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Jane E. Henney, Ph.D - Millennial World Congress of Pharmaceutical Sciences

"This text contains Dr. Henney's prepared remarks. It should be used with the understanding that some material may have been added or deleted during actual delivery."

Remarks by:
Jane E. Henney, Ph.D

Commissioner of Food and Drugs
U.S. Food and Drug Administration

Life after PDUFA, FDAMA and ICH
Millennial World Congress of Pharmaceutical Sciences

San Francisco, California

April 16, 2000

Good afternoon. It is a pleasure to be here to take part in this once-in-a-millennium World Congress.

I've been asked to talk today about the impact of three very important but very different milestones in FDA's history. These are PDUFA--the Prescription Drug Users Fee Act; FDAMA--the FDA Modernization Act, and ICH--the International Conference on Harmonization. Each of these is having, and will continue to have, a profound influence on the way FDA reviews the products it regulates. These changes are being felt not only in the United States, but around the world.

Each has brought major change to the way FDA conducts its business, yet they have a common thread, supporting the agency's long-standing commitment to high standards of the products we approve for the marketplace.

PDUFA brought us not only additional resources from user fees, but very demanding performance measures in the timeliness of the review of drugs and biologics. Patients, the industry and the agency are well served when we are able to respond to applications in a timely and predictable manner.

FDAMA was the most sweeping piece of legislation in FDA's modern history. Not only did it renew the Prescription Drug User Fee Act because of the agency's successful performance, but it codified many activities the agency had undertaken through a variety of reinvention initiatives.

The ICH has been a decade long effort and brings the traditional high standards of the U.S. FDA to the international arena. This harmonization of many aspects of an application forms the basis for a satisfying and successful relationship among the United States, Canada, the European community and Japan. Our countries share the goal of harmonizing our standards and simplifying the regulatory process that impacts a global marketplace.

Let me begin with the Prescription Drug Users Fee Act.

By providing additional resources from user fees, this Act has allowed us to hire a substantial number of additional reviewers and has set strict time frames for review of new products. It did not guarantee approval-FDA's high standard for review was to be maintained. This initiative has been very successful. FDA has met or exceeded its PDUFA goals, both in the development phase and in the review process. Today, we are accountable, and the industry knows what to expect from us in terms of our interactions and agreements with them throughout the review process. Our review timeframes are clear, allowing industry to better plan their product development and marketing strategies. We've also noted that higher-quality applications are being submitted and the review process is moving efficiently.

With the reauthorization of the Prescription Drug User Fee Act, the average time from submission of a drug application to approval has dropped from about 30 months to less than 12 months. There has been an increase in our workload as the number of new products we review each year has increased from a yearly average of 70 applications to 97 applications. At the same time, the time to market for new drugs has dropped by 18%. This has resulted in a savings to industry of approximately $ 2 billion. Their annual $140,000 PDUFA investment brings a very strong return. But the real beneficiaries of PDUFA are patients who gain access to new treatments in a shorter period of time.

These changes are due in large part to the expansion of our review staff. But it is also important to note that by having additional human and financial resources, we've been able to rebuild our infrastructure. We've expanded our information technology systems, and streamlined our review management processes. But like all organizations we know, we still have room for improvement.

Many of you may be familiar with the recent University of California San Diego Survey results. The survey found that FDA has improved in terms of communication and the clarity of requests for more data, our response time to industry has improved, and pre-submission meetings are leading to more satisfying results. These improvements have lessened the stimulus for industry to move offshore.

Areas of needed improvement also were noted. A point clearly made is that we need a better way to transition to new reviewers when one leaves in the middle of a review-often lured away by industry, I might add--and that there is room for improvement in the technical training of some reviewers.

It's critical that the agency have the scientific expertise and the financial resources to remain at the top of our game in reviewing these products in a timely fashion. Not only because of this survey but because of the impact that the tremendous increase in federal investment in research and development over the past several years, resulting in increasing numbers and complexity of products and technologies presented to FDA for review and approval.

We must be prepared with the best scientific talent to meet this challenge.

Let me spend just a few moments discussing FDAMA. This act was passed in 1997. Rather than legislation that is intended to correct a problem, it was legislation that permitted our preparation for the future. Much of the underpinning of this law recognized the coming era of increasing technological, trade, and public health complexities. FDAMA also recognized some things that shouldn't and wouldn't change: our longstanding commitment to protect and promote the public health.

While our activities have always been open to public scrutiny, FDAMA has given us the impetus to regularly and actively seek input from the many who are affected by our actions on how we can best accomplish the goals of FDAMA. We've held a series of meetings to do just this. The most recent was just last Wednesday at Duke University. The purpose of the meeting was to discuss the topic of leveraging-to explore possibilities for leveraging our resources at FDA with outside organizations having similar health goals.

We asked and listened to many who brought forward ideas-good ideas--about how we could meet our mutual goal of improved public health.

Some of the opportunities to leverage our own assets by working with other organizations are in the areas of safety-related research, safety review for new products, monitoring the safety of products on the market, assuring industry compliance with safety regulations, and educating patients and consumers on the safe use of FDA-regulated products.

There are many important aspects of FDAMA, such as third party review, dispute resolution, food additive petition review, and others. The list is long, but let me just cite one. This is in drug development for the pediatric population. Every year more than half of newly approved drugs that are likely to be used in children lack information to permit their safe and effective use for this population. Without adequate information, physicians are sometimes reluctant to prescribe certain drugs for their pediatric patients, or may prescribe them inappropriately. For literally years the agency was unsuccessful in getting industry to conduct clinical studies using pediatric patients for drugs that would ultimately be used in children.

FDAMA has provided industry with an incentive to study the pediatric use of drugs-a six-month extension of market exclusivity. This has proven to be remarkably effective.

Consider this...during the period between 1991 and 1997 (6 years), only 11 clinical trials involving pediatric patients were conducted on new molecular entities that would ultimately be used in children. FDAMA was passed in November of 1997, and guidance on pediatric exclusivity issued in July of 1998. Since July of '98, we have had 170 proposals from industry to study drugs in children, and of those 170 we have written 140 requests to industry to carry out the trials.

Very preliminary information indicates that 75-85% of those 140 studies will be undertaken. In this same time frame we have already received information on 20 completed phase four studies. Isn't it amazing what a little incentive will do? And for those products that are not eligible for the incentive but do represent products that would be beneficial to children, the FDA has promulgated a rule to bring this data in. Both of these initiatives should assure both prescribers and parents that children who need medication are receiving ones that have been well studied.

Let's move now to the international arena and discuss ICH. ICH actually refers to the International Conferences on the Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use.

Our world is shrinking. Trade barriers are coming down. Banking is largely an electronic process, with vast amounts of money being exchanged instantly, electronically. Stocks and bonds are traded over the Internet, 24 hours a day.

Thanks to the dizzying speed at which information technology is advancing, we can send or receive information from anywhere in the world...in milliseconds. Computers and computer chips are getting smaller, more complex, yet more economical.

Randall Tobias, former Vice Chairman of AT&T, offered this comparison to explain the astounding rate of advancement in computerization: "If we had similar progress in automotive technology, today you could buy a Lexus for about $2.00. It would travel at the speed of sound, and go about 600 miles on a thimble of gas."

Today, drug development and marketing are truly global operations. Pharmaceutical companies compete on a world-wide basis. Other advances are having an enormous impact in the pharmaceutical arena as well. Nanotechnology is becoming commonplace in the drug development process. Information is being generated at an astonishing rate. The types of data that were largely inaccessible in the past are now stored electronically, their information mined to learn from past successes and failures, to direct future efforts and zero in on the most likely drug candidates for development.

The success of the pharmaceutical industry depends on its ability to compete effectively and respond quickly in the global marketplace. Through the ICH process, regulatory agencies in the U.S., Canada, Europe, and Japan are leading the effort to streamline the drug approval process and create a level playing field across our countries' borders.

FDA-regulated products that are sold in the United States have always been required to meet our very high standards, regardless of where they are manufactured. By collaborating with our foreign regulatory counterparts and international standard-setting organizations to facilitate the compliance of imported products with FDA standards, we are better able to protect and promote the public health.

For the past ten years we've been working with Canada, the European Community and Japan on international harmonization. The primary focus has been on harmonizing technical requirements on specific issues such as chemistry standards, pharmacology and toxicity testing. We now have 50-60 agreed upon guidelines addressing very specific topics. Time consuming, yes-but well worth the investment of both time and human resources.

Our next area of focus will be on developing a common technical document, to standardize marketing applications in the U.S., Canada, Europe and Japan. We envision a core international document that will include all study reports, clinical studies, and pharmacology and toxicology information. By having such a core document, industries in participating countries will be able to submit the same document in every country, with local appendices to meet local requirements. We believe that the majority of it will be standardized among these countries.

I would, however, hasten to point out that while we've achieved a high level of harmonization in many areas, which is good, we've also agreed to protocols that were based on the science at the time. It's important to remember that all protocols must be continually upgraded as we learn more about performance and as new science becomes available.

We're also working on harmonizing the postmarket submission of data. The periodic safety update report will be a common core document allowing a company to create one report and submit it to all participating countries, again with certain local appendices.

Common nomenclature has been agreed upon for reporting adverse events. The phrases--heart failure, heart attack, cardiac seizure-conjure up many different meanings. By standardizing or agreeing to definitions, our ability to interpret signals worldwide takes a major step forward, particularly in the postmarketing phase of a drug.

Dr. Benet has asked me to give my perspective on the future of drug development in the new millennium. But I'm a Commissioner, not a clairvoyant. My thoughts are not completely gelled yet on the next 1000 years. We are seeing the beginnings of what many are calling the "G Revolution." Those opportunities and challenges offered in the fields of genetics and genomics.

Since the first human gene transfer clinical trial in the late 1980's, human gene therapy products have been one of the fastest growing areas of product development.

As I'm sure you know, within the foreseeable future the entire human genome will have been successfully mapped. The analysis of human DNA, chromosomes, proteins and other gene products will have an incalculable effect on the clinical management of patients in the future.

Gene therapy has the potential to revolutionize the treatment of diseases that are incurable or have inadequate treatments. Cell and gene therapy products constitute an emerging area of therapeutic intervention that has only existed for a decade.

The original rationale for gene therapy was to treat genetic diseases by replacing a nonfunctional or defective gene. Currently, gene therapy studies are examining a broad range of potential therapeutic interventions, including stimulating the body's immune reaction to tumors, inducing new blood vessels in the heart to alleviate heart attacks, and stopping the replication of HIV in AIDS patients. There is also renewed emphasis on gene therapies for genetic diseases such as hemophilia A and B, and cystic fibrosis.

While no gene therapy product applications for marketing have been submitted yet to the FDA for review and licensing, this is probably not far off. Between 1989 and 1993, 48 gene therapy investigational new drug applications (INDs) were submitted to FDA. In contrast, between the years 1993 until January 19, 2000, 240 gene therapy INDs were submitted to FDA. Of those, 55 were submitted in FY 1999.

Another aspect of the G revolution is upon us...pharmacogenomics, and the prospect of more individualized patient therapies. We're sure that one of the tools that will make this possible is the high throughput technique of microarray technology. This technology will allow physicians to characterize the genetically determined metabolic capabilities of a patient, specifically, pharmacogenetic variations that would predict toxicity or reduced therapeutic benefit if the person were given the standard dose of a drug.

With this information in hand, the physician could either choose a different treatment or tailor the dose or dose schedule of a drug based on the patient's ability to metabolize and eliminate the drug and its metabolites.

The customization of therapeutic products based on genotypic or phenotypic characteristics of the recipient is an emerging approach to the treatment of complex heritable conditions and diseases. The use of pharmacogenetics to tailor therapies and therapeutic products, and to select or exclude appropriate patient populations, will be relevant to many biologic and biotechnology products, particularly those used in cell and gene therapies.

And then there is the I revolution-the Internet-providing us a way to convey information to consumers like never before, and changing the form and format of our traditional brick and mortar industries. This revolution is causing all of us--in no matter what walk of life- to think how very different our lives are becoming.

As a result of both the G and the I revolutions, individually and as they converge, we will need to adapt, as we'll be called on to develop new and innovative approaches to our work. But there are some things we should not change at the FDA. One...our high standards for safety and efficacy. Two...that science be used to underpin all of our decisions. And three...openness and transparency to guide our processes. It's this winning combination that has served the public well and permitted our agency to be one in which consumers have confidence and trust.

Thank you for the opportunity to be here today.