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FDA's premarket review activities directly and strongly affect the public health by providing access to safe and effective new products and therapies. To speed this process, FDA works closely with industry to help it develop complete and well-prepared product applications. The relevant principle is that a confident and well-informed industry also becomes a partner in shouldering the management of risks.
One FDA approach to improving the clarity and availability of information about review processes has been to improve the processes themselves. In the last few years, FDA has streamlined its internal procedures for processing reviews by including more consultations with companies submitting applications, becoming more accountable, and by developing systems to track and control the flow of work. The number of forms required for new biologic products has been reduced. The changes also helped accelerate the reviews of new drugs and biological products.
To comply with a mandate in FDAMA, FDA has altered its computer system for tracking changes in how veterinary products are manufactured. The improved system monitors the applications for review of different categories of changes. The system also allows better tracking of time periods for review of these applications.
With regard to medical devices, the backlog of overdue device applications has been eliminated. In addition, FDA now allows outside scientists (called third parties) to review certain device applications. Information about this program, including who these third parties are and what they are allowed to review, can be found at http://www.fda.gov/cdrh/thirdparty/.
A 1999 survey by Pricewaterhouse Coopers (PWC) attests to the success of these efforts. As the table below shows, industry officials participating in the survey said that the clarity of FDA's requests for data, helpfulness of communications, and the speed of FDA's responses had all improved.
| Percent Agreeing 1997 |
Percent Agreeing 1999 |
|
|---|---|---|
| Requests expedite review | 46 | 56 |
| Communications helpful | 41 | 48 |
| Response in < 5 days | 52 | 64 |
FDA is also providing more information on how it makes its review decisions. The Agency has developed guides that explain how reviewers examine an application, what information they need, and how they analyze that information. These guides are available to the industry and the public. This strategy also has accomplished its purpose. In the PWC survey cited earlier, 63 percent of the firms questioned said that FDA guidances helped expedite reviews. This represents a 20 percent increase from two years ago.
Another helpful measure is FDA's recognition of 450 consensus standards for devices that had been developed with the help of industry and FDA by such organizations as American National Standards Institute (ANSI) and the International Standards Organization (ISO).
A manufacturer whose new product meets these standards needs to submit only a certificate of conformance instead of the extensive data routinely required in premarket applications. (See http://www.fda.gov/cdrh/national.pdf for a list of product standards).
FDA's extensive use of the Internet last year continued to make a major contribution to the transparency of the Agency's processes. Each FDA Center has a website that provides guidance to sponsors submitting applications as well as application forms that can be downloaded. The Agency's manuals of policies and procedures for evaluating submissions are also available on-line.
FDA's homepage on the Internet is the gateway to searchable databases of approved products and adverse event reports, information that can be helpful in designing better products. FDA believes that easy access to all information can only make its partnership with industry closer and more productive. (See appendix for websites)
FDA also continues to promote the electronic filing of applications. Computer submission helps both the Agency and the industry. It eliminates the need to ship and maintain large volumes of paper; enables FDA to make applications available more quickly to appropriate reviewers; and gives reviewers the improved capability to navigate through large applications, and to copy and paste information into their reviews.
Since late 1997, 45 percent of New Drug Applications (NDAs) have had at least one component submitted in electronic format. Fifteen percent of these submissions were completely electronic. In 1998, electronic submissions replaced the equivalent of nearly ten million paper pages. In 1999, the entire application could be sent electronically and there was a 30 percent reduction in the average number of paper volumes received over 1997. Generic drug submissions also may be made in electronic or paper format. For FY 1999, FDA received 46 electronic submissions for bioequivalence evaluation and 69 for manufacturing.
In 1999, FDA also finished a process to allow electronic submission of veterinary drug shipment notices (these notices are required when drugs under review are shipped for clinical testing). An evaluation showed that the processing time was reduced by two-thirds that of paper applications
About half of the patients who fill the nearly 3 billion prescriptions from their doctors each year don't take the medicine as prescribed. This risky practice can have serious consequences for their health. Adherence to proper medical regimen is particularly important for women, who spend almost two thirds of every health care dollar.
To alert women to the importance of safe use of medicines, FDA conducted in October 1999 a nationwide grass-root campaign, Take Time To Care. The program, which encourages women to educate themselves and their families about using medicines wisely, includes the distribution of an FDA brochure that delivers four messages: read the label; follow the regimen; ask your provider for more information; and keep a record of your medicines. Last year, 6 million copies of the brochure "My Medicines" were distributed from coast to coast in partnership with the National Association of Chain Drugstores and 80 national organizations
Educational grassroots programs were developed with our community partners to expand awareness of using medicines wisely. For example, nearly 100 media outlets brought the FDA message to 26 million readers and viewers. An independent survey found that 98 percent of recipients found the information in the booklet useful.
When millions of women learn how to avoid adverse medication events, the nation's potential public health (and economic) benefit can be enormous. For more information on this program, log onto http://www.fda.gov/womens/tttc.html.
Americans buy about 5 billion over-the-counter (OTC) drugs each year to treat their headaches, heartburn, coughs, colds and other routine health problems, but they are not always clear on how to use them. Many older Americans also find the print on OTC labels too small to be legible.
Last year, FDA published a rule to make these labels easier to read and understand. Under FDA's new rule:
FDA hopes the new "Drug Facts" labels will improve the way consumers choose and use OTC medicines, just as the simplified "Nutrition Facts" labels have helped consumers eat less fat and choose healthier diets.
According to the Centers for Disease Control and Prevention, there are an estimated 76 million cases of foodborne illness a year, causing 325,000 hospitalizations and 5,000 deaths. As part of the Partnership for Food Safety Education, FDA works with industry, consumer groups, and other government agencies to reduce the incidence of foodborne illness by educating Americans about safe food handling practices. The Fight BAC! campaign is a product of that unique partnership. BAC!, the focal point of the campaign, helps put a "face" on invisible foodborne bacteria. The four safe-handling messages -- "Clean! Separate! Cook! Chill!" -- provide consumers with consistent, brief, and positive actions they can take to reduce their risk of illness.
FDA has brought the educational campaign to many schools, senior citizens' centers, educational fairs, Indian reservations, and even the New York State Fair, which was attended by 3 million people.
For
National Food Safety Education Month 1999, FDA and U.S. Department of Agriculture
developed and distributed a "Cook It Safely" poster featuring BAC in
a frying pan and a 43- page Consumer Education Planning Guide with reproducible Fight
BAC! materials, including translations in Spanish and Chinese.
With assistance from FDA and state partners, a Memphis first grade teacher used the materials, including the Fight Bac web site, to develop innovative lesson plans. The youngsters generated materials of their own and even wrote a food safety "rap" song. They brought their enthusiasm home, where they influenced parents to avoid unsafe handling practices (for example, sampling raw cookie dough). The teacher and her program have received national recognition.
Numerous projects and activities for the Fight BAC! campaign are planned for the next several years. The focus continues to be on educating children, the general public, and those most at risk for foodborne illness. For more information, log onto http://www.fightbac.org/ or call FDA's new toll-free number 1-888-SAFEFOOD.
Clinical trials are conducted to determine whether new drugs or treatments are safe and effective. Carefully designed and performed clinical trials are the fastest and safest way to find out whether and how well an experimental treatment works. Once new therapies show promising results in laboratory and animal tests, researchers can begin planning clinical trials to test the therapy in people.
FDA has partnered with the National Institutes of Health (NIH) to develop a database that would provide patients, family members, health care professionals, and the public with easily accessible information on clinical trials for a wide range of diseases and conditions. The database, which was tested and improved according to suggestions from patients and patient advocates, contains information on more than 4,000 clinical trials. It can be found at www.ClinicalTrials.gov.
The database is very user friendly. The search engine responds to commonly used names of illnesses or conditions and does not require the use of scientific terminology. Each search gives the results for both the entered and related disease or condition. The site has also a "Browse" option that lists numerous illnesses and conditions. There is even an automatic spell check that may help users unsure of the spelling of a medical term!
The database is being developed in stages. In the current first stage, users will find information on approximately 4,000 primarily NIH-supported clinical studies. More than 2,800 of these trials are still recruiting participants. Later this year, information will be added on clinical trials supported by other federal agencies and the private sector. The database will be updated regularly.
Development of this registry was required by section 113 of the Food and Drug Administration Modernization Act of 1997. FDAMA required only a registry of clinical trials for serious or life threatening diseases; however, this database is designed as a comprehensive source of clinical trial information that will be more extensive than the law requires. The website of the data base includes links to other online health resources. The use of the database is free, and there is no registration or password needed to enter it.
Patient participation is critical to medical decision making, whether it involves a physician's choice of treatment or rule making by a government Agency. FDA is committed to expanding opportunities for patients to participate in FDA's decision making.
One of the most effective ways in which FDA helps empower consumers is by including patient representatives in advisory committees that consult FDA on the risks and benefits of new treatments for serious or life-threatening diseases such as cancer or AIDS.
Patients commonly discuss treatment options with their physicians, but the concept of patient participation in the medical product approval process is relatively new. FDA adopted the policy in the late 1980s after early experience showed that patient representatives can enlighten the advisory panels on such important issues as the sick person's tolerance of the product's side effects. In addition, patient representatives perform an important public health function by informing their own groups about the background of the Agency's product decisions. Their reports as insiders increase the transparency and understanding of FDA's processes.
For more information, log onto www.fda.gov/oashi/patrep/patbroc.html.
FDA inspects domestic firms to make sure their products meet all regulatory requirements. In all, FDA is responsible for the safety of products of more than 110,000 domestic establishments. Approximately 17,000 of these firms, primarily human drug, animal drug, biological, and medical device manufacturers, are required by FDAMA to be inspected at least every two years.
In recent years, the Agency has not achieved this level of coverage. As the table below shows, in FY 1999, FDA inspected this "statutory inventory" at a rate that, for most products, would result in average coverage of one inspection every three to four years.
| Product | Years to Cover |
|---|---|
| Human Drugs | 3.8 |
| Biologicals | 1.6 |
| Animal Drugs and Medicated Feeds | 4.0 |
| Medical Devices | 3.3 |
While FDA regards statutory inspections as high priority, it believes it most rationally uses its limited inspection resources by focusing on issues that pose the most serious public health risks. FDA has focused education and outreach on local industries with a history of compliance problems and on firms that manufacture high-risk products. Firms have reported that these efforts give them a better understanding of FDA requirements. Several other urgent projects are described below.
FDA is working with other federal food safety agencies and the seafood, meat, and poultry industries on a new, science-based approach to ensure high product quality. The object is to identify critical points where contaminants can enter the production process and affect the safety of the final product. Once these points are identified, the manufacturers can put in place appropriate controls to prevent contamination.
There is a clear delineation of functions between the producers and the regulatory agencies: The producers are responsible for the safety and quality of the food, and the government makes sure that this responsibility is carried out. Of the 4,100 firms inspected under this program in FY 1999, only 4 percent had problems that warranted corrective regulatory action.
FDA, in partnership with the National Conference on Interstate Milk Shipments, sponsored a voluntary pilot program to determine if similar, science-based approaches can be accepted as an alternative to the traditional inspection system for pasteurized milk.
In the fall of 1999, FDA began using a new inspection technique for some medical device facilities. This "Quality System Inspection Technique" assesses manufacturers' quality protection measures and gives FDA investigators greater flexibility in conducting efficient and effective comprehensive inspections. A validation study showed that this technique reduces overall inspection time by 44 percent and in-plant inspection time by 58 percent while increasing the firms' consistency and compliance. The Agency is in the process of explaining the new technique, which was developed in collaboration with stakeholders, to the industry.
Although no case of Bovine Spongiform Encephalopathy (BSE) or "Mad Cow" disease was ever identified in the U.S., FDA took numerous actions to prevent its emergence in the U.S. Even before the British government in 1966 announced its concern that BSE could cause in humans a new variant Creutzfeldt-Jakob disease, FDA had formally proposed a ruminant-to-ruminant food ban under the assumption that the origin of BSE in the UK was scrapie in sheep. FDA warned manufacturers of dietary supplements and health care products against the use of bovine-derived material from countries with BSE. Subsequently, FDA banned the use of animal tissues in feed for cattle and other ruminants. These steps have been reinforced by an outreach and compliance campaign that by the end of FY 1999 included over 7,200 inspections and covered almost 90 percent of the involved establishments.
FDA regulates many of the products used in America every day, from foods to drugs to medical devices. Some of these products, such as drugs, have inherent risks, while others, such as foods, can be risky if not handled properly. The Agency manages these risks by reviewing some products before marketing and monitoring all products after marketing. An important part of this post-marketing surveillance is the collection of reports on problems associated with FDA-regulated products. These problems are called adverse events.
Millions of injuries or illnesses occur every year from the use of FDA-regulated products. Nearly 9,000 people a year die from foodborne illness. For drugs alone, the estimated costs for related illnesses and deaths may be as much as $77 billion a year. FDA works with many groups--health-care professionals, consumers, food preparers, and industry--to develop a systematic approach to the problem of product-elated injuries.
FDA is pursuing a three-point strategy to counteract this situation.
* Under spontaneous reporting, FDA encourages and accepts reports sent in by others. Under active reporting, the Agency solicits reports from specific groups, basing the selection on statistical sampling.
FDA uses several postmarketing risk assessment approaches to enhance safe use of medical products. The Adverse Event Reporting System (AERS) for drugs and biological products includes approximately two million reports, about 278,000 of which were received in 1999.
FDA evaluates this data to identify any serious, rare, or unexpected adverse events. When a potential adverse reaction is detected, safety evaluators consult with product reviewers, medical officers and epidemiologists on available data and consider further options. Depending on the seriousness of the issue, FDA may decide to disseminate risk information, such as Dear Healthcare Professional letters, or it may initiate regulatory action, such as change of labeling or withdrawal of the product from the market.
Surveillance of animal drug adverse events is being improved by changing the way reports are reviewed. A state-of-the-art computer network has replaced an outdated, PC-based system for handling the database of reports on such adverse events. These reports are now available to all adverse drug event reviewers. A standard language is being used so the system can be maintained more easily. The increase in access and efficiency has been ten-fold.
To facilitate and speed up adverse event reporting, FDA has initiated a pilot program for electronic submissions, and developed an AERS retrieval system that makes this data quickly accessible by reviewers. In addition, FDA recently published a preliminary regulation that would require drug manufacturers to submit reports electronically.
The proposed rule would help harmonize worldwide reporting of postmarketing safety information and expedite detection of safety problems for marketed drugs. The Agency is also expanding the reporting requirements for manufacturers of biological products to include adverse event reports from unlicensed blood banks and transfusion services. FDA estimates that it would receive under the proposed regulation 116,000 reports a year.
In a report issued last year, "Managing the Risks of Medical Product Use," FDA's Task Force on Risk Management recommended the following steps to enhance the current system: 1) complete the AERS system; 2) integrate existing postmarketing information systems so that analytic tools, data entry, and editing can be uniformly applied; 3) enhance and intensify surveillance of newly marketed products; 4) enhance clinical and laboratory studies to develop new methods to improve product safety; and 5) develop new methods for improving inferences from the available databases. FDA is in the process of implementing these recommendations.
Surveillance of medical devices is being improved by replacing the universal reporting requirement for all health care facilities with a system that is smaller but population-based. This new system, MeDSuN, will provide more accurate information by using statistical sampling rather than trying to gather every report. Phase I of the project was completed in 1998, using a pilot program called DeviceNet to collect reports from carefully selected health care facilities.
The results indicate that a properly designed, adequately supported sampling system can provide better surveillance data than universal reporting. The number of reports under DeviceNet was nearly 20 times higher per hospital than under universal reporting. The report on DeviceNet was issued last year and is available at www.fda.gov/cdrh/postsurv/medsun.html. FDA plans to is continue with Phase II of the system and hopes to recruit up to 200 more hospitals into the network.
To combat foodborne illnesses FDA, in cooperation with CDC and USDA, has created FoodNet, a sentinel network that provides accurate estimates of the source and incidence of specific foodborne diseases in the United States. In 1999 FoodNet, a crucial component of the national integrated food safety system, was expanded to cover over 32 million people, or about 12 percent of the U.S. population. FDA and CDC concluded from the collected data that the rates of Campylobacter, Salmonella, and Crytosporidium infections have declined. CDC also used these data to make the first estimates of foodborne illness in this country based on an active surveillance system. The number of illnesses was estimated at 76 million and the deaths at 5,000 per year.
In 1999, FDA completed a three-year research plan to improve methods for detection, control, and prevention of microbial contaminants on fresh produce. As part of its comprehensive strategy to enhance food safety, FDA last year also completed and began validating a method for simultaneously detecting 13 species of pathogens in a single food sample. Yet another project completed last year was FDA's draft risk assessments for two common foodborne pathogens, Listeria monocytogenes and Vibrio parahaemolyticus. These assessments will help the Agency better understand the danger to humans from these organisms and make better decisions on how to control them.
To strengthen its increasingly important postmarketing surveillance of pharmaceuticals, FDA created the Office of Postmarketing Drug Risk. This office plans, directs, and collaborates on epidemiological studies to detect, explore and confirm safety signals, assess risks, and monitor medication errors.
FDA collaborates with states, industry, health care professionals and consumers to improve adverse event reporting. In the forefront of this effort is MedWatch, FDA's medical products reporting program. It serves two goals: (1) to educate health care professionals about the importance of monitoring and reporting adverse events to FDA and/or the manufacturer, and (2) to rapidly communicate the new safety information to the medical community, in order to improve patient care.
MedWatch, which is supported by MedWatch Partners, a coalition of more than 140 organizations of health care professionals and consumer groups, acts as the collection point for adverse event reports that can be submitted by phone, fax, mail, or over the Internet. The reports are evaluated and analyzed and, if necessary, trigger a rapid warning, labeling changes, product recall or other Agency decision. This information is disseminated to the MedWatch Partners and other subscribers of the program's free e-mail service. Last year, MedWatch posted over 50 safety notifications on its website. For more information about the program, log on /www.fda.gov/medwatch/.
FDA also makes a major effort to disseminate information and provide training to reduce the incidence of foodborne illness. Last year, FDA created an Internet page to make available information on adverse events from Special Nutritionals (www.cfsan.fda.gov/~dms/aems.html). In addition to outreach under the Fight Bac! Program, which last year was focused on foodborne risks for children and the elderly, (see www.fightbac.org), FDA last year organized 30 training courses in food safety for state and local retail food regulatory staff, and continued to promote adoption of the model Food Code. This code, which provides guidance on food safety, sanitation, and fair dealing for the retail food industry, so far has been adopted by 30 percent of the states. This exceeds the agency goal of signing up 25 percent by the end of 1999.
FDA has provided safe food handling education to food-service workers in hospitals, nursing homes, and day-care centers. Testing showed that this program effectively increased worker awareness of proper food handling techniques. In the future, the program may be expanded to include other food-service workers in such places as fast food restaurants and churches.
One of FDA's most demanding responsibilities is ensuring that imported products meet U.S. public health requirements. The volume and variety of FDA-regulated products is rapidly rising; last year, these shipments exceeded 5.5 million, almost four times what they were a decade earlier. To make the surveillance task even more difficult, imports arrive at 328 U.S. ports of entry including border crossings, airports, seaports, international mail facilities, and common carrier hubs and centers. FDA follows three strategies to protect consumers against imports that violate U.S. standards: prevention, detection and targeting.
FDA's primary strategy in the international arena involves the establishment of international standards and practices that help ensure that products exported to the U.S. meet FDA requirements. To this end, FDA participates in a variety of international forums and agreements that advance high public health standards, based on solid science.
In the past year, FDA made progress in implementing the pharmaceutical and medical device sections of the Mutual Recognition Agreement (MRA) between the United States and the European Union (E.U.). The current activities are focused on establishing the equivalence of public health protections in the U.S. and the 15 countries of the E.U. When in full force, the MRA will enable FDA and its counterparts in the E.U. to carry out each other's inspections of export facilities and to accept third-party evaluation of low risk medical devices manufactured for export.
FDA is also working with the international community to harmonize requirements for the manufacturing of human and animal drugs and medical devices. The harmonized technical standards enable firms everywhere to produce medical products more efficiently and ensure their admission to the U.S. and other markets. One program promotes the harmonization of technical requirements for the registration of veterinary medicinal products among the European Union, Japan, and the United States.
The Codex Alimentarius of the United Nation's World Health Organization and the Food and Agriculture Organization consists of sound food safety standards that have been developed and adopted by the world's nations over the last four decades. FDA, which has provided significant leadership and expertise for this effort, last year participated in 14 meetings of Codex Alimentarius committees. This work helps ensure the quality of food products entering the U.S.
FDA has over 50 agreements with its foreign regulatory counterparts around the world. These agreements have been established for a number of purposes including: (1) to provide a mechanism for the cooperative exchange of expertise and information to help ensure the safety and quality of covered products; (2) to facilitate working together to eliminate duplication of activities to enhance public health protection; and (3) to help achieve international harmonization of standards and procedures.
FDA inspects many foreign exporters' production facilities and screens their products at the border. Electronic screening allows conforming products to move quickly into commerce while identifying products that may need more review at the border.
FDA assesses foreign food safety systems to assure that a country's exports comply with standards established by U.S. laws. These assessments cover food production, storage, transportation and delivery. The main focus is on countries with a high volume of exports to the U.S., particularly of seafood and produce. In FY 1999, FDA conducted assessments of foreign food safety systems in Costa Rica, Nicaragua, Guatemala and El Salvador.
FDA completed 82 inspections of foreign food facilities in FY 1999, including 78 food plants and 4 farms that produce food products at high risk of microbial contamination. Of the first 26 inspection reports reviewed, 12 establishments had problems that FDA is addressing and 14 were in compliance with FDA regulations. The remaining reports are under review.
OASIS is FDA's automated system for deciding whether foreign products should be allowed into the U.S. Using such data as exporters' prior compliance with U.S. public health standards, OASIS screens shipments seeking to enter the country and clears 85% without paper submission. The system notifies importers' agents of its decision within minutes, thereby reducing the cost of bringing foreign products to the U.S. market.
This laboratory specializes in detecting counterfeit drugs and harmful substances -- for example, toxic components of herbal products. FDA is collaborating with the United Kingdom, Germany, Australia, Canada, The Netherlands, and Switzerland to develop technical data on active pharmaceutical ingredients and toxic substances in herbal products worldwide. The shared analytical and forensic methodologies are intended to slow the trafficking of illegal and dangerous substances, thus resulting in a greater level of consumer protection worldwide.
The third FDA strategy is to target suspect products at the border. A small percentage of import entries are examined at the border, and some -- fewer than one percent of all imports -- are sent to a laboratory for analysis. Some selections are based on FDA's prior experience with the product or exporter, and some are made at random to identify new problem firms or emerging health concerns.
Firms and products with poor histories of compliance are subject to automatic detention until the importer can prove that the product meets FDA standards. The Agency constantly refines its risk-based criteria for screening of imports as more information is entered into its automated review system.
For more information on FDA's Imports Program, visit www.fda.gov/ora/import/ora_import_program.html.
Table of Contents | Objectives (Part 1) | Objectives (Part 2) | Appendices