Charles M. Beasley, Jr and Roy Tamura: What We Know and Do Not Know by Conventional Statistical Standards About Whether a Drug Does or Does Not Cause a Specific Side Effect (Adverse Drug Reaction)
7. Regulatory requirements for investigational treatment exposure in development programs and their implications for ‘proof’ of presence or absence of an ADR
To what extent are regulatory authorities aware of the limitations? In its 1995 Guidance to Industry addressing the “Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions” (CDER 1995) exposures of 1,500 subjects to one or more doses (in intended multiple dose, clinical studies, generally not including single-dose, Phase 1 studies), 300-600 subjects for at least six months and at least 100 subjects for at least 12 months were specified (Center for Drug Evaluation Research 1995).
Multiple factors (e.g., a preclinical finding that would suggest rare potential toxicity) for individual potential drugs could result in the need for a greater number of exposures in the clinical development program studies.
These requirements were in line with The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) recommendations/requirements and apply to a wide range of potential drugs across a variety of disorders. For some disorders the potential drug can be tested against placebo while in many disorders the potential drug can only be tested as an add-on to single, standard therapy with a comparison to placebo added on to that therapy. With all the potential study variants to which these exposure requirements apply and all the differences in background incidences of events in the general population, the population with the disorder under study and the standard treatment when an add-on study must be conducted, it would be difficult to make precise statements about the incidence of ADRs that could be definitively ascertained and ruled out. However, the Guidance (CDER 1995) offers the following suggestions on what these exposure requirements will and will not be able to detect (Center for Drug Evaluation Research 1995).
“It is expected that short-term event rates (cumulative 3-month incidence of about 1%) will be well characterized.”
“The safety evaluation during clinical development is not expected to characterize rare adverse events, for example, those occurring in less than 1 in 1000 patients.”
The phrase “well characterize” is not expressly defined. It would seem to us to convey more than simply observing an AE that might be an ADR in the treatment population but in many cases falls short of a difference in incidence from that incidence with control that reaches conventional statistical significance in a proper inferential test. There is likely to be some reasonable estimate of the incidence of the AE that combines AEs due to the background with those that are ADRs with a reasonable degree of difference in incidences to believe to believe that the AE can be an ADR.
In a later Guidance Document addressing “Premarketing Risk Assessment” (CDER 2005), the following is included:
“Even large clinical development programs cannot reasonably be expected to identify all risks associated with a product. Therefore, it is expected that, even for a product that is rigorously tested preapproval, some risks will become apparent only after approval, when the product is used in tens of thousands or even millions of patients in the general population. Although no preapproval database can possibly be sized to detect all safety issues that might occur with the product once marketed in the full population, the large and more comprehensive the preapproval database, the more likely it is that serious adverse events will be detected during development” (Center for Drug Evaluation Research 2005).
Presumably, the reference to “adverse events” in the last sentence is to AEs that are ADRs. The statement above focuses on identifying ADRs but is equally applicable to the determination of the lack of a specific ADR associated with the drug under development. Here we have tried to quantitate these difficulties and limitations in RCTs, the gold standard for such determinations.
Center for Drug Evaluation Research. Guideline for Industry. The Extent of Population Exposure to Asses Clinical Safety: For Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions. Washington: U.S. Department of Health and Human Services. Food and Drug Administration; 1995.
Center for Drug Evaluation Research. Guideline for Industry. The Extent of Population Exposure to Asses Clinical Safety: For Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions. Washington: U.S. Department of Health and Human Services. Food and Drug Administration; 2005.
March 7, 2019