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U.S. Department of Health and Human Services

Science & Research

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Critical Path Initiative - Frequently Asked Questions

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What is the "Critical Path" of medical product development?

The "Critical Path" is the scientific process through which a potential human drug, biological product, or medical device is transformed from a discovery or "proof of concept" into a medical product. It consists of scientific tests and tools used to predict whether a product candidate will be safe and effective, to assess how prototypes interact with the human body, and to guide the sponsor in choosing an appropriate dose and regimen or device size and/or placement. It consists of scientific tools to manufacture the product at commercial scale and assess the quality of the manufactured product. In order to bring a product to market successfully and efficiently, product sponsors need scientifically sound approaches to these challenges.

What is a Critical Path tool?

Critical path tools are scientific or technical methods used to:

  • Predict whether a product candidate will be safe and effective, so the sponsor can decide which candidates to move to each successively more rigorous phase of testing,
  • Assess whether a product candidate is safe and effective, once the potential product is moved into human testing, or
  • Manufacture large amounts of the product, and assess the quality of the finished product.

Examples include:

  • Animal models of human disease - used to predict whether potential products will ameliorate the target condition and/or be toxic to humans.
  • "Biomarkers" - physiologic indicators (e.g., blood protein levels) that can be used to measure the progress of a disease or the effects of a treatment, often long before other indications are apparent in a patient.
  • Clinical trial designs - the scientific protocols that reliably assess the effects of a potential product on humans.
  • Quality assessment technologies – used to analyze product quality (e.g., durability of devices, stability of drugs).

What do you mean by "modernize" Critical Path tools? The report refers to "Opportunities," what does this mean?

Many of the tools used today to predict and evaluate product safety and efficacy, and to manufacture products, are badly outdated from a scientific perspective. We have not made a concerted effort to apply new scientific knowledge -- in areas such as gene expression, analytic methods, and bioinformatics -- to medical product development. There exists tremendous opportunities to create more effective tests and tools, if we focus on the hard work necessary to turn these innovations into reliable applied sciences.

Examples of Opportunities to use new science to modernize Critical Path tools include:

  • Development of good animal models for many conditions, including SARS and anthrax infection. New genetic technologies may make it possible to develop animal models that are more predictive of human responses to vaccines and treatments for these diseases.
  • Utilization of data mining and computer modeling. With improved information technologies and amassed data on the safety and efficacy of approved and failed products, there is opportunity to assemble data bases and develop computer models that can help predict safety outcomes and provide better trial designs.
  • Development of new biomarkers. New imaging technologies have the potential to contribute powerful new biomarkers for drug distribution, metabolism, and pharmacodynamics, and to be used as outcome measures. New microarray technologies, that can rapidly analyze the expression of thousands of genes, may make it possible to identify sets of biomarkers that are more predictive of clinical risks or benefits than single markers for a given condition.
  • Inefficient clinical trial designs. Innovative clinical trial design may make it possible to develop accepted protocols for smaller but smarter trials. For example, new statistical techniques may make it possible to reduce the number of people who need to receive placebo or to adaptively change the trial based on ongoing results.

Why does FDA think the Critical Path infrastructure needs to be modernized?

Despite important investments in basic biomedical research, the number of applications to the FDA for new drugs and biologics has declined over the past decade. Of more concern, product development is not becoming more efficient over time – a drug entering Phase 1 trials in 2000 was not more likely to reach the market than one entering Phase 1 trials in 1985. And we are seeing more product candidate failures in the later stages of product development -- the most expensive way to fail. Recent biomedical research breakthroughs have not improved the ability to identify successful candidates and bring the most promising products to patients in a timely and affordable manner.

We can see a wide range of opportunities to improve the efficiency of product development. But without a concerted focus on the applied science necessary to develop these new approaches, the inefficiencies and unnecessary costs of product development will continue to escalate.

How will the Critical Path Initiative help bring new treatments to patients?

With tools that can predict which product candidates do not hold promise early in the development process, product sponsors can redirect resources to more promising products. Early failures are efficient failures – they free up resources that would otherwise be invested in product candidates that will eventually fail. New Critical Path tools will help product sponsors devote those resources to new and better candidates, thus facilitating the availability of more new medical products for patients.

In addition, modern evaluation tools will be more informative -- we will learn more about products before they are approved. This will give doctors and patients the best available information about how to use the product to maximize its benefit and minimize side effects. In fact many of the tools being considered would help individualize therapy, by identifying who is likely to responds well to a treatment, and who should avoid it.

The "Innovation / Stagnation" report refers to FDA guidances as Critical Path tools? Why is an FDA standard or guidance a Critical Path tool?

FDA guidances are science-based documents that eliminate uncertainty about what FDA will accept as valid evidence of product safety, product efficacy, and manufacturing quality. This information acts as a guide or "compass" that product sponsors can use to design their product development pathways to most efficiently meet FDA requirements.

FDA guidances have been shown to improve chances of product success and shorten time to market. 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 development and approval of life-saving antiviral drugs, with time from first human use to market as short as 3.5 years. These standards greatly simplify effectiveness studies, thus reducing time and costs. Similarly, device guidances have been shown to reduce both product development time and the percent of applications found deficient on the first review cycle.

Why is the FDA the right entity to take responsibility for improving the Critical Path?

The FDA is not taking sole responsibility for improving the Critical Path. But it is the only entity capable of creating the focus necessary for this task. FDA is uniquely suited to serve as a hub for this effort, because it oversees evaluation of all U.S. medical products, and can identify the key product development hurdles that commonly cause setbacks for companies industry-wide. Because FDA is not a product development competitor, it can serve as a convenor for the coordination and information sharing necessary to identify and eliminate Critical Path hurdles. And because FDA sets the scientific standards for product development, only FDA can ensure that new Critical Path tools become the new standards for proving efficacy, assessing safety, and manufacturing medical products.

But industry, academic researchers, patient advocacy groups, and others are needed to do their part. Many of the Opportunities on the national Critical Path Challenges List will remain merely that -- unmet opportunities -- unless many people collaborate on the hard work of developing new tools for product development.

Will FDA collaborate with other public and private entities on Critical Path activities?

Yes. This is a complex task, requiring the expertise of all key stakeholders – academia, patient groups, government, industry, associations, and other private organizations.

Encourage other stakeholders to undertake work identified on the list. Some opportunities will require little or no FDA involvement, once the priority is identified. In these cases, FDA may play only a convening or communication role.

What is the FDA role in this collaboration?

FDA will play three roles. First, we will bring national focus to current product development issues, serving as a hub for problem identification and information exchange. Second, we will serve as the catalyst, to initiate projects and collaborations to help modernize the Critical Path. Third, we will encourage use of new Critical Path tools by accepting the results of the new tools as valid proof in product review (including up-dated science-based standards and guidances).

How does Critical Path research and science differ from investments in biomedical and translational research made by the Department of Health and Human Services, for example, through NIH research?

Critical Path science is the applied science partner of biomedical discovery science, and a productivity multiplier for our investments in basic and translational research.

  • Applied Science Partner. Critical Path research is complementary to basic and translational research, but dedicated to downstream product development concerns. All basic sciences need a corresponding applied science to turn concepts and prototypes into useful products. Critical Path science is highly pragmatic and targeted on identified biomedical science problems that are causing delays in product development.
  • Productivity multiplier. By eliminating bottlenecks in product development, Critical Path science allows us to realize more of the value of our investments in biomedical discovery research, in the form of more new products. Without answers to these questions for our new biomedical discoveries, they will remain as discoveries.

What is the Critical Path Initiative?

The "Critical Path" Initiative is FDA's effort to stimulate and facilitate a national effort to modernize the scientific process through which a potential human drug, biological product, or medical device is transformed from a discovery or "proof of concept" into a medical product.

The goal of the Critical Path Initiative is to bring new scientific discoveries -- in fields such as genomics and proteomics, tissue engineering, imaging, and bioinformatics -- to bear on product development, to improve the accuracy of the tests we use to predict the safety and efficacy of investigational medical products.

What role will the Opportunities List will play in the Critical Path Initiative?

The purpose of the Opportunities List is to provide concrete focus for public and private efforts and investments in new tools that could revolutionize product development. The long-anticipated announcement of the Critical Path Opportunities List signals the next vital step in the agency's Critical Path Initiative aimed at modernizing medical product development to deliver smart medical care that is personalized, predictive and preventive.

The list outlines an initial 76 "science projects" to bridge the gap between the quick pace of new biomedical discoveries and the slow pace at which those discoveries are currently translated into therapies for patients. The release of the list marks a starting point in identifying the essential development priorities to be accomplished under the agency's Critical Path Initiative.

Experts estimate, if accomplished, the new tests and tools developed under the Critical Path Initiative will modernize the drug development process by 2010 and help to get new medical discoveries to Americans faster and at a lower cost.

What does Critical Path have to do with Personalized Medicine?

Modern evaluation tools will be more informative -- we will learn more about products before they are approved. This will give doctors and patients the best available information about how to use the product to maximize its benefit and minimize side effects, based on each person's unique characteristics. Many of the projects on the List will help individualize therapy by identifying who is likely to respond well to a treatment and who should avoid it.

What are the key areas of focus for the Critical Path Opportunities List?

The list is comprised of highly-targeted research projects divided into six key areas:

  • Better Evaluation Tools -- Biomarkers and Disease Models
  • Streamlining Clinical Trials
  • Harnessing Bioinformatics
  • Moving Manufacturing into the 21 st Century
  • Products to Address Urgent Public Health Needs
  • At-Risk Populations

How did FDA determine the areas of focus for the Critical Path Opportunities List? How did we determine which projects would be on the list?

The List was developed through extensive consultation with private and public stakeholders, including an open public docket to obtain input on the most pressing scientific and/or technical hurdles causing major delays and other problems in the drug, device, and/or biologic development process. We also asked our reviewers for their views on the scientific and technical hurdles they see industry-wide. The Opportunities List is the compilation of what we learned.

The list released today is meant to spur a continued dialog among industry, academia, patient and professional groups and government organizations about the research priorities that need to be accomplished in our effort to modernize the medical product development process. We believe it is crucial to build a national infrastructure to support and continually improve the Critical Path Initiative, therefore, we must reach beyond specific opportunities and build collaborations to work together to encourage continued development of the Critical Path Sciences.

The six priority areas were chosen based on the topics which stakeholders and reviewers brought to our attention most often and discussions at public advisory committee meetings, and informed by our public health mission.

Is it too late to get a research project included in the initiative? How do I do this?

No, it is not too late. The list released today is meant to spur a continued dialog among industry, academia, patient and professional groups and government organizations about the research priorities that need to be accomplished in our effort to modernize the medical product development process. The projects on the list are examples of the type of work that needs to be done. Many opportunities, in a large number of diseases, need to be identified and worked up for inclusion on the list.

What will the effect of these projects be on the medical product development process? How will the Critical Path Initiative help bring new treatments to patients?

These projects will create new, scientific tools that can better evaluate which investigational products do not hold promise, either because they are likely to be too toxic or ineffective, and do so earlier in the development process. With this information, product sponsors can redirect resources to more promising products. Early failures are more efficient failures – they free up resources to be invested in product candidates more likely to successfully get to market. New Critical Path tools will help product sponsors devote those resources to new and better candidates, thus facilitating the availability of more new medical products for patients.

In addition, Critical Path calls for incorporation of new scientific approaches—such as genomics, proteomics and advanced imaging technologies—that will lead to more personalized, targeted therapies and preventives that are designed to be safer, more effective and of high quality.

Who will be in charge of conducting these projects?

We expect that the lead organizations will vary from project to project, depending on which organizations are interested in investing time and resources into that particular scientific issue. This work will require unprecedented collaboration among public and private sector partners. To facilitate completion of these projects in a timely manner, the FDA will act as a consultant in bringing together partnerships and consortia as our resources allow

Who are the possible partners?

Industry, academia, patient groups, professional societies, trade associations, other government agencies. Lead organizations will vary from project to project based on partnerships formed to accomplish each of the research priorities. Candidates can be any group with expertise, resources, and interest in improving medical product development.

What is the FDA role in this collaboration?

FDA will play three roles. First, we will bring national focus to current product development issues, serving as the hub for problem identification and information exchange. Second, we will serve as the catalyst, to initiate projects and collaborations needed to modernize the Critical Path. Third, we will encourage use of new Critical Path tools by accepting the results of the new tools as valid proof in product review (including up-dated science-based standards and guidance).

What is an FDA "guidance" and why is that an important Critical Path tool?

FDA guidances contain science-based recommendations that help eliminate uncertainty about what FDA will accept as valid evidence of product safety, product efficacy, and manufacturing quality. The guidance acts as compass that product sponsors can use to design their product development pathways to most efficiently meet FDA requirements.

FDA guidances have been shown to improve chances of product success and shorten time to market. 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 development and approval of life-saving antiviral drugs, with time from first human use to market as short as 3.5 years. Guidances greatly simplify effectiveness studies, thus reducing time and costs. Similarly, device guidances have been shown to reduce both product development time and the percent of applications found deficient on the first review cycle.

However, FDA cannot develop new guidances until the science needed for guidance development has been accomplished. Once this "Critical Path" science is completed, FDA can go through its guidance development process, which includes public notice and comment and often public Advisory Committee evaluation.

How does Critical Path research and science differ from investments in biomedical and translational research made by the Department of Health and Human Services, for example, through NIH research?

Critical Path science is the applied science partner of biomedical discovery science, and a productivity multiplier for our investments in basic and translational research.

Critical Path research is complementary to basic and translational research, but dedicated to downstream product development concerns. All basic sciences need a corresponding applied science to turn concepts and prototypes into useful products. Critical Path science is highly pragmatic and targeted on identified biomedical science problems that are causing delays in product development.

By eliminating bottlenecks in product development, Critical Path science will allow us to realize more of the value of our investments in biomedical discovery research, in the form of more new products. Without answers to these questions for our new biomedical discoveries, they will remain as discoveries.

I have some ideas for modernizing medical product development, how can I get involved in FDA's Critical Path Initiative?

You can contact the Office of Critical Path Programs at 301-827-1512, or go to the Critical Path Initiative Web page for more information.

 

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