By Marcello Cherchi, MD PhD
Essentially all interventions, including all pharmaceutical agents, have the potential to cause effects other than their intended ones. If those unintended effects are helpful, then we may refer to them as “fringe benefits;” an example might be when the medication topiramate, originally designed to treat some types of seizures, also turns out to reduce the frequency of migraines. If a drug’s unintended effects are undesirable, then we refer to them as “side effects” or “adverse effects;” an example might be when topiramate causes glaucoma.
For approximately every 10,000 chemical compounds tested, one of those compounds makes it to market; from the time a chemical compound is identified, it takes on average about 15 years to make it to market (Robuck and Wurzelmann 2005). Factors that contribute to this time include both the scientific research needed to develop and test the compounds, as well as the regulatory requirements to which pharmaceutical companies must adhere.
In the United States, the Food, Drug, and Cosmetic Act of 1938 required the Food and Drug Administration (FDA) to approve a drug before it came to market. The New Drug Application (NDA) process was modified by the Kefauver-Harris amendments in 1962 by requiring evidence of a drug’s efficacy, and that its benefits outweighed its risks. The FDA requires a drug to go through several phases in its development; the table below is from Robuck and Wurzelmann (Robuck and Wurzelmann 2005).
Phase 1
- First testing in human volunteers
- Establishes drug safety and pharmacology
- Low likelihood of receiving a therapeutic dose
- Generally require overnight stays in research facilities with frequent blood draws
- Total of 20–80 patients (usually healthy volunteers)
Phase 2
- Well-defined eligibility criteria and controlled comparisons with placebo or active control
- Often conducted as dose-ranging studies of short to medium duration (weeks to months)
- Establishes the potential effectiveness of a drug for a specific population and disease
- Larger number of subjects (100–300)
Phase 3
- Large studies to confirm safety and efficacy; involve hundreds to thousands of patients over longer duration of treatment (months to years)
- FDA usually requires 2 ‘‘adequate and well-controlled studies’’ for approval
- Adequate population size to achieve efficacy power greater than 80% with a type 1 error rate a = 0.5; must have p < 0.05 to declare efficacy
Phase 4
- Postmarketing studies that provide additional safety and efficacy data
- Must be conducted if the FDA approves the product on a ‘‘fast track’’ (i.e., before all premarketing data are compiled)
- Evaluates adverse events, pharmacoeconomic, and epidemiologic data
A notable point is that in Phase 1 of drug development, a pharmaceutical company is not yet attempting to assess whether a chemical compound actually works to treat a disease; rather, the company attempts to figure out whether a chemical compound is safe in humans. In this phase, the FDA requires the pharmaceutical company to report any symptom that any patient ever experiences after exposure to the chemical compound. Note that this means any symptom at all. Consequently, there are some very common human experiences (such as fatigue, headache, dizziness, stomachache) that show up on the list of “adverse effects” of nearly every drug available. Thus, one must bear in mind that the mere listing of a symptom as a “potential side effect” in the package insert of a medication does not guarantee that it is truly attributable to that medication, though to be sure, a given medication may be strongly associated with a particular symptom.
Another notable point in Phase 4, which begins after a drug comes to market, is that the FDA collects reports of possible adverse events of a medication. The idea is that an adverse event that is sufficiently rare that it did not occur in pre-marketing trials might become apparent in the post-marketing phase, when a much larger number of people in the general public begin to use the medication. In some cases, data collected in Phase 4 may lead the FDA to rescind a drug’s approval.
A helpful tool for evaluating potential adverse events is the FDA Adverse Event Reporting System (FAERS) which has a publicly available “dashboard” at:
One of the most useful features of this online tool is that it not only lists a drug’s reported adverse effects, but it also enables a user to see the frequency with which that adverse effect has actually been reported.
Another useful feature of this online tool is that it does not only track FDA-approved medications. It also provides information about medications that are not currently FDA-approved (such as betahistine), as well as other “non-medication” substances (such as ginkgo biloba). We encourage patients and practitioners alike to use this tool.
References
Robuck PR, Wurzelmann JI (2005) Understanding the drug development process. Inflamm Bowel Dis 11 Suppl 1: S13-6. doi: 10.1097/01.mib.0000184851.46440.a3
