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Lester M. Crawford, D.V.M., Ph.D. - Cleveland Clinic Foundation

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
Cleveland Clinic Foundation's
2004 Medical Innovation Summit

Remarks by

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


October 20, 2004

Good afternoon, and thank you, Paul (DiCorleto, Chairman of the Lerner Research Institute), for the introduction.

I am pleased and honored to be here and participate in this stimulating summit on medical innovation, and the promise it holds for America's patients and consumers.

There is a tendency to regard the Food and Drug Administration solely as a guardian of the United States public health standards and gatekeeper for regulated products. And there is no question that this is a big part of our mission. But in addition to managing risks, our agency is also increasingly involved in advancing innovation -- stimulating and encouraging new thinking, new means and new strategies for protecting and promoting the health of our public.

I want to note that this point that we get a lot of support in this effort in the Department of Health and Human Services. One recent example is a departmental task force on medical innovation that Secretary Thompson formed in May of this year. I have the honor to chair it, and I work closely with the other members, Drs. Elias Zerhouni from NIH, Mark McClellan from the Centers of Medicare and Medicaid Services, Julie Gerberding from CDC, and Andrew von Eschenbach from NCI.

We are charged with considering and promoting new health care ideas and solutions that would speed up the development of new medical technologies. The Secretary wants a report by the end of the year on what the Department can do to advance and make available medical innovation, including the stripping of red tape and improving interdepartmental cooperation.

Our task force has made good progress already. We've opened a public docket for comments and ideas, held meetings, and we have a group evaluating the submitted contributions. Some of them are being developed into working papers.

We plan to place the most important new concepts on the docket for review, and they will be open for discussion at a public meeting on November 8. I want to invite all of you to attend, and I hope that many of you will find time to participate.

Getting back to innovation efforts at the FDA, they are not exactly a brand new development: for example, FDA has been helping sponsors for more than a decade to design clinical trials for breakthrough therapies for cancer, AIDS and other life-threatening diseases. During the same time, the agency has accelerated its product reviews and invented new procedures to make critical therapies early and widely available.

But in recent years, our emphasis on innovation has become much more intensive and comprehensive. Our resources and our creativity are increasingly focused on exploration of new technologies and scientific findings that can be applied to contribute to our mission. We're reforming and modernizing our regulations on a scale unmatched in decades. We're creating novel cooperative relationships to pursue projects that are greater than our resources. And we're not afraid of out-of-box ideas that serve our objectives.

To borrow from Detroit, regulatory progress has become FDA's most important product. For example, our agency is deeply involved is the use of new information technology to help prevent medication errors, collect adverse events data, and improve our operational efficiency.

The best known of these innovations is our requirement, which was announced in February, that all prescription drugs and OTC products used in nursing homes and hospitals should be bar-coded with the National Drug Code Number to avoid mistakes in their dispensing and administration. The same principle is used in the implantable chips and scanners of the VeriChip system our agency approved last week. But we're also experimenting with other IT applications.

One of them is the Marconi demonstration project, which will enable us to receive data directly from health care providers using electronic medical records and standardized adverse event reports. It this project is successful, it could be the start of a new way to detect safety problems at the provider level.

Another pilot program is called MedSun. It's Internet-based, and involves collaboration between selected health care facilities and FDA to provide our agency with real-time information from clinicians about medical device-associated problems. The system also provides some of this information to other health care facilities where it can be used to improve patient safety.

In addition, we've introduced electronic reporting of adverse events by manufacturers of pharmaceuticals, and we are working with the National Library of Medicine on a system that will use Internet to provide physicians and pharmacists with up-to-date drug labeling information.

This are only a few examples of new information technology projects we're either considering or putting to work. A departmental task force, which I chair, is developing more ideas for medical uses of electronics, and we'll report on that to Secretary Thompson by the end of this year.

We're also trying to advance medical innovation by helping sponsors of urgently needed -- so-called "fast-track" -- drugs to design better clinical trials. We've just started the second year of two three-year pilot programs investigating whether this goal can be achieved by early or continuous consultations between our reviewers and the product sponsors.

One program enables sponsors to get early feedback by submitting sections of their marketing application before the entire document is completed. The other pilot provides more frequent communication starting very early in the drug development.

In addition, we're conducting an analysis of the basic reasons why so many drugs fail to pass their first review cycle, which invariably delays their approval and increases their cost. 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.

But these pilot project and technological innovations have been mere harbingers of two more far-reaching, recently launched programs that are my main topic today. I am referring to FDA's wholesale reform of the pharmaceutical Good Manufacturing Practices, and an unprecedented proposal called the "Critical Path" project -- two initiatives that are transforming the traditional culture and approaches of our agency.

I need to emphasize that these ground-breaking initiatives do not change our mission, which remains the same: the FDA continues to pursue the same goal of ensuring that health care products are safe, effective and of the highest quality, and that the 80 percent of our national food supply we regulate is safe and wholesome. 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 substantial degree, on successful innovation by the health care industry.

This perception is creating a new regulatory environment which is most distinctly represented by the two major initiatives I've mentioned. By undertaking the GMP overhaul and launching the "Critical Path" project, our agency has 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.

Most of you will remember that there were good reasons for this optimism: we saw the human genome being sequenced; there was an emergence of the highly promising genomic and proteomic technologies; and research was making marked progress in medical imaging, nanotechnology, tissue engeering and drug discovery.

Moreover, these dramatic breakthroughs were fuelled by matching increases in resources. The budget of the National Institutes of Health 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 development curve for new medical products that took shape in the last 10 years pointed downwards instead of up. In 1995, FDA received 44 applications for new biological licenses and in each of the following two years, it received 44 applications for New Molecular Entities. In 1999, 2000 and 2001, medical device manufacturers submitted to FDA respectively 64, 67 and 71 applications for original new products.

By the end of the last fiscal year, which ended just 20 days ago, we'd received applications for just 51 new medical devices, three fewer than the previous year. The application receipts for drugs and biological products, were slightly higher than in the fiscal year 2003, but they still lagged far behind the totals of 10 years ago. All told, in the last 12 months we received 28 submissions for New Molecular Entities and 20 new biological license applications.

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 our national health care bill, which went up from 7 percent of 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 drug output that we could do something about. Some of the 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 experts specifically trained to inspect highly complex and high-risk drug facilities. We are currently developing curricula for the training of these specialists. In addition, we are testing a new approach for achieving rapid and objective resolution of scientific and technical questions or issues that may arise during or as a result of FDA inspections.

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.

As part of the GMP reforms, we are vigorously advancing the use of new information technology, which I've already mentioned. For example, we've recently finalized a guidance that encourages manufacturers to adopt the latest technological advances in record-keeping, and using electronic signatures. Fast and reliable exchange of adverse event and other medical information is high on our agenda.

For example, we've 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 choosing 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 regulatory reform 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.

Another new FDA strategy is to encourage new drug ventures by facilitating the development of, and access to, critically needed medications. A significant new addition to this program is our partnership with the National Cancer Institute on a task force that's advancing the development and review of new technologies 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 of this year 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, and we're working to clarify clinical endpoints for myeloma and lung, colon, prostate and breast cancers, and to improve 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 issued a final rule for revised spore-former requirements that provides greater flexibility for manufacturers in producing biologic countermeasures.

These and many other initiatives 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. I am referring to 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 phenomenon and reached conclusions that motivate FDA's most far-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.

The objective of this program is both enormously ambitious and critical if we are to overcome the current drought in drug innovation. In essence, we're trying to change the fact that decades after drug testing became commonplace, 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. And 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.

Historically, this proportion used to be 14 percent. Of those drugs that manage to reach the final stretch 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.

I should add that the report is not the first FDA attempt to ease the drug firm's uncertainties when it starts a candidate product along the critical path. For example, we now hold well over 2,000 meetings a year focused on questions involving product development plans. We're also putting a lot of effort into updating old guidances and writing new ones on how to develop critically needed medical treatments. In the case of medical devices, these documents are almost doubling the likelihood of the product approval, and the approvals are 33 percent faster.

But while these actions have been helpful, they do not address the greatest shortcoming of the processes along the Critical Path, which is a lack of scientific insights that are essential for translating an experimental substance into a safe and effective health care product.

This is a crucial problem, and the objective of our Critical Path initiative is to find a solution.

In FDA's view, the state of applied sciences that are used for medical product development lags behind the striking advances in the basic sciences that can make medical breakthroughs possible. As a result, the drug development process is obscured by uncertainties that frequently culminate in unexpected obstacles and project failures -- failures that could be avoided if the obstacles could be foreseen at the start of the development process.

The implied message of our Critical Path document is that investment in basic research, while certainly necessary, is not enough to regenerate the lagging drug innovation. The need is for greater investment in research that will yield scientific methods and standards to illuminate the product's way to the FDA approval and the marketplace.

Specifically, what's lacking are new predictive tools -- including assays, standards, computer modeling techniques, biomarkers, and validated surrogate endpoints for use in clinical trials -- that would enable sponsors to separate promising candidates from probable failures early in the development process. By abandoning or redesigning the product before it enters the costly clinical studies, sponsors could avoid great financial losses and increase the return on biomedical investment.

Our Critical Path report calls for sophisticated development tools especially in three critical areas: product safety, which now is explored through animal toxicology and in time-consuming, expensive, and sometime risky clinical trials; the product's medical effectiveness, which can be extremely difficult to prove; and the product's potential for reliable large-scale manufacture.

For example, by applying genomic and proteomic techniques, we can develop safety assessment programs for new biomaterials. With better scientific methods, we can design better animal models, new biomarkers, and surrogate end-points for clinical safety and effectiveness.

We can improve standardization and automation of clinical research. We can develop novel and improved clinical trial designs and analytical methods for evaluation of safety and effectiveness that can reduce costs. We can also apply modern engineering and cutting-edge scientific knowledge to medical product manufacturing.

The public health benefits of such developments would be prodigious: information provided by these tools would help physicians to identify patients who are likely to benefit from a medication, as well as those who are at risk for side effects.

Economic gains would be also great: for example, the use of predictive biomarkers could reduce the necessary size of clinical trials and facilitate the product approval process, thereby saving the sponsor millions. We estimate that a mere 10-percent improvement in predicting products' failures in clinical trials could reduce the development cost per drug by $100 million.

Creating such predictive tool kit, of course, would be a project of much greater magnitude than the FDA could carry out alone -- and fortunately, that is not necessary. Considerable amount of work to strengthen basic and translational research is already being done by the National Institutes of Health and in the private sector. There are many academicians and companies that collect critical path data and establish their correlation.

No one, however, is assembling this information and formulating from it generalized principles that would guide faster and more accurate product development and evaluation. This is a major shortcoming -- but it is a deficiency that our agency is well equipped to remedy.

FDA is uniquely qualified to provide this essential analysis and guidance because our reviewers have the most comprehensive information about the developmental hurdles that trip up new products. We also have the necessary expertise for prioritizing research and pursuing it in cooperation with our stakeholders while safeguarding confidential commercial information.

We are therefore in the best position to organize a nation-wide program in which experts from government, academia, and private sector can cooperate in designing a better pathway for developing new treatments. We're already hard at work on this project.

Since our critical path report came out, FDA has been eliciting stakeholders' views on developmental issues. We are now preparing to post on the Internet a list of National Critical Path Opportunities that will identify areas of product development that could benefit most from innovative approaches and emerging technologies. After the list is made public, we will then invite our partners to tackle the necessary research.

Incidentally, we are still looking for suggestions on how to best improve the predictability of product development. If you have any ideas to offer, please send them to us.

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 the IND stage. FDA is also considering using drug and disease models as part of the pre-IND meetings. This approach, we believe, can help sponsors reduce the number of clinical trials and make safer and earlier decisions whether to stop development.

I could go on describing still more ways we're 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.

What the projects I've described make clear -- I hope -- is 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 the medical profession and health care industry, which is the development of novel, critically important therapies for our and the world's patients.