach that has both
        reduced the use of primates for testing and sped the testing
        process.

    -   With the potential resurgent need for smallpox vaccination, FDA
        scientists developed a new technique to detect the presence of
        contaminating virus in smallpox vaccine products. This technique
        can also be applied to characterization of othervaccine and
        cellular products.

2.  FDA collaborated with industry and scientific groups to develop the
    data that allowed international adoption of a transgenic mouse model
    for drug carcinogenicity testing. This assay takes less time, saves
    two thirds of the cost, and uses half as many animals as a
    traditional study.

3.  FDA has mined its databases to develop structure-activity
    relationship software to help identify molecular substructures with
    potentially negative toxicologic properties early in the development
    process.

    **Towards a Better Safety Toolkit**

There are currently significant needs, but also significant
opportunities, for developing tools that can more reliably and more
efficiently determine the safety of a new medical product.

Examples of tools that are urgently needed include better predictors of
human immune responses to foreign antigens, methods to further enhance
the safety of transplanted human tissues, new techniques for assessing
drug liver toxicity, methods to identify gene therapy risks based on
assessment of gene insertional and promotional events, and efficient
protocols for qualifying biomaterials.

Opportunity: Proteomic and toxicogenomic approaches may ultimately
provide sensitive and predictive safety assessment techniques; however,
their application to safety assessment is in early stages and needs to
be
expanded.[^[22]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f22%23f22)
Targeted research aimed at specific toxicity problems should be
undertaken.

Opportunity: As biomedical knowledge increases and bioinformatics
capability likewise grows, there is hope that greater predictive power
may be obtained from in silico (computer modeling) analyses such as
predictive toxicology. Some believe that extensive use of in silico
technologies could reduce the overall cost of drug development by as
much as 50
percent.[^[23]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f23%23f23)

-   FDA\'s files constitute the world\'s largest repository of in vitro
    and animal results that are linked with actual human outcomes data.
    Further datamining efforts that effectively protect proprietary data
    could form the basis for useful predictive safety models.

-   Use of extant clinical data may help construct models to screen
    candidates early in the development process (e.g., for liver
    toxicity).

Opportunity: There is an urgent need to develop tools to accurately
assess the risk of new drugs causing heart rhythm abnormalities. For
instance, there are ongoing international efforts to develop, test, and
validate nonclinical models that may be useful in predicting human risk.
In addition, the clinical risks associated with a small degree of QTc
interval prolongation need to be fully defined.

The above are only a few of the opportunities FDA reviewers and outside
experts have identified.

**Getting to the Right Safety Standards**

Because safety issues are a significant cause of delay and failure
during development, some have advocated simply lowering safety
standards. This is not a preferable solution. For ethical human testing,
there is wide agreement that reasonable assurance of safety must be
achieved before clinical trials begin. Patients, prescribers, payers,
and the public share the expectation that marketed medical products will
have a well-understood safety profile and a positive benefit/risk
analysis. Today\'s problems arise from the inability to confidently
predict safety performance in a timely and efficient manner. Current
tools are not only cumbersome, they are also imprecise and thus leave
considerable residual uncertainty. The degree of uncertainty inherent in
current techniques can result in conservative standard setting. We need
new tools that can eliminate problem products early and can better
predict ultimate safety performance. Applied critical path research
provides the real opportunity for improving our ability to identify
safety issues early and manage the remaining risks appropriately.

**Tools for Demonstrating Medical Utility**

Predicting and subsequently demonstrating medical utility (also called
benefit or effectiveness) are some of the most difficult and important
challenges in product development. Currently available animal models,
used for evaluating potential therapies prior to human clinical trials,
have limited predictive value in many disease states. Better predictive
nonclinical screening methods are urgently needed. In many cases,
developers must gamble on the results of the large-scale, expensive
trials necessary to assess effectiveness in people. Such human trials
are currently highly empirical, because most sources of variability in
human responses are not understood and thus cannot be controlled for. It
is clear to many in the field that new scientific advances have the
potential to revolutionize clinical development. However, the path from
scientific innovation to usable tool is not clear.

FDA has identified a number of opportunities for targeted efforts in the
area of effectiveness (see next section) and, where feasible, has
undertaken targeted action. For example, FDA scientists developed
statistical methods to control reader variability in trials of imaging
devices and made the analysis software publicly available. Use of this
method allows developers to reduce the sample size of imaging device
trials by as much as 60
percent.[^[24]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f24%23f24)
Similarly, FDA analysis of hypertension trials using automated blood
pressure monitoring allowed for elimination of the placebo group in such
trials.

Adopting a new biomarker or surrogate endpoint for effectiveness
standards can drive rapid clinical development. For example, FDA
adoption of CD4 cell counts and, subsequently, measures of viral load as
surrogate markers for anti-HIV drug approvals allowed the rapid clinical
workup and approval of life-saving antiviral drugs, with time from first
human use to market as short as 3.5 years. FDA convened the data
holders, conducted analyses in conjunction with industry and academia,
and provided guidance on trial design. Similarly, FDA adoption of the
eradication of H. pylori as a surrogate for duodenal ulcer healing
greatly simplified the path of those therapies to the market. FDA often
approves vaccines based on their meeting validated surrogate markers for
achieving protective levels of immunity. This greatly simplifies
effectiveness studies, thus reducing time and costs.

Highlights of other recent FDA efforts are provided on the following
page. Although there are many examples of successful outcomes, similar
efforts are needed in many other areas of product development to improve
the process for getting safe and effective new treatments to patients.

Highlight: Answering the Challenge of Bioterrorism \-- Evaluating
Efficacy

With the increasing challenges of bioterrorism, there is both a need and
an opportunity for animal models that are relevant and predictive of
countermeasure effectiveness in humans, since effectiveness testing in
humans is often not feasible. In some cases, approval can be granted on
the basis of animal model findings. FDA and its partners can play a
major role in both developing such models and helping define appropriate
and efficient pathways for their use in product development. Such
efficiency is critical both for proper stewardship of what are often
limited or ethically sensitive animal resources, as well as for ensuring
reliable threat preparedness in a timely manner.

-   FDA developed an immunocompromised mouse model for studying the
    efficacy of treatments for smallpox vaccine side effects.

-   FDA defined appropriate animal studies to evaluate the efficacy of
    next generation anthrax vaccines.

-   Working with government and academic scientists, FDA developed
    protocols for the efficient use of animal models to evaluate
    antimicrobial efficacy against bioterrorist threat agents.

Highlight: Trial Design for Digital Mammography \-- Overcoming Clinical
Trial Hurdles

Although the initial approval of digital mammography did not include
this claim, it was believed that digital techniques would prove more
accurate than the conventional screen film. A 40,000-patient study would
be needed to evaluate this.

No company was able to do a 40,000-patient study. FDA proposed a trial
in which four companies would each do a study of 10,000 patients, using
a common protocol. The National Cancer Institute (NCI) was willing to
conduct the study. The results from the four arms of the study could be
pooled. The pooled trial will be able to test whether digital
mammography is superior to conventional screen-film, and each firm will
be able to use results from its own product. The trial costs have been
shared among the companies and the NCI. The trial is completely enrolled
and in the 1-year follow-up phase.

**Towards a Better Effectiveness Toolkit**

We believe targeted efforts in a variety of areas could substantially
improve the efficacy toolkit. These efforts, a few examples of which are
listed here, can only be successful with the collaboration of industry,
academia, and the patient and health care communities.

Opportunity: FDA actions and the subsequent passage of the "Best
Pharmaceuticals for Children
Act"[^[25]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f25%23f25)
have spurred a significant increase in the number of pediatric studies
of pharmaceuticals. Although the results of each individual trial have
been informative for the particular drug studied, a significant
opportunity now exists for analysis of what has been collectively
learned about the pharmacokinetics, pharmacodynamics, safety, and
efficacy of drugs in children. Such an analysis could begin to build a
knowledge base to better inform future pediatric studies.

Opportunity: \"The appearance of new quantitative measuring technologies
absolutely galvanizes new drug
research.\"[^[26]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f26%23f26)
Additional biomarkers (quantitative measures of biological effects that
provide informative links between mechanism of action and clinical
effectiveness) and additional surrogate markers (quantitative measures
that can predict effectiveness) are needed to guide product development.
In some cases, datamining and analysis, with possibly a single
additional clinical trial, may be all that is necessary to confirm the
surrogacy of a particular marker. In other cases (e.g., the NIH\'s
Osteoarthritis
Initiative[^[27]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f27%23f27)),
epidemiologic studies on disease natural history must be undertaken to
provide data on markers of disease processes. For biomarkers that
currently appear promising, specific projects need to be undertaken to:

-   Assemble existing data on the association of the marker with
    clinical outcomes

-   Assemble existing data on the performance of the marker during
    intervention trials compared to the performance of current outcome
    measures

-   Identify any data gaps or remaining uncertainties

-   Identify clinical trials under development in which the remaining
    questions could be addressed in a straightforward manner

As previously stated, strengthening and rebuilding the disciplines of
physiology, pharmacology, and clinical pharmacology will be necessary to
provide the capacity to develop and evaluate new biomarkers and bridge
across animal and human studies.

Opportunity: Imaging technologies, such as molecular imaging tools in
neuropsychiatric diseases or as measures of drug absorption and
distribution, may provide powerful insights into the distribution,
binding, and other biological effects of pharmaceuticals, but their
predictive value needs further study and evaluation. New imaging
technologies will ultimately contribute important biomarkers and
surrogate endpoints, but how soon these new tools will be available for
use will depend on the effort invested in developing them specifically
for this purpose.

Opportunity: For many therapeutics, effectiveness criteria are best
defined by the practitioners and patients who use the products. Much
work needs to be done on clinical trial design and patient-driven
outcome measures to ensure that endpoints in new therapeutic areas
accurately reflect patient needs and values. Community (health
professional and patient) consensus on appropriate outcome measures and
therapeutic claims can lay a clear development path for new
therapeutics, especially when there is international regulatory
harmonization.

Opportunity: The concept of model-based drug development, in which
pharmaco-statistical models of drug efficacy and safety are developed
from preclinical and available clinical data, offers an important
approach to improving drug development knowledge management and
development decision
making.[^[28]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f28%23f28)
Model-based drug development involves building mathematical and
statistical characterizations of the time course of the disease and drug
using available clinical data to design and validate the model. The
relationship between drug dose, plasma concentration, biophase
concentration (pharmacokinetics), and drug effect or side-effects
(pharmacodynamics) is characterized, and relevant patient covariates are
included in the model. Systematic application of this concept to drug
development has the potential to significantly improve it. FDA
scientists use, and are collaborating with others in the refinement of,
quantitative clinical trial modeling using simulation software to
improve trial design and to predict outcomes. It is likely that more
powerful approaches can be built by completing, and then building on,
specific predictive modules.

There are many important additional opportunities in the area of
clinical trial design and analysis. More clinically relevant endpoints
need to be developed for many diseases. Enrichment designs have the
potential for providing much earlier assurance of drug activity.
Bayesian approaches to analysis need to be further explored.

Opportunity: The emerging techniques of pharmacogenomics and proteomics
show great promise for contributing biomarkers to target responders,
monitor clinical response, and serve as biomarkers of drug
effectiveness. However, much development work and standardization of the
biological, statistical, and bioinformatics methods must occur before
these techniques can be easily and widely used. Specific, targeted
efforts could yield early results.

**Getting to the Right Effectiveness Standards**

In an era of concerns about health care affordability, we need to make
sure that new medical products are effective and provide accurate
up-to-date information about using them so patients and doctors can make
smart decisions about health care. As health care costs rise, patients,
medical professionals, and health care purchasers are all demanding more
value from the medical treatments they use. With more treatments in
development than ever before, finding better ways to demonstrate their
effectiveness for particular kinds of patients is essential for making
sure that all Americans get the most value from their health care
dollars.

**Tools for Characterization and Manufacturing**

The industrialization challenges posed by the demands of physical
product design, characterization, scale-up, and manufacturing are often
little understood outside of FDA and the pharmaceutical and device
manufacturing
communities.[^[29]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f29%23f29)
Many product failures during development are ultimately attributable to
problems relating to the transition from laboratory prototype to
industrial product. It is crucial that technical standards (e.g.,
assays, procedures, or reference standards) and improved methods for
design, characterization, and product manufacture are available to
improve predictability in this area.

Developing interim standards is especially important for novel
technologies and can help keep product development on track as a new
field matures. Otherwise, innovators are put in the position of having
to invent standards in addition to inventing new products. At the same
time, interim standards must allow for flexibility, innovation, and
change as new fields develop. This takes expertise, effort, and
collaboration among industry, academia, and FDA.

For example, recombinant proteins and monoclonal antibodies have
provided significant therapeutic advances over the last 15 years. During
this time, FDA has issued multiple technical guidance documents on
topics such as characterization of production cell lines, manufacturing
and testing techniques, specifications, stability evaluation, and
changes to manufacturing
processes.[^[30]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f30%23f30)
Recent guidances address the use of transgenic animals or bioengineered
plants as production methods for such products.

As new industrialization challenges are identified during the review
process, Agency scientists routinely hold scientific workshops, conduct
research, collaborate with academic and industrial scientists and
synthesize the emerging data. Recently, when safety problems developed
with gene therapy adenovirus vectors, the need for a better potency
standard was recognized. FDA collaborated with industry and governmental
partners to develop the currently available reference standard for
characterization of adenovirus vectors. To stimulate the needed vaccine
development efforts, FDA scientists recently developed a breakthrough
synthetic technology for conjugate bacterial vaccines that increases
yields three fold and also lowers costs. For additional examples, see
Highlights below.

Highlight: Industrialization

In the area of medical devices, blood glucose monitors represent a
critical technology for many of the 16,000,000 diabetics in the United
States. Numerous new devices are being developed for blood glucose
monitoring.

-   FDA helped develop a uniform testing protocol to evaluate glucose
    meter performance and compared the measurements to the hexokinase
    (HK) laboratory method incorporating reference materials developed
    by the National Institute of Standards and Technology.

-   It was determined that separate accuracy and precision goals should
    be defined for extreme ranges to keep pace with changing clinical
    demands for tighter glucose
    measurement.[^[31]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f31%23f31)

Highlight: Industrialization Standards

Together with CDC and industry, FDA was able to help make available
difficult-to-obtain standards and samples needed for the successful
rapid development and evaluation of West Nile Virus nucleic acid blood
donor screening.

**Towards a Better Manufacturing Toolkit**

Rapid, successful development of new medical technologies depends on the
concomitant availability of adequate methods to characterize,
standardize, control, and mass produce them. Applied research in these
areas is required to provide the infrastructure necessary for
translating laboratory prototypes into commercial products. There are a
number of urgent needs in the industrialization area. FDA is actively
working on guidance in many of these areas to the extent permitted by
available resources.

Opportunity: Additional characterization procedures and standards for
expanded stem cell and other cellular products, bioengineered tissues,
and implanted drug-device combinations (e.g., drug-eluting stents) are
urgently needed. For example, developing test standards for coronary
stent compressibility will decrease the likelihood of failed designs and
allow smaller clinical trial programs.

Opportunity: The pharmaceutical industry generally has been hesitant to
introduce state-of-the-art science and technology into its manufacturing
processes, in part due to concern about regulatory impact. This led to
high in-process inventories, low factory utilization rates, significant
product wastage, and compliance problems, driving up costs and
decreasing productivity. FDA has led an initiative to stimulate the use
of process analytical technologies \-- automated sensors that monitor
and control processes \-- and other modern manufacturing technologies
that can improve efficiency and increase flexibility while maintaining
high-quality standards. Further research and data sharing are necessary
to make these efficiencies a reality.

Opportunity: Scientists involved in reviewing medical devices at FDA
report an urgent need for predictive software to model the human effects
of design changes for rapidly evolving devices. We believe that such
software may be attainable with a concentrated effort, by assembling
currently available data and identifying existing data gaps.

**Getting to the Right Manufacturing Standards**

Problems with scale-up and mass production can also slow development and
escalate costs. Currently, FDA is involved in an extensive, multi-year
effort to incorporate the most up-to-date science into its regulation of
pharmaceutical manufacturing and to encourage industry to adopt
innovative manufacturing
technologies.[^[32]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f32%23f32)
Moreover, we are also looking critically at areas where FDA regulation
may have slowed adoption of improvements.

The availability of efficient, science-based standards for product
characterization and manufacturing creates a win-win for consumers,
patients, and the industry.

**A Path Forward**

Greater success along the critical path demands greater activity in a
specific type of scientific research that is directed at modernizing the
product development process. This critical path research \-- highly
pragmatic and targeted in its focus on issues such as standards,
methods, clinical trial designs, and biomarkers \-- is complementary to,
and draws extensively from, advances in the underlying basic sciences
and new technologies. Without a concerted effort to improve the critical
path, it is likely that many important opportunities will be missed and
frustration with the slow pace and poor yield of traditional development
pathways will continue to escalate.

Dealing with product development problems is the day-to-day work not
only of clinical research and product developers, but also of FDA review
scientists. The Agency frequently attempts to resolve problems
identified during the review process. Extensive experience in evaluating
and working to overcome hundreds of product development challenges and
roadblocks has enabled FDA to intervene in a targeted manner, helping to
reduce or remove specific obstacles in areas critical to public health.
However, there are a host of additional opportunities where more
progress is both necessary and possible. Due to the scope of the
existing problems in product development and the expected surge in
products resulting from investments in translational research, we
believe that critical path research and standards programs should be
high priority to help ensure that scientific innovations can be
translated efficiently into public health benefits. These additional
efforts should be targeted towards removing specific identified
obstacles in development. Although there are numerous public and private
groups with expertise to help develop solutions, we believe that FDA is
ideally positioned to bring together the stakeholders to identify and
address the most significant problems. We believe that efforts targeted
at significant challenges and roadblocks have yielded important returns,
and can have even greater public health benefits in the near future.

**The Orphan Products Grant Program**

FDA\'s Orphan Products grant program provides an instructive example of
a successful targeted intervention. This program provides up to three
years of very modest funding (\$150,000-300,000 per annum) for clinical
development costs of qualified products. Between 1989 and 2003, FDA
approved 36 novel products (including 23 novel drugs) participating in
this program. Thus orphan grant recipients have been an appreciable part
of the 20 to 40 new drugs approved yearly during the last 14 years,
despite the fact that industrial development of drugs for such limited
uses is traditionally very hard to stimulate and only limited funding
has been
available.[^[33]{.underline}^](http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html#f33%23f33)
Recipients of orphan grants also benefit from advice and direction from
FDA scientific reviewers on surmounting development obstacles. This
program is widely viewed as a major success in assisting in development
of treatments for rare diseases, at a very modest investment. FDA is
conducting an internal review of how the successes of the Orphan
Products development research might be applied to other kinds of
critical path problems.

**The Next Steps**

The slowdown in new medical products reaching patients in recent years
despite growing public and private investment in R&D and tremendous
progress in the basic biomedical sciences illustrates that better
biomedical ideas alone are not enough. We must also ensure the
successful movement of those ideas along the critical path of
development, ultimately delivering reliable, safe, and effective
treatments to patients at affordable prices. We must achieve
breakthroughs in the way we get these treatments to patients and make
them practical and efficient to develop and produce. This is an
essential step in achieving more timely, affordable, and predictable
access to therapies based on the latest biomedical insights \-- that so
far are having little impact on patient care. If we do not work together
to find fundamentally faster, more predictable, and less costly ways to
turn good biomedical ideas into safe and effective treatments, the
hoped-for benefits of the biomedical century may not come to pass, or
may not be affordable.

Ensuring that the development pathway keeps pace with biomedicine is
crucial to advancing the health of Americans. This must be a joint
effort involving the academic research community, industry, and
scientists at the FDA, and it must be launched soon to have a timely
impact. In the months ahead:

-   FDA will lead in the development of a national Critical Path
    Opportunities List intended to bring concrete focus to the tasks
    that lie ahead

-   We will develop this list through extensive consultation with all
    public and private stakeholders.

-   In addition, FDA will make internal changes to intensify its ability
    to surface crucial issues and to support high-priority critical path
    research efforts.

Since FDA is involved in setting standards for the development of new
medical products, we must take proactive steps to use the best science
to guide the development process and ensure that development standards
are rigorous, efficient, and achieve maximum public health benefit.

We look forward to working with the scientific and product development
communities to take advantage of this unprecedented opportunity to
improve the health of the public and its access to affordable,
innovative treatments.

![](media/image2.png){width="1.0416666666666666e-2in"
height="1.0416666666666666e-2in"}

**Figures 1-8**

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height="6.167361111111111in"}

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height="5.375694444444444in"}

 

![](media/image2.png){width="8.333333333333334in"
height="8.333333333333333e-3in"}

**Footnotes**

1\. The term medical product includes drug and biological products as
well as medical devices.

2\. See
[[http://www.fda.gov/opacom/hpview.html]{.underline}](http://www.fda.gov/opacom/hpview.html).

3\. For purposes of this document the terms novel or new refer to
applications for medical products of a type that have never before been
submitted to the Agency (i.e., new molecular entity - NME).

4\. See
[[http://www.fda.gov/cdrh/consumer/mda/index.html]{.underline}](http://www.fda.gov/cdrh/consumer/mda/index.html).

5\. Tufts Center for the Study of Drug Development, Backgrounder: How
New Drugs Move Through the Development and Approval Process, Boston:
November 2001; and Gilbert J, P Henske, and A Singh, \"Rebuilding Big
Pharma\'s Business Model,\" InVivo, the Business & Medicine Report,
Windhover Information, Vol. 21, No. 10, November 2003.

6\. Finkelstein R, T Miller, and R Baughman,\"The Challenge of
Translational Research\--A Perspective from the NINDS,\" nature
neuroscience supplement, Vol. 5, November 2002.

7\. See
[[nihroadmap.nih.gov/overview.asp]{.underline}](http://nihroadmap.nih.gov/overview.asp).

8\. See
[[http://spores.nci.nih.gov/applicants/guidelines/guidelines_full.html#1b]{.underline}](http://spores.nci.nih.gov/applicants/guidelines/guidelines_full.html#1b).

9\. See [[www.mdbio.org]{.underline}](http://www.mdbio.org/).

10\. Eggermont A and H Newell, \"Translational Research in Clinical
Trials: The Only Way Forward,\" European Journal of Cancer, Elsevier
Science, 37 (2001). EORTC also set up in October 2002 the Translational
Research Advisory Committee to support and provide expert advice on
translational research projects conducted within EORTC.

11\. Rowett, L, \" U.K. Initiative to Boost Translational Research,\"
Journal of the National Cancer Institute, Vol. 94, No. 10, May 15, 2002.

12\. Baumann M, SM Bentzen, W Doerr, MC Joiner, M Saunders, et al.,
\"The Translational Research Chain: Is It Delivering the Goods?, Int. J.
Radiation Oncology Biol. Phys., Vol 49, No. 2, 2001, Elsevier Science.

13\. Gilbert J, P Henske, and A Singh, \"Rebuilding Big Pharma\'s
Business Model,\" In Vivo, the Business & Medicine Report, Windhover
Information, Vol. 21, No. 10, November 2003.

14\. Lloyd I, \"New Technologies, Products in Development, and Attrition
Rates: R&D Revolution Still Around the Corner,\" in PARAXEL\'S
Pharmaceutical R&D Statistical Sourcebook 2002/2003.

15\. Boston Consulting Group,\" A Revolution in R&D: How Genomics and
Genetics Will Affect Drug Development Costs and Times,\" in PAREXEL\'s
Pharmaceutical R&D Statistical Sourcebook 2002/2003.

16\. Duyk J, \"Attrition and Translation,\" Science, Vol. 302, October
24, 2003.

17\. Horrobin DF, \"Modern Biomedical Research: An Internally
Self-Consistent Universe with Little Contact with Medical Reality?,\"
Nature Reviews Drug Discovery, Vol. 2, No. 2, February 2003.

18\. Glassman RH, and AY Sun, \"Biotechnology: Identifying Advances from
the Hype,\" Nature Reviews Drug Discovery, Vol. 3, No. 2, February 2004.

19\. The Agency publishes 50 to 75 draft and final guidances each year,
including guidances resulting from involvement in the International
Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH).

20\. FDA, "[[Improving Innovation in Medical Technology: Beyond
2002,]{.underline}](http://www.fda.gov/bbs/topics/news/2003/beyond2002/report.html)"
January 2003.

21\. Rotman, D, \"Can Pfizer Deliver?\" Technology Review, February
2004.

22\. Petricoin EM, V Rajapaske, E H Herman, A M Arekani, S Ross, et al.,
\"Toxicoproteomics: Serum Proteomic Pattern Diagnostics for Early
Detection of Drug Induced Cardiac Toxicities and Cardioprotection,\"
Toxicologic Pathology, 32(Suppl. 1):1-9, 2004.

23\. PricewaterhouseCoopers, \"Pharma 2005 Silicon Rally: The Race to
e-R&D\" Paraxel\'s Pharmaceutical R&D Statistical Sourcebook 2002/2003.

24\. See, for example, Wagner RF, SV Beiden, G Campbell, \"An Approach
to Multiple-Reader, Multiple-Case Receiver Operating Characteristic
Analysis: Controversial -- or Subtle?,\" Acad Radiol. 2003, Oct;
10(10):1176-7; Wagner RF, SV Beiden, \"Independent Versus Sequential
Reading in ROC Studies of Computer-Assist Modalities: Analysis of
Components of Variance,\" Acad Radiol., 2003 Feb; 10(2):211-2.

25\. Public Law 107-109, Jan. 4, 2002.

26\. Niblack J, \"Biomarkers and Surrogate Endpoints,\" GJ Downing, ed.
Exceptional Medical Int. Congress Series, 1205, Elsevier, 2000.

27\. See
[[http://www.niams.nih.gov/ne/oi/]{.underline}](http://www.niams.nih.gov/ne/oi/).

28\. Sheiner LB, \"Learning VS Confirming in Clinical Drug
Development,\" Clin. Pharmacol. Ther., 1997, 61:275-291.

29\. See, for example, the Washington Fax interview with John La
Montagne, Deputy Director of the National Institute of Allergy and
Infections Diseases, National Institutes of Health, June 9, 2003.

30\. See Agency guidances at
[[http://www.fda.gov/opacom/morechoices/industry/guidedc.htm]{.underline}](http://www.fda.gov/opacom/morechoices/industry/guidedc.htm).

31\. Chen ET, JH Nichols, SH Duh, G Hortin, \"Performance Evaluation of
Blood Glucose Monitoring Devices,\" Diabetes Technology & Therapeutics,
5(5):749-768, 2003.

32\. See \"A Risk-Based Approach to Pharmaceutical Current Good
Manufacturing Practices (cGMP) for the 21st Century\" at
[[http://www.fda.gov/cder/gmp/]{.underline}](http://www.fda.gov/cder/gmp/).

33\. For comparison, FDA approved a total of 21 novel drugs in 2003.

 

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