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Jane E. Henney, M.D. - Mid-America Coalition on Health Care

"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, M.D.
Commissioner of Food and Drugs
U.S. Food and Drug Administration

Mid-America Coalition on Health Care
Managing Medical Risk: Current and Future Challenges

Kansas City, Missouri

March 27, 2000


Good evening. I appreciate the opportunity to be here tonight.

I would like to share with you the many challenges facing FDA in the area of risk management.

It is FDA's fundamental responsibility to assure the safety of the many products it regulates-everything from drugs for humans; drugs and feed for animals--those you consume or those that you adore; biologics such as gene therapy, blood and vaccines; medical devices from tongue blades to pacemakers; to foods and food additives; cosmetics, diagnostics; and some things you may not realize, like microwave ovens and other radiation-emitting devices. In assuring the safety of medical products, the agency is always in the business of weighing their benefits against their risks. And there are inherent risks associated with nearly all of the products we regulate.

At the turn of the century, health care in this country was generally provided by a family practitioner who treated patients from cradle to grave. Today, medical products are developed and used within a complex system involving a number of key participants. These include:

  • the industry that develops and tests products and submits applications for approval to the FDA;
  • the FDA, which has an extensive premarketing review and approval process and uses a series of postmarketing surveillance programs to gather data and assess risks;
  • participants in the health care delivery system, including health care practitioners and insurers-and many others represented in this room
  • patients, who rely on the ability of this complex system to provide them with needed products while protecting them from harm.

It is important to note that FDA evaluates benefits and risks for the population. The health care provider considers the benefits versus risks for the individual patient, and the patient typically decides, with understanding of the risks and benefits, and in terms of his or her personal values, whether to use a particular product.

What are some of the challenges we face in managing the risk of medical products?

First and foremost are the tremendous advancements in science and technology. Both government and the private sector have invested enormous resources in biomedical research and biotechnology. The result of this investment is, and will continue to be, a wealth of new products and technologies that will be presented to the FDA for our review and approval before they are introduced into the marketplace.

In order to make these judgements, it is essential that the FDA have the scientific talent to adequately assess the safety and effectiveness of these novel products and technologies. Our scientists must be current in their fields of expertise, quick learners in new areas, and have the creativity and ability to collaborate with other scientists in the FDA and outside the agency. In short, we must be able to anticipate and access the cutting-edge science that will be needed to regulate the products of future technology.

Our scientists help to establish standards for product performance and potency, provide data to support regulatory decisions on product safety and information to consumers for the safe use of products, and provide the basis for science-based regulatory policies. The safety of vaccines, acceptable levels of mycotoxins such as fumonisin B1 in corn products, more rapid methods of detecting pathogens in food, better understanding of the significance of antibiotic resistance, are all examples of the products of research from within FDA laboratories. A high quality staff and robust regulatory research program are critical for supporting, in a scientifically sound fashion, the review and regulatory decisions we make every day.

We must be scientifically sound, consistent, and predictable in our review of products and issues that surround product approvals. It is equally vital to maintaining credibility that our decision-making be open and transparent to the lay public, health professionals, the regulated industry, and any party who depends on the outcome of FDA's decisions. All should have access and the ability to provide input and feedback to us.

The benefits of a strong regulatory agency such as the FDA are many. The most important benefits are enjoyed by patients and consumers who need safe and effective products. But benefits are also realized from an economic standpoint, for a high-quality, science-based regulatory agency attains credibility and respect on a global scale, stimulating innovation, enhancing U.S. competitiveness abroad, providing a predictable and level playing field for industry, and encouraging increased foreign investment in this country.

Let's talk about the judgements that are rendered as we make decisions about which products are safe and effective and ready to move to the market place.

Calling a product "safe" does not mean that there is no risk associated with its use. In reviewing drugs, biologics, and devices, the FDA spends a considerable part of the review weighing the benefits of a particular product against its risks. There is a continuum of uncertainty that is tolerated, depending on the seriousness of the illness. For a drug that is intended to treat a life-threatening illness, and for which there is no other available treatment, more uncertainty would be tolerated. We all recognize that most patients faced with grave diseases are willing to assume greater risks. As an oncologist I have often seen this kind of risk willingness by patients first hand.

On the other end of the spectrum, little or no uncertainty would be tolerated for remedies for alleviating minor symptoms of the common cold.

I want to assure you that uncertainties about risk do not prevent us from making decisions. An increasing number of drugs, biologics, and devices are being approved every year, many of which are new molecular entities and represent significant advances over those that were available previously. The U.S. now leads the world in terms of timeliness of review of new drugs and biologics without compromising a very high standard of safety. The average review time for drugs is less than 12 months and for drugs for serious and life-threatening conditions less than 6 months.

Every medical product approved by FDA has undergone an extensive evaluation of its safety and effectiveness, and the risks associated with its use.

But at the time of the review it is not feasible, indeed, possible, for the agency to identify every potential risk associated with the use-and abuse-of a medical product. A key question is how extensively drugs should be studied to uncover adverse reactions before approval of a product. It should be obvious that there is less certainty with a study of 500 people than one with 5,000 or 50,000 people. Still, there are risks that we don't discover during clinical trials because some adverse events are very rare or may be only associated with a subset of the population that is unusually sensitive compared to everyone else.

A less obvious reason that risks unseen in clinical trials appear when the drugs are used in the real world is that in clinical trials, the drugs are only studied for the condition for which the drug was developed, and with all other factors carefully controlled. Once the drug is on the market, it may be prescribed for a condition other than that for which it was approved, may be given using a different dosing regimen, or it may be used in conjunction with a variety of other drugs, foods, or dietary supplements that could interact with the drug. And the product will be used in numbers of people much greater than were used in the clinical trials, potentially uncovering side effects not previously seen.

The recent report from the Institute of Medicine entitled "To Err is Human" has brought renewed attention to the issue of risk management by all of us in the health care delivery system. This IOM report indicates that medical mistakes are responsible for the deaths of about 98,000 people every year.

An important point made in the IOM report is that the majority of injuries and deaths in the U.S. that are attributable to medical products are from known side effects, and not from unexpected ones.

The findings of this study confirmed what the FDA said in its earlier report issued last May, "Managing the Risks from Medical Product Use: Creating a Risk Management Framework".

Since most medical products have some inherent risks associated with their use, some greater than others, as these products enter or are in the market place it remains our responsibility to identify the risks, and communicate that information effectively to physicians, nurses, pharmacists, patients, consumers, and anyone else who may be affected by those risks or their management. Risks involving specific subpopulations of people, for example, children or pregnant women, must be clearly conveyed.

FDA cannot and should not do this work alone. The entire health care delivery system must have adequate safeguards in place. This begins with the development, manufacture, and approval of a product, and continues with physician prescribing practices, pharmacy dispensing, and proper administration of the product to patients in a hospital setting, or at home by the patients themselves.

Communication, feedback and correction-throughout the entire system--about the benefits and risks of a drug or other product for a particular use, is critical to the health care system's effort to reduce the incidence of medical errors. Communication, feedback and correction needs to take place between drug companies and physicians, between physicians and patients, between pharmacists and patients, on the product label and package insert, and in any advertisements promoting a particular product.

The agency is now committing considerably more resources to post-market surveillance of FDA-regulated products than it ever has in the past. Doctors, pharmacists, and patients can report serious adverse events to the FDA through our MEDWATCH system, or they can report effects to the manufacturer who, in turn, must report the incidents to the FDA. The agency frequently sends "Dear Health Professional" letters to inform doctors, pharmacists, and others of new safety issues. Sometimes the new information warrants a change in the product's labeling, or more rarely, the product's withdrawal from the market.

In other words, products must be developed, tested, manufactured, labeled, prescribed, dispensed, and used in a way that maximizes benefit and minimizes risk.

There are two specific areas representing new challenges to the FDA's system of managing risk. The first area I like to call the "G Revolution," which refers to 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.

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. There have also been over 800 amendments (for example, changes to the product, new protocols, etc.) to gene therapy INDs submitted every year.

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. But with these scientific breakthroughs will come the inevitable need for oversight to ensure public safety, the privacy rights of individuals, and reliability of testing results.

The recent death of 18 year old Jesse Gelsinger following infusion of genetically engineered viruses into his liver as part of a novel gene therapy trial, has stimulated intense public and congressional debate and scrutiny over this case as well as the recent discovery of lax reporting of adverse events to the NIH. Both the NIH and FDA have taken steps to strengthen existing guidelines and establish new interagency processes for monitoring all gene therapy trials.

Two major initiatives undertaken by FDA and NIH are the "Gene Therapy Clinical Trial Monitoring Plan" and the "Gene Transfer Safety Symposia."

To make oversight of clinical trials more rigorous, FDA will require that sponsors of gene therapy trials routinely submit their monitoring plans to FDA. FDA will review these plans and ensure the quality of the monitoring. The agency will also perform surveillance and "for cause" inspections of clinical trials to assess whether the plans are being followed and whether monitoring has been adequate to identify and correct critical problems.

In a second new initiative--the series of Gene Transfer Safety Symposia--FDA and NIH will enhance patient safety by providing critical forums for the sharing and analysis of medical and scientific data from gene transfer research.

In order to protect human subjects and also increase public knowledge of adverse events, FDA and NIH have taken steps to remind sponsors of their reporting requirements. FDA has also reminded clinical investigators and sponsors of their responsibilities to report adverse events.

Another coming attraction to the G revolution, this time referring to pharmacogenomics, is the prospect of more individualized patient therapies. One of the tools that will make this possible is a high throughput technique known as microarray technology. This 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 biotechnologic products, particularly those used in cell and gene therapies.

Another example of individualized therapy is the custom medical device, a device that is requested of the device manufacturer by a physician for a specific patient. A custom device is a one-of-a-kind device designed for an immediate need and for which the need is not likely to reoccur. Essentially, the physician and the manufacturer work together to design the device for the specific circumstance. For such devices, it would be virtually impossible to conduct a clinical trial, and--assuming the device does meet all the criteria defining it as a custom device--the device would be exempt from premarket approval.

What will be our capacity to review such products? The FDA has experience evaluating data in clinical trials representing very small numbers. Orphan products are those that treat diseases or conditions affecting fewer than 200,000 people. That program reached a major milestone last year by approving the 200th designated orphan product. In 1999, 78 drugs and biological products received designation as orphan products--a 16% increase over 1998.

The second area of new challenges to our risk management system has to do with the "I Revolution"-- information technology and the Internet.

Risk management of medical products now extends to venues that never existed before. We now have an issue of enormous promise, but also substantial concern-the Internet. Much of this was very well described in yesterday's Kansas City Star. In the health care area alone, the number of products and services available to consumers over the Internet is increasing exponentially. Online prescription drug sales by reputable pharmacists is one area with clear benefits to consumers. Patients can order new and refills of prescriptions, and obtain information on how to use a medication properly, 24 hours a day. This is a real boon for those patients who live in rural areas, those who are clearly disabled or just find it difficult to get to the drug store. This convenience, access and privacy are very strong and important attributes of this means of transaction. In addition, there is a wealth of science and health information available on the Internet, much of which is provided by legitimate and credible sources, and some of which is not.

Not all Internet purveyors of medical products and advice are as scrupulous as the reputable pharmacist in your corner drug store. Normally, there are standard safeguards to protect consumers against unsafe drugs--including the requirement that drugs be dispensed only for valid prescriptions and that new prescriptions be issued only after a physical exam. Unfortunately, the Internet purchase can bypass all of the public health safeguards.

What is the FDA doing about this problem?

First, we have expanded our public education efforts to warn consumers about dangerous practices involving Internet sales of drugs that are not FDA-approved, or sites that offer prescription drugs with little or no involvement or interaction with a health care professional. It is critical that we get this message out so that consumers become more "internet-savvy" and less likely to be taken in by erroneous health information-better able to evaluate the credibility of the source, and learn to spot illegal or unethical drug sales practices. Our FDA Home Page is an important resource for the public to gain information about online drug sales. [Buying Medical Products Online--Shop Smart!"]

Second, we are expanding our enforcement activities against illegal online sales of drugs through collaboration with other interested parties at the federal and state levels.

We have developed partnerships with the State Boards of Pharmacy, Boards of Healing Arts, and State Attorneys General in order to take swift action against the illegal sales of prescription drugs in the U.S. The Attorneys General in both Kansas and Missouri have been very active in this area. As you know, state jurisdictions end at the state line, opening up the opportunity for illegal practices to be carried on across state lines. So when the pharmacy is in one state, the pharmacist in another, the doctor in a third, and the patient in the fourth--a Federal presence, whose jurisdiction can span these boundaries, can stop this illegal activity wherever it occurs.

We are optimistic that with this dual approach of using educational and enforcement tools, you will be better protected from some of the dangers associated with online prescription drug sales.

There are many challenges before us in this business of managing risk, and others are on the horizon. Addressing each of these will require the most current and scientifically sound information and thinking on the part of FDA, and coordination and communication with all segments of the health care community.

There is an inscription written on a church in Surrey, England:

"A vision without a task is but a dream.
A task without a vision is but drudgery.
A vision and a task is the hope of the world."
This organization is offering such hope for this great community. I wish you well in your endeavors. Thank you for the opportunity to be here today.