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)

Outline

          This commentary builds on topics Beasley briefly addressed in his response (Beasley 2018) to Blackwell’s reply (Blackwell 2017) to an earlier comment of Beasley (Beasley, 2017) in response to Blackwell’s essay about Corporate Corruption in the Psychopharmaceutical Industry (Blackwell 2016).  The primary purposes of the commentary are to:

1.      illustrate the sample sizes required to infer with reasonable certainty that some adverse medical event is caused by a drug; and

2.      illustrate the sample sizes required to infer with reasonable medical certainty that some adverse medical event, while possibly observed during administration of a drug, is not caused by the drug.

          We focus on adverse medical events that are in frequently observed in temporal association with the administration of a drug and are likely to be medically serious.  The point that is made in illustrating these sample sizes is that for such adverse medical events the inference that a drug caused or did not cause the events is not based on robust empirical evidence.  Furthermore, obtaining such robust medical evidence would be a practical impossibility.

The commentary progresses in sections as follows:

1.      A section that provides definitions of technical terms that have a precise meaning in the domain of drug safety/pharmacovigilance as these terms will be used in the commentary.

2.      An introductory section that restates our purposes and briefly describes some complexities of the time course of observation of an adverse medical event over time that is caused by a drug.  While these complexities can complicate a correct analysis of whether such an event is or is not caused by a drug, we address the simplest case in sections that follow.

3.      A section that discusses the variability that can occur when a subset of a population of interest is selected for inclusion in a study in terms of what would be observed in the total population compared to the subset.  Such variability is an important topic as it is relevant to an understanding of sample size computations.  As a special case of this variability, we discuss what can be inferred when no events or outcomes of interest are observed in a subset of a population of interest that is embodied in the statistical Rule-of-3.

4.      A section that discusses samplesizes in studies where the objective is being able to infer that an effectoccurs under the assumption that the effect does not occur.

5.      A section that discusses sample sizes in studies where the objective is being able to infer that an effect does not occur under the assumption that the effect does not occur.

6.      A section that illustrates the extreme rarity of events that would be of interest in the assessment of the safety of a drug.  This section provides context for understanding the incidence of an event associated with a drug that is used in our sample size calculations.

7.      A section that discusses regulatory requirements for drug exposure (number of patients) in development programs for drugs used on a long-term basis in the treatment of disorders that are not acutely life-threatening.  This section further discusses what regulatory authorities acknowledge regarding the limitations of such sample sizes in determining with reasonable certainty what events are caused by a drug before its approval.

8.      A section that briefly enumerates some of the methods used to attempt to determine events caused by a drug, both before and after its approval, which are not as robust as a study or set of studies, using appropriate controls.

References:

Beasley CM Jr. Comment on Barry Blackwell’s Corporate Corruption in the Psychopharmaceutical Industry. inhn.org. Controversies. March 23, 2017.

Beasley CM, Jr. Response to Barry Blackwell reply to Charles M. Beasley Jr.’s comment on Barry Blackwell’s Corporate Corruption in the Psychopharmaceutical Industry. inhn.org. Controversies. January 12, 2018.

Blackwell B. Corporate Corruption in the Psychopharmaceutical Industry. inhn.org. Controversies. September 1, 2016.  

Blackwell B. Reply to Charles M. Beasley Jr.’s comment on Barry Blackwell’s Corporate Corruption in the Psychopharmaceutical Industry. inhn.org.Controversies. July 13, 2017.

November 29, 2018