Food and Drug Administration Modernization Act of 1997

FDA Plan For Statutory Compliance
November 1998

Part Two (continued)

Objectives E and F

Objective E

Establishing mechanisms, by July 1, 1999, for meeting the time periods specified in this Act for the review of all applications and submissions described in subparagraph A (Objective A) and submitted after the date of enactment of the FDAMA.

In the spring of 1999 FDA plans to reevaluate where it stands in relation to this objective. The Agency plans to make information on this objective easily available to Congress, the public, regulated industry, and other stakeholders. FDA is exploring making this information available on the Internet.

Objective F

Eliminating backlogs in the review of applications and submissions described in subparagraph A (Objective A), by January 1, 2000.

Objectives E and F are directly related. The strategies followed to achieve Objective E will also achieve Objective F. By making improvements and changes to the review process to meet the time frames for reviewing applications and submissions, any backlogs for them will be eliminated. Therefore, this section will address both objectives.

1. Identification of Needs

While, the Prescription Drug User Fee Act of 1992 (PDUFA) has been a great success, there is a gap in performance for applications not covered by PDUFA that needs to be filled for FDA to meet its statutory review requirements. In addition, public expectations, internal time frames, and PDUFA goals provide important benchmarks for FDA performance.

FDA needs to reduce total product development time, meet statutory review requirements, expedite and add value to new technologies, maintain high-quality interactive reviews, and target laboratory work to support and expedite science-based reviews. FDA has successfully adopted a number of innovations and re-engineering approaches to improve review performance. FDA has now reached the point, however, where additional improvements toward meeting statutory requirements cannot occur without additional resources.

FDA ultimately needs to speed safe and effective products to the American public by reducing the overall development and review time for new products without compromising product quality and safety.

2. Stakeholder Views

Making new products available to the public more quickly and streamlining the product development and review process while ensuring safety are important goals.

Some consumer advocacy groups want the Agency to assign the highest priority to expediting the development and review of drugs, while others expressed fear that meeting review deadlines could result in safety risks.
"Replace the resource-intensive [Generally Recognized as Safe] GRAS petition process with a streamlined notification system. Finalize the GRAS notification regulation." [trade association]

Using a risk-based strategy for reassigning resources is a major Agency strategy. A number of stakeholder comments seemed to support this strategy.

A major health organization stated that many blood products have been in the public arena for a long time, and placing such products on the lowest review requirement tier would allow the transfer of resources to new products.
A health professional society said that FDA should reassess the risk-benefit of analysis of lifestyle-modifying drugs and subject them to a different type of scrutiny than that which is used to treat or to prevent disease or other medical conditions. Also, they said it is hard to argue that it is worth taking a lot of work with a new drug product which in no way adds therapeutic benefit.

A number of stakeholders said that proper implementation of fast-track provisions will expedite entry into the marketplace for drugs for serious and life-threatening illnesses.

A biotechnology industry council suggested that the PDUFA II goals be applied first to fast-track products. They also said that definitions need further clarification and a broad, flexible definition is needed for "serious and life- threatening illnesses." The council also suggested that quarterly conferences be held to discuss surrogate end points and that fast-track designation should be done by directors of review divisions.

There was both support for the Agency's strategy for implementing third-party reviews and also concern about the strategy.

A major trade association said that more medical devices should be added to the list for using third-party reviews.
A regulatory organization said that FDA should continue to offer its reviews as an alternative to third-party reviews and that FDA should carefully review the third- party evaluations just as it would the work of its own staff.

A major concern of industry stakeholders was that FDA communicate what is expected of them in developing and testing new products and in providing evidence for approval.

A major trade association said that FDA should make its procedures transparent, particularly in terms of Good Review Practices (GRPs). Various documents such as GRPs and reviewer handbooks should be provided to industry and other stakeholders to provide a better understanding of the workings of FDA and to allow industry to bring its procedures into conformity.

Improving the efficiency of the review process by implementing an electronic submission and review process was also an industry priority.

A biotechnology industry representative suggested that information flow and documentation needs to be handled more efficiently and suggested that this could be done through the establishment of a standard electronic information exchange environment that would set the standards for industry.

Animal drug industry stakeholders placed a high priority on FDA implementing the recently enacted Animal Drug Availability Act (ADAA).

Full implementation of the ADAA was an issue brought up by many of the stakeholder groups, including drug manufacturers, livestock producers, and feed producers. All of the speakers who mentioned it strongly urged FDA to devote whatever resources were necessary to fully implement ADAA.

3. Current Innovations/Reinventions

FDA has been pursuing a number of strategies for many years to improve on-time performance in reviewing applications and submissions, especially for new products. Many of these strategies were developed in conjunction with the Agency's stakeholders. Many strategies focus on speeding up the review process and encompass risk-based priorities, re-engineering FDA processes, information technology, communications with industry and other stakeholders, and scientific support for reviews.

Strategies also focus on the drug development stage (i.e. pre-Investigational New Drug [pre-IND] and IND), and on assisting industry during the testing and pre-application process. A day saved in developing a new therapy is just as valuable as a day saved in reviewing it. FDA is working with product sponsors to ensure that they know what is expected of them so that product testing and preparation of the application are more effectively and efficiently done. As PDUFA has shown, these pre-application efforts have resulted in higher quality applications, faster reviews, and an increasing approval rate. Non-PDUFA applications have benefitted from PDUFA improvements and innovations. However, FDA performance on non-PDUFA applications still needs improvement.

FDAMA start-up and additional workload may reduce review performance in the near term, especially for medical devices and other non-PDUFA products. The growing complexity of medical devices requires that more time be spent interacting with sponsors and keeping guidelines up to date. Increased guidance and interactions with industry are resource- intensive activities. These factors will challenge FDA's ability to meet time frames.

Establish Risk-Based Priorities

FDA is focusing more on actual and potential risks in establishing priorities. FDA will identify and concentrate resources on high-risk, high-impact products or work areas, those where its direct intervention helps consumers and health care professionals the most. Despite current and anticipated budget constraints, resources will be redirected; and while some key areas will be increased, some low-risk product areas will be decreased. Several examples of these effects include:

Exempting low-risk medical devices from the premarket notification requirement;
Using a threshold of regulation approach for very low risk noncarcinogenic indirect food additives.
Giving priority to high-risk, food safety-related, food additive petitions.
Conducting risk versus benefit communications research to assess the public's ability to understand risks versus benefits in drug information and to develop useful and meaningful ways of presenting important information about a drug's known risks and benefits.

FDA's research agenda includes development of more predictive animal and non-animal models for safety and efficacy evaluation. FDA scientists are developing new approaches for use in predicting risk associated with human toxicity; developing computer-based systems to aid in the assessment of human toxicity; and conducting research on specific agents, concepts, or methods that can be applied to questions of human health and safety.

In addition to the risk-based priorities, FDA has identified high-impact areas such as pregnancy labeling, antibiotic resistance, medication errors, consumer information and direct-to-the consumer advertising policies that require the expenditure of further resources. In conjunction with stakeholders, FDA already is devising innovative strategies and methods to address the public health impact of these emerging issues.

Re-engineer FDA Processes

The Agency has been working to change its culture to fulfill its dual mission of promoting and protecting public health. As a result, FDA has been re-engineering many of its product review processes for the last several years. In fact, many provisions of FDAMA codified results of re-engineering efforts initiated by the Agency. The following provides highlights of a variety of re-engineering efforts, resulting from FDAMA, other laws, stakeholder input, and the Agency's own initiative.

The introduction and expansion of the Project Management System (PMS) to expedite review processes for both CDER and CBER established team-based project management programs designed to improve the quality and efficiency of the drug review process. These programs have demonstrated their effectiveness and continue to be refined and enhanced. Team-Based Project Management is a powerful technique combining the use of multidisciplinary teams led by project managers and scientific leaders who use the tools and techniques of project and resource tracking. Review disciplines are organized into multidisciplinary teams early in the review process to develop a review plan and commit to target interim and milestone completion dates. Teams meet periodically to exchange information, discuss significant aspects of the applications, review progress toward meeting target completion dates, and make resource adjustments. Project management is being used throughout the Agency.

FDA is committed to the implementation of the third-party review provision of FDAMA and is already pursuing that program. A key factor will be to apply lessons learned from the earlier third-party pilot program for medical devices. The fact that the earlier pilot worked well for the limited number of manufacturers who participated in the program, combined with the expanded list of eligible devices under FDAMA, should go a long way toward attracting additional submissions from industry.

FDA plans to issue guidance that describes its fast-track policies and procedures. To ensure compliance with the legislatively mandated time frame of 60 days for designation, FDA is using management tools similar to those which have contributed to FDA's success in meeting PDUFA goals. The guidance will include the Agency's definition of "a serious or life-threatening condition." In accordance with the statutory mandate, FDA currently is working with NIH, sponsors, and its advisory committees in the timely evaluation of proposed surrogate end points. For many years FDA has been working with sponsors to develop surrogate end points that are reasonably likely to predict clinical benefit for serious and life-threatening conditions.

Streamlining efforts will be focused on reducing the overall time required for product development. More guidance and meetings will be provided during the development process to assist firms in conducting appropriate clinical trials and in developing the scientific evidence needed to gain approval of new products.

During FY 1998 CFSAN implemented a proposed notification procedure for independent GRAS determinations. The Agency's current plan is to codify this process during FY 1999. Once codified, this procedure will largely replace the resource-intensive GRAS affirmation petition process with a less resource-intensive notification process.

Other efforts to simplify regulatory approaches and to reduce the burden on stakeholders include:

Implementation of a phased review process as in CVM where CVM works with the sponsor throughout the research and development process and reviews technical sections of a New Animal Drug Application (NADA) as they are completed;
Implementation of additional premarket notification programs in lieu of requiring preapproval before marketing (For example, CFSAN has worked to prepare for implementation of a premarket notification program for food contact substances established by FDAMA.);
Development of GRPs for Agency reviewers ( CBER and CDER conducted a series of workshops to develop an action plan that will evolve into guidelines that describe and develop GRPs guidance. A reviewer's handbook is also being developed.);
Development of a list of approved drugs for which additional pediatric information may produce health benefits;
Elimination of certain labeling requirements;
Amendment of regulations to provide additional flexibility for health claims on foods and to clarify nutrient content claims; and
Allowing use of abbreviated study reports in an NDA.

Capitalize on Information Technology

FDA is aggressively moving towards an electronic regulatory submissions environment. The benefits of electronic submissions include:

lower paper handling costs for FDA (e.g. document room contract, offsite storage, onsite storage);
quicker access to information by reviewers (e.g. no waiting for a paper copy and no rekeying of data for analysis; and
time and cost savings during product development (most firms have their data in electronic format and won't have to waste time creating/delivering a paper submission to FDA).

Work More Closely With External Stakeholders

A common theme in all of the improvements to the review process has been an intensive effort to improve communication with sponsors and manufacturers. This dialogue, which occurs by telephone, by videoconference, and in person, helps manufacturers understand what FDA is looking for in product submissions. Explanations include what information will be needed and why. Unresolved questions are resolved on the spot. Communication with industry continues to improve, with more companies taking advantage of opportunities to consult with FDA.

These efforts have already contributed to improved review performance. For example, CDRH has zero backlogs of 510(k)s, Pre-Market Approvals (PMAs), and PMA supplements. In addition, CDRH has begun implementing additional meetings as required by FDAMA, such as determination meetings, where a prospective PMA applicant may request a meeting to determine the type of scientific evidence necessary for PMA approval; agreement meetings, where prior to submitting an Investigational Device Exemption (IDE) application, a sponsor may request a meeting with FDA to discuss the specific investigational plan for a class III or implantable device; and 100-day PMA meetings, where within 100 days after the submission of a PMA, the sponsor may request a meeting to discuss the application.

FDA is working to make Agency processes transparent by providing a variety of information in a variety of ways including:

Increased sponsors/applicants meetings;
Presubmission conferences;
Presentations to industry about a variety of topics on the most common GMP deficiencies that prevent approval;
Providing potential applicants with assistance during the development process;
Comprehensive guidance for preparation of submissions to FDA; and
Initiating industry education programs/services regarding studies and safety data needed to support petitions and notifications.

FDA continues to rely on outside advisory committees for advice in reviewing product applications. Outside experts add a wide spectrum of judgement, outlook, and state-of-the-art experience to FDA's decisionmaking process. These expert advisors add to FDA's understanding, so that final Agency decisions reflect a balanced evaluation. FDA is working to improve the advisory committee process and make-up of committees to address stakeholder concerns.

FDA participates in international harmonization activities that can result in reduced regulatory burden for the regulated industry, much of which markets products throughout the world. By harmonizing requirements to the maximum extent possible, the industry hopes to reduce the costs involved in bringing products to market. Activities are underway in the Codex Alimentarius forum to develop and adopt a standard for food additives. Activities to date have also included work toward major parts of common technical documents that could be used for premarket filings in the three major industrialized markets. Efforts are underway with medical devices to identify areas of divergence in the various regulatory requirements, with an eye toward ultimate harmonization of requirements. With drugs and biologics, these activities should result in both higher quality products regardless of production site, and their getting on the market quicker due to reduced conflict in regulatory requirements in major markets. By relying both on manufacturer self certification of conformity with international harmonized standards as part of the accepted premarket application and on third-party reviewers for preliminary 510(k) determinations, FDA has reduced the demand on staff to review original documentation.

Strengthen the Scientific and Analytical Basis for Regulatory Decisions

Addressing the adequacy of the research and scientific infrastructure is one of FDA's highest priorities, especially as it supports the review of pre-market applications. Laboratory work is targeted to develop in-house scientific expertise, scientific guidance, and science-based standards. In-house scientific expertise is used to consult on product reviews, especially in areas of emerging technologies. Guidance can benefit both applicants and review staff in developing and reviewing applications. FDAMA requires FDA to recognize and use appropriate standards in the application review process for medical devices. Evidence that a product meets established standards will expedite the review process.

FDA still faces shortages of certain expertise, especially through attrition. Some positions are very difficult to recruit. FDA needs to use a number of pay incentives (higher initial pay, bonuses, comparability allowances, etc.) to attract and retain medical officers, especially for certain specialties. Other positions include pharmacokinetics specialists, statisticians, and computer specialists. As a result, FDA sometimes is lacking critical skills in the review area such as having an orthopedic surgeon to review surgical devices.

4. Plan for Meeting Statutory Requirements and Public Expectations

Because of the success of PDUFA, FDA will continue to use PDUFA submission and review mechanisms to improve the review performance of non-PDUFA applications and reduce product development time. Ultimately matching PDUFA's success without additional resources comparable to those provided by user fees is problematic.

PDUFA is different from some European review systems in that it provides the certainty of a result within a definite time. Examples of the submission and review mechanisms used to accomplish this are: 1) presubmission consultations; 2) refuse-to-file authority and increased application quality; 3) project management; and 4) complete first actions.

Several interlocking strategies will be used to meet FDA's review goals. To ensure wise use of reviewers' time, FDA will continue to re-engineer its product review processes in many areas and will continue to look for more effective means of shortening processes without sacrificing quality and safety concerns. Second, several initiatives are underway to reduce the direct review burden on the Agency by reducing the requirement for pre-approval in some areas and replacing it with an industry notification process. Third, consultation with product sponsors early in their research and development process will raise the likelihood that high-quality commercial applications will follow and make their way through the FDA system in the shortest time possible. Finally, all of FDA's product review centers will continue to automate their application submission and review tracking systems. This should result in not only faster review times, but also increases in Agency productivity. Without an infusion of resources, however, it is unlikely that FDA will be able to meet its statutory obligations in all product areas.

Additional Steps

Make available and reassign more resources by using a risk-based priority system and seek additional resources as needed. FDA will redirect resources to high-risk and high-impact product areas and decrease resources in areas that pose a lower risk or benefit.

Expand collaboration with product sponsors to expedite product development.

Provide more productive interactions with industry through up-to-date guidance review, industry education, and reviewer training.

Increase efforts with other industrialized countries to harmonize product protocols.

Expand electronic submission and review systems.

Target laboratory support for emerging technologies.

Expand use of third-party reviews.

5. Performance Goals for FY 1999

The table provided in this section highlights some key PDUFA and non-PDUFA applications and summarizes the time frames, performance goals, baseline performance, and the number of applications overdue. A more comprehensive table and listing of applications and submissions covered by this Plan are in Appendix D.

The PDUFA time frames and performance goals are the result of in-depth negotiations between the drug industry and FDA. Industry and FDA determined that both the time frames and the percentage goals were realistic, achievable with the additional user fee resources, and desirable. The PDUFA time frames for drug applications differ in some cases from the FD&C Act statutory requirements. Biologics applications are covered by the Public Health Service Act, which does not have any statutory time frames. Also, the PDUFA goals do not stipulate that 100 percent of applications be completed on time. In many cases, however, a 100 percent performance level was achieved. Industry is pleased with the certainty of a timely action and response from the review process and the net result of a higher percentage of applications being approved faster. Patients have benefitted by having more therapies available more quickly. Performance goals for PDUFA applications are based on the PDUFA time frames.

Performance goals for non-PDUFA applications are based primarily on the statutory time frames with two exceptions. Non-PDUFA biologics applications have no time frames. FDA has voluntarily adopted the original PDUFA time frames for these applications. Also performance goals for food and color additive petitions are based on 360 days, twice the statutory time frame of 180 days. This is being done to provide realistic targets as the petition review process is being re-engineered.

FDA has developed clear performance goals that will enhance and further expedite reviews for product applications. Setting these goals has provided a valuable management tool for identifying performance expectations and assessing achievements. Using the PDUFA model, performance is measured based on the percentage of applications acted on within the appropriate review time frame. The on-time performance measure is important because it represents definitive decisions both to approve and not to approve. An accurate portrayal of the timeliness of the Agency's decision making should focus on the length of time to all decisions, both positive and negative.

Overdue applications are those whose review period exceeded the time frames and were under active review at the end of the fiscal year.

Highlighted below are key performance goals for FY 1999 in the area of application review. These goals represent applications for new and priority products and for new medical uses of approved products. For more complete information see the table at the end of this section and Appendix D.

FY 1999 Performance Goals
Review 90 percent of priority NDAs/PLAs/BLAs within 6 months.
Review 90 percent of priority efficacy supplements within 6 months.
Review 70 percent of blood PLAs/BLAs within 12 months.
Review 50 percent of PMAs within 180 days.
Review 30 percent of food and color additive petitions within 360 days.

Time Frame	Relevant Statute	Percentage of First Actions Within Time Frame--FY 1999 Performance Plan Goal	Percentage of First Actions Within Time Frame--FY 1997 Baseline (Estimate)	Overdue*
PDUFA:
Review Priority NDAs within 6 months (CDER) (PDUFA II commitment letter)	Section 101(4) of FDAMA. FD&C Act Sec. 505 (b)	90 percent	100 percent	0
Review Standard NDAs within 12 months (CDER) (PDUFA II commitment letter)	Section 101(4) of FDAMA. FD&C Act Sec. 505 (b)	90 percent	99 percent	0
Review Priority NDAs/PLAs/BLAs within 6 months (CBER) (PDUFA II commitment letter)	Section 101(4) of FDAMA. FD&C Act Sec. 505 (b) for NDAs. None for PLAs/BLAs.	90 percent	100 percent	0
Review Standard NDAs/PLAs/BLAs within 12 months (CBER) (PDUFA II commitment letter)	Section 101(4) of FDAMA. FD&C Act Sec. 505 (b) for NDAs. None for PLAs/BLAs.	90 percent	100 percent	0
Review priority efficacy supplements within 6 months (CDER & CBER) (PDUFA II commitment letter)	Section 101(4) of FDAMA. FD&C Act Sec. 505 for NDAs. None for PLAs/BLAs.	90 percent	100 percent	0
NON-PDUFA:
Review ANDAs within 180 days (CDER)	FD&C Act Sec. 505(j)	60 percent	54 percent	142
Review and act on blood and source plasma PLAs/BLAs within 12 months (Internal time frame) (CBER)	No statutory requirement.	70 percent	83 percent	4
Review PMAs within 180 days (CDRH)	FD&C Act Sec. 515(d)(1)(A)	50 percent	65 percent	0
Review 510(k)s within 90 days of receipt	FD&C Act Sec. 510(k) and (n)	90 percent	98 percent	0
Review food and color additive petitions within 360 days. (CFSAN) Goals are based on 360 days. FY 1997 baseline based on 180 days (statutory requirement).**	FD&C Act Sec. 409 and Sec. 721	30 percent	24 percent (within 180 days)**	52
Review NADAs and ANADAs within 180 days (CVM)	FD&C Act Sec. 512(c)(1)	None	75 percent	6

* The number of applications overdue at the end of FY 1998.

** For petitions received in FY 1996, using the previous petition review procedure, 24 percent of petitions received "first action" within 180 days. CFSAN re-engineered the petition review process in FY 1998 and redefined "first action." FY 1997 figures and FY 1999 and FY 2000 estimates are not directly comparable.

FY 2000 Performance Goals are not identified in this Plan. Specification of these goals is dependent upon final determination of the President's FY 2000 Budget submission to Congress.

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