Fact Sheet
FOR IMMEDIATE RELEASE
August 15, 2006 |
Contact: HHS Press Office
(202) 690-6343
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DRUG SAFETY IS A FOREMOST PRIORITY OF THE FOOD AND DRUG ADMINISTRATION
Overview: Modern drugs provide critical health benefits: they combat pain, extend longevity, and improve quality of life. FDA�s drug review process, which ensures that all medicines on the U.S. market meet the highest standards of safety and effectiveness, is recognized worldwide as second to none. A major component of this program, which accounts for at least half of its resources, is an ongoing assessment of each product�s safety. In addition to a comprehensive evaluation of the safety results from clinical trials, this effort includes a complete appraisal of how each new drug is metabolized, how it interacts with other drugs, and how its safety or effectiveness may potentially change in people of different genders, ages, and races.
FDA grants marketing approval to a drug after a sponsor demonstrates that its benefits outweigh its risks for a specific population and a specific use, thereby meeting the statutory standards for safety and effectiveness. However, no amount of study before marketing will ever yield all the information about effectiveness or all the risks of a new drug. FDA recognizes that there is no way of anticipating all possible effects of a drug from the clinical trials that precede approval. That is why the Agency operates a post-market drug safety program designed to collect reports on and assess adverse events identified after a drug is approved and becomes widely used.
FDA uses information from post-marketing clinical trials, adverse event reports filed by drug manufacturers, spontaneous reporting by physicians, pharmacists, and consumers, and observational studies to identify clinical problems in marketed products. FDA staff monitors this information and looks for emerging patterns. The Agency initiates action as needed.
FDA requires the pharmaceutical industry to comply with current good manufacturing practice (CGMP) that lead to high product quality, consistency, and purity; to utilize appropriate drug marketing and labeling to assure safe use of drug products; and to continuously monitor and evaluate the safety, quality, and effectiveness of drug products and respond appropriately to identified problems.
FDA therefore uses a large portion of its resources in inspections of pharmaceutical sponsors and manufacturers to ensure adherence to these requirements. FDA monitors reports of drug quality problems, coordinates recalls of defective products with manufacturers, and samples marketed products for laboratory analysis to assure that the high quality of the nation�s drug supply is maintained.
Drug quality issues, whether they involve lack of adherence to the CGMPs or actual product defects, are monitored by the Agency very carefully to ensure that the medication will perform as intended over its lifecycle. When FDA finds any deficiencies, it works with sponsors and manufacturers to correct the problems, and it may initiate regulatory actions such as seizures or injunctions. FDA also monitors pharmaceutical approval, labeling, and advertising practices to ensure adherence to the the Food, Drug, and Cosmetic Act and its implementing regulations.
In addition to these systemic protections, in recent years, the FDA has launched novel reforms to upgrade drug safety by modernizing drug development and surveillance. The Agency is also exploring new approaches for keeping counterfeit drugs off the U.S. drug market.
FDA�s DRUG APPROVAL PROCESS
Pre-Approval Focus on Safety
FDA�s focus on safety begins at the earliest stages of drug development. Before beginning any human trials, the sponsor of the drug (usually a drug company, but it may also be an individual researcher) must perform extensive animal toxicity studies. This research provides guidance on initial dosing and points to areas of safety that will need special attention during human trials. FDA thoroughly reviews the results of animal studies to make sure that the candidate drug can be safely tested in humans. Clinical trials with human subjects are conducted usually in three phases, and are closely scrutinized by both researchers and FDA reviewers.
Phase I Studies
The first trial of the use of a drug in humans routinely has two primary goals: to assess the most common side effects, and examine the range of doses that patients can take safely. Phase I studies also provide information on drug kinetics and metabolism, drug-drug interactions, and, often, on the effects of the drug on the specific human physiology. Laboratory tests in these studies are usually extensive, and may even include measures of individual organ function, such as assessment of the heart by electrocardiogram. Phase I trials may be conducted in healthy volunteers as well as in patients with the disease that the experimental drug is intended to treat. In general, these studies produce initial safety data and useful guidance on the appropriate dose of the drug.
Phase II Studies
These clinical studies are mostly focused on the effectiveness of the tested drug in patients with the disease or condition to be treated. This testing also further identifies short-term, relatively common side effects of the drug. Phase II studies are closely monitored and may involve up to several hundred patients. The trials are also well controlled: some patients receive the tested drug, and their results are compared with other patients who receive a placebo, a different dose of the test drug, and/or another active drug. At the conclusion of these studies, FDA and the sponsor usually meet to determine how the drug�s development should be studied in Phase III and how to design and conduct those additional trials.
Phase III Studies
Researchers design Phase III trials for a still greater number of patients and build on the data gained from the first two phases of trials to provide more information for evaluating the overall benefit-risk relationship of the drug. The larger number of patients -- typically 5,000-6,000, some of whom use the drug for up to two years -- makes possible detection of adverse events that are less frequent and that develop only after longer exposure.
Phase III studies establish the basis for extrapolating the results to the general population. After analyzing the data from all the clinical trials, the drug�s sponsor submits a new drug application (NDA) or biologics license application (BLA) to FDA for its review and approval for its marketing in the United States. FDA�s assessment of the safety aspects of these applications represents about half of the review effort, and it is critical to the determination of whether the products can be marketed.
Phase IV Studies
Even if the Phase I-III clinical studies yield evidence of a drug�s safety and effectiveness, the FDA may decide that its full effects can only be evaluated when it is tested for a longer period of time. Provided that the drug meets important medical needs, the Agency may allow such product to be marketed while the sponsor carries out additional long-term Phase IV studies.
Chemistry, Microbiology, Manufacturing, and Labeling/Marketing Assessment
Prior to FDA�s approval of a drug, the entire spectrum of chemistry, microbiology, pharmacology, and manufacturing processes is comprehensively reviewed to ensure product quality, consistency, and purity in a manufacturing setting. Manufacturing sites are inspected and/or reviewed to verify good manufacturing practices with quality systems that provide consistent high quality production.
Laboratory methods are validated, and labeling is reviewed and approved, along with marketing plans (such as distribution by prescription only). For some high-risk drugs a special plan (Risk Minimization Action Plan, or RiskMAP) is developed to assure that the drug will be used only in appropriate settings to maximize its benefits and minimize its risks. This may involve monitored or restricted distribution of the drug with special controls in place to deter inappropriate use.
Post-Approval Risk Assessment
Once FDA approves a drug, the post-marketing monitoring stage begins. The sponsor is required to submit to the FDA safety updates on the drug. In case of serious and previously unidentified risks, this information must be provided in an expedited fashion; less urgent safety issues are reported to the agency periodically. The submitted data include adverse events that had been reported to the sponsor as well as results of new published and unpublished studies.
In addition to these required reports from the drug sponsors, health care providers and patients send voluntary adverse event information the FDA�s MedWatch program. The bulk of the more than 400,000 required and voluntary reports that the Agency receives each year is stored in a computerized database and analyzed for frequency and seriousness by FDA epidemiologists and safety evaluators. The FDA�s response to information from this surveillance takes into account the frequency of the adverse events, their seriousness and how they affect known public health benefit of the product compared to its evolving risk profile.
FDA conducts periodic inspections of drug manufacturing establishments to ensure their adherence to good manufacturing practices and appropriate monitoring of adverse drug experiences. FDA has a trained regional workforce that conducts these inspections under comprehensive protocols. The Agency reviews periodic reports from each manufacturer of an approved drug and other sources of information, and follows-up with manufacturers on identified problems. This follow-up may be informal, a formal inspection or investigation, and may lead to regulatory or legal action with the firms involved.
Regulatory Actions
There are many possible regulatory actions that FDA can take when a new safety concern about a drug arises. Decisions about regulatory responses to evidence of a drug safety risk take into account many factors. A rare adverse event, even a serious one, may or may not by itself be sufficient to remove the drug from the market. FDA generally allows continued marketing of the drug if its public health benefit outweighs its known risks, but may seek labeling revision to better reflect new information on appropriate use.
For example, the FDA may ask the manufacturer to add to the labeling information on adverse reactions not previously listed, new warnings describing conditions under which the drug should not be used, or new precautions advising physicians on measures to minimize risk.
In addition, FDA often issues Public Health Advisories and information sheets for health care providers and patients that discuss new safety information. In the event of reports of death or life-threatening injury, FDA and the sponsor may consider restricting the distribution of the product or removing it from the market.
The choice of the FDA action will depend on the characteristics and frequency of the adverse events; the seriousness of the disease or condition for which the drug provides a benefit; the availability of alternative therapy; and the consequences of leaving the disease without a treatment.
FDA protects consumers from unapproved and misbranded drugs, particularly when they are associated with safety issues. The Agency may take enforcement action against firms that market unapproved drugs, particularly if they raise safety concerns associated with the product�s ingredients or labeling.
FDA and state regulatory authorities also protect consumers from unsafe products compounded by pharmacies. FDA may act against compounded products that are not sterile, are found to be contaminated or to have potency deficiencies which could cause serious and non reversible injury to patients. In addition, FDA routinely assesses drugs imported into the U.S. and prevents entry of drugs that could pose a serious public health hazard to U.S. consumers.
FDA�S DRUG SAFETY INITIATIVES
Since 2003, the FDA has launched major regulatory reforms aimed at fundamentally modernizing the drug development process and upgrading drug safety. The agency is also exploring the use of modern information technology to protect Americans against medications that are unsafe, unapproved, improperly labeled, and potentially harmful to patients.
Critical Path of Drug Discovery
In March 2004 the FDA released a report, �Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products� (www.fda.gov/oc/initiatives/criticalpath/whitepaper.html) that describes how to modernize medical product development by making it more predictable and less costly.
Because of the limitations of current methods, clinical testing -- the �critical path� to new drug approval -- often fails to detect important safety problems, either because the problem itself is uncommon or because the tested population is not representative of patients who will eventually be taking the drug. As a result, safety hazards of new drug products may only emerge after their development has cost millions of dollars -- sometimes, after the product is on the market.
The Critical Path report outlines how FDA can collaborate with academic researchers, product developers, patient groups, and other stakeholders to design novel ways and state-of-the-art tools for foreseeing potential safety pitfalls, thereby making drug development -- including individualized therapies -- more predictable, faster, and less costly.
Enhancing the Safety of Medical Products
More specifically, the FDA has proposed a collaborative research effort to modernize diagnostics, such as pharmacogenomic tests and imaging techniques, which are currently used for the assessment of the safety and effectiveness of new products. The new performance standards and predictive tools would not only provide faster and more reliable answers about the safety and effectiveness of investigational products, but could also be used to monitor the safety of drugs on the market.
In addition to improved safety tools, the Critical Path research also focuses on new means to help individualize therapy by identifying patients who will respond to certain medications and, very importantly, protect those for whom they would pose a high risk for serious side effects.
Although unprecedented in its scope, extent of cooperation and far-reaching aims, Critical Path is not a fundamental departure for FDA. Rather, it builds on the agency�s proven �best practices� for expediting the availability of promising medical technologies.
November, 2004 Drug Safety Plan
As part of a November, 2004 initiative, the FDA has taken the following steps to strengthen its drug safety program:
(1) sponsored a study by the Institute of Medicine to evaluate the entire current U.S. drug safety system, with an emphasis on the effectiveness of the post-marketing surveillance. This inquiry, now in process, will also assess what additional measures are necessary to enhance the confidence of Americans in the safety and effectiveness of their drugs;
(2) implemented a program that ensures that the opinions of dissenting scientific reviewers on drug safety are formally addressed as part of FDA�s decision-making on that product�s approval, and that this process is transparent;
(3) filled the vacant post of the Director of the Office of Drug Safety, following a nation-wide search for the best-qualified candidate. ODS is responsible for overseeing the post-marketing safety program for all drugs;
(4) published final versions of three FDA guidances to help pharmaceutical firms manage risks involving drugs and biological products. These documents will assist pharmaceutical firms in identifying and assessing potential safety risks before and after a drug reaches the market; and
(5) prepared plans for additional workshops and advisory committee meetings to discuss complex drug safety and risk management issues with foremost experts in the U.S. health care community.
Drug Safety Oversight Board
Since February 2005, the FDA has been implementing additional novel measures for promoting a culture of transparency, openness, and enhanced oversight within the agency.
The cornerstone of this effort has been the establishment of the Drug Safety Oversight Board (DSB), which consists of top medical experts internal and external to the Agency. DSB�s role is to provide independent drug safety oversight and advise the FDA on the management of drug safety issues, including the dissemination of emerging drug safety information to health care professionals and patients.
DSB�s is mainly responsible for the following functions:
establishing policies for the management of drug safety issues; identifying, tracking, and overseeing management of weighty drug safety issues, and adjudication of involved organizational disputes; tracking important emerging safety issues and ensuring that they are resolved in a timely manner; ensuring that FDA�s decisions about a drug�s safety reflect the input and perspective of impartial experts in and out of the Agency.
In addition, DSB is charged with increasing the transparency of the FDA�s decision-making process by establishing new and expanding existing communication channels to provide drug safety information to the public.
The DSB will contribute to this process in two major ways:
(1) By selecting information to be placed on Drug Watch, a proposed FDA Website for alerting prescribers and patients to certain emerging and possibly serious side effects or other safety risks associated with previously and newly approved drugs. The postings may also suggest measures that patients and practitioners can take to prevent or mitigate harm from a hazardous medication, in some cases even before the FDA has decided on a regulatory action.
(2) By overseeing the development of patient and professional information sheets:
THE COUNTERFEIT DRUG PROBLEM
U.S. law defines counterfeit drugs as those sold under a product name without proper authorization, where the identity of the source of the drug is knowingly and intentionally mislabeled in a way that suggests that it is the authentic approved product. Counterfeit drugs are illegal, and many pose a potentially serious health threat.
Although the vast majority of drugs sold in the U.S. are legitimate, in recent years there has been an increased influx of counterfeit drugs on the U.S. market. Some of these drugs are shipped to individual buyers who order them in good faith from mostly foreign-based Internet pharmacies. The FDA is confronting this illegal trade in cooperation with foreign regulatory agencies and by explaining the dangerous nature of these imports to the U.S. public.
A potentially more serious public health hazard is the increase in sophisticated efforts to introduce counterfeits into legitimate U.S. drug distribution channels. This trend has been reflected in the workload of the FDA�s enforcement components, including the Office of Criminal Investigations (OCI), which has sharply risen in part as a result of greater vigilance by state and federal law enforcement agencies. In FY 2004, OCI initiated 58 counterfeit drug cases, almost double the 30 cases initiated in FY 2003.
Although most of the detected counterfeit drugs were interdicted before they entered domestic distribution, the FDA is concerned that the U.S. drug supply is under an unprecedented attack. In 2003, the FDA therefore established a Counterfeit Drug Task Force and tasked it with examining the counterfeiting threat and report on ways of confronting it.
The Task Force�s blueprint, which is available at www.fda.gov/counterfeit, identifies measures that the public and private sectors can take to address six critical areas:
- Securing the legitimate drug products and their packaging;
- Securing their movement through the U.S. drug distribution chain;
- Enhancing regulatory oversight and enforcement;
- Increasing penalties for counterfeiters;
- Heightening vigilance and awareness of counterfeit drugs; and
- Increasing international collaboration.
Securing the Product, its Packaging, and its Movement
The Task Force Report emphasized the critical need to protect the drug supply through the latest information technologies. Although still in development, by 2007, these technologies are expected to be capable of authenticating drugs and tracking and tracing them in the supply chain. Radio-frequency identification (RFID), the most promising technology for ensuring the record of a drug�s origin and distribution -- the product�s so-called �pedigree� -- is already being tested in actual use.
RFID technology uses a tiny radio frequency chip containing essential data in the form of an electronic product code (EPC). By tying each product to a unique electronic serial number, the unit can be tracked electronically through every part of the supply chain. With FDA�s support, the development and implementation of EPC/RFID is being vigorously advanced by researchers and firms.
A critical part of this massive undertaking is the designation of standards for the type of technology and the systems to be used for storing and sharing the �pedigree� information. The FDA has cooperated in the exploration of these issues in many industry and government meetings and workshops, and in November, 2004 issued a Compliance Policy Guide for RFID feasibility studies and pilot programs.
Since then, several members of the supply chain have announced their intention to move forward with RFID pilot programs, and three major pharmaceutical firms have begun RFID-tagging some of their products that are believed to be susceptible to counterfeiting.
The FDA continues encouraging this notable progress in confronting the menace of counterfeiting. Among its many other contributions, the agency has published a protocol for studies of the impact of radio frequency on drug and biological products; it is analyzing the effects of several RFID systems on certain liquid pharmaceuticals; it is providing advice on the application and use of authentication technologies; and it continues to facilitate standard-setting for the planned �electronic safety net� for our drug supply.
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Note: All HHS press releases, fact sheets and other press materials are available at http://www.hhs.gov/news.
Last Revised: August 15, 2006
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