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Testimony on Improving Reviews and Approvals by Michael A. Friedman, M.D.
Food and Drug Administration
Public Health Service
U.S. Department of Health and Human Services

Before the Senate Committee on Labor and Human Resources
March 19, 1997


The Food and Drug Administration's (FDA or the Agency) primary mission for 90 years has been to promote and protect the public health. That remains our core mission. FDA's responsibilities involve more than $1 trillion worth of products, many of which are vital for human health and sustenance. our diverse activities include, but are not limited to, reviewing, approving and monitoring- the manufacture and use of prescription drugs, generic drugs, animal drugs, vaccines, biologicals, medical devices, food additives and color additives; licensing blood banks; monitoring clinical investigations; inspecting food manufacturers; monitoring imported products; accrediting mammography facilities; and assuring the safety of cosmetics.

I know you share our view that all Americans expect and deserve the assurance that the medicines they take or the medical devices they use are safe and really work, and that the foods they eat are safe, wholesome, and properly labeled. The assurance that FDA is vigilant and active, every day, is so fundamental to what we expect in public health protection that it is almost taken for granted. Because of the protections in the food and drug laws, and the Agency's implementation of those laws, Americans do not have to worry about the safety or effectiveness of literally thousands of products they use every day, from breakfast cereal to pain relievers, from contact lenses to vaccines.

For more than nine decades, we have been protecting consumers against an ever-growing number of public health risks. At the same time, we have been providing the framework through which consumers have the opportunity to benefit from new, and often better, products. In doing so, we face many challenges: keeping pace with unprecedented medical and scientific breakthroughs; an ever expanding workload; evolving expectations regarding consumer access to meaningful health information; and the globalization of manufacturing, trade and consumption. An important measure of our value as an Agency, and of our success at fulfilling our mission to promote and protect the public health, has been our ability to keep pace with these changes. It is a measure by which, I believe, we have done very well.

At the same time, we have become keenly aware of how important it is to be open to change, and of the need for critical examination of how we do our jobs. We recognize that the industries we regulate have important contributions to make to public health and operate in a dynamic and demanding marketplace. We heard from consumers that timeliness had to be considered as well as thoroughness. We heard from the members of this Committee and others in Congress that there were problems in how we do our job, and we very much appreciate the leadership of this Committee on these issues. Our internal assessments revealed the need for changes, and the Administration's reinventing government mandate demanded attention to addressing outdated and unduly burdensome regulatory practices. We want you to know that we heard the messages, and we set about to address the problems. There is much work still to be done. Please know that the Agency, the Department of Health and Human Services and the Administration are committed to working with Congress on bipartisan legislation that will help us do our job of promoting and protecting public health as well as we can.

The responsibilities with which we are charged, the scientific and public health challenges that confront us, and our shared expectations of how we do our job result in demands that have exceeded and will continue to exceed Agency staffing and resources. It is incumbent upon us, therefore, to maximize the public health return that we obtain from every dollar. This is a principal theme that guides our efforts at the Agency. For the public to be well served, neither the Agency nor the industries we regulate can afford to waste a single dollar on regulations that are unnecessarily burdensome or serve no useful purpose; outmoded approaches to regulatory compliance that place form over substance; or rationales that enshrine 'how we have always done it" over innovations that show how we can perform better.

I want to thank the Committee for the opportunity to present an update on the substantial progress FDA has made over the past several years in improving its performance; and to share with you some of the problems we are working on and some others we need your help to address. If we are to focus our energies, as we must, on continuing to improve our efficiency and effectiveness, it is imperative that we understand what currently is working well, and what problems must be addressed.

We believe that what we are presenting to you today represents genuine and fundamental change, improvements that have been made possible through the concerted cooperative efforts of many: the Congress, consumers and patients, health care professionals, industry and the Agency. We are particularly proud of the progress we have made in the area of product approvals, the area that has been targeted by the Agency's critics. The Agency has focused on approval times, and as I will describe today, we have seen real results. We know much remains to be done. Just as we are continuing to work with industry and consumer groups to identify and solve problems administratively, we look forward to working with you and your colleagues in the Senate and House on bipartisan legislation that will help us better promote and protect the public health.

Much of the progress FDA has made over the past few years has been instigated by our Center Directors. Increasingly, they have been successfully providing strong, consistent management and insisting on accountability for performance based on outcome. They are instituting management reforms ranging from team review to more effective use of outside experts and are introducing elements of sound risk management by allocating scarce resources to programs having the greatest public health benefit. Their efforts have been supplemented by the vigorous pursuit and implementation of more than thirty FDA reinvention initiatives as part of President Clinton's and Vice President Gore's National Performance Review. These efforts are helping us to speed new cancer drugs to patients, to target our limited resources to higher risk medical devices, and to regulate emerging therapies derived from human tissue utilizing a coherent framework that matches the level of regulation with the potential risks to patients. These reengineering efforts do not compromise our high standards for safety and effectiveness on which the American public relies. Through these efforts, we have learned important lessons about the kind of changes that will result in getting safe and effective drugs and devices to patients more quickly.

I will describe some of the things we have done, and the impact these efforts have had on our ability to function more efficiently and effectively. I will focus on three - areas: product review times; regulatory streamlining; and management reforms. I will then address the key problem areas the Agency is now addressing and the challenges we see in the future.


No area of FDA's responsibility has been more closely scrutinized by Congress, industry, health professionals and the public than the approval process for new drugs, or more specifically, the speed with which new therapies of proven effectiveness and safety are made available to those who need them. For years there has been public discussion of the so-called "drug lag," the concern that new therapies were consistently being approved in Europe more quickly than in the United States. Today we are approving drugs in time periods that are as fast or faster than any country in the world with a comparable system of patient protection. And we are doing it while maintaining the standards for safety and efficacy that make FDA approval the gold standard for the world.

Let me, therefore, begin by citing our most important results last year under the Prescription Drug User Fee Act of 1992 (PDUFA). As you know, PDUFA provides additional resources linked to our commitment to meeting demanding review goals without sacrificing high public health standards. This important five-year authorization will expire in October.

Consistent with the recommendations of the Vice President's 1993 National Performance Review report, the FY 98 budget proposes $236,813,000 in reauthorized and new user fees to finance FDA activities, approximately $91,000,000 of which represent PDUFA reauthorization. Combined with the $7,459,000 in fees already authorized for export certification and the certification of . insulin and color additives, this bring the FY 1998 User fee level to $244,272,000. Specifically, the budget proposes to reauthorize PDUFA and MQSA and to collect new fees in each-of the major programs. These fees will be dedicated to FDA program activities and will be implemented in conjunction with performance measures and goals.

After more than four years' experience with the program there is no doubt in my mind that the PDUFA approach works. Under PDUFA we are making decisions on breakthrough drugs in six months or less, and on all other drugs in 12 months or less. The Agency consistently has met its annual performance goals. In fact, we have exceeded them in almost every goal category. When combined with our internal management initiatives, the additional resources provided by PDUFA bring important products to patients more quickly, and without sacrificing quality.

Last year's record of drug approvals by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) illustrates why reauthorization of PDUFA is a top priority for FDA.

All drugs approved by FDA are important, but none are as meaningful in bringing hope to patients as new molecular entities (NMEs). These are products that include active ingredients never before marketed in this country. The number of NMEs approved each year is regarded as a real indication of meaningful medical progress. Last year, that progress was exceptional: FDA approved 53 NMES, nearly twice as many as the year before.

Let me put last year's figures into perspective by referring back to the passage of the Kefauver-Harris amendments in 1962. The average annual total of NMEs in that decade was 13.7. In the 1970s, the corresponding figure went up to 17.3. In the 1980s, the average was 21.7 NMES, and in the first half of this decade, the average was 25.6 NMEs. That is less than one-half of the 53 NME approvals last year.

Also, last year's approval times were much faster than in the . past. In the late 1980s, median times to NME approval approached 30 months. The median time to approval for the 53 drugs approved in calendar year 1996 was 14.3 months, less than half the time it took as recently as the late 1980s. [Chart 1]

The NMEs approved by FDA in 1996 were not limited to one area--they covered a spectrum from cancer, to asthma, to Alzheimer's Disease, to multiple sclerosis. New cancer drugs approved last year were notable for their effectiveness against a broad spectrum of cancers: Hycamtin is used for the treatment of patients with metastatic carcinoma of the ovary; Camptosar for those with colorectal cancer; Taxotere for women with advanced breast cancer; Gemzar for patients with cancer of the pancreas; and Nilutamide for men with cancer of the prostate. The NME category included also Accolate, the first of a new class of drugs for asthma; Aricept, the second treatment for Alzheimer's disease; and Copaxone, a treatment of relapsing-remitting multiple sclerosis.

Several of the NMEs approved last year, including two drugs for cancer and three for HIV, were approved in six months or less. Crixivan, a protease inhibitor for the treatment of HIV, was approved in just 1.4 months. Twelve of the NMES, including three protease inhibitors, were developed--from the first commercial Investigational New Drug submission to marketing approval--in less than six years. The Agency and industry should look to the development of these products as models for future drug development.

The Center for Biologics Evaluation and Research (CBER) also had a productive year. Last year it completed 17 major biological approvals, as compared with 12 such approvals the year before. Last year's major biological approvals included RespiGam, the first medication to protect infants against respiratory syncytial virus, a potentially fatal disease; Avonex, the second interferon product for multiple sclerosis; and Verluma, a new diagnostic imaging agent that can determine the extent of small cell cancer in different parts of the body at one time. The median approval time for the 17 biological products was 14.9 months, 15 percent faster than in 1995.

The public health also has been well served by the approval of the acellular pertussis vaccine, which is safer than the traditional whole-cell pertussis vaccine. Another notable approval issued last month was for a new recombinant Factor IX for treating people with Factor IX deficiencies. This product does not make any use of plasma derived proteins, and therefore presents no risk of transmitting viral infection.

Moreover, the total number of new drugs and biological products--including NMEs -- approved in the last calendar year was 139, which is 63 percent more than the total the year before. [Charts 2-3] New Drug Applications (NDAs) accounted for 131 of these products, and their median time to approval was 15.4 months, 7 percent faster than the 16.5 months the year before.

All of this suggests that American patients are getting the medications they need faster and more efficiently. Indeed, the most recent international data confirm this. At the end of last year we looked at the new centralized drug approval process of the European Union (EU)--the system that is said by some to be better than ours. We looked at the 15 new drugs that had been approved both by the FDA and the EU centralized procedure. The U.S. approved them faster than the EU. The median time for FDA review and marketing approval in the U.S., for those 15 common drugs, is 5.8 months. The median time for review by the Committee for Proprietary Medicinal Products and final EU authorization for a company to sell those 15 common drugs in Europe is 12.2 months. Sometimes drugs are not submitted at the same time, and it is possible that the U.S. could be faster and American patients still be waiting. But that is not the case for these 15 drugs. In 11 instances, the drugs were first approved in the U.S. In one instance, EU authorization came three days ahead-of the FDA approval, and in three instances, the EU authorization came first.

Of particular note, according to the January 1997 issue of Scrip Magazine, more pharmaceutical companies chose the U.S. in 1996 for the introduction of their NMEs into market than any other country. There were 16 introduced in the U.S. (as compared to eight in Japan, seven in UK, six in Germany and three in Denmark).

Not all of our improvements, however, have been due to resources added by PDUFA. Under the PDUFA framework, the Agency was assured of adequate resources to do the job and - the job was defined clearly through performance goals. How to achieve those goals was left to Agency management, and accountability to Congress was assured through the five year reauthorization process. The commitment of Agency management to streamline and improve the way we regulate has extended well beyond the drug review process.


As a-striking example, the Center for Devices and Radiological Health (CDRH) improved its Premarket Approval Application (PMA) review times, while maintaining the review times for the 510(k) abbreviated applications. PMAs, which are full safety and efficacy submissions, are required for novel or high risk devices; whereas 510(k)s, which represent 98 percent of all device submissions, are abbreviated submissions covering devices that are substantially equivalent to devices already on the market. In fiscal year 1996, CDRH approved 43 PMAS, a six year high, and of these 24 were major new products, an all-time high. [Chart 4]

One of the notable PMA products approved in 1996 was the Thoratec Ventricular Assist Device System that serves as a bridge to cardiac transplantation. The Center also approved many first-of-a-kind products such as the Ultramark 9 High Definition Ultrasound System, an aid in differentiating benign from malignant breast lesions; the Seprafilm Bioresorbable Membrane, used for reduction of post-surgical adhesion; and the Reliance Urinary Control Insert, a device intended for the management of stress urinary incontinence in adult women.[Chart 5]

Eight of the 15 PMAs submitted to the Agency in the first half of fiscal year 1996, received a first action within the 180 day deadline. This performance was significantly better than in 1994 or 1995.

We not only are approving more PMAs for increasingly complex devices: we have improved performance on the time to first action, and the PMA approval time in FY 1997 is coming down by 25 to 30 percent from any of the last three years. CDRH and the Agency are focusing now on further bringing down the PMA review times, just as we have done for NDAS. But this depends not only on the management improvements we initiate, but also on the level of resources available to do the work and on the adequacy of the applications submitted.

CDRH has made notable progress over the last three years in bringing down review times for 510(k) applications. In fiscal year 1996, the median review time for devices that received a finding of substantial equivalence was 85 days. The reviews were nearly twice as speedy as the 1993 peak of 144 days. The average 510(k) review time in fiscal year 1996 was 110 days, down from the peak of 184 days in fiscal year 1994. Overall, CDRH has shortened review times significantly, without sacrificing the increased scientific and medical rigor of the reviews. While we are not totally satisfied with our performance, we are steadily moving in the right direction. [Chart 6]

Among the important device approvals completed by CBER last year were two new test kits for the detection of HIV infection. One of these kits is designed for screening donated blood for HIV-1 antigen, a substance that in most cases is detected before the virus antibodies. By reducing the so-called "window" period, when donors may be HIV infected but their tests are- still negative for HIV antibodies, the antigen screening could prevent an estimated 5-10 transfusions of HIV-infected blood a year.

The other HIV test kit approved last year was the first system that includes collection of blood samples at home. It was developed to facilitate blood testing of persons who are at risk of HIV, but do not visit a medical facility to have their health status checked. In addition, FDA also approved the Amplicore HIV-1 monitor test, the first test approved for the quantification of the HIV-1 virus in human blood.


The Center for Food Safety and Applied Nutrition (CFSAN) has' implemented several initiatives to speed up the food additive petition review process and reduce the inventory of pending petitions. For example, the Center has reassigned scientists from other program areas; allocated additional resources to modernize its electronic information processing infrastructure, and to contract for the services of "third party" technical reviewers; and used various means--from one-on-one meetings to the World Wide Web--to provide guidance to petitioners on how to improve the quality of their submissions to the Agency.

The effort has paid off in reduced petition inventory and faster reviews. In June, 1995, there were 295 petitions in the CFSAN inventory, including food and color additive petitions, GRAS affirmation petitions, and citizen petitions. By the end of last calendar year, the Center had received an additional 82 petitions, but the inventory was 60 petitions be-low the total in June 1995. During calendar year 1996, CFSAN took final action on 88 petitions, 54 of which were approvals--the highest number in any year in a decade. (Chart 7] Moreover, the median time from receipt to approval of food and color additive petitions decreased from 37 months for petitions approved in fiscal year 1993 to 27 months for petitions approved in the last fiscal year. Again, we have not yet achieved the results we want, but we are continuing to advance toward them.

In 1996, the Center for Veterinary Medicine (CVM) approved more animal drug applications (78) than in any preceding year with a record number of - ',,significant" approvals (13). "Significant" approvals are for a new chemical entity, new species, or new dosage form combination products. This is particularly impressive given the increasing complexity of the applications being submitted to the Center.

In order to accomplish these improvements, CVM examined, whether, and if so how, its own organizational structure, culture, and ability to communicate with its stakeholders may have contributed to the dearth of approved animal drug products. This "self" analysis has led to substantial shifts in the internal mind set of the Center and a desire to build a more flexible product approval process.

CVM's recent regulatory initiative to reengineer and streamline the animal drug application review and approval process is a good example of how far we have come. By meeting with sponsors prior to the submission of Investigational New Animal Drug Applications and encouraging phased and direct reviews of an application's technical sections, CVM provides sponsors with important guidance while their products are still in the development stage. This should reduce the time it takes to review and approve new animal drugs, as well as decrease the time and resources drug sponsors spend on developing animal drugs. Full implementation of these changes was made possible through enactment of the Animal Drug Availability Act of 1996 (ADAA). The phased and direct review process now being implemented by CVM has received strong positive endorsements from animal drug sponsors. .

Passage of the ADAA was the culmination of over two years of highly effective interactions between CVM, Congress, and a variety of animal health industry stakeholders. It reflects the commitment CVM has made to build more productive relationships with those stakeholders, wherever possible, to advance the common goal of moving more safe and effective animal drug products onto the market.

The collaborative working relationship that has resulted in reshaping the new animal drug approval process is a model, we believe, of the type of constructive interaction that must occur between FDA and all of its stakeholders if we are to respond successfully to the public health issues we will face in the next century. There was agreement between all of the parties involved on the problems that needed to be corrected. That agreement, in turn, enabled them to design and implement appropriate changes. Where those changes could not be accomplished through administrative action by the Agency, the parties worked with members of Congress to craft appropriate legislative changes.


As I stated above, the Agency has pursued and implemented over thirty reinvention initiatives under President Clinton's and Vice President Gore's National Performance Review. These reinvention initiatives, along with the significant number of streamlining efforts undertaken by the Agency on its own, are indisputable evidence that, the Agency has a deep commitment to improving our regulatory processes. I would like to describe several of the more significant initiatives, and have attached to my testimony an appendix that sets forth summaries of our efforts and accomplishments.

1. Regulation of Therapies Derived From Human Cells and Tissue

Perhaps no area of the Agency responsibility has been more significantly affected by our reinvention initiatives than the regulation of biologicals. Just a-few weeks ago, we announced a new regulatory framework for therapies derived from human cells and tissues. This framework was developed based on scientific considerations after extensive discussions with industry, academics and professional groups. It provides a tiered approach with the level of regulation proportionate to the degree of risk. Little or no regulation would be imposed on some products, with the degree of oversight increasing with the potential risk, so that extensively processed and novel products would require FDA's approval before they could be marketed. All tissue processing facilities would be required to register with the FDA and to list their products, and all labeling and promotion of these products would have to be clear, accurate, balanced, and non-misleading.

In designing this new approach, FDA focused on five broad public health and regulatory questions:

  • How can the spread of communicable diseases be prevented?

  • What processing controls are needed to prevent contamination and preserve the integrity of cells and tissues? -

  • How can clinical safety and effectiveness be assured?

  • What labeling is necessary, and what kind of promotion is permissible, so that the product may be used properly?

  • How can FDA best monitor and communicate effectively with the cell and tissue industry?

The proposed framework was developed after discussion with a variety of stakeholders, industry scientists and managers, trade associations, and patients groups, focused on defining the problems such regulations needed to address. This proposal has been well received, and we expect will be improved through the further input we expect to receive during the comment period.

2. Other Batik Reforms

In our first biologics reinvention initiative announced in 1995, we eliminated the establishment license applications and individual lot release requirements for well characterized therapeutic batik drugs. According to the biotechnology industry, these changes alone will save their companies millions of dollars, reduce required paperwork by thousands of pages, and cut drug development time by months. We also have clarified an important issue with respect to construction of batik manufacturing plants. In the past, some companies have built full-scale plants,. at a cost of millions of dollars, only to have approval of a product denied. We are now very clear that batik companies have the flexibility to use a pilot facility.

3. Supplemental Applications and the New Use Initiative

Just as the tissue initiative focuses on regulating proportionate to risk, the Agency's New Use Initiative, announced last week, focuses on helping new drug sponsors establish proof that their products are effective without excessive or redundant studies. The issue of what constitutes sufficient evidence of effectiveness has been debated for years by the Agency, the scientific community, industry and others. Sound evidence of effectiveness is a crucial component of the Agency's risk-benefit assessment for a new product or new use of an already approved product. The need to adequately describe benefits and side effects represents a major component of drug development time and cost. We understand, as well, that drug sponsors may be reluctant to pursue applications for new uses because of concerns that such efforts are too burdensome and costly. We all recognize that the conduct of studies in excess of those necessary to demonstrate effectiveness and toxicities is undesirable and wasteful.

The methodologies underlying drug development and clinical evaluation has evolved significantly. To ensure that drug development programs can be targeted specifically to what is necessary to properly establish effectiveness and safety, and to illustrate how the submission of applications for new uses, in particular, need not be unduly burdensome, the Agency released for comment the "Draft Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products" (the Evidence document). This document, the key element of the Agency's "New Use Initiative," articulates the Agency's view concerning the quantitative and qualitative standards for demonstrating effectiveness of drugs and biologics. In addition to helping sponsors target drug development efforts, this articulation of policy will assure greater consistency and predictability to FDA's assessment of clinical trial data submitted in support of drug effectiveness.

At the same time the Agency released the Evidence document, it also released a second draft guidance document for public comment, "Guidance for Industry: FDA Approval of New Cancer Treatment Uses for Marketed Drug and Biological Products," illustrating the applicability of the principles set forth in the Evidence document specifically to new uses for drug products to treat cancers. [A significant percentage of drugs used to treat cancer patients are used "off-label."] That is, they are used for purposes for which they have not been approved. The high incidence of off label use of anticancer and other types of drugs is problematic. We know that some off-label uses are not sufficiently safe and effective. On the other hand, when such uses are properly studied and described, this information should be made available widely to the health care community and the public. The best result for health care practitioners and patients would be for these uses to be in the approved labeling. In other words, FDA should review the data to determine the benefits and toxicities. This best case scenario will occur, however, only if the Agency has an effective supplemental application process and only if industry submits these applications. The requirements for what constitutes appropriate evidence of effectiveness must be clear and reasonable, and the applications must be reviewed expeditiously. We believe that this guidance will help to make the supplemental application process a more useful and effective tool for getting additional uses in the labeling of drugs and biologics.

This initiative on - new cancer treatment uses follows on four FDA Initiatives announced last spring to improve patient access to promising new cancer therapies. This is being accomplished by:

  • Shortening approval times for cancer treatments by recognizing that tumor shrinkage is often an early indicator of a treatment's effectiveness. Previously, FDA required definitive evidence of improvements in survival time or quality of life before a drug's approval. Basing approval on evidence of tumor shrinkage--which can be more easily and quickly demonstrated--can speed up access to promising new therapies;

  • Encouraging pharmaceutical companies to submit expanded access protocols in the United States for cancer therapies that have been approved by recognized foreign regulatory authorities--thus helping to make promising cancer therapies approved by foreign countries available to cancer patients even before the products are approved in the United States;

  • Improving the therapy review process by ensuring that all FDA cancer-therapy advisory committee meetings include an ad hoc member who has personal experience with the illness for which a new product is being considered; and

  • Making it easier for investigators to test new uses for cancer therapies already on the market by reducing the number if IND applications filed for additional studies of already approved therapies.
4. Protecting the Food Supply: Hazard Analysis Critical Control Point System

Another area of science based reform is in the regulation of foods. Our challenge in the foods area is to develop a comprehensive approach for assuring food safety that is built on reducing problems in the food supply. our food safety system must be based on a broad view, from farm or fishery to the dinner table; from the foreign processing plant to the local retail establishment.

Our current system of food safety regulation is often reactive. What we need is a system that more satisfactorily focuses on preventing problems in the food supply. This is a shared responsibility of industry and FDA, and we have taken the first step toward developing the tools appropriate to the task we face in this new paradigm. FDA, working with the food industry, is creating a comprehensive scheme to build safety controls into the food production system with the Hazard Analysis Critical Control Points (HACCP) system of regulation. This system is now being applied to seafood and may be applied to other food commodities in the future. This system replaces the old system that places too much emphasis on detecting and correcting problems after they occur with a system that places more emphasis on of preventing them in the first place.

HACCP, as you know, is a science-based, state-of-the-art process for building safety into the production, handling, and storage of food. It is a safety assurance process that emphasizes prevention and that places major' responsibility for food safety with the industry that produces and manufactures food. HACCP's principles focus on identifying safety hazards and establishing controls to prevent those hazards at critical control points. Those control points are monitored during operations to provide processors immediate information on whether their operations are under control. Under FDA's seafood HACCP regulation, the results of this monitoring are documented in records to which FDA inspectors have access. HACCP will enable the seafood industry to continually self-monitor product safety to prevent problems, and will enable FDA to survey manufacturers' compliance over time (as opposed to the "snapshot" view of a manufacturer's compliance that FDA inspectors had before HACCP) and carry out more targeted and focused--and therefore more efficient--inspections. These HACCP concepts, which are entirely in concert with the Vice President's program to reinvent federal government operations to make them work better and cost less, have been well supported by the seafood industry. Implementation of HACCP and its possible extension to the rest of the food supply will be a major priority over the next decade.


The foundation on which, in my view, all of the Agency's efforts to improve performance stand is effective management of all our processes. Effective management is the vehicle that turns the written formulation or promise of reform into tangible outcomes that have measurable impacts on promoting and protecting public health. Process management is the tool through which our commitment to do better translates into improved performance. Some of the management improvements we have undertaken have contributed to the improved product approval times referenced in the first section of this testimony. Our efforts in this regard, however, have not been limited to the product approval programs. Effective management reforms have been a particularly important focus in all parts of the Agency. I would like to describe several of these initiatives.

1. Team Reviews/Project Management

In late 1993, both CDER and CBER established team-based project management programs designed to improve the efficiency of the drug review process. Since that time, these programs have demonstrated their effectiveness and continue to be refined and enhanced.

Team-Based Project Management is a powerful management technique combining the use of multidisciplinary teams led by project managers and scientific leaders who utilize the tools and techniques of project and resource tracking. Review disciplines are organized into multidisciplinary teams early in the review process (within 45 days of the receipts of an NDA) 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 (PDUFA performance goals), and make resource adjustments. Consequently, a proactive management approach is employed in achieving the Centers' review performance goals.

Both Centers will be expanding use of these programs to encompass the Agency's activities in other areas such as the preinvestigational, investigational and post marketing phases of the product development process. Our intent is to ensure that sponsors have a better understanding of the Agency's expectations for the review process at each stage of drug development.

Another example of process improvement resulting from, and contributing to, the culture of continuous quality improvement is the formulation of Good Review Practices (GRPs). CDER and CBER are implementing the GRP initiative because the organizations recognize the importance of training their reviewers. This initiative is designed to enhance the clinical review practices of CDER and CBER reviewers by standardizing review procedures and providing a mechanism for ongoing feedback. The result will be guidelines, analogous to the good manufacturing practices (GMPs) prescribed for industry, that reflect the most current trends in drug and biologic review. Implementation of the GRPs will improve the consistency, efficiency and quality of reviews as well as promoted the science of regulatory review that is responsive to evolving medical technologies.

2. Medical Device Initiative Pilot--Device Facility Inspections

FDA's Office of Regulatory Affairs is responsible for management of the Agency's field operations. Through plant inspections and other field activities, the investigators, compliance officers, laboratory personnel and field office directors are the eyes and ears of the Agency. With approximately 1099 investigators responsible for thousands of drug, device and food establishments, it is imperative that their efforts be highly effective, results oriented and targeted to serious public health concerns. To assist in this effort, the ser field organization has held a series of grassroots meetings across the country on a variety of topics.

Based on the feedback obtained through one such grassroots meeting with the medical device community, the Agency and regulated industry developed a facility inspection pilot project designed to enhance communication and facilitate compliance. The' pilot was in response to concerns that a more open, cooperative approach to regulatory compliance that would still preserve the Agency's regulatory independence but would better serve to enhance public health protection. The pilot program was conducted during the 1996 calendar year.

This nationwide pilot program consisted of three components: 1) pre-announced inspections, 2) annotation of inspections reports to identify promised or completed corrective actions, and 3) post-inspection correspondence to let the device establishment know its compliance status. Preliminary evaluation of this pilot indicates that the medical device industry felt it was highly effective. These procedures enabled companies to-better prepare for inspections; gave the Agency and companies a record of the inspection that reflected immediate company actions to correct, or the agreement to make corrections; and provided companies documentation of "'clean" inspections, when no problems were identified.

3. Guidance Documents

One of the themes that runs throughout the Agency's efforts to improve its performance is the importance of involving all stakeholders both in defining the problems that exist and in developing appropriate solutions. This model of public participation, reflected in so many of the initiatives I have been discussing, is most clearly delineated in the procedures the Agency has promulgated for the issuance and use of Agency guidance documents. Concerns about the absence of public input on guidance documents and the inappropriate application of such guidance were raised in a Citizen's Petition filed by the Indiana Device Manufacturers Council and were the subject of a hearing chaired by Congressmen Shays and McIntosh. In response to these concerns, the Agency undertook a thorough review, across all Agency components, of guidance document procedures. We found inconsistencies and lack of clarity, and we set about to fix it. The result is a new set of procedures, "Good Guidance Practices," that now will be uniformly applied by every Agency component.

The purpose of Good Guidance Practices is to ensure that (1) Agency guidance documents are developed with adequate public participation, (2) guidance documents are readily available to--- the public, and (3) guidance documents are not applied as binding requirements. To ensure adequate public participation, the Agency is taking a number of steps. First, the public will have an opportunity to comment on all guidance documents. For those guidance documents that are most important to the regulated industry (because they are directed to the industry and set forth first interpretations, more significant changes in interpretation or policy, or unusually complex scientific or highly controversial issues), public input will be sought prior to implementation, except in limited circumstances. For all other documents, the opportunity for public comment generally will be provided following issuance of the document. Second, for the most controversial/significant documents, the Agency also may hold public meetings or take a draft of the guidance to an advisory committee. Finally, the Agency will keep the public apprised of its plans for future guidance, and will provide the public an opportunity to suggest new or revised guidance and to suggest drafts of guidance documents for adoption by the Agency.

To ensure the availability of guidance documents, the Agency will use its home page on the World Wide Web as well as the Federal Register. The Agency is taking steps to ensure that the public has access to a comprehensive list of all current guidance documents and clear directions on how to obtain copies of those documents.

To ensure that guidance documents are not being applied as binding requirements and that the Good Guidance Practices are being followed in all respects, the Agency will take steps to educate its staff and to monitor the development and use of guidance documents. For those instances when the Good Guidance Practices are not followed or they fail to achieve the๑r purpose., .@the Good Guidance Practices describe the available appeals mechanisms.

4. Medical Device Review Pilot

For some time, there has been considerable discussion about the European system of device review, whereby third-party, nongovernment bodies review device applications. There are legitimate, serious questions as to whether-such a system would implementation, except in limited circumstances. For all other documents, the opportunity for public comment generally will be provided following issuance of the document. Second, for the most controversial/significant documents, the Agency also may hold public meetings or take a draft of the guidance to an advisory committee. Finally, the Agency will keep the public apprised of its plans for future guidance, and will provide the public an opportunity to suggest new or revised guidance and to suggest drafts of guidance documents for adoption by the Agency.

To ensure the availability of guidance documents, the Agency will use its home page on the World Wide Web as well as the Federal Register. The Agency is taking steps to ensure that the public has access to a comprehensive list of all current guidance documents and clear directions on how to obtain copo submit 510(k)s for the devices included in the pilot program may contract with an FDA-recognized third-party review organization and submit a 510(k) directly to the third party, instead of FDA. Persons who do not wish to participate in the pilot may continue to submit 510(k)s directly to FDA; in either case, final marketing decisions are made by FDA.

FDA approved seven organizations as eligible to perform third party reviews. The Agency published a list of 251 types of devices included in the pilot program. To date, FDA has received only five applications reviewed by third parties under this program. The Center is working hard to increase industry's awareness of the pilot and to expand the number of categories of products eligible for third party review by writing guidances to reviewers on an accelerated schedule. FDA continues to monitor the program, and has invited comments from device manufacturers and other interested persons on this issue, and we look forward to working with the Committee on this issue.

5. OASIS - Operation and Administrative Support System for Import Support

One of the most demanding tasks of our Office of Regulatory Affairs, whose inspectors and investigators operate in offices throughout the United States and Puerto Rico,- is surveillance of the rapidly mounting imports of FDA-regulated products. While the number of our port-of-entry personnel has increased only modestly, the number of shipments with products within FDA purview has increased from 500,000 in 1970 to nearly 3.7 million last year. FDA is responsible for ensuring that these imports meet the same safety, effectiveness and quality standards as products produced domestically.

Obviously, this is an enormous task. We cannot examine every item, yet we need a way to assure the safety of each product imported. We need to know what is coming into the country, but the process to provide clearance for imports had become laden with time-consuming paperwork. To make this process more efficient, we undertook to develop a phased information systems initiative to support automation of the import clearance process. Phase I, the Electronic Entry Processing System (EEPS), was implemented nationwide in 1994 in conjunction with the U.S. Customs Service. EEPS provided FDA the electronic tools to communicate messages to brokers on the preliminary admissibility of their shipments. Last year, ORA began implementing Phase II, called Operational and Administrative System for Import Support (OASIS). This system uses a set of decision criteria based on the Agency's past experience with import risks and surveillance sampling techniques to determine whether a shipment is admissible, or whether FDA needs to look at it more closely. OASIS will greatly speed FDA's handling and clearance of imported products by maintaining electronic communications between the Agency and the brokers. With OASIS, the broker receives FDA's initial admissibility determination on every shipment within eight minutes after the broker submits the necessary data to the Agency. For eight out of ten shipments, the initial FDA clearance is final. The paperless system, whose implementation will be completed by the end of September, will cover every U.S. port of entry where FDA-regulated products arrive by sea, land and air.

6. FDA and the Global Marketplace: International Harmonization

The regulatory framework administered by the Food and Drug Administration (FDA) to provide public health and safety protection to American consumers is a model that many countries strive to emulate. At the same time, FDA recognizes that we operate in an increasingly more global, more interdependent market environment, and that American consumers can realize significant public health and economic benefits from efforts by FDA to share information, explore opportunities to collaborate on assessments and product reviews, and harmonize standards with its foreign counterparts. Growing demands on FDA's resources to assure the safety and efficacy of greater numbers of increasingly more complex products produced both here and abroad, absolutely mandate that FDA seek ways in which it can share its regulatory workload while maintaining public health protection for American consumers. Science driven harmonization can curtain duplication and thereby significantly reduce the cost of new drug development, in terms of the risks to which patients are exposed, the experimentation with animals, the regulatory costs to government and the cost to industry.

For many years, FDA has actively engaged in the kinds of information exchange that lay the foundation for the development and maintenance of high international standards, and pave the way for harmonization activities. We have entered into numerous Memoranda of Understanding (MOU) with other governments to ensure that their products intended for export to the United States adhere to our strict standards of health and safety protection. We also participate in limited and focused education and training initiatives that instruct others in how to conduct their activities so that products shipped to the U.S. will be in accord with U.S. requirements. We exert leadership in a number of international standard-setting organizations.

FDA has been a strong supporter of, and participant in, the Codex Alimentarius Commission (Codex). Codex is an international standards-setting organization for food safety composed of national governments from more than 150 countries. The work of Codex is increasingly important with the recognition of Codex as the relevant international standards-setting body for food safety in the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS) resulting from the Uruguay Round of multilateral trade negotiations.

Since its inception, Codex has developed in excess of 200 Commodity Standards, more than 40 codes and guidelines, about 2,500 pesticide/commodity maximum limits, and has reviewed the safety of over 500 food additives and contaminants. FDA, through its participation on most Codex Committees, provides scientific and regulatory expertise and forcefully presents U.S. views at the committee meetings.

FDA plans to amend its regulations and procedures for consideration of standards adopted by Codex. This action is being taken to provide for the systematic review of the Codex Standards in order to enhance consumer protection, promote international harmonization and fulfill obligations of the United States under international agreements.

In recent years, we have put considerable effort into the work of the International Conference on Harmonization (ICH), working closely with our regulatory counterparts in Japan and the European Union, as well as the three areas' organizations representing the major research and development pharmaceutical companies (e.g., the Pharmaceutical Research and Manufacturer's Association (PhRMA)). The goal of ICH is to harmonize across all three regions the requirements for data submitted to support safety, efficacy and quality determinations in new drug applications, and to develop guidelines for the industry based on the harmonized requirements. The past six years of effort have produced over 40 new harmonized guidelines, and another 20 are in various stages of development and review. The ICH effort is one of the best examples of a forward-thinking Agency that is willing to work not only with its regulatory counterparts, but with the regulated industry as well, to develop guidelines harmonized to the highest standards while also eliminating costly duplication of effort. Similar efforts are underway in the areas of medical devices and veterinary drugs.

Additionally, for the past three years we have been involved in negotiations to give limited recognition to inspections of drug and device facilities by European Union authorities and to expand the third party device review to include European Union notified bodies. A successful agreement has the potential to save resources for both sides, however, FDA must be satisfied that such an agreement would not compromise our responsibility for protecting American consumers.

I began this presentation outlining the Agency's accomplishments for two reasons: first, to demonstrate through concrete example that this Agency understands the importance of change. We have tried to be as responsive as possible to concerns expressed by Congress, consumers, and the industry and have undertaken reforms in response to these external criticisms. But change also has been driven by the Agency's own commitment to efficiently and effectively accomplish its mission. Five years ago few believed that we would be approving drugs in twelve months or less. Not only have we reached that goal, but we are now working cooperatively with industry to develop more open,, cooperative and productive inspection procedures, and to restructure the regulation of tissue-based therapies to match regulation to risk. In each of these areas, and many others, we listen to the criticisms, engaged all of-the stakeholders in defining the problem and worked with them on devising solutions that preserved and enhanced critical public health- protections.

The second reason I began with our accomplishments is to illustrate that we in FDA are doing things very differently now than we have in the past. It is now time to focus on what remains to be improved. I will now turn to what we are doing to address such areas and to what we see as the challenges facing the Agency in the coming years.


Building on the lessons we have learned about the importance of-problem solving with strong public participation, we began a dialogue with industry, patient, and consumer groups regarding the issues that have been raised and debated over the past several years in the context of FDA legislation. We have begun the process by asking ourselves and others, what are the problems that need to be solved in order to more efficiently and effectively do our job. By defining problems first, we hope to ensure that proposed solutions will enhance our performance.

We are farthest along in our discussions with the drugs and biologics industries and we believe that together we are making significant progress. Agency staff with technical expertise in the relevant areas have been working with technical experts from the industry to identify the problems and develop proposed solutions. It has been useful to have the technical experts work together because they deal with the relevant issues on a daily basis and they are best equipped to understand the problems and to develop and evaluate proposed solutions. We expect that some of the proposed solutions will be administrative and others will be legislative.

What we have found thus far is that there is strong agreement that the high standards we apply in our work must be maintained, and that our limited resources should be devoted to activities of sufficient public health importance to justify the expenditure of both public and private resources. In other words, there must be tangible public health benefit from what we do and what we require.

In the drugs and biologics areas we have been working with industry groups on a range of issues of concern to the industry. For example, the drugs and biologics industries believe that the Agency requires the submission of unnecessary paper copies with drug applications. The industry believes that this results in the submission of much unnecessary data. The technical working group for this issue has been evaluating whether summaries of certain types of trials can be submitted an d whether any parts of the drug application can be eliminated. Discussions also are focusing on issues relating to when a manufacturer has to get Agency approval of manufacturing changes, dispute resolution, the use of advisory committees for dispute resolution, a mission statement, and the Agency's development and use of guidance documents.

In the coming weeks we also will be considering a number of issues that we believe are important to more efficient and effective performance. For example, in the area of drugs and biologics, we want to discuss extending the Agency's records inspection authority to over-the-counter (OTC) drugs. Under current law, the Agency has records inspection authority over prescription drugs, but not OTC drugs.

Another proposal relates to making more information about drugs under development and review available to patients. This is a concept that has strong support from the consumer and patient groups. We believe that a number of our ideas will have wide industry support. These include the elimination of some very specific prescription drug labeling requirements, elimination of the labeling prohibition on describing products as having FDA ""approval", and creation of a risk-based time-frame for inspections. Under current law, FDA is required to inspect firms every two years. We are proposing to change this so that low risk products or firms would be inspected less often than high risk products or firms.

Mr. Chairman, I believe that our joint efforts with industry, consumer, and patient groups will provide useful information to the members of this Committee. We look forward to working with you and your staff on these very important issues.

In addition to these efforts, the Agency is continuing to develop and implement changes that will improve productivity. In drugs, we are committed to moving to an entirely paperless application process in the next five years. This is an enormous undertaking, but one which is essential if w e are to manage the ever increasing workload we expect in the coming years. In devices, the Center has initiated a top to bottom review of the three primary program areas--premarket review, postmarket reporting and inspections--in order to identify and focus its resources on the high-risk, high-impact product or activities where the Agency's intervention helps consumers and health care practitioners the most.

We recently proposed new labeling of over-the-counter drugs on which Americans depend for the vast majority of their day-today health care needs. This proposed labeling will provide consumers with easier to read and understand information about the products' benefits and risks, and how they should be used. The proposed rule results from several years of Agency work with consumers and industry groups and is our latest effort to give consumers accurate reliable information about the products that affect their health. VI. FUTURE CHALLENGES TO ENSURING PUBLIC HEALTH


Perhaps the most important challenge we face is the staggering pace of scientific and technological innovation that affects almost everything we do. New science and technology result in new types of products, which require us to expand our scientific expertise to comprehend the complexities of these products so that we can make sound judgments about their safety and effectiveness.

Devices such as virtual reality image-guided surgery, digital mammography systems, and totally artificial organ replacements are on the horizon. Our Center for Biologics is continually faced with new product technologies such as somatic cell and gene therapy, xenotransplants, and the genetic tests spawned by the Human Genome Project. The technologies used to produce and administer biological therapeutics and vaccines and to regulate the blood supply are changing rapidly, raising a host of new challenges for the Agency. For example, the potential for direct injection of nucleic acids to induce humoral and cellular immunity against infectious agents is one of the most important MP issues in vaccine research today. FDA is currently considering the safety issues that developers of these DNA vaccines may need to address before these vaccines are tested in humans.

These new technologies offer tremendous opportunities for patients and it is imperative that FDA be prepared to evaluate them and get promising products to patients expeditiously. It is a challenge at which we are working very hard.


FDA oversees the safety of all fresh and processed foods, except meat, poultry and some egg products. FDA regulated products range from ospital stays associated with microbial foodborne illnesses are estimated to cost more than $3 billion a year, and the estimated total costs due to foodborne illnesses are at least $5.6 billion. These costs, both in lives and economic consequences, are unacceptable, particularly in light of the fact that most of these illnesses are preventable. The Administration, through its recently announced its Food Safety Initiative, is placing a very high priority on taking steps to enhance its capacity to prevent food borne illness and to respond more efficiently to illness outbreaks when they do occur.

The funds requested under the President's National Food. Safety Initiative are required to enhance the Agency's ability to carry out a number of functions critical to both preventing foodborne illnesses and to acting quickly to respond and prevent further illnesses when outbreaks occur. These important functions are illustrated by the story of the outbreak last fall of E. coli 0157:H7 in unpasteurized apple juice.

We were first alerted when one of our food scientists spotted on the Internet a reference to a previously unreported E. coli 0157:H7 outbreak in the state of Washington. After a diligent inquiry we found the person associated with the Internet notice -- a University of Washington physician who had uncovered a cluster of patients with Hemolytic Uremic Syndrome, an extremely serious illness caused by E. coli 0157:H7 in which blood cells dissolve and the kidneys suffer seospital stays associated with microbial foodborne illnesses are estimated to cost more than $3 billion a year, and the estimated total costs due to foodborne illnesses are at least $5.6 billion. These costs, both in lives and economic consequences, are unacceptable, particularly in light of the fact that most of these illnesses are preventable. The Administration, through its recently announced its Food Safety Initiative, is placing a very high priority on taking steps to enhance its capacity to prevent food borne illness and to respond more efficiently to illness outbreaks when they do occur.

The funds requested under the President's National Food. Safety Initiative are required to enhance the Agency's ability to carry out a number of functions critical to both preventing foodborne illnesses and to acting quickly to respond and prevent further illnesses when outbreaks occur. These important functions are illustrated by the story of the outbreak last fall of E. coli 0157:H7 in unpasteurized apple juice.

We were first alerted when one of our food scientists spotted on the Internet a reference to a previously unreported E. coli 0157:H7 outbreak in the state of Washington. After a diligent inquiry we found the person associated with the Internet notice -- a University of Washington physician who had uncovered a cluster of patients with Hemolytic Uremic Syndrome, an extremely serious illness caused by E. coli 0157:H7 in which blood cells dissolve and the kidneys suffer severe damage.

The first clue to the cause of the outbreak was provided by state and local officials in Seattle who had interviewed the patients and found that they all had consumed the same brand of apple juice. Samples of the suspected product were brought to FDA's Seattle laboratory, which began testing them for the presence of E. coli 0157:H7.

Commissioner Kessler was notified and he initiated a conference call beginning at 9 o'clock that night. Over the next seven hours, 46 people--experts from FDA, CDC, state and local health authorities, and representatives of the manufacturer-discussed the various aspects of the outbreak. As the conference concluded, at 4 a.m., the manufacturer's decision to recall the already distributed contaminated products was reaffirmed, and a press release was issued warning the public against consuming the juice they had already bought. As a result of this rapid intervention, the outbreak was limited to 66 Americans and Canadians. Tragically, one of them--a little girl in Colorado-died of complications of this food borne disease.

We were able to help contain the outbreak thanks to the fast reaction and cooperation from federal, state, and local public health officials as well as from the juice manufacturer, who instituted an immediate recall of the products, placed their inventory on hold, and warned the public against consuming the juice they had already bought.

But we also were fortunate. Kings County, Washington has a disease surveillance system similar to the CDC's sentinel site system.-- If the same outbreak had taken place in other areas of the country we might not have made the connection until many more people had become ill. A key element of the President's National Food Safety Initiative is the expansion of this important sentinel system.

Second, Federal health officials took charge of the situation rapidly and received prompt cooperation from all the relevant federal, state, local and industry participants in the incident. But this was a fairly unusual experience. For the emergencies that take place under less favorable circumstances, we need to have effective and consistent coordination in place before the outbreak takes place.

Similarly, if we knew more precisely how this deadly form of E. coli 0157:H7 grows and multiplies, how it contaminates the food and how it is transmitted to humans, we-could take steps to lower the risk of it occurring and act more quickly and decisively when events of this sort take place. Another key element of the food safety initiative is directed toward bringing us closer to the knowledge we need to devise educational programs to teach consumers and food retailers how to avoid and combat such contaminants. Increased surveillance and inspections are other components of the proposed integrated approach to reducing the incidence of foodborne illness. As noted above, the Administration's Food Safety Initiative proposes to enhance FDA's and USDA's support of the Centers for Disease Control and Prevention's system of Sentinel sites for identifying disease outbreaks.

As I noted earlier, even though 66 people became sick, and tragically one child died in this apple juice-related outbreak, we were very lucky. The toll of illness aid death-could have---been much higher. It is time to bring food safety into the contemporary world of computerized communication and modern science. Congress and the Clinton Administration already have taken significant steps: The Safe Drinking Water Act of 1996 includes responsible regulatory improvements to-help states and water systems prevent drinking water contamination problems and the Food Quality Protection Act of 1996 includes important provisions that will protect us all, and especially our children, from hazardous pesticide residues in food. Similarly, FDA has taken a major step with issuance of the HACCP regulations discussed above. There is much, however, that remains to be done. We have to address the ongoing problems associated with the need for safe, effective drugs for use in food-producing animals, chemicals used in processing and packaging, appropriate labeling for foods and food ingredients, and the range of environmental contaminants that come into play at various points in the process.

FDA will need to maintain the scientific expertise in the areas of toxicology, microbiology, chemistry, nutrition, molecular biology and food technology that has provided us with the ability to evaluate the safety of new products. FDA is determined to take the approach that results in safe new food products, without needlessly impeding the use of new technologies that can give manufacturers the ability to produce better foods and provide consumers expanded choices.

In all of these new areas of challenge -- rapid changes in science and technology, foods, animal drugs -- our job does not stop with evaluating and approving for marketing new safe and effective products. We must develop even more sophisticated surveillance and compliance mechanisms that target public health risk and help assure that the public continues to be protected once products are marketed and used. -


Before closing, I want to mention one last challenge. It is the challenge to protect our children against the devastating effects of tobacco use. I mention it because the impact of all of our efforts to develop new drugs and prevent the spread of disease will pale in comparison to what we accomplish if we break the cycle of addiction to cigarettes: an addiction that kills more than 400,000 Americans every year--more than acquired immune deficiency syndrome, alcohol, car accidents, murders, suicides, illegal drugs, and fires combined.

For the Past two and half years, the Agency conducted an extensive investigation into the public health aspects of the use of tobacco. We found evidence that nicotine is addictive; that it produces pharmacological effects which are the primary reason why people use tobacco; and that manufacturers know these facts.

The most striking discovery, however, was that the enormous public health burden linked with tobacco products overwhelmingly starts when the users are young; a stage of life that's most carefree and susceptible to risk-taking. Eighty-two percent of adults with any history of smoking had their first cigarette before the age of 18, and more than half of them had already become regular smokers by that age.

Each year, one million youngsters in this country become regular smokers--and one-third of them will die prematurely of lung cancer, emphysema, and similar diseases linked to their addiction. About three million of our adolescents smoke, and another one million boys use smokeless tobacco. Tobacco use and nicotine addiction can be properly called a "pediatric disease."

The Agency issued regulations intended to (1)- reduce the appeal these products have for young people by restricting their advertising and promotion, (2) eliminate under age access to these products by restricting their sale and distribution to children and adolescents.

This year, we--together with our sister public health agencies and state and local authorities--are embarking on an enforcement program designed to reduce young people's use of tobacco products by 50 percent in seven years. It is an enormous undertaking: despite the fact that it is against the law in all 50 states to sell cigarettes and smokeless tobacco to minors, our young people purchase an estimated 1.26 billion dollars' worth of tobacco products each year. And the problem is getting worse. Smoking rates among 8th graders have increased 50 percent since 1991.

As a public health agency we feel a deep obligation to see this program carried out, just as we feel a deep obligation to implement the Mammography Quality Standards Act, the most important advance in the public health protection for the nation's women. Protecting their children--our youth--from nicotine and tobacco is an equally urgent and deserving task whose future benefits will far outweigh the current funding needs.


Two years ago President Clinton explained the guiding philosophy in our examination of how we are performing: ""protect people, not bureaucracy; promote results, not rules; get action, not rhetoric." That is what we have been trying to do. We are working hard to make FDA more efficient and maintain the high quality of work.

The two pillars of FDA's success, and the reasons why we have the confidence of the American public, are our independence and scientific expertise. In the end, it is FDA's independence that gives the American people confidence in the Agency's decisions. They know that when FDA approves a drug, that approval is made independent of commercial-interests. While we recognize that working with industry and consumers to bring the best expertise to bear on problems is important, we must not overlook the importance of making regulatory decisions in an environment of independence.

The second pillar--scientific expertise--is equally important. Some of the leading experts on clinical trials work for FDA. This is one of the reasons why drugs approved in this country are an immediate international success. Our laboratories can and do detect food contaminants ranging from pathogens in food to pesticide residues. That is why the U.S. food supply is respected around the world.

We look forward to working with you to ensure that the Food and Drug Administration meets its expansive and challenging mission in the most efficient and effective manner possible. ***(There are several charts attached to this testimony)

Chart #1
New Molecular Entities (NMEs)

During Calendar Years 1989, 1993, & 1996: Median Approval times were ate 29.3, 23, and 14.3, while the numbers were at 23, 25, and 53.

Chart #2

New Priority Drugs Approved in 1996

  • AID - 6
  • Cancer - 9
  • ALS - 1
  • Alzheimers - 1
  • Spinal cord/ multiple sclerosis - 2
  • Antidepressants - 1
  • Antipsychotics - 1
  • Antifungal - 1
  • Antiparasitic - 1
  • Orphan Metabolic - 2

Chart #3
New Biologics Approved in 1996


  • Blood Diagnostics - 7
  • Cancer Diagnostics - 3
  • Heart Disease - 1
  • Skin Test - 1


  • Hepatitis A - 2
  • Haemophilus b - 2
  • DTaP - 2


  • Cytokines - 4
  • Growth Factors - 2
  • Recombinant Thrombolitic Enzymes - 2
  • Immune Globulin - 1

Chart #4
PMA Approvals Decision Cohort
FY Number of Applications
93 24
94 26
95 27
96 43

Chart #5

Breakthrough Devices -- Approved in FY 1996 & FY 1997

  • Laser system to treat esophageal cancer
  • Less invasive BPH treatment
  • Urinary insert for stress incontinence in women
  • Lasers for surgical treatment of nearsightedness
  • A device that makes reading pap smears easier
  • In vito tests to identify cancer recurrences
  • Ventricular assist device for failing hearts
  • Fetal bladder stent under HDE

Chart #6
Food & Color Additives and GRAS Petitions
Completed 1986 - 1996M
Year Receipts Final Actions Differences
1986103 80 -23
1988 83 68 -15
1989 80 62 -18
1990 69 57 -12
1991 73 38 -35
1992 57 62 5
1993 54 73 19
1994 44 59 15
1995 53 64 11
1996 40 88 48

Chart #7
510 (K) First Action Performance within 90 Days -- Receipt Cohort
1st Action <= 90 Days # Total # Received
2636 6310
4414 6452
4933 6078
4995 5316

Percentage Receipt
FY 93 -- 42%
FY 94 -- 68%
FY 95 -- 81%
FY 96 -- 94%


Over the past two years, the Food and Drug Administration has critically examined and acted to improve its performance. Through various mechanisms, including reports produced in conjunction with the Vice President's National Performance Review and through legislative proposals, FDA is implementing a wide variety of reforms that reduce burden on industry, make the agency more efficient, and more effectively promote and protect the public health. The following are some of the areas that the agency has focused on in this process:


Accelerating drug approval times: FDA approved 53 new "breakthrough" drugs and biologics in calendar year 1996, double the rate of years past. With new resources from the Prescription Drug User Fee Act, the agency has met all of its performance goals for both drugs and biologics, and reviewed 98% of last year's applications on time. IMPACT: Makes valuable new therapies available to patients more quickly. In fact, drugs and biologics in the U.S. are now being approved as fast or faster than any other country in the world.

Accelerating the approval of cancer therapies by using surrogate endpoints such as reduction in tumor size, rather than waiting for the development of data demonstrating survival benefit.

  • IMPACT: Shortens the total time for first and subsequent marketing approvals for a wide range of cancer therapeutics. Patients will have access to promising cancer therapies at an earlier time than was previously possible.

Expanding U.S. patients' access to investigational cancer therapies that have been approved in other countries.

  • IMPACT: Patients will have broader access to promising cancer therapies sooner.

Clarifying where one study is sufficient to demonstrate efficacy. This draft guidance explains how the agency evaluates effectiveness in the context of overall review for drug, and biological product approvability.

  • IMPACT: Helps industry to have a better understanding of how to develop new products, reducing the time it takes to bring a drug or biological product to FDA for review.

Simplifying the filing process by consolidating 21 different review application forms for biotech drugs, blood, vaccines, and other drugs into just one form.

  • IMPACT: Enables companies to provide higher quality submissions and reduces industry time to prepare ap; agency resources will be freed up to accomplish other review activities.

Permitting the use of small-scale and pilot facilities during development of biologics.

  • IMPACT: Results in manufacturers having lower start-up costs and enables them to more quickly begin production of new biological products.

Changing the policy that required biotech companies to designate one person as a "Responsible Head" (a single person appointed to deal with the FDA on all matters).

  • IMPACT: Allows industry more flexibility to assign control and oversight responsibility within a company.

Allowing distributors' and selling agents' names to be prominently displayed on biological product containers, labels, and labeling.

  • IMPACT: Enables companies, in particular small, start-up biotechnology firms, to more readily enter into manufacturing, packaging, and distribution arrangements and thereby bring products to market more quickly.

Reducing the number of manufacturing changes that require agency pre-approval for biological products.

  • IMPACT: Enables industry to modernize facilities and processes more easily; saves both industry and FDA time and resources.

Developing strategic, risk-management based plans to accommodate increased need for inspecting and sampling manufacturing sites abroad.

  • IMPACT: Streamlines inspectional and sampling activities while focusing resources on areas of greatest potential risk.

Accepting a summary report of toxicology; agency resources will be freed up to accomplish other review activities.

Permitting the use of small-scale and pilot facilities during development of biologics.

  • IMPACT: Results in manufacturers having lower start-up costs and enables them to more quickly begin production of new biological products.

Changing the policy that required biotech companies to designate one person as a "Responsible Head" (a single person appointed to deal with the FDA on all matters).

  • IMPACT: Allows industry more flexibility to assign control and oversight responsibility within a company.

Allowing distributors' and selling agents' names to be prominently displayed on biological product containers, labels, and labeling.

  • IMPACT: Enables companies, in particular small, start-up biotechnology firms, to more readily enter into manufacturing, packaging, and distribution arrangements and thereby bring products to market more quickly.

Reducing the number of manufacturing changes that require agency pre-approval for biological products.

  • IMPACT: Enables industry to modernize facilities and processes more easily; saves both industry and FDA time and resources.

Developing strategic, risk-management based plans to accommodate increased need for inspecting and sampling manufacturing sites abroad.

  • IMPACT: Streamlines inspectional and sampling activities while focusing resources on areas of greatest potential risk.

Accepting a summary report of toxicology findings based on unaudited, draft toxicologic reports of completed studies to start Phase I trials in humans.

  • IMPACT: Allows new drugs to be brought to clinical testing faster.

Implementing the Electronic Submission Project in the Office of Generic Drugs, providing for electronic submission of bioequivalence data using a user-friendly program, available on the World Wide Web, called Entry and Validation (EVA).

  • IMPACT: Increases efficiency of reviews and reduces review times for generic drugs.

Implementing new Adverse Event Reporting System (AERS), which redesigns the current spontaneous event reporting system for adverse events.

  • IMPACT: Improves efficiency of drug regulatory process through standardizing reporting format technology and automating functions, including electronic processing, analysis, archiving, and FOI response.

Implementing the Establishment Evaluation System (EES) to replace the current system(s) used to request and track pre-approval inspections.

  • IMPACT: Increases efficiency by improving communication and planning of establishment evaluations between the Office of Review Management, New Drug Review Divisions, the Office of Compliance, and the field by upgrading the processes of entering, tracking, responding to inquiries, reporting, and overall project management for pre--approval inspections.

Accelerating device approval times: FDA approved 43 premarket applications in fiscal year 1996, the largest number in recent times. FDA has also eliminated the backlog of overdue 510(k) applications, and over 90%-of 510(k) applications are now being acted on within 90 days of receipt.

  • IMPACT: Makes medical devices available for marketing much faster than they have been in recent years, thus making more therapies available to patients.

Increasing the percent of original investigational device exemption (IDE) applications approved during the first 30-day review cycle from 30% two years ago to over 70% in fiscal year 1996.

  • IMPACT: Makes more therapies available to patients by allowing clinical studies of new, investigational devices to begin more quickly.

Reducing the backlog of pre-market approval (PMA) supplements from a peak of 173 a few years ago to 17 at the close of fiscal year 1996.

  • IMPACT: Enables manufacturers to make changes to their devices more quickly.

Exempting 275 additional low-risk medical device categories from premarket notification. Over the past few years, 293 had previously been exempted. Now one-third of all device categories (74% of all Class I devices) do not need to apply to the agency before marketing.

  • IMPACT: Eliminates premarket review for these devices, meaning that they can reach patients sooner and companies can realize returns on their research faster. FDA can shift resources to activities of greater public health impact.

Streamlining the review of PMA supplements by implementing two initiatives: a "real time" review process for some types of supplements whereby the reviews are completed rapidly during a meeting or teleconference with the firm; and a pilot program to reduce inspection requirements for manufacturers submitting a supplement for a change in their manufacturing site.

  • IMPACT: Helps to further reduce backlogs in the PMA supplement program and enables manufacturers to make changes to their devices more quickly.

Implementing a pilot program for external non-government reviews of devices.

  • IMPACT: Tests a new way of clearing new devices, which will help determine if such a system can speed the review of these devices while maintaining public health protection, whether the independence of the review process can be maintained, and if such a system will be less costly.

Completing guidance for the industry on when a change to an existing device requires the submission of a new 510(k).

  • IMPACT: Enables manufacturers to make changes to their devices more quickly.

Implementing a 1990 law for humanitarian use devices that exempts them from effectiveness requirements under certain criteria.

  • IMPACT: Enables "orphan" devices (those used for serious rare diseases that affect a small portion of the population) to be brought to market more quickly, at a lower cost.

Proposing a rule allowing for use of investigational devices to treat seriously ill patients when no alternative is available.

  • IMPACT: Makes more therapies available to those who most need them but have no appropriate alternative.

Revising the current good manufacturing practices regulations to add design controls and to harmonize them with international standards.

  • IMPACT: Gives the device industry modernized regulations that are harmonized with other standards, thereby reducing burden on industry.

Maintaining a Facts-on-Demand program and World Wide Web access to device-related programs and publications.

  • IMPACT: Makes access to up-to-date information readily available; in 1996, the two systems were accessed 50,000 times annually and 20,000 times per month, respectively--mostly by industry.

Broadcasting teleconferences on significant program activities and new initiatives such as the third party pilot program, adverse event reporting, federal requirements for mammography, the quality system regulation, and national x-ray trends.

  • IMPACT: Enhances communication with industry and results in improved quality of submissions and compliance with the law.

Continuing implementation of the Mammography Quality Standards Act and monitoring its impact on mammography quality, including radiation exposure levels.

  • IMPACT: Improving the ability of a health professional to detect suspicious tissue (data collected from over 9,000 facility inspections showed a reduction in radiation dose and an improvement in film qualities).

Implementing science-based control systems and monitoring requirements for assuring safety for food processing and handling for seafood.

  • IMPACT: Improves the safety of seafood by identifying and preventing hazards in food production operations and stimulating improvement in safety practices by establishing science-based control systems and appropriate performance standards.

Reforming the food additive petition review process by committing additional agency and contract resources, establishing performance goals, and instituting a "threshold of regulation" approach for very low risk non-carcinogenic indirect food additives (an abbreviated process that avoids the extensive review and formal issuance of a regulation normally required for food additives).

  • IMPACT: Addresses major complaints about food additive review procedures and response times.

Working toward harmonizing food safety requirements with our international partners to optimize safety of food moving in global trade, and facilitate international trade in food.

  • IMPACT: Maintains the high standards for safety- and quality of food produced in or imported into the U.S. and improves the safety and quality of foods produced and sold in foreign countries.

Developing pilot programs to enhance use of private and state or local laboratories for analyzing food imports.

  • IMPACT: Enables the agency to learn how best to make further use of non-FDA labs for monitoring and analyzing imported foods.

Improving the approval process of FDA's veterinary medicine program 1996 was the most productive year in the last ten years-with 78 approvals, including a record number of "significant" approvals (13).

  • IMPACT: Enables products of major importance to the animal health industry and producers to be brought to market more rapidly.

Reengineering and streamlining the animal drug approval process by encouraging presubmission conferences with sponsors, early protocol reviews, and utilization of sponsor-monitored methods trials. The incorporation of phased and direct review of applications has met with strong positive endorsements from animal drug sponsors.

  • IMPACT: Encourages greater dire ct interaction with animal drug sponsors at every stage of the drug development process. Provides manufacturers with greater guidance and application reviewers with quicker access to pivotal data. Promises to cut application review times and to reduce the time and resources drug sponsors spend developing drugs.

Eliminating unnecessary requirements for importing food-derived from animals into the U.S.

  • IMPACT: Eliminates,.or makes less burdensome, an unnecessary approval requirement and advances international harmonization of regulatory requirements.

Eliminating the burdensome medicated feed application process and replacing it with a simple, one-step process of feed mill licensing.

  • IMPACT: Results in an estimated savings to industry in excess of $1 million per year, and a savings to FDA of $200,000 yearly that is currently allocated for the processing of MFAs.

Approving a wide range of priority therapies for patients with the most serious illnesses: in the past year, FDA has approved 6 therapies for AIDS, 9 therapies for cancer, 6 vaccines, 12 important diagnostic tests, and new agents to treat difficult conditions such as Lou Gehrig's disease, multiple sclerosis and Alzheimer's disease.

  • IMPACT: Makes high priority therapies more rapidly available for patient use.

Issuing the "Good Guidance Practices" document, which sets forth the agency's policies and procedures for the development, issuance, and use of guidance documents.

  • IMPACT: Increases outside participation in the agency's development of guidance documents and helps to ensure that guidance documents are developed, issued and used uniformly and are not treated as binding requirements.

Permitting sponsors of therapies to disseminate information to health care professionals in certain textbooks and peer-reviewed journal articles.

  • IMPACT: Allows more information to be made available to doctors when treating patients, without diminishing incentives for research.

Reducing the number of instances where an environmental assessment is required as part of a product application.

  • IMPACT: Spares industry the expense of preparing assessments that FDA has found unnecessary. FDA will not have to spend resources reviewing EAs for products that will not have a significant effect on the environment.

Expanding the ability of drug and device firms to export products to other countries.

  • IMPACT: Enables industry to have wider markets for its products and will be encouraged to maintain operations in this country. FDA can redirect resources used for the current export approval program to more pressing public health matters.

Developing a new computer system for overseeing imports.

  • IMPACT: Enables FDA to handle ever-increasing numbers of imports (3.5 million/year) and saves the import community millions of dollars because -. of rapid decision-making.

Consulting with industry on various new ideas for streamlining government through 16 grassroots meetings around the country in all areas of FDA jurisdiction.

  • IMPACT: Develops action items with the regulated industry which have resulted in such things as the successful medical device pilot on announced inspections and an action plan concerning private laboratories.

Developing the Compliance Achievement Reporting System (CARS).

  • IMPACT: Promotes and captures effective and efficient compliance outcomes and helps foster a cultural change in FDA field activities from one of "policing" to one of open communication and cooperation with the regulated industry.

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