FDA Overview (cont.)

Product Approvals (Drugs and Food)

The FDA regulates an enormous number of companies. As of November 2000, the FDA's Official Establishment Inventory, the FDA's database of establishments regulated by the agency, included 135,885 firms including these:

• 64,756 food and cosmetic firms



• 37,839 device and radiological health firms (of which roughly 9,500 are mammography facilities)



• 17,625 human drug firms



• 7,702 animal drug and feed firms



• 4,223 biologic firms



• 2,320 storage warehouses



• 1,420 miscellaneous food-related facilities

In addition, there are about 1,500 dietary supplement manufacturers, ingredient suppliers, and wholesalers.

Some establishments, such as drug and medical device firms, are required to register with the FDA. Other companies such as dietary supplement manufacturers, warehouses, and, until recently, food firms are not required to register with the FDA. These numbers are subject to fluctuation. Indeed, a report from the HHS Office of the Inspector General took the agency to task after a telephone survey of 100 randomly selected firms suggested that as many as 16% of the businesses listed in the Official Establishment Industry (21,742 firms) may no longer be in operation.

The Office of the Inspector General (OIG) also pointed out that some firms that belong in the inventory may not be included, although the OIG's study did not directly address this issue. New requirements that food establishments register with the FDA and new information technology may help reduce inaccuracies in the database.

FDA requirements vary depending on the type of product being produced. Regulations pertaining to some of the key FDA-regulated commodities are discussed here.

The FDA recently announced plans to take several steps to improve the agency’s review of "innovative" biologic, drug, medical device and veterinary products (FDA, Improving Innovation, 2003).

The FDA hopes its efforts will facilitate the use of advanced technology and speed the agency's review and approval of new types of medical treatments. The agency plans to take a number of steps, including publishing information for manufacturers about the "design and execution of clinical trials" for cancer, diabetes, and obesity treatments; attempting to reduce delays in the review of new products by improving communication with manufacturers early in the review process; and providing additional guidance about "three emerging areas of technology": cell and gene therapies, "novel drug delivery systems" or treatments that take advantage of improved scientific understanding about how an individual’s genetic makeup impacts the effectiveness of the medications they are taking (pharmacogenomics)."

Drug Approval: Drugs are defined in section 201(g) of the FD&C Act as (1) articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to these compendia; (2) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; (3) articles (other than food) intended to affect the structure or any function of the body of man or other animals; (4) ingredients of these products.

• Drugs that include new active ingredients or new excipients (other components of the drug) are formulated differently from existing products, are delivered by new route or are intended for new or additional uses must be approved by the FDA.



• In most cases, at least one and generally more than one clinical study on human beings will be necessary for a drug to be approved. As the FDA points out, there is a need for independent substantiation of results that are subject to variation because clinical investigators and patients participating in one study may differ from those in another study. In some cases, however, the FDA will approve a drug based on the results of a single, multi-center clinical study.



• The FDA has finalized a 1999 rule allowing approval of drug and biological products to treat biological, chemical, or radiological toxicity based on clinical studies conducted in animal models, when tests in humans are not ethical or feasible because of the danger of the substances involved (such as anthrax). Tests in animals may be sufficient to allow approval of the product when the drug's metabolism is well-understood, and when the effect of the product on an animal species will reflect the effect in human beings.



• Before drugs can be tested in humans, extensive preclinical testing in the lab and in animals is required. Drugs may require 4-8 years of preclinical testing before testing in humans begins. Nonclinical tests provide information about how the drug may function within the body and the possible toxicology (adverse effects) of a drug.



• Laboratory tests intended to furnish evidence for drug approval must be conducted in accordance with the FDA's good laboratory practice rules (21 CFR 58), which impose recordkeeping, personnel training, animal handling, and equipment requirements. The FDA inspects laboratories to ensure compliance with these rules and may delay approval or reject an application for drug approval if these rules are not followed.
  
  
  • Drug testing: Before clinical testing of new products begins, companies must submit an investigational new drug application (IND) or investigational new animal drug application (INAD). The IND becomes effective within 1 month unless the FDA places a clinical hold on the application or on the clinical trial once in progress because it finds deficiencies such as concerns about the qualifications of the researchers, which occurs 5-20% of the time.
  
  
  
  • The FDA also may withdraw an IND, thereby prohibiting further use of the drug. Animal tests provide safety data and help establish if the drug should proceed to clinical testing.
  
  
  
  • The IND will specify how the sponsoring company, institution, and researcher plan to further investigate the safety of the drug in human subjects and discuss the toxicological and pharmacological data obtained in preclinical studies.
  
  
  
  • Treatment INDs permit companies to make drugs available to patients who are not part of clinical trials if the drug is intended to treat serious illnesses such as AIDS and trials are currently in progress.
  
  
  
  • Clinical trials: There are 3 phases of clinical trials.
    
    
    • Phase I trials help determine how the drug is metabolized, help establish the optimal dose, and involve fewer than 100 people. These studies may help researchers gauge the proper dose of the product.
    
    
    
    • Phase II trials may involve 100-200 patients and explore the safety and effectiveness of the product as well as side effects and may involve hundreds of patients. Early phase II studies may try to assess the efficacy of the drug, while later studies may evaluate how much better (if at all) the drug is than a placebo given to patients with similar conditions and characteristics.
    
    
    
    • If these studies suggest the drug is effective, phase III trials, which examine the long-term safety and efficacy of the product and often involve thousands of patients throughout the country, may begin. These pivotal studies will try to gather the information needed to gain FDA approval. The FDA has issued many guidelines related to the conduct of clinical trials and may meet with sponsors during the clinical trial process.
    
    
    
  • Clinical trials must be conducted in accordance with the FDA's good clinical practice rules, a series of regulations published by the FDA, which require institutional review boards to review clinical study protocols, informed consent from subjects and monitoring. The FDA's Office for Good Clinical Practice, part of the Office of the Commissioner, is a focal point within the agency for clinical trial issues and helps set the agency's policies on these issues and working with the department's Office of Human Research Protection. Although the Bioresearch Monitoring program inspects clinical trial sponsors, institutional review boards and investigators can reject studies, halt studies, disqualify sponsors or researchers from working on studies, and send Warning Letters or take other enforcement action against facilities or individuals that fail to comply with Good Clinical Practices.
  
  
  
  • Institutions conducting clinical tests must establish institutional review boards (IRBs), which ensure that studies are conducted ethically and with due regard for patient safety. IRBs should be staffed by experts who can represent different perspectives and are familiar with health issues. IRBs may include physicians, other health professionals, scientists, nurses, lawyers, and community or patient representatives. Researchers conducting clinical trials to gain approval of FDA-regulated products are required to gain the informed consent of patients prior to their enrollment in clinical trials, which means that they must tell patients about the study's goals and the risks and benefits to the patient and ensuring that the patient understands and acknowledges that he or she has been provided with this information.
  
  
  
  • Most trials involving new drugs, however, are funded by pharmaceutical companies, which hire clinical study coordinators and monitors to ensure that FDA regulations are followed or pay contract research organizations to monitor the studies. An industry trade group, PhRMA, has published voluntary guidelines spelling out the obligations of companies conducting trials to protect patients, minimize conflicts of interest among clinical investigators, and adequately monitor trials and publish results.
    
    
    • Reliable information about clinical trials and in-depth coverage of trials is provided by a number of government agencies and nonprofit organizations and has been the subject of well-written special reports by mainstream newspapers such as an August 2001 report from The Tennessean titled "Inside a cancer trial: what science learns from one life." A comprehensive, patient-friendly report published in February 2002 by the American Association of Health Plans and ECRI, a nonprofit research organization, titled Should I Enter a Clinical Trial: A Patient Reference Guide for Adults with a Serious or Life-Threatening Illness discusses the FDA and other federal agencies involved in regulation of clinical trials, the benefits and drawbacks for patients of participating in different stages in clinical trials, the reasons why clinical trials are necessary, informed consent, key terms and insurance coverage issues. The Guide is available on the AHIP and ECRI Web sites. The FDA's Office of Special Health Issues lists articles and FDA-produced brochures about clinical trials.
    
    
    
    • Information about ongoing trials is available from federal government and clinical trial Web sites at Clinical Trials.gov, Center Watch, the National Cancer Institute, and other sources listed in the AAHP/ECRI report. Associations (such as the Amyotrophic Lateral Sclerosis Association), pharmaceutical companies, and contract research organizations that help pharmaceutical companies conduct and monitor clinical trials (for example, Amgentrials.com and Acurian), and university-affiliated centers or Web sites also may maintain their own lists of clinical trials (see the Internet Stroke Center, affiliated with the Washington University School of Medicine) for certain diseases or conditions. Also, the National Institutes of Health maintains a database of clinical trials.
    
    
    
  • As the General Accounting Office noted in a recent report, "[t]here are many examples in the medical literature of sex differences in the way men and women absorb, distribute and metabolize drugs." Likewise, in some cases the effects of drugs may differ in minority populations and it is important that clinical trials include a wide variety of people from all backgrounds because a medical product will be prescribed to people of varying backgrounds. This means that it is important that women and minorities are adequately represented throughout the entire clinical study process. In a July 2001 report, the General Accounting Office reviewed 36 new drug applications submitted to the FDA between August 1998 and December 2000. The GAO found that 52% of study participants overall were women. However, the study recommended more FDA scrutiny because women were found to be underrepresented in earlier phase I or phase II trials when the drug dose is established and because some sponsors are not following requirements that NDAs provide certain data on the safety and efficacy of the drug in men and women.
  
  
  
  • The Food and Drug Modernization Act of 1997 (section 115) encouraged the FDA to increase women and minority enrollment in clinical trials. The FDA has issued guidance and promulgated regulations encouraging sponsoring institutions to ensure that women and minorities are adequately represented in clinical trials and that drugs are labeled to reflect effects among different subpopulations.
  
  
  
  • The FDA also recently issued draft guidance designed to encourage a "standardized approach for collecting race and ethnicity information in clinical trials" (FDA, FDA Issues Guidance, 2003). The agency believes that this effort will allow "early identification of differences in response among racial and ethnic groups during the evaluation of safety and effectiveness of FDA-regulated products," according to an FDA press release.
  
  
  
  • Although the FDA has not issued specific guidance regarding the enrollment of minorities in clinical trials, the FDA's Office of Special Health Issues has studied minority enrollment in clinical trials, and FDA has issued guidance and promulgated regulations encouraging sponsoring institutions to ensure that women and minorities are adequately represented in clinical trials and that drugs are labeled to reflect effects among different subpopulations.
  
  
  
  • Many drugs used in children are approved based on clinical studies conducted in adults. In 1994, more than 70% of drugs lacked pediatric drug labeling. Because children may require different doses and experience different adverse events than adults, it is crucial they too must be included in clinical studies.
    
    
    • Pediatric rule: Under the so-called Pediatric Rule (21 CFR 314.55(a), 21 CFR 601.21(a), first introduced in 1998, companies introducing new active ingredients for biologics and drugs, and new dosage forms or indications for existing biologics and drugs, are supposed to assess the effects of the drugs in children and include information about pediatric use of product in their postmarketing reports. Generic drugs and orphan drugs are exempt from this requirement, and manufacturers may petition the agency to waive this requirement for other drugs. For instance, products intended to treat diseases that rarely occur in children, such as Alzheimer disease or osteoarthritis, "are likely to be granted a waiver." On the other hand, certain biologic products and drugs that are (a) already marketed but used in a substantial number of children or (b) would provide a meaningful therapeutic benefit over existing treatments for pediatric patients both may be subject to the requirements of the rule where inadequate labeling could pose significant risks if studies in children are not conducted. Failure to comply with the rule may render a product misbranded.
    
    
    
    • The pediatric rule allows the FDA to require a pediatric assessment of safety and effectiveness of certain drugs or biological products. But the FDA also can offer incentives to companies to study how drug products affect children. A provision in the Food and Drug Modernization Act of 1997 offers 6 months of pediatric exclusivity to companies conducting pediatric studies in children in response to an agency request.
    
    
    
    • In general, the 6-month exclusivity provision "has done more to generate clinical studies and useful prescribing information for the pediatric population than any other regulatory or legislative process to date," according to an HHS report to Congress. A Washington Post article reported that since 1997 pediatric studies involving roughly 60 medications have been conducted in pediatric populations and "studies of another 100 or so are underway" (Kritz, 2002). These studies have prompted significant labeling changes for commonly prescribed medications.
    
    
    
    • However, gaps remain because some drugs ineligible for the exclusivity, such as certain antibiotics, have not been adequately studied in children, and certain other drugs have not been adequately studied within certain age groups for which the drug may be widely prescribed (such as Ritalin in children under 6). For example, few studies have been conducted in children under 2. In addition, the pediatric exclusivity provision applies only to drug products not to biologics.
    
    
    
    • The FDA believed that even with FDAMA's pediatric exclusivity the pediatric rule was needed to address some of the gaps left by the pediatric exclusivity provision. Both manufacturers of new drugs for which the sponsor is required to conduct a pediatric assessment under the [pediatric] rule and manufacturers of already marketed drugs may qualify for exclusivity. The benefit of the pediatric rule from the FDA's perspective, at least is that the agency can require manufacturers to conduct pediatric studies should they choose not do so on their own and further require manufacturers of currently marketed products not eligible for exclusivity under the modernization act to conduct such studies. However, the FDA has indicated that it will force manufacturers of already marketed drugs to conduct such studies only under compelling circumstances such as its use in substantial numbers of pediatric patients. Further information on the pediatric rule, pediatric exclusivity, and other issues is available at the FDA's pediatric medicine site.
    
    
    
    • The pediatric exclusivity provision was set to expire in 2002 but was reauthorized by Congress in January 2002 in the Best Pharmaceuticals for Children Act (BCPA). The law was strongly endorsed by professional groups such as the American Academy of Pediatrics (AAP). The new law addressed certain gaps by allowing National Institutes of Health to fund studies of certain drugs, such as antibiotics, that still may be used but no longer are patented, establishing a pediatric pharmacology advisory committee at FDA; requiring labeling changes to reflect knowledge gained from pediatric studies within the six-month exclusivity period; establishing an Office of Pediatrics at the FDA; and requiring that the FDA publish regulations to ensure that labeling for drugs given exclusivity include a number for adverse event reporting. In addition, the law requires the FDA to work with companies to ensure children from ethnic and racial minority groups are adequately represented in clinical studies and a study on inclusion of children from minority groups in such studies must be completed by January 2003. In January 2003, the Department of Health and Human Services determined that 12 drugs would be tested in pediatric populations in 2003 and 2004 using funds allocated under the BCPA.
    
    
    
    • Even after the BCPA was enacted, the American Academy of Pediatrics and other prominent medical professional organizations continued to believe that the pediatric rule was necessary because, as noted, the BCPA does not apply to all biologic and drug products. But support for the pediatric rule is not unanimous. In 2000, three nonprofit groups—the Competitive Enterprise Institute, the American Association of Physicians & Surgeons, and Consumer Alert—asked a federal court to overturn the pediatric rule after the FDA rejected a citizens' petition they filed with the agency. The 3 organizations argued that drug and biologic manufacturers not the FDA should determine how their products are labeled. The organizations also expressed concern that pediatric testing requirements could delay the approval of new drugs intended for use in adult populations. In October 2002, a judge in the United States District Court for the District of Columbia ruled that the FDA did not have the authority to issue the pediatric rule and that in passing the BCPA, which calls for voluntary pediatric testing, is "incompatible" with the mandatory testing scheme envisioned by the pediatric rule (FDA Warning Letters, 2002; Kaufman, 2002).
    
    
    
    • A bipartisan group of 10 legislators, including Senator Hillary Clinton (D-NY), Senator Mike Dewine (R-Ohio), Rep. Sherrod Brown (D-Ohio) and Rep. Henry Waxman (D-Calif.) sponsored a bill that would amend the Federal Food, Drug & Cosmetic Act. Manufacturers would be required to conduct tests so that the dose, effectiveness, and safety of new biologic and drug products in children could be determined. The bill was approved by the Senate Health, Education, Labor & Pensions Committee but not voted on by the full 107th Congress. Supporters of the congressional effort to enact the pediatric rule into law criticized the court’s ruling and pledged to continue their efforts. The Department of Health and Human Services said in December 2002 that it would seek to work with Congress to enact the pediatric rule into law. Such a law is needed because the BCPA does not apply to off-patent medications or products not subject to the pediatric exclusivity provisions, according to an HHS press release (HHS, 2002).
    
    
    
    • Companies must submit reports of adverse events during clinical trials and update the FDA on the progress and findings of the trials.
    
    
    
  • FDAMA Fast Track provisions: Under the Food and Drug Modernization Act of 1997, the FDA tries to rapidly approve "priority" medications intended for serious illnesses and for which no alternative currently is available.
    
    
    • After clinical testing is conducted, drug companies must submit new drug applications (NDAs) for human (21 CFR 314) and animal drug products. The NDAs contain information about the product's chemistry and manufacturing controls, pharmacokinetics of the product, draft labeling, and clinical, safety and statistical data.
    
    
    
    • Under the third rendition of the Prescription Drug User Fee Act (PDUFA III), which will run from 2003 through 2007, in exchange for user fees paid by drug and biologic companies, the FDA is supposed to review at least 90% of NDAs within prescribed time frames: 6 months for "priority" drugs that offer new treatments or represent significant improvements over existing treatments and 10 months for "standard" drugs that do not offer such benefits. FDA reviewers will review the scientific data contained within the NDA to ensure that the drug is safe, effective, and manufactured in accordance with good manufacturing practice regulations. The FDA has developed good review practices to try to improve the review process and communicate expectations to industry. As can be seen from diagrams of the review process posted by CDER offices, the review process can be extremely complicated and requires companies to address FDA concerns throughout the approval. The FDA will inspect companies prior to approval to ensure compliance with FDA requirements. If new information becomes apparent to the company while the NDA is being reviewed, the company must file an NDA Amendment to bring these facts to FDA attention.
    
    
    
    • If an NDA is not approved, a company can appeal the decision within the agency, seek review by an HHS Administrative Law Judge and take the matter to federal court. Advisory committees may help the agency review new drugs. The process is not open to the public.
    
    
    
    • If the NDA is approved, companies will obtain the approved labeling information, package insert, and approved uses from the agency. Labeling for prescription drugs is generally geared toward physicians and other health professionals rather than consumers, although the advent of direct-to-consumer advertising has made such information more relevant to consumers in recent years. Labeling is required to include the chemical name of the drug, indications, contraindications, pharmacology, precautions, possible adverse reactions, clinical study information, and information to be given to patients. Specific requirements on content and format of labeling for human prescription drugs are available. Professional labeling is published in the Physicians Desk Reference. The FDA may require that additional information be provided by physicians or companies for certain products such as Lotronex and Accutane that may be associated with adverse events.
    
    
    
    • Patients also may receive information from pharmacists when they obtain prescription products. This information is written by private database companies. A 1996 law required the FDA to evaluate the adequacy of private-sector prescription drug information given to patients and to ensure that 95% of patients receive useful patient information at the time of dispensing by 2006. Currently, 89% of patients receive such information from their pharmacies. But in light of a recent study finding that many patients have difficulty understanding the information provided and that consumers may not be adequately informed about possible adverse events or contraindications, an FDA advisory panel, the drug safety and risk management advisory committee, recently voted that the FDA should reject self-regulation by the medical database companies that provide the information to pharmacies.
    
    
    
    • Public Citizen, a consumer group, recently filed suit against the FDA because of deficiencies in the "medication guides" provided by pharmacies. The complaint, filed in the U.S. District Court for the District of Columbia, claims that the current "private sector initiative" has failed to fulfill the terms of the 1996 law because, as the FDA study showed, the information often was not useful to consumers and was "extremely difficult to read." Public Citizen wants the court to order the FDA to allow public comment about alternative approaches to providing patient safety information at pharmacies (Public Citizen, 2003).
    
    
    
    • A company's obligations do not end once an application has been approved. The agency has issued good manufacturing practice regulations to which the companies must conform in their manufacturing. Products not manufactured in accordance with good manufacturing practice regulations may be adulterated or misbranded and subject to seizure.
    
    
    
    • Companies must also submit adverse events to the FDA and report changes in the drug's formulation, manufacturing, or labeling. Doctors or patients may submit a form to the FDA discussing the name of the product, date, patient medical history, laboratory data, and nature of the event through the agency's MedWatch program. Manufacturers and hospitals are required to report such events. Health professionals and consumers are encouraged to report these events, and consumers may find more information in an FDA Backgrounder entitled Problem Reporting.
    
    
    
    • The FDA received 250,000 adverse event reports in 2000, but although this sounds like a great many, medical experts and scientific studies have suggested that only 1-10% of adverse events are reported to the FDA. An FDA learning module for physicians suggests that if studies concerning the incidence of adverse drug reactions in hospitalized patients are accurate, then it is possible that more than 2.2 million adverse drug reactions occur in hospitalized patients each year. In addition, the FDA module points out that thousands of additional adverse events may be experienced by patients in nursing homes and patients who are treated on an outpatient basis. The report attributes the frequency of adverse drug reactions to "many" factors, including the growing number of drug products available to physicians and patients, the fact that many patients are taking multiple medications and the large number of prescriptions being written by physicians (the report states that "2;.8 billion prescriptions were filled by patients in 2000).
    
    
    
    • The FDA stated bluntly in its fiscal year 2002 performance plan that "[w]e believe there is serious under-reporting of adverse events." The FDA is hoping to increase publicity about adverse event reporting, improve product labeling, enhance its ability to respond to reported events, and create a Medical Product Surveillance Network (MedSUN) to encourage hospitals to report adverse events to help address this problem.
    
    
    
    • Most MedWatch reports (roughly 80%) are submitted by manufacturers since they are required to submit such reports. Report may be submitted by phone, fax, Web. Serious adverse events must be reported within 15 days. Companies and executives who fail to report such information in a timely manner can be subject to FDA enforcement action or lawsuits from adversely affected patients.
    
    
    
    • Drugs may be approved by the FDA on the condition that manufacturers conduct so-called Phase IV or postmarketing studies. Some concern has been expressed that certain drug manufacturers may not be completing these studies in a timely manner.
    
    
    
    • If an approved product is subsequently shown to be unsafe, the company continually violates GMP regulations or is linked with a high number of adverse events, the product may be withdrawn from the market or its distribution restricted to specialist physicians, require bolded or "black box" warnings on the label or other labeling changes or require the company to perform further studies on the drug, known as phase IV studies.
    
    
    
    • All medications have risks as well as benefits. The FDA, Council on Family Health, and National Consumers League have published English- and Spanish-language versions of a pamphlet about drug interactions and other problems that may occur when taking medications. The pamphlet is available from the Council on Family Health. The FDA has taken a number of steps to reduce the risk of medical errors associated with prescription drugs and other products, such as proposing to amend professional labeling requirements so that the labels are easier for health professionals to read and, more recently, preparing to hold a public meeting to consider adding bar codes to drugs and devices to reduce medical mix-ups.
    
    
    
• Drug Labeling
  
  
  • FDA regulations distinguish labeling from advertising, defining the latter more broadly. Labels are defined under 201 (K) of the Act as a display of written, printed or graphic matter upon the container of any article. Labeling is defined under section 201 (m) of the Act, to include "all labels and other written, printed, or graphic matter" that accompany a drug.
  
  
  
  • Examples of labeling identified in FDA regulations include booklets, exhibits, journal articles, and audio or visual presentations. Labeling must indicate the drug's "established name, proprietary name (if any), adequate directions for use, and adequate warnings" (Pines, 1998).
  
  
  
  • FDA labeling regulations require that the labeling be "consistent with approved uses" and include notice of contraindications and side effects. Information contained on Web sites is considered labeling, not advertising. Drug and device labeling is examined by the FDA as part of the drug or device approval process.
  
  
  
  • Prescription drug abuse: The FDA and Substance Abuse and Mental Health Services Administration (SAMHSA) announced a joint radio and TV campaign to publicize the dangers of prescription drug abuse. A survey conducted by SAMHSA in 2001 suggests that 15% of 18- 19-year-olds and 8% of children 12-17 admitted abusing prescription drugs at least once. Pain relievers such as OxyContin and stimulants such as Ritalin and depressants such as Valium are commonly abused among patients, SAMHSA and FDA officials said during a news conference (FDA/SAMHSA, Prescription Drug Abuse Rising Rapidly, 2003).
  
  
  
  • In addition, state and local governments are creating prescription drug monitoring programs to crack down on prescription forging and "doctor shopping," which occurs when patients "li[e] about pain, anxiety, or some other condition to a physician in order to obtain medication, or takes the same problem to multiple physicians to obtain and fill multiple [prescriptions]" (Gebhart, 2002). Fifteen states now have established prescription drug monitoring programs.
    
    
    • Generic drugs: When new drugs are introduced, they are patented by brand-name drug companies. When these patents expire, other companies can make drugs using the same active ingredient. These drugs are known as generic drugs. Generic drug companies must submit an abbreviated new drug application demonstrating that their products are bioequivalent to a drug product already on the market. Information about generic drugs is available at CDER's Office of Generic Drugs home page.
    
    
    
    • According to the FDA, 44% of prescriptions provided to patients are for generic drug products (FDA, Generic Drugs, 2002). The FDA has published an electronic version of the Orange Book, which can be searched by active ingredient (such as desloratadine), proprietary name (for example, Clarinex) or by company (in this example, Schering-Plough). As an FAQ document on the Orange Book Web site states, both generic and brand-name drugs can be found by performing a search using the active ingredient.
    
    
    
    • The Hatch Waxman Act or Drug Price Competition and Patent Term Restoration Act of 1984 allowed generic drugs to be more quickly approved by allowing manufacturers to file an abbreviated new drug application and providing 180 days of exclusive marketing time to the first generic drug company that successfully challenges a listed drug patent.
    
    
    
    • The law also provides market exclusivity for drugs with new chemical entities or drugs for which new indications have been approved for a certain period of time above and beyond that provided by patent law and requires that a generic drug be withdrawn from the market if its brand name precursor is withdrawn (as for a safety reason). The Act also extends the drug's patent to account for time it takes for the FDA to review and approve a new product.
    
    
    
    • An ANDA contains information similar to a new drug application filed by a brand name drug company: labeling and manufacturing process information and a comparison to the precursor drug. The generic product must be formulated similarly to the precursor drug and function in the same manner. Generic drugs are reviewed by CDER's Office of Generic Drugs.
    
    
    
    • The generic company must, as part of its ANDA, provide information about the expiration of the patent held by the brand name drug company. If the company holding the patent disagrees with the generic company's interpretation, it may file suit, delaying approval of the generic product. Recently, some members of Congress have asserted that brand name companies are intentionally trying to delay the introduction of generic products by filing frivolous lawsuits when patents are about to expire and laws aimed at speeding access to generic drug products are now the subject of Congressional debate. As with NDAs, companies must submit amendments when the manufacturing process is changed or new information becomes available.
    
    
    
    • Following a scandal in which several FDA and generic drug company employees were convicted of offering and/or accepting bribes, Congress passed the Generic Drug Enforcement Act in 1992, which allows the FDA to debar drug companies or individuals convicted of misconduct in the drug approval process prohibiting these companies from introducing products. The agency also can revoke approval of a generic product approved based on fraudulent regulatory submissions, The FDA also can delay generic drug approvals and fine companies up to $1 million and individuals up to $250,000 for violations of the Act.
  
  
  • Over-the-Counter (OTC) drugs: OTC drugs are available to consumers without a prescription. Drugs are classified as OTC based on their safety profile, the degree to which their benefits outweigh risks, and the difficulty of using them. According to the Center for Drug Evaluation and Research Handbook, there are 100,000 OTC products currently marketed.
  
  
  
  • Because many drugs were marketed before the development of current regulations requiring proof of safety and efficacy, the FDA is developing OTC drug monographs, which CDER's handbook defines as a "kind of recipe book" covering acceptable ingredients, doses, formulations, and labeling for various kinds of OTC ingredients. Seventeen panels were tasked in 1972 under the OTC Drug Products Review with reviewing ingredients. After an advanced notice of proposed rulemaking is published in the Federal Register, and after 30-60 days for public comment, a tentative final monograph will published in the Federal Register. Monographs apply to active ingredients in certain classes of drugs such as antifungal products.
  
  
  
  • An OTC ingredient will be classified as generally recognized as safe and effective, not generally recognized as safe and effective or, in some cases, the FDA will rule that more information is needed. A new drug application may be required if an active ingredient or delivery method of an OTC drug is changed or if more information becomes available.
  
  
  
  • If a drug conforms to the requirements of an OTC monograph, it may be marketed without further review. Some OTC drugs also may be relabeled to conform to the monograph. For other drugs a new drug application is required. These drugs are reviewed by the Center for Drug Evaluation and Research's Division of Over-the-Counter Drug Products.
  
  
  
  • Manufacturers of prescription drug products may petition to have their drugs switched to OTC, a process called an Rx-to-OTC switch by filing a supplemental New Drug Application or by petitioning for an FDA monograph. CDER will consider the toxicity of the drug and the ability of consumers to understand the disease or condition the drug treats.
  
  
  
  • The study needed to support an OTC switch must show that the product will be safe for over-the counter use and that consumers can understand the labeling information, know when the drug should and should not be used, and will comply with the labeling instructions. Studies are reviewed by the FDA's Nonprescription Drug Advisory Committee and a committee with expertise in the area for which the drug is used (for example, dermatology and gastroenterology).
  
  
  
  • According to the Consumer Health Products Association, 80 ingredients once available only by prescription now are available OTC. (See a graphic representation of the OTC review process.) Some examples of products that have been switched are these:
    
    
    • Anti-diarrhea drugs (loperamide/Imodium A-D, Maalox)
    
    
    
    • Analgesics (ibuprofen [Advil, Motrin], naproxen sodium [Aleve])
    
    
    
    • Antifungal drugs (clotrimazole [non-oral formulation/Femcare, Gyne-Lotrimin])
    
    
    
    • Acid reducers (cimetidine [Tagamet], famotidine [Pepcid])
    
    
    
    • Products intended to promote hair growth (minoxidil 2% [Rogaine])
    
    
    
    • Nicotine addiction treatments (Nicotine transdermal systems [Nicoderm CQ, Nicotrol, Nicorette gum])
    
    
    
  • More recently, FDA panels have recommended approval for Claritin (loratadine) and Prilosec (omeprazole) to be sold OTC (FDA, FDA Approves OTC Claritin, 2002).
  
  
  
  • A new OTC label, which will be required on all OTC products within the next 5 years, is designed to highlight information that is important to consumers (The New Over-the Counter Medicine Label: Visit the US Food and Drug Administration, Consumer Drug Information site). OTC drugs must be labeled with the name of the product, active ingredients, inactive ingredients, purpose of the product, warnings, and directions for use.
  
  
  
  • OTC drug manufacturers are subject to FDA inspection. Most OTC products, as noted here, also are required to have tamper-resistant packaging. In some cases, as with aspirin, the products must also be difficult for children to access (child-resistant).
  
  
  
  • Animal Drugs: A new animal drug is defined in section 201w of the Act as "any drug intended for use in animals other than man, including any drug intended for use in animal feed."
    
    
    • New animal drugs must be generally recognized as safe or a new animal drug application must be approved by the FDA. An Investigational New Animal Drug Application must be filed before clinical testing in animals begins. Drugs intended for use in animals are reviewed by the Center for Veterinary Medicine's Office of New Animal Drug Evaluation and drugs intended for use in animals consumed as food are evaluated to ensure that residues of the drug will not prove harmful to humans.
    
    
    
    • Animal drugs may be approved not only to promote animal health but also to "enhance the production efficiency of food animals" (Lambert and Perron. 2000). If the drug is intended to promote health, a new animal drug application is required. NADAs contain information concerning safety, efficacy, residue detection, manufacturing, labeling and the impact of the drug on the environment.
    
    
    
    • Consideration of the drug's environmental impact is necessary because medications used in aquaculture, for instance, may impact not only the fish to which the medication is provided but also nearby fish and species.
    
    
    
    • If the animal is intended for human consumption, then part of the safety information for this application must address how to ensure that humans are not exposed to residues of this drug in the animals' meat, milk, or other edible byproducts, or at least how to minimize the quantity of drug to which humans are exposed. For instance, the drug may be withdrawn for a certain period of time before the animal goes to market so that residues of the drug are cleared from the animal's body prior to marketing.
    
    
    
    • The CVM will consider how the drug is likely to be used in practice, the cumulative effects of exposure, and the safety effects of the drug and metabolic byproducts.
    
    
    
    • Other drugs may be used to increase animal productivity. For instance, some drugs may increase the animals' ability to gain weight. These drugs also require NADAs and must consider human exposure to drug residues.
    
    
    
    • Some animal drugs are available over-the-counter, while others require a prescription. Certain drugs, called veterinary feed directive drugs, also require a prescription and may be added to medicated animal feed.
    
    
    
    • The CVM also regulates animal drug advertising and labeling. Labeling will be considered by CVM during the approval process.
    
    
    
• Biologic products
  
  
  • In 1902, Congress enacted the Virus Act of 1902 that gave the government its first basis for regulating the processes used for manufacturing biological products. Under the Public Health Service Act, "[b]iologic products are defined as "any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, applicable to the prevention, treatment or cure of diseases or injuries to humans. Biological products include, but are not limited to, bacterial and viral vaccines, human blood and plasma and their derivatives, and certain products produced by biotechnology, such as interferons and erythropoietins."
  
  
  
  • In 1972, the FDA was given formal authority to regulate biologics products; previously vaccines, blood products and other biologics products were regulated by the National Institutes of Health.
    
    
    • Biologic products are approved based on provisions in the Public Health Service Act but as CBER explains "because most biological products also meet the definition of "drugs" under the Federal Food, Drug, and Cosmetic Act (FD&C Act), they are also subject to regulation under FD&C Act provisions."
    
    
    
    • At present, CBER is the Division within the FDA with responsibility for monitoring, blood and blood products, vaccines, allergenics, and a wide variety of newer products related to advancements in biotechnology. Vaccines for animals are regulated by the U.S. Department of Agriculture.
    
    
    
    • A biologic product may be a drug or a device. Under an intra-agency memorandum, some in vitro diagnostic devices related to blood screening and testing are regulated by CBER rather than CDRH.
    
    
    
    • Like drug companies, INDs must be submitted before clinical testing begins. Companies must submit a biologics license application, which requires the same type of information as an NDA. Supplements are required when significant changes are made.
    
    
    
    • Samples of labeling and advertising must be provided to CBER when first distributed. A biological drug must include a package insert and the expiration date. CBER conducts preapproval inspections of biologics facilities. Through Team Biologics, the Center and Office of Regulatory Affairs conduct periodic inspections of facilities to ensure GMP compliance. If significant noncompliance is found, the FDA can revoke the facilities license under section 351 of the Public Health Service Act or require the company to recall certain products.
    
    
    
    • Problems with vaccines are reported through the vaccine adverse event reporting system (VAERS). The system has received roughly 123,000 reports of adverse events. About 85 percent of these events are mild reactions while the remainder concern more serious complications. VAERS reports are submitted by manufacturers, physicians and patients.
    
    
    
    • Blood establishments must conform to good manufacturing practice requirements and report adverse events to the FDA.
    
    
    
• Medical devices
  
  
  • The Medical Device Amendments of 1976 required devices to be approved by the FDA prior to marketing. A medical device is defined in section 201(h) as "an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article including any component, part or accessory, which is (1) recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or (3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent on being metabolized for the achievement of its primary intended purposes."
    
    
    • Manufacturers can apply for an investigational device exemption for preapproval use during clinical trials, submit a premarket notification showing that their device was equivalent to devices already approved by the FDA or submit a premarket approval application.
    
    
    
    • Clinical trials conducted under an IDE must be reviewed by an institutional review board. A 510(k) contains labeling information, manufacturing information, and information about how the device will be used and devices to which it is substantially equivalent. The FDA reviews roughly 5,000 510(k) applications each year. PMAs contain clinical trial information, scientific data, a description of the device, and the indications for the device.
    
    
    
    • The Amendments established 3 kinds of devices.
      
      
      • Class I devices such as bandages and gloves and stethoscopes are subject to general controls, which include labeling, premarket notification requirements, recordkeeping, registration, reporting, and tracking requirements and adherence to quality systems regulations. Manufacturers must submit premarket notifications to show new devices are substantially equivalent to those already on the market.
      
      
      
      • Class II devices such as thermometers and endoscopes are subject to special controls as well. Special controls may include postmarket surveillance, clinical trial, or performance requirements.
      
      
      
      • Class III devices such as contact lenses, pacemakers, and heart valves are subject to both general and special controls. Manufacturers of Class III devices must submit premarket approval applications demonstrating safety and effectiveness, which require extensive clinical studies.
    
    
    • Most Class I and certain Class II devices have been exempted from premarket requirements in order that the FDA may redirect the resources that would be spent on reviewing such submissions to more significant public health issues. Classifications of devices can be searched by key word at the FDA's Classification Database. Devices may be reclassified as experience and knowledge about a device increase.
    
    
    
    • To help ensure that their products consistently meet applicable requirements and specifications, medical device companies must conform to quality systems requirements that were the subject of a 1996 rule. To comply with the quality systems regulation, device companies must have in place production and process controls, quality systems designed to prevent problems, facility and equipment controls, labeling and packaging controls, record-keeping procedures, and methods of correcting and preventing problems, such as tracking devices and reporting adverse events. Companies must further conduct quality audits to ensure that they are complying with the requirements, hire properly educated and trained personnel and have an adequate organizational structure such that company managers can ensure compliance and identify problems in manufacturing.
    
    
    
    • Since 2000, the FDA has conducted inspections using the quality systems inspection technique (QSIT) to ensure companies are complying with the quality systems regulation. Device firms are inspected using the quality systems inspection technique that examines seven subsystems: corrective and preventive action, design controls, management controls, production and process controls, recordkeeping, material controls, and facility and equipment controls.
    
    
    
    • The Safe Medical Device Amendments of 1990 simplified the 510(k) process and requires device manufacturers to submit adverse event reports under certain conditions. The law also changed the PMA requirements and states that substantial equivalence means the same intended use and technological characteristics as the predicate device already on the market to which the new device is equivalent.
    
    
    
    • This law also requires the FDA to designate which Center has jurisdiction over a combination product. For instance, although they are technically medical devices, certain in vitro diagnostic tools are regulated by CBER rather than CDRH because they are used to screen donated blood. Another example: photodynamic therapy, in which laser light is used to activate a drug injected into the body. PDT is used to fight certain types of cancer. PDT is regulated primarily by the CDER rather than CDRH, although medical devices (lasers) are involved as well as photosensitizing agents, drugs that are activated by light. However, the various Centers do work together in considering combination products and, since PDT involves both a drug and device product is involved, manufacturers must fulfill both new drug application and premarket approval requirements.
    
    
    
    • A newly established Office of Combination Products, headed by Mark Kramer, who formerly directed the agency's combination products program, will help improve the FDA's review process for these products (FDA, FDA Establishes Office of Combination Products, 2002).
    
    
    
    • Medical Device Amendments 1992 further detailed medical device tracking and adverse event reporting requirements.
    
    
    
    • If a manufacturer fails to follow regulations or studies show the device is not safe or effective, the FDA may reject the PMA or 510(k). Manufacturers must register with the FDA. Companies also must report adverse events and serious injuries within 30 days under medical device reporting requirements. Hospitals and other user facilities must file such reports with the FDA within 10 days if patient deaths are involved and must report serious injuries to the manufacturer. Consumers may report problems with medical devices to the FDA's MedWatch system.
    
    
    
    • Corrections and removals of devices from the market to protect consumers also must be reported to the FDA (122; Ted Wilson, The Medical Device Approval Process, A Practical Guide to Food and Drug Law And Regulation, Chapter 157-158) and manufacturers must track patients using certain implants and other devices and their physicians (124). If the manufacturer knows that the device will be used in a way that differs from the labeling, they must provide instructions on these additional uses as well.
    
    
    
    • Adverse medical device events, known as medical device reports (MDRs), are reported to the FDA’s Manufacturer and User Facility Device Experience Database. Manufacturers and user facilities such as hospitals are required to report deaths and serious injuries that they believe to be related to medical devices. As with pharmaceutical products, the MAUDE database devices must be labeled in accordance with FDA requirements including the manufacturer’s name and location, and "adequate directions for use" of the device. The CDRH is pilot testing a Medical Product Surveillance Network (MedSun) that would facilitate the reporting of adverse events by hospitals. If successful, the program may be expanded to include "several hundred" hospitals, nursing homes, and other facilities that use medical devices.
    
    
    
    • The FDA recently finalized a rule that would allow the agency to require manufacturers of certain devices to conduct postmarket surveillance for up to 3 years in order to identify serious adverse events that may be unanticipated at the time the device is approved for marketing. The FDA estimates that "at most" 30 devices each year will be subject to the rule, and the rule will apply to devices implanted in the body and devices that sustain or support life outside of hospitals.
    
    
    
    • The Medical Device User Fee and Modernization Act, signed into law in October 2002, will allow the FDA to collect user fees for timely premarket review of medical devices and will provide the FDA with additional funds for postmarket surveillance of these products. The law also mandates that the FDA establish an Office of Combination Products within the Office of the Commissioner that will help coordinate the "timely and effective" review of novel products, imposes new labeling requirements (where feasible devices must "prominently and conspicuously" identify the name of the manufacturer) and requires additional performance data for reprocessed single-use devices, requires the FDA to establish a program to allow third-party inspections of certain medical device establishments by qualified personnel, requires the FDA to issue additional guidance about pediatric clinical trials involving medical devices and the safety of medical devices used to treat children, and requires additional research on the safety of silicon breast implants.
    
    
    
• Radiological products
  
  
  • Radiological devices also are regulated by the CDRH. Under section 531 of the FD&C Act, electronic devices that emit ionizing or non-ionizing radiation or sonic, infrasonic or ultrasonic waves are subject to FDA jurisdiction. Some of these devices such as lasers, x-rays, tanning equipment, and ultrasound machines also may be medical devices, but television receivers, microwave ovens, and laser range finding devices, as "radiation emitting electronic products," also are subject to FDA regulation. These devices are subject to varying levels of reporting and record-keeping requirements.
  
  
  
• Foods and Food Additives
  
  
  • Foods are defined in section 201(f) of the Act as "(1) articles used for food or drink for man or other animals; (2) chewing gum, and (3) articles used for components of any such article." Foods must be manufactured in accordance with good manufacturing practice regulations that require adequate sanitation, cleaning, and steps to reduce microbial contamination.
    
    
    • Food additives also are regulated by the agency. A food additive is "any substance the intended use of which results, or may reasonably be expected to result, directly or indirectly, in it's becoming a component or otherwise affecting the characteristics of any food."
    
    
    
    • If an additive is added directly to a food, a company may submit a food additive petition indicating the quantity of substance in the finished food, the environmental effects, toxicology data, the chemical identity of the substance, and how the substance will be manufactured. The FDA will evaluate the additive to ensure there is "reasonable certainty of no harm under intended conditions of use." Food additives are considered unsafe under section 409 of the FD&C Act unless approved by the FDA or generally recognized as safe by food safety experts.
    
    
    
    • A food additive petition may assert that the ingredient is generally recognized as safe (GRAS) by food safety experts or may provide data from studies demonstrating the safety of the additive.
    
    
    
    • If the agency approves the petition, it will publish a regulation in the Federal Register and amend the Code of Federal Regulations accordingly. For instance, in July 2002 the FDA published a notice in the Federal Register regarding approval of Neotame as a sweetener in food based on petitions initially filed by Monsanto and subsequently sold to the NutraSweet company. Depending on how it is applied to food, neotame is up to 13,000 times sweeter than sugar. To gain approval, the company performed 113 preclinical and clinical studies in both humans and animals, including 6 short-term and long-term human clinical studies.
    
    
    
    • As an alternative to a petition, a company may submit a GRAS notification to the Center for Food Safety and Applied Nutrition. Under a proposed rule, GRAS notifications are reviewed in as little as 90 days while food petitions, such as the petitions relating to neotame, may take years to be approved. GRAS notifications may require the submission of more data (eg, toxicological data) than food additive petitions.
    
    
    
    • The Delaney Clause prohibits the presence of carcinogenic additives in food.
    
    
    
    • Indirect food ingredients that may have contact with food because they are part of the packaging material or come into contact with the food when it is being prepared are also subject to FDA regulation. If an indirect ingredient becomes part of the food (for example, if a chemical in the packaging migrates onto the food) premarket notification is required. A food contact substance is "any substance intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if such use is not intended to have any technical effect in such food." Companies must notify FDA 120 days before they begin to use these substances (21 USC 348 h(1),(6). Companies can submit GRAS notifications or food additive petitions for these substances or argue that an ingredient is present at a threshold below the level for FDA regulation.
    
    
    
    • Color additives are used for "imparting color" to foods (21 CFR 70; Fundamentals of Regulatory Affairs, Chap. 5, Drug Master Files, Registrations, Color Additives, United States Adopted Names (USAN) p. 33). For instance, a fruit punch may contain Red #40. Color additives must be manufactured in conformance with FDA good manufacturing practice regulations and must receive premarket approval from the FDA. Under the 1960 Color Additive Amendments, the agency can regulate the amount of color substance used in products and require labeling and premarket testing. In a dispute between the FDA and industry regarding safety, the 1960 law mandates that the companies, not the FDA, have the burden of proof of showing the additive is safe for human consumption. The law also contains a provision, known as the Delaney Clause, which prohibits color additives that cause cancer in humans or animals. Products must indicate which additives are used. Certain additives are banned entirely from FDA regulated products.
    
    
    
    • The FDA recognizes four classes of color additives: those used in foods, drugs and cosmetics; those used externally in drugs and cosmetics; those used in drugs and cosmetics but not foods and under the 1976 Medical Device Amendments, those used in or with medical devices (such as contact lens solutions).
    
    
    
    • Natural flavors are defined as "an essential oil, extractive; protein hydrolysate or other substance including any product of roasting, heating or enzymolysis that contains flavoring.

Next: Food Labels »

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