Improving Innovation in Medical Technology: Beyond 2002

Agency-wide initiatives to speed development of new medical technologies will be a major thrust in FDA's new strategic plan. The initiatives will be implemented through pre-market review programs in the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH) and the Center for Veterinary Medicine (CVM).

Three key areas have been identified for increased effort:

1. Examining root causes of multi-cycle reviews, to identify and address avoidable delays and multiple cycles in review of new products,
2. Instituting a continuous improvement/quality systems approach throughout pre-market review and
3. Expanding collaborative clinical and pre-clinical guidance development, to reduce uncertainty and increase efficiency for innovator product development.

These initiatives are the result of a new agency-wide Work Group charged with identifying and acting upon the best opportunities to improve the transparency, quality, and efficiency of agency processes and agency-sponsor interactions to facilitate new medical technology development. The Work Group includes the Directors of the four therapeutic product centers and their respective directors of new product review. The Work Group will remain active to implement these initiatives, and will be the focal point of further steps to improve FDA's review of new medical technologies. As part of a related initiative on improving patient safety, the Agency is also developing new post-market initiatives to achieve improvements in the safe use of FDA-regulated products at a lower cost.

On June 12, 2002, the President signed into law the Public Health Security and Bioterrorism Response Act, which included a reauthorization of the Prescription Drug User Fee Act. Also, on October 26, 2002, the Medical Device User Fee and Modernization Act was signed into law. These provide new and increased user fees that would significantly improve the quality and frequency of communications between FDA and the sponsors of drugs, biological and device products.

1.0 Background

FDA pre-market review of therapeutic technology spans the four product centers: CDER, CBER, CDRH, and CVM. A review of the products approved in 2002 shows good news for consumers based on the significant number of innovative, and in some cases life-saving, products that were approved for marketing. A review of the data with regard to application submissions, however, demonstrates trends toward decreased numbers of applications for truly innovative products. Furthermore, a review of the statistics for the median time from application submission to FDA approval (see Table 1) also shows some trends toward increasing total approval times for certain categories of products. These observations are of concern to FDA and present some clear opportunities for improvement for both product innovators and for FDA in 2003 and the future. In this document FDA reviews its product approval performance for 2002 and outlines new initiatives to further improve its performance in this area.

1.1 FDA Product Approvals in 2002 and Challenges for 2003

During calendar year 2002, FDA approved a large number of new products, many of which represent significant advances for patients and physicians by providing new options to treat serious, disabling, or life-threatening diseases. These approvals are in keeping with FDA's mission to make safe and effective medical products available to the American public in a timely manner and are expected to positively impact the public health.

Counterbalancing this positive news from 2002 are some trends of decreases in submission of new applications for truly innovative new products. These innovative new therapies include new molecular entities (NMEs) among the 'priority' and 'standard' new drug applications (NDAs), biologics licensing applications (BLAs), and pre-market approval (PMA) applications for new Class III devices¹, and significant original new animal drug applications (NADAs These trends are of concern to FDA, however, over the same period, FDA has seen a substantial increase in the number of applications for new products that will provide patients with more choices in areas where comparable therapeutic options already exist. These include non-NME NDAs, human drug and biologic efficacy supplements, generic drugs, and biologic and device 510(k)s.

With regard to median total approval times, FDA is reporting mixed results for 2002. For some product categories FDA is reporting essentially the same or decreased median total times to approval for 2002 compared to 2001. For other product categories FDA is reporting increases in median total times to approval for 2002 compared to 2001. The data for the various categories of applications for the four centers are summarized in the table below.

Some of the data on total approval times warrant further discussion. First, FDA is reporting a significant increase in median total approval time for priority NDAs and priority NMEs. FDA believes that this represents a statistical artifact that is primarily related to the decreased numbers of new priority NDAs and priority NMEs submitted for review in 2002 and 2001. The decreased number of new applications, which have a potential for a short total approval time, results in a skewing of the median total approval time upward as older applications that were received in prior years are approved after having undergone multiple-cycle reviews. Second, FDA is reporting a decrease in total approval time for standard NMEs, which is important given concerns in 2000 and 2001 that the total approval times for this important category of applications was increasing. FDA is also reporting a decrease in total approval time for NDA efficacy supplements even though the number of such applications approved increased dramatically in 2002 compared to 2001. Finally with regard to BLAs and BLA supplements FDA is reporting mixed data, however, FDA believes that it is important to note that the small numbers of applications approved in each category makes it difficult to reach any conclusions regarding trends in these categories.

Table 1 -- Pre-market Approvals for CY 2001 and 2002

The continued approval of a significant number of new products in these established areas is good news for consumers, but the trend of declining numbers of really 'new' products presents a challenge to both industry product developers and to FDA, whose mission includes increasing patient access to safe and effective new products. The agency has recently committed to achieving measurable long-term improvements in disease outcomes; this can only be accomplished by enabling successful new technology development.

1.2 Factors contributing to decline in new product applications.

The declining number of new therapy applications is the result of a variety of factors, some of which can be addressed or influenced by FDA activities. The declining number of new applications can also affect the summary statistics for time to approval, giving greater weight to the typically few problematic applications that require multiple cycles of review [to address all critical safety and efficacy questions] before approval. What follows is a brief discussion of contributing factors cited by industry analysts or identified by FDA. Following that, we describe what FDA plans to do to address the slowdown.

An examination of time trends in the number of application submissions versus the number of approvals shows a close correlation; the number of approvals might be considered to be lagging indicator of application submissions and product development productivity. FDA has observed that submissions of NMEs and, most importantly, priority NMEs, have been declining in recent years. This drop has also been noted by the European Medicines Evaluation Agency (EMEA)¹⁰. Industry analysts have also noted a "lack of acceleration in new molecular entity new product flow is occurring at the major pharma level despite significant increases in R&D spending".¹¹

Why is this happening? A number of factors are probably involved. Potential factors include:

• The past investment climate. With total development time averaging about ten years, today's applications are the result of R&D that began a decade ago. Industry data show that in the early nineties, the growth rate in R&D investments dropped to the lowest level in 20 years. This dip may be having an impact now.
• Industry analysts have cited the difficulty of capitalizing on the vast quantities of genetic, genomic and proteomic data now becoming available. Some analysts think that this 'deluge' of data has actually caused reduced R&D productivity, as industry shifts from traditional chemistry to cutting edge biotechnology.¹²
• FDA has observed that mergers within the industry may be causing elimination of candidate drugs that are within the same class. This phenomenon would decrease the number of "me-too" drugs submitted.
• European regulators, facing a similar trend, have cited recent mergers as a factor: merged entities select only the most promising prospective "blockbusters" for further development. The net result of a corporate merger on the size of the company's product pipeline is described as, "Twenty plus twenty equals twenty".
• The managed care environment is also decreasing the incentive to develop numerous "me-too" drugs when several members of a class have been approved. This also can be seen once the first generic within a class is approved.
• Some have suggested that FDA has increased study requirements and the increased cost and time delays have contributed to a slowdown in applications. Scientific advances over the past several years have enabled earlier detection of life-threatening cardiac risks and drug interactions; these advances have protected patients from harm. Earlier discovery of these problems enables companies to shift resources to other candidates, but may also have resulted in a temporary slowdown in submissions.
• Many of the "easy targets" for drug development have already been utilized. Some industry analysts have note that pharmaceutical R&D focus has shifted to develop drugs for chronic and more complex diseases with large market potential. These conditions, however, often involve much larger patient populations and/or longer-term studies that require more expensive trials to document safety and efficacy.
• Some cite "increased FDA conservatism" triggered by recent drug withdrawals. The current withdrawal rate for NMEs approved under PDUFA (2.5%) is not higher than the pre-PDUFA rate (2.7%). There is no evidence of an excess rate of withdrawals in recent years. Furthermore, an analysis of the percentage of first-cycle approvals for priority NMEs over the 10 years of PDUFA does not show any evidence of a systematic change in the likelihood that a priority NME application will be approved on the first cycle. With regard to standard NMEs, there may be a slight trend toward decreased first-cycle approvals in the last several years of PDUFA II, however, it is difficult to ascribe this observation to FDA "conservatism" given the concurrent shortening of the PDUFA review clock for standard NDAs from 12 to 10 months during this time period.

Some of these factors also apply to new biologics. In addition, some emerging biological therapeutics present new challenges for product testing, characterization and manufacturing controls.

These challenges are important for the future health of patients and the future health of the pharmaceutical and biotechnology industries. The branded pharmaceutical and biotechnology industries depend on innovative R&D to produce new medical treatments that are key drivers of long-term growth.

Analysts suggest that commercial markets for certain existing drug classes have become saturated, decreasing the profit opportunities to be gained by developing variations in the same drug class. Industry financial analysts suggest that pharmaceutical companies therefore turn to more innovative and riskier scientific research to create new markets, and this type of research increases R&D costs.

Device innovators face similar challenges. Although the device industry overall presents a more positive growth picture, that may be a reflection of the success of the handful of large companies with widely diversified product portfolios and the manufacturing infrastructure to develop new products without incurring major additional costs. The picture is less robust for the much larger number of small firms that are often the drivers of innovation. These firms, like small biotechnology companies, are much less likely to be publicly traded and rely heavily on venture capital. According to investment analysts, venture capitalists have slowed their funding for the most innovative, emerging device companies because investors are concerned about both the risks that such products may not succeed and about regulatory uncertainty. Investors are described as being biased against the most innovative investments because they are looking for predictability.¹³

FDA plans to take steps to address both the longer times to approval and the lower numbers of new applications. The agency has identified ways to address the longer time to market approvals the agency is reporting for some new product areas. FDA also plans to take steps where possible to support the development of important new therapies.

In sections 2 and 3 below, we discuss factors that affect delays in review of new product applications, and outline FDA plans to address those factors. In section 4 we outline FDA plans to help address factors affecting new technology development.

2.0 Reducing Delays and Costs in Product Approvals by Avoiding Multiple Review Cycles

2.1 Factors that cause unnecessary delays in new product approvals

Approvals that take more than one cycle to complete are not in the best interest of the public, the agency, or the company submitting the product application. Multiple-cycle reviews prior to approval requires substantial additional resources on the part of the agency and the sponsor and are not an efficient or effective use of either party's resources. From a public health standpoint, multiple-cycle reviews means that safe and effective new products are not available to patients and healthcare providers in a timely manner. As an example, although FDA has generally been meeting its PDUFA review time goals (6 months for priority applications and 10-12 months for standard applications), actual time to approval can be much longer when an application goes through multiple cycles.

Whether or not a product can be approved in a single cycle depends on whether the application contains sufficient, scientifically valid information on safety and effectiveness to meet the agency's standards for approval (i.e., that there is evidence that the demonstrated benefits of the product outweigh its known risks.) The basic premise at the time of the submission of the application to the FDA is that the application is complete and contains the data needed to support the claims the company wishes to make for the product and that the company is prepared to manufacture the product in a consistent, quality manner in compliance with good manufacturing practices. As deficiencies are noted during the review of an application, the Agency attempts to work with the company to address these deficiencies during the time allowed for the review cycle. Minor deficiencies can often be so corrected without having to resort to a second review cycle. However, major deficiencies usually need substantial time between cycles for companies to develop the data necessary to address adequately the deficiencies noted during the review. FDA believes that reducing deficiencies to a minimum prior to application submission would result in the most efficient use of agency and company resources and would facilitate getting scientifically-substantiated, well-manufactured products to patients as quickly as possible.

To further understand the reasons for multiple-cycle reviews of products before approval, the CDER recently undertook a retrospective study to determine the causes for approval delays for standard and priority NME NDAs. For standard NME NDAs the study looked at applications with total approval times greater than 12 months from January 1, 2000 to December 31, 2001. For priority NME NDAs the study looked at applications with total approval times greater than 6 months from January 1, 2000 to August 30, 2001.

For standard NMEs the study found that 57% of applications approved during the specified timeframe had total approval times of greater than 12 months. The range of approval times was 12.1 to 54.4 months. For those applications with approval times greater than 12 months, final approval occurred after 1 to 4 review cycles (3.5% in one cycle, 48% in two cycles, 45% in three cycles, and 3.5% in four cycles). An analysis was done of the primary reason for delay in approval for each cycle. For brevity, only the primary reasons for delay on the first review cycle will be reported. The most frequent primary reason for delay on the first cycle was demonstration of the safety of the product (38%) followed by concerns related to demonstration of efficacy (21%), manufacturing facility concerns (14%), labeling issues (14%), chemistry, manufacturing, and controls issues (10%), and submission quality (3%).

For priority NMEs, the study found that 48% of the applications were fully approved in one cycle of 6 months or less review time and 52% of applications approved during the specified timeframe had total approval times of greater than 6 months. The range of total times to approval was 6.6 to 54.4 months. For those applications with total times to approval greater than 6 months, final approval occurred after 1 to 3 review cycles (18% in one cycle, 46% in two cycles, and 36% in three cycles). The most frequent primary reason for delay in approval on the first cycle was chemistry, manufacturing, and controls issues (46%) followed by safety issues (27%), efficacy issues (18%), and manufacturing facilities issues (9%).

A similar, though less comprehensive study, was undertaken the CBER for BLAs approved during calendar year 2001 that had extended total approval times. This study showed that the most frequent primary reasons for delay were issues related to major changes in product manufacturing (7 of 11 applications) followed by clinical issues (safety and/or efficacy).

The findings from these retrospective analyses suggest that in most cases the delays in approval are related to factors that are beyond FDA's control during the application review period; i.e., issues related to adequate demonstration of safety, efficacy, and product quality. However, the study did demonstrate potential areas for improvement in FDA's review process for certain applications that may have resulted in shorter times to approval.

In addition, the findings of these retrospective analyses of causes for delays in approval emphasize the important of communication between FDA and the sponsor during the product development phase so that various deficiencies can be addressed prior to submission of the application or avoided altogether by better drug development practices. Clear understandings of agency expectations and timely communications between FDA and application sponsors can increase the likelihood that a submitted application contains the necessary information for timely approval in the first round. For example, insufficient FDA-industry interactions may result in late identification of important problems and other avoidable concerns that lengthen the time and cost of product development when discovered late in the development or review process and necessitate further data development and delays in product marketing approval.

To help avoid multicycle reviews whenever possible, FDA will implement strategies to increase the quality of FDA-sponsor communications with the goal of increasing the quality and completeness of sponsor applications at the time of initial submission. Key elements of this strategic initiative are to identify and address, in collaboration with industry sponsors, the "root causes" of poorly designed and executed drug development programs and inefficient first cycle review performance for all medical products. With the 2002 reauthorization of PDUFA and expected appropriations in 2003, we expect that these initiatives can be implemented or initiated in 2003 for new drugs and biologics. For medical devices and animal drugs, the initiatives will proceed as rapidly as possible, based on the available resources.

FDA expects these new initiatives to help it achieve its public health mission of promoting and protecting patient health:

• Reducing time to market for new medical products will result in earlier patient access to safe and effective treatments, which will improve population health as a result of new treatment options being available.

Reducing time to market can reduce industry development costs, potentially leading to investment in more new technologies as well as to lower costs of new treatments. According to the most recent published study on the cost of pharmaceutical innovation, each one-month reduction in NDA review time translates into an average of $2.5 million savings in capital costs for the drug innovator.¹⁴ In addition, a recent study from the Tufts Center for the Study of Drug Development suggests that the development costs of a new drug could be reduced by $100,000,000 if the development time is reduced by 18.9% or the clinical success rates is improved by 25.2 to 25.6%, or if company out-of-pocket preclinical costs were reduced by 29.8%.¹⁵

2.2 Reducing avoidable delays in time to approval

2.2.1 Addressing the root causes of longer review times for human drugs and biologics

For applications that are ultimately approved, the causes of cycling can include deficiencies in sponsors' applications, communication problems during the review process, or difficulty finishing final negotiations on such topics as labeling. Sometimes additional review cycles are necessary to resolve important issues regarding safety, quality, or efficacy; but in other cases the extra cycles could be avoided, saving time and effort. FDA plans collaborative efforts to evaluate the root causes of multiple cycles and, based on the results of this evaluation, to take actions to prevent avoidable cycling. Efforts will include retrospective analysis of the reasons for multiple cycles, prospective analysis of the quality of submissions, review process and communications between FDA and sponsors during the first cycle, and a formal evaluation of the impact of newly implemented good review management principles in CDER and CBER on the time to application approval.

Retrospective analysis of the reasons for multiple review cycles in approvals in recent years. The approach would be similar to earlier retrospective analyses described earlier in CDER and CBER and would be expanded to all centers. Careful analysis of the data from these studies will guide FDA initiatives to address the problems of poor quality applications, lack of the needed clinical data (need for improvement in focusing clinical study designs), difficulties in manufacturing scale-up, and the need for earlier and clearer communications between FDA reviewers and sponsors.

In FY 2003 CDER and CBER will implement First Cycle Review initiatives that will increase the clarity and frequency of communications between FDA and industry sponsors, which should lead to better applications, earlier identification and remedying of application deficiencies and is likely to result in more first cycle approvals for drugs that demonstrate safety and effectiveness. The First Cycle initiative calls for identification of substantive deficiencies identified during the initial filing review, for original New Drug Applications (NDAs) and Biologics Licensing Applications (BLAs).

FDA is committed to provide sponsors with notification of deficiencies prior to the goal date for 50% of submitted applications in FY03, 70% of applications in FY04, and 90% of applications in FY05-07.

Another component of this initiative is the publication of Good Review Management Principles (GRMP) with provisions for both FDA reviewers and industry sponsors. The GRMPs call for more consistent communication of issues identified during the review that may affect the approval of the application, with emphasis on early communication of easily correctable deficiencies, including appropriate use of Discipline Review letters, anticipating/planning for Advisory Committee meetings, and planning to provide labeling comments and scheduling time for feedback to sponsors before the action goal date, and training of review staff. The draft GRMP guidance is undergoing internal refinement and review; FDA plans to publish a final guidance by the end of FY03.

The agency will formally evaluate the effectiveness of first cycle review, including prospective evaluation of process and communications from perspective of both FDA and industry. Analysis will include identification of best practices, by FDA and by industry, that facilitate the review process. FDA expects that the contract for this work will be awarded by the end of FY03.

Addressing causes rooted in product development before submission first cycle review. Better communication and process transparency during the first cycle can reduce delays for some applications, but others go through multiple cycles because they present more serious deficiencies, that would have been more efficiently and effectively addressed if identified much earlier in product development. This is true, for example, in cases where the data in the application are inadequate to support the claim in submitted labeling, or the company cannot demonstrate that it is able to make the product according to current standards of acceptable quality and consistency.

The most effective way for FDA to help a company address these problems is through earlier sponsor consultation with FDA at earlier development milestones, including pre-IND submission, at the end of Phase 1, and at the end of Phase 2.

In FY2003 the FDA human drugs and biologics review program have begun work on a Continuous Marketing Application initiative that will enhance sponsor access to early guidance and feedback via two pilot programs. The first applies to fast track products that have demonstrated significant promise as a therapeutic advance in clinical trials, and will provide an early discipline review of the relevant portions (reviewable units) of the sponsor's NDA/BLA submitted in advance of the complete application. The second pilot applies to fast track drugs or biologics that are intended to treat serious or life threatening diseases, and provides for FDA-sponsor agreement to engage in frequent scientific feedback and interactions during the IND phase of product development.

Joint CDER/CBER draft guidances on the CMA initiative are being developed and are expected to be published in the Federal Register in the near future, with final guidance to be published by the end of FY2003.

2.2.2 Reducing Delays in Medical Device Reviews

Although there are differences between the human drug and biologics review programs and the program for medical devices, device application sponsors and CDRH reviewers face similar challenges.

To help reduce unnecessary delay in device review, CDRH will clearly define time frame for FDA to make decisions on PMAs including decision goals, which are analogous to drugs and biologics goals for 'complete review' of a submitted application. The Center has committed to work toward the goal that (a) 80% of submissions received in fiscal year 2006 will have an FDA decision in 320 days, and (b) 90% of submissions received in fiscal year 2007 will have an FDA decision in 320 days.

In addition, CDRH plans to increase the use of national and international recognized standards in premarket submissions to reduce review times. A recent analysis of review times for 510(k) approvals found that 510(k)s for products for which FDA had developed guidance are approved in two-thirds the time it takes to approve 510(k)s without such guidance. CDRH plans to increase the development of guidance documents, in particular Special Control Guidance Documents, to clearly communicate FDA's expectations as to the regulatory requirements and scientific information expected in a premarket submission in order to assist industry in preparing better submission. In addition, CDRH plans to revise the PMA filing guidance document to clearly define the criteria for filing a premarket approval (PMA) application in order to avoid filing of submissions that are not ready to be reviewed.

The center also plans to train the reviewing staff on implementation of the least burdensome principles to eliminate unnecessary burdens or requirements, and to increase meeting attendance at professional meetings in order for the review staff to be familiar with latest technology and development in their device area. The center will also work to increase reviewers' attendance at meetings organized by trade associations in order to communicate FDA's scientific expectations and regulatory requirements.

2.2.3 Reducing Delays in Animal Drug Reviews

CVM's plans the following initiatives to reduce review cycle times are directed at clarifying FDA review expectations, increasing reviewer-sponsor communications and increasing the quality of industry applications submissions, as well as implementation of recommendations to improve the quality and efficiency of the animal drug review process following an independent third party evaluation. The following specific steps are planned:

• Publication of the Final Rule on Pre-submission Conferences
• Implementation of the GFI #132 - Draft Guidance for Industry: The Administrative New Animal Drug Application Process
• Implementation of GFI #152 Draft Guidance for Industry: Evaluating the Safety of Antimicrobial New Animal Drugs With Regard to Their Microbiological Effects on Bacteria of Human Health Concern
• Analysis and Implementation of Recommendations from the Third Party Evaluation of the CVM Pre-Market Review Process

3.0 Improving the review process through a quality systems approach to medical product review

Review of new medical products is a challenging and constantly changing task: the relevant technologies are changing rapidly, new innovations are occurring in statistical methods and in data systems to support product evaluations, and in many respects the information surrounding the safe and effective use of medical products is becoming more complex. It is therefore important that FDA reviewers remain knowledgeable of advances in science and technology and apply this cutting edge knowledge in a consistent fashion to their review and decision-making activities.

To help FDA reviewers keep up with the latest relevant developments in the biomedical, statistical, and risk assessment sciences, to provide the highest quality of safety review, to continue to improve efficiency in its operations, and to attract and retain the best possible scientific talent, FDA is committed to the full implementation of a continuous learning/ quality systems approach to medical product reviews. This is needed to address identified and potential inconsistencies in the review process within review organizations and across review organizations; a lack of consensus among expert reviewers on what constitutes "quality review"; opportunities to provide better and more relevant training for review staff and review managers; and better support for rigorous scientific review through better analytic tools.

Results of the successful implementation of a continuous learning approach will include:

• Better quality reviews performed more effectively and efficiently: reviewers will have a clearer, more consistent understanding of what to do;
• Better reviewer skills and review tools: reviewers will have better support for how to do it;
• Stronger, more effective agency: FDA review organizations will become well-integrated learning organizations focused on sharing knowledge and being transparent both within and outside the agency;
• Enhanced staff satisfaction and morale.

These goals will be captured in FDA's strategic plan. Higher-quality, more efficient reviews will help ensure that more safe and effective medical treatments reach the public more quickly.

In addition, FDA is committed to undertaking aggressive efforts to recruit and retain the best and the brightest review scientists. FDA believes that this can be accomplished by highlighting the public health importance of the work done by FDA reviewers, providing opportunities, protected time, and funding for training and professional development activities, and continuing ongoing agency efforts to enhance compensation and other quality of work life initiatives.

All 4 therapeutic product centers will be developing a continuous improvement/quality management approach to the premarket review process. FDA will begin this broad effort in CDER and CBER, using outside expert consultants for analysis, training and technical assistance funded through Performance Management initiative of PDUFA 3. The approach will then be extended (via separate funding) to CDRH and CVM. Examples of elements of a quality system to be implemented over the next several years, with the assistance of a contractor:

• Training for managers on the institution and maintenance of a quality system, including training of quality assurance and quality improvement
• Identification and steps to address scientific and medical continuing training and educational needs of staff
• Further development of review standards (scientific and process)
• Institution of peer review of the review process and content
• Enhanced training for reviewers and review managers on good review practices

3.1 Instituting quality systems in review of new drugs and biologics

CDER and CBER will develop a "quality system" approach to the drug review process. Elements of such a quality system include determining and continually evaluating best practices/standards for both the process and scientific content of drug and biologics review, assuring that all staff are adequately trained, measuring performance against the standards, and using performance results to make improvements. Inherent in a quality system for drug review is a continuous evaluation and improvement of the review standards, where needed, as well as continuous evaluation and improvement in review performance as measured against the standards.

CDER and CBER have taken some steps towards implementing a quality system. These include:

• Development and implementation of review document templates in the relevant disciplines. Independent evaluation of the use of these templates has begun.
• Completion of a draft "Good Review Practices" document related to review of safety information.
• Implementation of a Quality assurance program
• Initiation of "Regulatory Briefings" to bring difficult regulatory issues to Center leadership for discussion.
• Refuse-to-file and clinical hold review committee discussions.
• Development and implementation of many "MaPPs" (SOPs) for the process of review.
• Over the next 6-12 months, the center will accelerate these activities,
  • Continuing to evaluate and finalize review templates for all review disciplines
  • Improving quality systems in control laboratory accreditation.

Implementing of the Common Technical Document (CTD) and the electronic CTD (eCTD) will also be key elements in better quality, consistency and communication with sponsors. The Common Technical Document is a common format for submissions to regulatory agencies in the US, EU and Japan that was developed under the auspices of the International Conference on Harmonization of Technical Requirements for Pharmaceuticals (ICH). The CTD and its electronic version, the eCTD, will replace multiple region-specific required formats. FDA will accept CTD and eCTD formats within FY 03. The agency plans to extend this standard format to IND submissions in the future. Benefits include:

• Significant reduction in resources and time to compile applications for the same product in the three regions.
• Easier exchange of information between industry and regulator
• The eCTD will further streamline the process, augmenting resource and time savings.

3.2 Implementing medical device quality initiatives

In addition to participation in the planned cross-center continuous improvement/quality management initiatives, CDRH has begun work to implement a "quality review" program quarterly to assess the quality of premarket reviews. This effort includes soundness of scientific/regulatory conclusions, consistency, adherence to regulations/policies/Sops (including least burdensome principles), and effectiveness of review management. As part of a better review system, CDRH plans to improve CDRH Information Technology capability to better handle electronic submissions.

4.0 Improving Product Development and FDA Review Process through Developing Clear Guidance

4.1 Better Guidance for Targeted Clinical Areas

Clinical guidances provide important information to industry on the design and execution of the clinical trials needed to support an approval. These guidances can help structure claims, offer proven standardized approaches to evaluating efficacy and give insights into safety testing. FDA has targeted guidance development and publication as a priority.

Within the next year, the agency will pursue guidance development for oncology products, including:

• The Division of Oncology Drug Products is initiating a series of collaborative discussions with the American Society of Clinical Oncology about appropriate endpoints for clinical trial design for cancer therapies, by type of cancer and stage of disease. The first discussion is scheduled for January 2003 and will address lung cancer.
• A final version of "IND Exemptions for Studies of Lawfully Marketed Cancer Drug or Biological Products" (currently in draft) is expected to be completed by the end of the year.

In addition, FDA plans to form cross-center working groups to develop joint disease guidance for development of products to treat diabetes and obesity. It is anticipated that these guidances could be developed over the next two to three years, in collaboration with the relevant scientific community, utilizing workshops, advisory committee meetings, and other scientific venues. Workshops could include specifically invited subject matter specialists on the disease in question, as well as other interested parties including patient groups and other advocacy groups.

Workshops and other venues could be used to address issues including:

• Current state-of-the-art for therapy of the disease or condition
  • Implications for selection of control groups for clinical trials (e.g., inclusion of placebo controls vs. control groups receiving standard therapy)
  • Requirements for therapies in experimental subjects (e.g., type I diabetes & insulin requirements for some trials of supplementary therapeutic agents)

• Natural history of disease in relation to study design & development of valid clinical endpoints for trials
  • Statistical evaluations to determine requirements for trial size, scope, and enrollment issues
  • Disease variations in sub-populations (e.g., male/female, ethnic, racial, etc. may effect expected outcomes, responses to therapeutic agents, etc.)

• Safety issues for new therapies related to disease condition
  • Factors related to the disease or condition to be treated which raise potential safety concerns (e.g., concomitant conditions or therapies that might raise concerns about potential toxicities, adverse interactions, or other adverse effects)
  • Effects of disease or condition to be treated on pharmacokinetics (therapeutic agent metabolism, clearance, etc.)
  • Any potential manufacturing or formulation issues (consistency throughout trial, etc.)

• Risk management
  • Assessment of risk vs. benefits
  • Decisions on potential exclusions from initial trials of subgroups of patients for whom initial risks may outweigh potential benefits
  • Parameters for monitoring of trials (clinical assessment, laboratory testing, etc.)
  • Definition of safety endpoints (i.e., what would lead to suspension of trial)

• Informed Consent
  • Requirements for optimum presentation of risks & potential benefits (requirements for risk communication)

• Monitoring of clinical trials
  • Timely review of safety & efficacy data to assure prompt response to data consistent with defined safety or efficacy endpoints
  • Appropriateness of patient selection, difficulties in achieving recruitment goals defined in study design, etc.

The results of these discussions would be made available in guidances and other relevant formats.

4.2 Better Guidance for Emerging Technology Areas

FDA sees the opportunity to play a unique and critical role to greatly facilitate technology innovation by reducing regulatory uncertainty and increasing the predictability of product development by clarifying development and regulatory pathways for emerging technologies. Also critical for these products is improving the quality and efficiency of sponsors' nonclinical (eg., including product manufacturing and quality assessments) and clinical studies.

Critical to FDA's effectiveness in this role is the availability and retention of the highest level of scientific expertise and innovative thinking within the agency itself. One of FDA's proposals to accomplish this goal (also a priority of Commissioner, Dr. Mark McClellan) is to enrich our own staff by developing an agency-wide continuous national program which allows respected and scholarly individuals to spend time at FDA (e.g., 3-6 months) to inject innovative thinking into the current regulatory science and review process. The individuals would come from the domains of chemistry, pharmacology/toxicology, clinical pharmacology, biostatistics and clinical practice.

To further support the successful development of products in areas of new therapeutic technology, FDA plans to undertake center cross-cutting initiatives to develop regulatory pathways in three key areas of emerging technology: cell and gene therapy, pharmacogenomics, and novel drug delivery. The specific activities in these areas are currently under discussion and more detailed plans will be forthcoming. Currently plans and illustrative activities are outlined below.

4.2.1 Cell & Gene Therapy

FDA plans to establish product development "[education] partnerships" for cell and gene therapy that will help guide drug developers in their development of evidence that such therapies can safely combat disease. Within the next year and a half, FDA will sponsor a series of conferences and workshops, in partnership with the National Institutes of Health and/or scientific societies, aimed at developing standards for the human study and manufacturing of these potentially vital new technologies. For example, FDA and the American Society for Gene Therapy will bring together gene therapy researchers from around the nation to discuss and define how toxicology studies can be designed and carried out to support licensure of gene therapies. FDA and the National Cancer Institute will expand their joint programs on proteomics and genomics to help develop standards for safety, purity and potency of tumor vaccines. These initiatives will augment agency guidance to enable sponsors to focus studies to yield maximum information during product development.

The following are will be planned for implementation or to happen in the next year to 18 months:

• CBER-CDRH Intercenter Review and Research focus group for Tissue Engineering products (joint review of TE products, research on microarray, developmental biology for biological standards for TE)
• CBER-CDER focus group on tumor vaccines for consistency on product, pharmtox and clinical review
• CBER-American Society for Gene Therapy Workshop on long term toxicology studies for Gene therapy products
• FDA-IABS Conference on Development of Therapeutic Cancer Vaccines in Los Angeles -- April 2003
• FDA-NIH (NCI) IAGs on genomics and proteomics to develop standards for purity, potency, biomarkers for tumor vaccines
• FDA-NIH MOU with National Institutes of Neurological Diseases and Stroke to develop funding initiatives for research that addresses FDA needs for preclinical safety studies, especially for neural stem cells
• FDA-NIH cosponsored workshop on Stem Cells and Regenerative medicine

4.2.2 Pharmacogenomics

Certain new therapies will be developed along with genetic or phenotypic tests that can identify the responding subpopulation, detect individuals who need a different dose, or find people who are prone to a certain toxic effects. Development of these test/therapy combinations must be facilitated, because they have the potential to maximize drug benefits while minimizing toxicity. However, their regulatory path has been fraught with uncertainty. Over the next 18 months, FDA will:

• Issue guidance on when and how to submit pharmacogenomic information to FDA during drug development. This guidance will facilitate exploratory use of pharmacogenomic screening during drug development and will clarify when such information would be considered part of the drug safety evaluation (within the next 6 months)
• Hold a workshop on issues involved in co-development of a pharmacogenomic test and a drug.(this year)
• Issue joint guidance (CDRH-CDER) on the regulatory pathway for such combinations. (In 18 months).

4.2.3 Novel Drug Delivery Systems

Novel drug delivery systems present a wide diversity of technologies and applications, e.g., infusion pumps, drug-eluting stents, lasers for photodynamic therapy, hyperthermia devices, etc. Most of these products require application submissions to, and reviews by multiple centers, and multiple offices and divisions within those FDA centers. The complexity of the review issues vary dramatically from product to product, ranging from simple device/complex drug combinations to simple drug/complex device products. The novel technologies and regulatory uncertainties can present challenges for product innovators.

FDA will engage in a series of cross-agency efforts to help address these challenges. As part of this initiative the agency will:

• Perform an internal survey of all of the various types of drug delivery systems currently known both marketed and under development
• Initiate a CDRH working group to analyze the review issues related to those products including commonalities and differences
• Expand the working group to include representatives from CDER and the Office of Combination Products to gain their perspectives on these issues and look at ways to improve the process
• Develop documents, e.g., draft MOU, Guidance and concept papers, to discuss ways to improve the efficiency of regulating these products
• Organize a stakeholder meeting to discuss and comment on draft documents and finalize documents
• Implement process improvements

The agency anticipates that these activities would occur, and guidance documents would be developed over the next 12 months.

Footnotes

Improving Innovation in Medical Technology: Beyond 2002 -- Executive Summary

Press Release