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The Theory of Drug Safety (Pharmacovigilance)

Why a company needs a drug safety group and how it is constituted. The mission of a drug safety group within a pharmaceutical company. A brief history of the U.S. FDA’s safety duties and functions. The FDA’s mission. Pressures on the corporate safety department and the FDA. An overview of the safety functions of government agencies outside the United States.

A century or two ago, the requirements for the safety and efficacy of drug products were either nonexistent or poorly defined at best. In 1906, the Pure Food and Drugs Act prohibited interstate commerce of mislabeled and adulterated drugs and food within the United States. This covered some safety aspects of drugs but not efficacy. The FDA had, at that time, no jurisdiction or control of efficacy claims made for drugs. In 1912, the law was changed to cover false and fraudulent claims made for drugs. However, the law did not mandate safety and, in effect, unsafe products could be and were marketed. The FDA could not seize unsafe drugs and was limited only to issuing public warnings.

In 1937, a company in the United States marketed elixir of sulfanilamide, which contained diethylene glycol (similar to antifreeze). More than 100 people (including children) died from this product. Because the law did not require safety testing for drugs, the company had done none. As a result of this, the Federal Food, Drug and Cosmetic Act was passed into law in 1938. This law required safety testing to be performed and submitted to the FDA in a New Drug Application (NDA). Additional laws were passed in the 1940s requiring testing for purity, strength, and quality of many drugs. The next major event was the thalidomide disaster of the early 1960s, when the NDA for thalidomide was valiantly opposed by Dr. Frances Kelsey at the FDA because of insufficient safety information despite strong pressure to approve it. Though never marketed in the United States, thalidomide was extensively used in the investigational setting, and by 1962, the terrible teratogenic (birth defect) aspect of the drug became known as babies were born with severely deformed arms and legs (phocomelia). In 1962, the Kefauver-Harris Amendment became law and introduced the modern era of drug regulation. Drug manufacturers now had to demonstrate to the FDA both safety and efficacy before marketing a new drug. In 1971, the National Drug Experience Reporting System was begun as was the publication of “The FDA Drug Bulletin” to alert physicians and pharmacists to drug issues. In 1985, the regulations on AE reporting for marketed drugs were strengthened, and new requirements for Investigational New Drug Applications (INDs) were introduced. Over the years, the FDA has had multiple reorganizations and alterations in its structure and function as the overseer of drug safety and efficacy in the United States. The result is the complex system of AE collection, analysis, and reporting that we know today. See a brief history of the Center for Drug Evaluation and Research (CDER) on the FDA’s website (Web Resource 4-1).

The regulations, laws, guidances, rules, and other relevant documents covering drug safety are detailed, arcane, and scattered throughout multiple places in the Code of Federal Regulations for the United States and the various venues for European Union (EU) and member state documents. Each individual country in the European Union and most others in the world have their own set of local laws, regulations, and guidances (often available only in the local language). Most are updated fairly frequently.

Most countries’ regulations are fairly similar in requiring all or almost all serious AEs and some nonserious AEs to be reported quickly if there appears to be a potential impact on public health, and at periodic intervals for more routine AEs. Most countries also require some form of aggregate reporting of serious and nonserious AEs at periodic intervals (e.g., every 3 months, 6 months, yearly, every 3 years), depending up whether the drug is in clinical trials or on the market and whether it is new or old. Although the rules are similar throughout the world, they are sufficiently different in detail (“the devil is in the details”) to be infuriating and well nigh impossible to track, categorize, and keep up to date without personnel in each country tracking such matters. The major documents for the United States and the European Union are listed below. Those with an asterisk should be read and digested by anyone doing drug safety for a living. The contents of these documents are topics of this book.

The United States regulations do not explicitly state that a department or group must exist to deal with drug safety. Rather, sponsor obligations are spelled out. To do this adequately, an organized system or department is necessary.

The European Union regulations are more specific and require that a formal pharmacovigilance system be put in place (from Volume 9A—Pharmacovigilance. Rules Governing Medicinal Products in the European Union, published by the European Commission, Directorate Enterprise, Regulatory Framework and Market Authorisations [Version September 2008]: “All Marketing Authorisation Holders are required to have an appropriate system of pharmacovigilance in place” (Section 2.2.3).

Drug safety in the United States is covered under several sections of the Code of Federal Regulations. A searchable version of 21CFR is available on the FDA’s website (Web Resource 4-2).

• The United States Code of Federal Regulations, Title 2, Chapter 312 covers INDs. 21CFR312.32 covers IND safety reports, including expedited 7- and 15-day reports. Section 21CFR33 covers the IND annual reports. The NDA regulations are found in section 21CFR314.80.
  

  Updates to regulations are published in the Federal Register and are viewable on its website (Web Resource 4-3). The Food, Drug and Cosmetic Act is available at Web Resource 4-4.

  
  

  FDA has created several Web pages for industry:

  
  

  Drugs: Web Resource 4-5.

  
  

  Devices: Web Resource 4-6

  
  

  Biologics: Web Resource 4-7

  
  

  Dietary supplements: Web Resource 4-8

  
  

  Guidance documents: Web Resource 4-9

  
  

  MedWatch: Web Resource 4-10

  
  
• In addition, MedWatch has an automatic e-mail notification system that sends out free safety updates periodically. Information is available on its website (Web Resource 4-11).
  
• In August 1997, the FDA issued a short Guidance for Industry entitled “Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report.” This document covers the four data elements needed for an AE report, solicited information, and nonserious labeled cases. See the CDER website (Web Resource 4-12).
  
• In March 2001, the FDA published a Guidance for Industry entitled “Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines.” This document has not been formally issued as a final regulation, however. It is worth reading to better understand the FDA’s more or less current thinking on safety reporting. See the CDER website (Web Resource 4-13).
  
• CDER has a guide for FDA field inspectors on what to look for when doing inspections on safety matters. It is worth reading (though it is a bit old) and can be found on the CDER’s website. 7353.001 Chapter 53 is called “Postmarketing Surveillance and Epidemiology: Human Drugs” (Web Resource 4-14).
  
• In March 2003, the FDA published proposed new regulations markedly altering the reporting requirements in 21 CFR parts 310, 312, 314, 320, 600, 601, and 606. These proposals have been nicknamed “The Tome.” They have been issued for clinical trials (21CFR312) but not yet for the postmarketing requirements. They are expected soon. For the complete text, see Web Resource 4-15.

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