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If you believe you are having a reaction to a drug you can't assume that the doctor knows about all possible adverse reactions. The FDA knows there is a problem, but how are these reports actually handled?

Precision medicine trials with extensive phase 4 tracking must be implemented, the current situation is a real problem.

Characterization of New Drug’s Safety Profile Before Marketing

It is worth considering how well a drug’s safety is defined prior to its approval and marketing. This will indicate how confident practitioners can be that a new drug’s safety profile has been fully defined.

Most new drugs are approved with an average of 1,500 patient exposures and usually for only relatively short periods of time. However, some drugs cause serious ADRs at very low frequencies and would require many more exposures to detect the reaction. For example, bromfenac (Duract) was a non-steroidal anti-inflammatory agent (NSAID) that was removed from the market in 1998, less than 1 year after it was introduced. Bromfenac caused serious hepatotoxicity in only 1 in 20,000 patients taking the drug for longer than 10 days.1 To reliably detect the toxic effects of a drug with a 1 in 20,000 adverse drug reaction frequency, the new drug application database would have to include 100,000 patient exposures. A drug that is tested in a few thousand people 11 may have an excellent safety profile in those few thousand patients. However, within a short time after entering the market, the drug may be administered to several million patients. That means that for drugs that cause rare toxicity, their toxicity can only be detected after, not before, marketing.

If one case of hepatotoxicity is seen during pre-marketing testing, it can be difficult, if not impossible, to ascertain whether it was secondary to the drug or just the background rate of disease that is seen in the population.

So, the safety profile for new drugs that come on the market is never totally defined because new drugs are studied only in relatively small and homogenous patient populations. The complete safety profile of a new drug will be defined only after it has been approved and is in use on the market.




Health care providers have misconceptions about reporting ADRs.1–3 These misconceptions include the ideas that: 1) All serious ADRs are documented by the time a drug is marketed; 2) It is hard to determine if a drug is responsible for the ADR; 3) ADRs should only be reported if absolute certainty exists that the ADR is related to a particular drug; and, finally, 4) One case reported by an individual physician does not contribute to medical knowledge. Let’s look at each one of these points.

1) As we have seen, rare ADRs are usually NOT documented by the time a drug is marketed.

2) It can be hard to determine if an individual drug caused a reaction in a complicated patient receiving multiple medications. However, the temporal relationship of a reaction with regard to the administration of a new medication can be helpful. Also, biological plausibility (asking if the drug’s mechanism of action makes this possible or likely) can also be helpful. The bottom line is, even when in doubt about whether a drug caused the reaction, report it.

3) A suspicion of an adverse drug reaction should be reported. A health care provider does not have to be absolutely certain that a drug caused a reaction. All reports contribute to the heightening of the awareness of FDA safety scientists as they monitor all of the evidence to evaluate the potential for drug-related toxicity.

4) One individual report CAN make a difference. Many drug withdrawals began with one clinical report that initiated further investigation. In the example case in this module, a single report ultimately led to the removal of terfenadine from the market. This report potentially saved many lives and led to a better understanding of the mechanism involved in causing torsades de pointes. Almost all drugs are now evaluated prior to being released on the market for their potential to induce cardiac arrhythmias, also as a result of this single case report.