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Lester M. Crawford, D.V.M., Ph.D. - R&D Leaders' Forum

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

Speech before
R&D Leaders' Forum

Remarks by
Lester M. Crawford, D.V.M., Ph.D.
Acting Commissioner of the FDA


October 5, 2004

Good afternoon, and thank you, Brenton (James, Director of Regulatory External Relations, GlaxoSmithKline) for the introduction.

It's a great pleasure and honor to be here. For the person in charge of the United States Food and Drug Administration, addressing the leaders of pharmaceutical industry is always an honor and a pleasure -- but it's also a professional obligation. To brief this important audience on new public health policies and actions, and to learn about the industry's needs and concerns, is an integral part of the regulator's job.

Today, this dialogue is particularly timely because of several recently initiated, seminal programs that are transforming the traditional culture and approaches of our agency. These ground-breaking initiatives do not change our mission, which remains the same: the FDA continues to have the same time-honored objective of ensuring that health care products are safe, effective and of the highest quality. What has changed, and significantly so, is the manner in which we pursue these constant goals.

In the last two years, our agency has embarked on a new strategy for safeguarding the health of American consumers, which is based on the recognition that any substantial improvement of the public health depends, to a large extent, on successful innovation by your industry.

This perception is creating a new regulatory environment, an atmosphere that's most distinctly reflected in two major initiatives. One of them is our reform of the pharmaceutical Good Manufacturing Practices, which was launched two years ago. The other one is FDA's Critical Path program, which was announced in March and was discussed this morning by my colleague, Professor Stanski.

Through these two far-reaching undertakings, our agency assumed -- for the first time in its century-old history -- a measure of responsibility for innovation in the pharmaceutical industry.

Both of these programs have been developed by our agency in response to developments that took place -- or more appropriately, did not take place -- since the mid-1990s, when all of us in the health-care community had high hopes for major pharmacological breakthroughs.

There were good reasons for this optimism: in the last decades of the last century, we saw the human genome being sequenced; the emergence of novel, highly promising genomic and proteomic technologies; and marked advances in medical imaging, nanotechnology, tissue engeering and drug discovery.

Moreover, these dramatic advances in basic sciences were supported by major increases in resources. The budget of the National Institutes of Health, which fund a prodigious amount of health-related research, was more than doubled in the decade following 1993. Pharmaceutical R&D investment, which is even more directly focused on new therapies, during the same ten years shot up 250 percent.

And yet, the drug development curve that took shape in the last 10 years ran in the opposite direction from what had been expected. In 1996, FDA received 44 applications for the approval of New Molecular Entities. By 2003, that total was down to 25. In 1995, biotech firms submitted to our agency 44 Biological License Applications. By the end of the 2003 fiscal year, the number of BLA submissions was 14.

The figures for the just-ended Fiscal Year 2004 are somewhat higher, but still well below the totals 10-11 years ago. As of September 27, our centers for drugs and biologics received between them 20 BLAs, 8 of which were for medical devices using biologic products. In addition, our drug center received 28 applications for NMEs, or three more than in 2003.

As if the slow-down in drug development alone was not bad enough, we've seen a staggering rise in its costs. In the early 1990s, drugs were brought to the market for approximately $800 million each. Last year, the corresponding expense was estimated as high as $1.7 billion.

The mushrooming costs helped fuel a sharp increase in the United States health care bill, which went up from 7 percent of our government spendings in 1970 to 23 percent in 2003. Per capita health expenses in the U.S. rose about 10 percent each in 2001 and 2002, and last year increased an additional 7 and a half percent. According to a recent estimate, the U.S. will spend this year almost $1.8 trillion for health care, or about $6,000 per person.

Worst of all, at the end of the decade that was expected to bring a slew of major new therapies, patients are still waiting for more effective treatments for Alzheimer's disease, cancer, AIDS, autism, cystic fibrosis, diabetes, morbid obesity, heart diseases, and many more ailments that afflict millions.

When patients lack needed therapies, FDA is duty-bound to investigate the reasons, and that's what we did. Our analysis identified several factors that contributed to the dismal trends of the last ten years. One obvious, and yet frequently overlooked, reason for the meager pharmaceutical innovation is the enormous complexity of novel drug development. Relatively simple therapies have been long on the market; the challenges that remain present scientific difficulties of unprecedented order of magnitude.

Another factor we noted is the frequency of mergers and other business arrangements. As a result of these actions, some drug development plans have been abandonned, and candidate drugs were withdrawn from testing.

These causes of the innovating drought were outside the FDA purview. But our study also showed that there were additional obstacles to new drugs output that we could do something about. These stumbling blocks were in our regulatory domain, which has been in need of modernization and updating.

Therefore, two years ago, we set the FDA on a fundamentally new course by developing the two unprecedented initiatives I've mentioned: a complete overhaul of the pharmaceutical GMPs, and the Critical Path initiative focused on the drug development process.

The objective of the comprehensive, broadly-based GMP reform is to facilitate the adoption of greater efficiencies in drug manufacture; the goal of the Critical Path program is to eliminate or reduce the hazards that cause products to fail FDA's standards for approval.

The GMP overhaul, which is catching up with almost 25 years-worth of scientific and technological developments affecting drug manufacture, is now nearimg completion. The measures we've adopted incorporate risk-based principles, science-based policies and standards, and integrated quality systems, and are meant to encourage drug firms to modernize their manufacturing processes. We hope that these innovations will lower the production costs and increase the availability of more affordable medications, and thereby strengthen the public health.

Risk-based approach is a particularly prominent basic principle of the GMP reform. One example is FDA's redesigned product validation policies described in a recently issued compliance policy guide entitled "Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Premarket Approval."

The document acknowledges the centrality of advanced engineering principles and control technologies for ensuring batch quality, and avoids specifying the need to manufacture a certain number of commercial-size validation and conformance batches.

Similar approach is also embodied in two FDA draft guidances. One of them deals with process analytical technologies that provide a framework for the adoption of state-of-the-art technological advances in drug development, production and quality. The other new guidance, now under development, is focused on the application of the GMPs to Phase I trials. The purpose of this measure is to ease the progress of new drugs through the early stages of development.

Another aspect of our regulatory work that's being reorganized on the basis of risk-management principles is the agency's inspection system. For example, we're in the process of creating a pharmaceutical inspectorate, a first-of-its-kind, state-of-the-art program that will be staffed by a cadre of carefully selected experts specifically trained to inspect highly complex and high-risk drug facilities. We are currently developing curricula for the training of these specialists.

Yet another example of the agency-wide application of risk-based principles is several draft documents published earlier this year that provide guidance on the management of safety hazards that can arise throughout a product's entire lifecycle, including premarketing risk assessment; development and use of risk minimization plans; and good pharmacovigilance practices and pharmacoepidemiologic assessment.

There are still more reform projects in the works, and we plan to announce some of them shortly. We're making particularly intensive efforts to modernize regulatory functions by using new information technology. For example, we've recently finalized a guidance that encourages adoption of the latest technological advances in maintaining electronic records and using electronic signatures.

We're also working closely with other government agencies, academia, and industry to develop standards for the electronic exchange of critical information, such as medical data and adverse events reports. FDA has already adopted an annotated electrocardiogram wave-form data standard for the exchange of ECG data collected in clinical trials. And earlier this year we took another significant step forward by adopting the so-called Study Data Tabulation Model, a system designed to greatly speed up secure exchange of data from clinical trials in human drugs.

These electronic standards, which were developed by a consortium of pharmaceutical companies, will help automate the largely paper-based clinical trials research. We're planning to extend their use to include information on the study protocol, planned assessments and interventions, and statistical analysis plans. The system will also foster easier communication and collaboration among researchers, enhance data integration, and help reduce data management barriers to sharing the trial data.

Yet another key objective of this effort is to standardize the format for the voluminous and not always well organized electronic submissions of investigational new drug applications, which have to be reviewed before drugs can be tested in clinical trials. By doing away with the need to laboriously rearrange the contents of the product submissions, we expect to achieve greater research efficiencies, easier data management, and lower costs.

As part of our commitment to help advance drug innovation, we're conducting a retrospective study of the root causes of product failures in the first cycle reviews. An early outcome of this project is a new guidance and training for our reviewers on Good Review Management Principles, which include early notification to sponsors.

In addition, we've launched three pilot projects exploring regulatory changes that could facilitate, speed up, and lower the cost of drug development.

One of them is designed to achieve rapid and objective resolution of scientific and technical questions or issues that may arise during or as a result of FDA inspections. The other two involve the review of continuous marketing application for fast-track products. One program enables sponsors to get early feedback by submitting sections of their marketing application before the submission is complete. The other provides more frequent communication starting in even earlier phases of development.

Another new FDA strategy is to encourage new drug ventures by facilitating the development of, and access to, critically needed medications. A significant part of this program is our partnership with the National Cancer Institute on a task force that's advancing the development and review of new technology for prevention, diagnosis, and treatment of cancer.

One of our contributions to this vital cause is the streamlining of requirements for the studies of investigational new drugs. For example, a new FDA guidance published in January provides exemptions from a need of FDA's approval when using approved oncology drugs to conduct investigational studies. Our task force is also exploring the use of proteomics and imaging for biomarkers. We're also in the process of clarifying clinical endpoints for myeloma and lung, colon, prostate and breast cancers, and improving the use of bioinformatics in cancer drug development.

Yet another area where we're working closely with industry is developing and ensuring the supply of products to counter terrorism.

These projects include the identification of existing products that may be useful as medical countermeasures, and support for the availability of essential preventions and therapies for smallpox, botulinum toxin, anthrax, plague, nerve agents, inonizing radiation and other potential threats. For example, we have developed a final rule for revised spore-former requirements that provides greater flexibility for manufacturers in producing biologic countermeasures.

These and many other initiatives I don't have time to mention should yield significant public health benefits, and facilitate pharmaceutical progress. Important as they are, however, most of our innovations do not address what you and I know constitutes the most formidable obstacle to a vigorous and productive new drug development, which is the unpredictability of its outcome.

I think we would all agree that pharmaceutical development is still an art -- a matter of intuition, luck, and trial and error instead of what it should be, a mechanical process driven by science-based facts or probabilities. Lack of these insights at the start of the development process exposes novel drugs to unforeseen obstacles.

These unexpected hazards, according to some estimates, cut down to just 8 percent the chances that a candidate drug in Phase I trials will ever receive an FDA approval. Of those drugs that reach almost the end of what we call the critical path, and enter the late stages of Phase III studies, fully one half fails to show the necessary evidence of safety and effectiveness.

We've investigated this deleterious phenomenon and reached conclusions that motivate FDA's most fa-reaching initiative I mentioned earlier. It is set forth in a report published in March in a white paper entitled "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products." The document is posted on FDA's website, and I highly recommend it to your attention.

I will not spend much time on the findings and remedies suggested in the report, which were described this morning by my colleague, Dr. Stanski. But I do want to emphasize the key points of this seminal initiative, which illustrates best the FDA's commitment to help industry revitalize drug innovation.

The Critical Path intiative is not about drug discovery; it is not about misuse of confidential commercial data; and it is not about adding new regulations. What it is about is an overdue upgrading of the technologies and sciences you use to translate new basic discoveries into therapies that strengthen the public health.

The applied sciences at our disposal are lagging far behind the rapid progress of basic science, and we must catch up. The critical path must not continue to be the dark bottleneck of drug development that stifles medical progress. We must find a way of illuminating the drug's progress by using modeling, simulation, and quantitative disease models to create more informative and predictive development designs.

This is an effort well beyond FDA's limited resources, but our agency can and is ready to play a central role in helping to organize it and coordinate the many necessary research projects. We've already started developing the basic information by asking our stakeholders in several public meetings on what kind of research could help dispel the critical path uncertainties.

We will soon post a list of such projects on the Internet, and invite our stakeholders to chose those they want to undertake. Needless to say, no one is more cordially invited and better qualified than you, the pharmaceutical R&D leaders, to examine the list and select a research area in which you want to participate.

We are aware that a considerable amount of translational research is already underway in academia and industry, but no one coordinates these efforts and use their results to develop scientific principles. This is a task for which the FDA is well equipped, and is ready to undertake.

Incidentally, one Critical Path research project is already being carried out by our agency. The goal is to facilitate early, small-scale proof-of-concept studies before a drug reaches IND stage. FDA is also considering using drug and disease models as part of the pre-IND meetings. By using this approach, we believe sponsors can reduce the number of clinical trials and make safer and earlier decisions whether to stop development.

I could go on describing still more FDA initiatives that illustrate our new strategies for actively aiding pharmaceutical progress.

For example, we are forming a Council on Pharmaceutical Quality that will be charged with with policy development and implementation of certain quality management systems.

We are preparing a new paradigm for the chemistry, manufacturing and controls review of new drugs: instead of giving sponsors a long list of deficiencies, we'll produce a prioritized list indicating which deficiencies most critically affect the product's safety and effectiveness. The agency will also list less urgent items -- such as maximizing product shelf life and improving the manufacturing process -- that sometimes could be addressed after the drug is on the market.

Another coming project is a draft guidance on the role of quality systems in the pharmaceutical GMPs; final guidance on aseptic processing in the manufacture of sterile drugs; a draft guidance on GMPs for combination products; and a proposal to amend the safety reporting requirements for these products in line with the formats and standards adopted by the International Conference on Harmonization and the World Health Organization.

But I hope that I have managed to make clear our new regulatory philosophy. In order to better protect and strengthen the health of our public, FDA is committed to speed up and make more efficient the process of product review; do all it can to help reduce development barriers along the Critical Path; maintain transparent and high-quality procedures; and communicate early and productively with product sponsors.

We are confident that these new policies will advance the goal that FDA and consumers share with your industry, which is the development of novel, critically important therapies for our and the world's patients.