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The United States Food and Drug Administration (FDA) and MedWatch

The “granddaddy” of drug safety “regulatory agencies” dates back to eighteenth-century Japan, when the eighth shogun, Yoshimune Tokugawa (1716–1745), upon recovering from an illness, awarded 124 medicinal traders in Osaka special privileges to examine medicines throughout the country. However, the safety of the medicines was difficult to guarantee despite these efforts. A shrine in Osaka, called Shinnosan, was created and dedicated to Shinno, the guardian of the pharmaceutical industry and the divine founder of medicine from China. This information was found at the Osaka tourism website (Web Resource 21-1).

Since the time of the shoguns, multiple other government authorities have become involved in drug safety. In the past 20 or so years, the number of organizations devoted to drug safety has increased markedly, in particular outside the United States. This chapter deals with the U.S. Food and Drug Administration (FDA) and focuses on the major players involved in handling drug safety.

The FDA handles safety in several different areas. The two largest areas touching drug safety are the Center for Drug Evaluation and Research (CDER) and MedWatch.

The FDA has undergone and continues to undergo major changes following various controversies, drug withdrawals, investigations, and changes in the law. This chapter will summarize the key divisions and functions that deal with drug safety (CDER, Risk Management, MedWatch, CBER, and CDRH) and will outline some of the initiatives currently under way that will lead to further changes in the next several years.

This is the prime center in the FDA for handling drugs. CDER handles new drugs from the IND stage (when a product first moves into human study) to the evaluation of the NDA for approval or rejection of the request to market the product in the United States. CDER then evaluates the postmarketing safety of the product. Although simple in theory, the actual practice is complex and has evolved over time. It continues to change and should be viewed as a work in progress.

The organization chart is posted online and is quite useful. It gives names, addresses, and contact information (Web Resource 21-2). There are more than 20 “offices” in CDER covering many areas, including biotechnology, new drug evaluation, counterterrorism, pediatric drug development, generic drugs, compliance, and, of course, drug safety. There are also advisory committees that consist of outside experts who meet periodically to review data and advise the FDA on various issues, including drug approvals and policy issues. See CDER’s website (Web Resource 21-3). There are advisory committees made up of external members that give expert consultation to the FDA (Web Resource 21–4). There is an advisory committee on Drug Safety and Risk Management that looks at safety issues.

The FDA reorganizes periodically. The current structure is as follows: the Office of the CDER Center Director has under it approximately 13 offices, including the Office of Surveillance and Epidemiology. This office has under it five divisions:

• Division of Pharmacovigilance I & II (2 divisions): The staff includes safety evaluators whose primary role is to detect and assess safety signals for all marketed drug products. They work closely with medical reviewers in the Office of New Drugs so that potential safety signals are placed in the context of existing preclinical, clinical, or pharmacologic knowledge of the drugs in question.
  
• Division of Epidemiology: The staff reviews epidemiologic study protocols increasingly required of manufacturers as postmarketing commitments. They evaluate various postmarketing surveillance tools that may be incorporated into risk management strategies, such as patient registries and restricted distribution systems. They estimate the public health impact of safety signals by evaluating computerized databases and the published literature.
  
• Division of Medication Error Prevention and Analysis: The staff provides premarketing reviews of all proprietary names, labels, and labeling in CDER to reduce the medication error potential of a proposed product. The division also provides postmarketing review and analysis of all medication errors received.
  
• Division of Risk Management: The staff handles data resources, risk communication, and outcomes and effectiveness research components of drug safety risk management programs (REMS). This division oversees MedWatch, risk communication research, and activities such as Medications Guides, Patient Packet Inserts, and pharmacy information surveys, and international regulatory liaison activities (such as videoconferencing) for all drug and biologic postmarketing safety issues.

In 2005, the FDA created the new Drug Safety Oversight Board (DSB), which advises the CDER Center Director on handling and communicating important and emerging drug safety issues. The board meets monthly and is composed of representatives from three FDA Centers and six other federal government agencies: the Agency for Healthcare Research and Quality (AHRQ), Centers for Disease Control and Prevention (CDC), Department of Defense (DOD), Indian Health Service (IHS), National Institutes of Health (NIH), and Department of Veterans Affairs (VA). See Web Resource 21-5. The DSB provides scientific and regulatory recommendations on drug safety and communication issues and policies to the senior FDA management on

• Potentially significant drug risks and safety issues
  
• Effective communication of drug safety information to healthcare professionals, patients, and the general public
  
• Establishment of general policies regarding drug safety issues and approaches to resolving internal FDA policy differences and disagreements
  
• Disputes between a sponsor and CDER concerning a Risk Evaluation and Mitigation Strategy (REMS) that occurs after approval of a prescription product if the sponsor requests DSB review

FDA’s SOP for the board is available at Web Resource 21-6.

The FDA has an extensive, useful website, although the information tends to be scattered and difficult to find. There is a search engine that is somewhat useful. The website has extensive information on how the FDA works, its history, drug availability, counterfeits, internet purchases of drugs, labeling and medication guides for drugs on the market, signals, REMS, guidances, laws and regulations covering pharmaceuticals (as well as devices, biologics, radiologics, OTC products, nutraceuticals and more). The main CDER website (Web Resource 21-3) lists late news and provides a jumping off point to other CDER information, including:

• “FDA Basics”: Fundamental information on the various divisions, functions, and leaders at FDA (Web Resource 21-7).
  
• “Drug Specific Information”: This is an alphabetical list of drugs that have an information sheet, Early Communication about an Ongoing Safety Review, or other important information (Web Resource 21-8).
  
• “Development & Approval Process for Drugs”: Information on how drugs are developed and approved (Web Resource 21-9).
  
• “Guidance, Compliance, and Regulatory Information”: For industry. This key page for pharmacovigilance (PV) professionals has links to information on laws, acts, rules, good review practices, enforcement activities, surveillance, postmarketing commitments requirements, warning letters, enforcement actions, new guidance documents, cyber letters, and the CDER manual of policies and procedures (Web Resource 21-10).
  
• “Information for Industry”: A page for the pharmaceutical industry with links to guidances, postmarketing information, the Prescription Drug User Fee Act (PDUFA), warning letters, electronic submissions, the Orange Book (approved drug products with therapeutic equivalence evaluations), abbreviations, and types of applications (Web Resource 21-11).
  
• “MedWatch”: See below for more detailed information (Web Resource 21-12).
  
• “Drugs at FDA”: A link to the page that has an alphabetical list and search engine to find approved drugs by name, active ingredient, or application number (Web Resource 21-13).
  
• “Recalls, Market Withdrawals & Safety Alerts” (Web Resource 21-14).

FDA has launched a “one-stop shopping” safety portal in which safety reports for nearly all products regulated by FDA (and NIH) can be reported. Food (human or animal), drugs, biologics, blood products, gene-transfer research issues, and more can be reported by manufacturers, healthcare professionals, researchers, public health officials, and “concerned citizens.” This portal is being developed and changes will be made as experience is gained. It allows for initial and follow-up reports. One can enter a case as a “guest” or one can establish an account and use it repeatedly. See Web Resource 21-15. It is not meant for emergency reporting. See also their FAQ page (Web Resource 21-16).

Other pages of interest include:

• “Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS)”: This page contains information about ongoing signals (Web Resource 21-17).
  
• “Postmarket Drug Safety Information for Patients and Providers”: This site contains information on postmarket study requirements and commitments, a link to the clinical trials registry, and other safety-related information.
  
• “Approved Risk Evaluation and Mitigation Strategies”: This site contains information and links to REMS that are in place (Web Resource 21-18).
  
• “Guidances”: This site contains FDA’s new, current, revised, and withdrawn guidance on all areas, including Drug Safety, ICH, OTCs, Good Review Practices, and the FDAAA Food and Drug Administration Amendments Act (Web Resource 21-19).
  
• “Postmarket Drug Safety Information for Patients and Providers: Selected Safety Regulations”: This page has links to the relevant sections of the Code of Federal Regulations covering safety matters for drugs and biologics, as well as INDs, NDAs, and labeling (Web Resource 21-20).
  
• “Warning Letters”: A site with many years of warning letters for all matters, not just safety, that are browsable and searchable by company, issuing office, and so forth (Web Resource 21-21).
  
• “Pregnancy & Lactation Labeling” (Web Resource 21-22).
  
• “Prescription Drug User Fee Act (PDUFA)”: The main web page for information on PDUFA, with several links (Web Resource 21-23).
  
• “Office of Surveillance and Epidemiology (OSE)” (Web Resource 21-24).
  
• “Guidance, Compliance, & Regulatory Information”: This page has links to the various laws, acts, guidances, and so forth.
  
• “Surveillance: Post Drug-Approval Activities”: Links to the staff guide, regulations and policies, advertising, and promotional information.
  
• “Adverse Event Reporting System (AERS)”: This site has the description of the FDA drug safety database, with data files and statistics (Web Resource 21-25).
  
• “MedWatch to Manufacturer Program”: The system whereby FDA informs manufacturers of SAEs that are received directly by FDA (see “MedWatch” below) (Web Resource 21-26). Note the MHRA in the United Kingdom has a similar program (Web Resource 21-27).
  
• “DailyMed”: This is actually an NIH website that provides “high quality information about marketed drugs.” It is not a complete listing but does have information on more than 7000 drugs. See the Drugs@FDA site (Web Resource 21-28).
  
• “Medication Guides” (Web Resource 21-29).
  
• “Medication Errors” (Web Resource 21-30).
  
• “Safe Use Initiative”: FDA’s program to reduce preventable harm from medications (Web Resource 21-31).

The FDA website is extensive, and almost everything that one wants to find relating to the FDA, drugs, and drug safety are present, though often not easy to find. In addition, FDA changes its websites frequently, and pages may jump or move, or URLs may be dead links. It may be necessary to search for the new URL using the FDA search engine on the home page. Note that most of the drug safety information is in the CDER section of the website.

On the FDA website there is extensive information on risk management initiatives, which are covered in Chapters 30 and 31. Other FDA activities are covered in this chapter and in other chapters in this book.

In 1997, the federal government put forth a global framework for federal risk management of drug products (Web Resource 21-32). The fundamental concepts include the following:

• Risk assessment is the estimation and evaluation of a risk in the pre- and postmarketing areas.
  
• Risk confrontation determines the acceptable level of risk in the large context, including social and community values as well as the technical judgments of professionals. This includes the use of advisory committees, which get input from various concerned stakeholders. In addition, the FDA has relationships with various groups of health professionals, consumer and patient advocacy groups, industry organizations, and other governmental agencies to gather information and advice.
  
• Risk intervention is the evaluation of alternative risk control actions, selection among them, and their implementation. After the risks are identified and assessed, they must be managed or minimized. The FDA can refuse to allow the product to be marketed if the product’s risk outweighs its benefits. If the product is permitted on the market, the FDA minimizes risk by various mechanisms, including the review and approval of the original labeling and any subsequent changes. FDA also regulates the advertising and promotion of marketed products. Promotional materials must not be false (i.e., they must conform to the label and be substantiated), and they must not be misleading (i.e., they must be balanced and include the material facts). FDA also tracks medication errors and can act on issues there. FDA also can require other risk minimization measures, including mandating education for product users, limiting product distribution (e.g., to specific hospitals or specialists), requiring prescriber qualifications, training, or informed consent, etc. The FDA may also require postapproval clinical or epidemiologic studies after marketing. In severe or urgent situations, there are various mechanisms to remove products from the market.
  
• Risk communication is aimed at conveying the needed information to the public. There are ongoing and rapidly changing mechanisms of risk communication using traditional as well as new social media mechanisms to convey information to consumers and healthcare practitioners. The internet and various new means of wireless communication challenge all parties to get the correct message out in the large sea of information. The product labeling (Package Insert) has been the classic mechanism of communication. The FDA has redone and revised how labels are made and communicated both to patients and practitioners. This is a controversial area as some feel the changes make labeling more complete but less useful and more ponderous. Medication guides for patients are also used in risk programs. Whether these changes lead to lowering risks for particular products remains to be seen. Another controversial area is Direct-To-Consumer advertising and promotion, which is allowed in the United States but not in many other developed countries. Whether this promotes product use that is safer or more dangerous is a much-debated topic, with no clear answer.

The MedWatch program is the FDA’s national pharmacovigilance program. It provides clinical information about safety issues involving prescription and over-the-counter drugs, biologics, medical and radiation-emitting devices, and special nutritional products (e.g., medical foods, dietary supplements, and infant formulas). See the MedWatch site (Web Resource 21-12).

The website provides “one-stop shopping” for information or links to information on medical product safety alerts, recalls, withdrawals, current new and hot topics, educational materials and a glossary, the NIH Daily Med site (Web Resource 21-33), from the National Library of Medicine, containing up-to-date drug labeling information, Medication Guides, drug-specific information (more labeling), drug shortages, and more.

There is also a set of links to receive periodic e-mail notifications and RSS feeds (which you can have automatically sent to your internet home page if it accepts such feeds).

Another little-known MedWatch function is the MedWatch to Manufacturer Program (Web Resource 21-26), which allows drug and biologics manufacturers to receive certain SAEs submitted directly to FDA that would not otherwise be known to the manufacturer. One can subscribe at anytime after approval for a period of 3 to 4 years.

The other key part of the MedWatch site is information on reporting serious AEs to the FDA using the MedWatch form, which comes in two very similar varieties—the 3500 form for the public to voluntarily submit AEs and the 3500A form for mandatory reporting by manufacturers.

An information page for health professionals describes the systems used for drug and device reporting (Web Resource 21-34), which then has links to the other pages giving further information. There is a link to a downloadable PDF version of the MedWatch voluntary form for the public and the mandatory form (3500A) for manufacturers. There is also a link to an online reporting form for the public (Web Resource 21-35).

There is a page (Web Resource 21-36) with information for industry on the three key SAE reporting areas. Information and links to the appropriate regulations and forms are included:

• OTC Products and Dietary Supplements (Web Resource 21-37)
  
• Drug/Biologic/Human Cell, Tissues and Cellular and Tissue-Based Product Manufacturers, Distributors, and Packers (Web Resource 21-38)
  
• Human Cell & Tissue Products (HCT/P) Adverse Reaction Reporting (Web Resource 21-39)

For newly approved new chemical entities, FDA has a MedWatch to Manufacturer Program, whereby certain serious cases sent directly to FDA are transferred to the manufacturer (Web Resource 21-26).

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