Clinicians and patients acknowledge the major role played by drugs in modern healthcare. Understanding how chemicals affect body homeostasis at the molecular level serves as the foundation for developing new therapeutic agents and provides the basis for rational pharmacotherapy. However, drugs seldom exert their beneficial effects without also causing adverse drug reactions (ADRs). This therapeutic dilemma lends credence to the statement that there are no “absolutely” safe biologically active agents.

With the exception of overdose, an ADR is defined by the World Health Organization (WHO) and the U.S. Food and Drug Administration (FDA) as “a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function.”1,2 The phrase "response to a drug" means that a causal relationship between the therapeutic agent and the ADR is at least a reasonable possibility.

Based on data from the American Medical Association, the incidence rate of ADRs after the administration of FDA-approved drugs is approximately 1 in 123 (0.81%); or 2.2 million per year, 183,333 per month, 42,307 per week, 6,027 per day, 251 per hour, and 4 per minute.3 Death rate extrapolation from the ADRs is 108,000 per year, 9,000 per month, 2,076 per week, 295 per day, and 12 per hour.3 The term “incidence” refers to the annual diagnosis rate, i.e., the number of new cases of ADRs diagnosed each year.

The FDA has one of the most rigorous approval requirements in the world to authorize the marketing of new drugs (Table 1).4,5 However, clinical trials cannot, nor are they expected to uncover every potential ADR. Pre-marketing study cohorts generally include less than 5000 subjects. ADRs that occur at a low frequency can easily be missed. In addition, pre-marketing clinical trials are of relatively short duration. ADRs that develop with chronic use and those that have a long latency period may also escape detection.

Table 1. The Chronology of Testing and Introducing New Drugs.4,5
Preclinical testing
(3 to 6 years)
Clinical trials
(5 to 9 years)
Post-marketing surveillance
  • Laboratory studies
    • Isolation or synthesis of a new chemical
  • Animal studies
    • Assess safety and biological activity
  • Pharmaceutical Company files an Investigational New Drug (IND) application with the FDA
    • FDA approval
  • IND reviewed and approved by the Institutional Review Board where the studies will be conducted
    • Progress reports on clinical trials submitted to FDA annually
  • Phase I (several months):
    • 20 to 100 healthy volunteers
      • Dosage range
      • Safety profile
  • Phase II (several months to several years):
    • Several hundred volunteers with a specific disease
      • Short-term effectiveness
      • Adverse drug effects
  • Phase III (1 to 4 years):
    • Several hundred to several thousand volunteers with a specific disease
      • Long-term effectiveness
      • Adverse drug effects
  • Pharmaceutical Company files a New Drug Application (NDA) with the FDA
    • FDA approval
  • Monitoring for safety during post-marketing clinical use to determine the true risk-benefit profile of the new drug
    • Pharmaceutical Company must continue to submit periodic reports to the FDA
      • Case reports of adverse drug reactions
      • Quality control records
    • FDA may require additional clinical trials (Phase IV studies)
5000 to 10,000 biologically active agents evaluated5 to 10 biologically active agents approved for clinical trials1 biologically active agent approved for marketing

Most studies also exclude children, women, and the elderly and are seldom representative of the population exposed to the drug after FDA approval. Consequently, pre-marketing clinical trials detect only those ADRs that occur more frequently than 1 in 1000 subjects, which are then listed in the product's initial labeling (package insert) at the time of approval. In order to have a 95 percent chance of detecting an ADR with an incidence of 1 in 10,000 subjects, a population of 30,000 would have to be exposed to the drug.

ADRs can range from mild to severe illness and can lead to hospitalization, permanent disability, or death. The old term "side effect" as used in the past, described not only negative (unfavorable) reactions; but, at times, concurrent positive (favorable) effects as well. The FDA recommends that this term no longer be used and should not be regarded as synonymous with ADRs.2 Oral healthcare providers should be aware of the spectrum of ADRs and be actively involved in monitoring for and reporting such drug effects.

ARDs may be explained by one of five mechanisms: (1) “on-target” adverse reactions, (2) “off-target” adverse reactions, (3) cytotoxic reactions, (4) immune-mediated reactions, and (5) idiosyncratic reactions, i.e., reactions of unknown mechanisms.6 A drug or drug class may produce toxic or adverse reactions by one or several of these mechanisms. In Adverse Drug Reactions – Part I, the discussion is limited to mechanisms (1), (2), and (3). Mechanisms (4) and (5) are discussed in Adverse Drug Reactions – Part II.