This report replaces the version posted on March 16, 2004. It contains a revised Figure 2,
`which now reflects fiscal year data for both BLAs and NMEs, and minor editorial changes.
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`INNOVATION OR STAGNATION
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY ...........................................................................................................................i
`
`INTRODUCTION ......................................................................................................................................1
`
`INNOVATION OR STAGNATION?..........................................................................................................3
`
`NEGOTIATING THE CRITICAL PATH..................................................................................................7
`
`SCIENTIFIC AND TECHNICAL DIMENSIONS ALONG THE CRITICAL PATH...................................9
`
`A BETTER PRODUCT DEVELOPMENT TOOLKIT IS URGENTLY NEEDED ..................................11
`
`TOOLS FOR ASSESSING SAFETY......................................................................................................16
`
`Towards a Better Safety Toolkit................................................................................................17
`
`Getting to the Right Safety Standards......................................................................................20
`
`TOOLS FOR DEMONSTRATING MEDICAL UTILITY .......................................................................20
`
`Towards a Better Effectiveness Toolkit ...................................................................................21
`
`Getting to the Right Effectiveness Standards .........................................................................25
`
`TOOLS FOR CHARACTERIZATION AND MANUFACTURING .........................................................25
`
`Towards a Better Manufacturing Toolkit.................................................................................27
`
`Getting to the Right Manufacturing Standards .......................................................................28
`
`A PATH FORWARD .............................................................................................................................29
`
`The Orphan Products Grant Program......................................................................................30
`
`The Next Steps ............................................................................................................................30
`
`LIST OF TABLES AND FIGURES
`
`Figure 1: 10-Year Trends in Biomedical Research Spending .............................................................2
`
`Figure 2: 10-Year Trends in Major Drug and Biological Product Submissions to FDA ..................2
`
`Figure 3: Investment Escalation per Successful Compound .............................................................4
`
`Figure 4: The Critical Path for Medical Product Development.........................................................4
`
`Figure 5: Research Support for Product Development......................................................................6
`
`Figure 6: Working in Three Dimensions on the Critical Path..........................................................10
`
`Figure 7: Industry - FDA Interactions During Drug Development ..................................................12
`
`Figure 8: Problem Identification and Resolution During the FDA Review Process......................14
`
`Table 1: Three Dimensions of the Critical Path...............................................................................10
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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 product1 development path is becoming increas-
`ingly 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 com-
`mon diseases, prevalent third world diseases, prevention indica-
`tions, or individualized therapy is becoming increasingly challeng-
`ing. 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 bio-
`medical revolution may not deliver on its promise of better health.
`
`1The term medical product includes drug and biological products as well as
`medical devices.
`
`i
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`What is the problem? In FDA’s view, the applied sciences needed for
`medical product development have not kept pace with the tremen-
`dous 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 sci-
`entific 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 pre-
`dictability and efficiency along the critical path from laboratory con-
`cept to commercial product. We need superior product develop-
`ment science to address these challenges — to ensure that basic dis-
`coveries turn into new and better medical treatments. We need to
`make the effort required to create better tools for developing med-
`ical 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.
`
`A new product
`development
`toolkit...is
`urgently needed
`to improve pre-
`dictability and
`efficiency along
`the critical path
`
`ii
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`Many accomplished scientists in academia, government, and indus-
`t ry are working on these challenges, and there has been much suc-
`cess in recent years. But the fact remains that the pace of this devel-
`opment work has not kept up with the rapid advances in product dis-
`c o v e ry. The result is a technological disconnect between discovery
`and the product development process — the steps involved in turn-
`ing new laboratory discoveries into treatments that are safe and
`e ff e c t i v e .
`
`Although the FDA is just one participant in advancing development
`science, we have an important role to play. Because FDA's standard s
`a re 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 eff e c t i v e
`new medical tre a t m e n t s .
`
`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 pro-
`tect the public health, FDA is responsible for ensuring that safe and
`e ffective medical innovations are available to patients.2 As part of its
`re g u l a t o ry role, FDA must use available scientific knowledge to set
`p roduct standards. During clinical testing, FDA scientists conduct
`ongoing reviews of emerging data on safety, eff i c a c y, and pro d u c t
`q u a l i t y. Agency reviewers see the complete spectrum of successes
`and best practices during clinical trials, as well as the failures, slow-
`downs, barriers, and missed opportunities that occur during pro d u c t
`development. When serious problems emerge in the development
`p rocess or common problems continue to re c u r, FDA scientists
`attempt to address them by bringing them to the attention of the sci-
`entific community, or by conducting or collaborating on re l e v a n t
`re s e a rch. As an example of such work, the Agency often makes guid-
`ance documents publicly available that summarize best practices in
`a development area and share FDA insights into specific issues or top-
`ics. Sponsors re p o rt that the availability of guidance documents has
`been shown to foster development and innovation in areas of thera-
`peutic need, to improve the chances of initial success of a marketing
`
`2 See http://www.fda.gov/opacom/hpview.html.
`
`iii
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`application, and to shorten the time it takes to get safe and eff e c t i v e
`t reatments 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 cre-
`ate a new generation of performance standards and predictive tools.
`The new tools will match and move forward new scientific innova-
`tions 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 sup-
`port 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 pri-
`vate sector, these goals can be achieved.
`
`FDA is planning
`an initiative that
`will identify and
`prioritize the
`most pressing
`development
`problems and...
`the greatest
`opportunities for
`rapid improve-
`ment
`
`iv
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`Innovation or Stagnation?
`
`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 pub-
`lic 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 cri-
`sis 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.
`
`1
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`Innovation or Stagnation?
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`2
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`Innovation or Stagnation?
`
`Innovation or Stagnation?
`Challenge and Opportunity on the Critical Path to
`New Medical Products
`
`The sequencing of the human genome four years ago raised wide-
`spread hope for a new era in the prevention and treatment of disease
`created by the ongoing investment in biomedical research (Figure 1).
`But that new era has not yet arrived. Instead, 2000 marked the start
`of a slowdown in new3 drug and biologic submissions to regulatory
`agencies worldwide (Figure 2). The submission of innovative med-
`ical device applications has also slowed recently.4 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 await-
`ed 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 are a major barrier to invest-
`ment 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 antibi-
`otics, has slowed significantly during the past decade. Inventors of
`candidate artificial organs, bioengineered tissues, and other novel
`
`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.
`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," In Vivo, the Business & Medicine Report,Windhover Information,Vol. 21,
`No. 10,November 2003.
`
`3
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`Innovation or Stagnation?
`
`4
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`Often, develop-
`ers are forced to
`use the tools of
`the last century
`to evaluate this
`century’s
`advances
`
`Innovation or Stagnation?
`
`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).
`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 cre-
`ativity 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).
`
`In response to the widening gap between basic biomedical knowl-
`edge and clinical application, governments and the academic com-
`munity 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 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
`
`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.
`
`5
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`Innovation or Stagnation?
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`6
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`“Massive invest-
`ments in one
`part of the net-
`work are likely
`to be at least
`partly wasted
`unless the other
`links are
`strengthened as
`well”
`
`Innovation or Stagnation?
`
`• National Cancer Institute's (NCI) Specialized Programs of
`Research Excellence (SPOREs)8
`• MdBIO, a private nonprofit corporation that supports the growth
`of bioscience in Maryland 9
`• The European Organization for the Treatment of Cancer (EORTC)
`is committed to making translational research a part of all cancer
`clinical trials10
`• The British government announced the National Translational
`Cancer Research Network to facilitate and enhance translational
`research in the United Kingdom11
`
`Although necessary for product development, these translational
`research efforts will not yield the hoped-for results without an anal-
`ogous 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 strength-
`ened as well."12 A third type of scientific research is urgently need-
`ed, 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 criti-
`cal path for product development success (Figure 5).
`
`Negotiating the Critical Path
`
`To get medical advances to patients, product developers must suc-
`cessfully progress along a multidimensional critical path that leads
`from discovery or design concept to commercial marketing.
`
`8 See http://spores.nci.nih.gov/applicants/guidelines/guidelines_full.html#1b.
`9 See 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 proj-
`ects 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.
`
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`Innovation or Stagnation?
`
`The goal of
`critical path
`research is to
`develop new...
`scientific and
`technical tools...
`that make the
`development
`process itself
`more efficient
`and effective
`
`8
`
`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 represent-
`ing 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 his-
`torical success rate of about 14 percent.13
`In other words, a drug
`entering Phase 1 trials in 2000 was not more likely to reach the mar-
`ket than one entering Phase 1 trials in 1985.14 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 predict-
`ing failures before clinical trials could save $100 million in develop-
`ment costs per drug.15 In the case of medical devices, current capac-
`ity 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 stag-
`nate 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.
`
`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.
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`

`Innovation or Stagnation?
`
`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 com-
`mercial product (Table 1 on the following page). These three dimen-
`sions are interdependent, and in none is success assured. The vast
`majority of development costs are attributable to these three dimen-
`sions.
`
`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 on the following page).
`The traditional tools used to assess product safety — animal toxicol-
`ogy 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 prod-
`uct safety leads to failures during clinical development and, occa-
`sionally, 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 invest-
`ment, 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.16,17 The current scientific understanding of both
`physiology and pathophysiologic processes is of necessity reduc-
`
`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.
`
`9
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`Innovation or Stagnation?
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`10
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`Innovation or Stagnation?
`
`tionistic (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 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., physiolo-
`gy, 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 pro-
`grams 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 assess-
`ment 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 urgent-
`ly needed. The Agency oversees all U.S. human trials and develop-
`ment programs for investigational medical products. As part of its
`
`18 Glassman RH, and AY Sun, "Biotechnology: Identifying Advances from the
`Hype," Nature Reviews Drug Discovery,Vol. 3, No. 2, February 2004.
`
`11
`
`Abraxis EX2083
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 18 of 38
`
`

`

`Innovation or Stagnation?
`
`12
`
`Abraxis EX2083
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 19 of 38
`
`

`

`Agency review-
`ers see the suc-
`cesses...fail-
`ures...and
`missed opportu-
`nities
`
`Innovation or Stagnation?
`
`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 aca-
`demic scientists over development issues (Figure 7). Agency review-
`ers 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 informa-
`tion. In fact, since the details of most failed programs cannot possi-
`bly be shared publicly or for applied research purposes, FDA holds
`the only broad, cross-cutting knowledge about how certain investi-
`gational products fail, why certain therapeutic areas remain under-
`developed, and when certain development hurdles persist despite
`advances in technology that could mitigate them. Indeed, these fail-
`ures may trigger regulatory