Editorial: Wine and drug evaluations: lessons on making comparisons of noninferiority

Wine rating is best performed under blinded conditions. Sur-prisingly, it is sometimes not possible to distinguish whitefrom red wines when blindfolded. Knowing that the wine isexpensive increases the client’s appreciation. The risks ofmigraine attacks and hangover are not estimated in the ratings,and we look to unbiased experts’ books and columns beforeshopping (Van Zyl, et al., 2008). However, how do we knowwhether one wine is just as good as another? That question may not go down well with competitive winemerchants. Drug regulators, although, request data to showthat one treatment is no better or worse than another. Aswith wine quality, that cannot be established with mathemati-cal accuracy, a certain degree of flexibility is accepted, pro-vided that the drug data are of comparable quality.Drug regulators were primarily concerned with drug safetyrather than efficacy. FDA came about in 1938 when manypatients died from a pharmacy contamination of sulphanila-mide. Following the thalidomide teratogenicity disaster in1956–1962, a solid regulatory foundation was laid for assessingthe utility of human medicines by strict standards. This nowgoverns all aspects of drug testing. The first version of the Dec-laration of Helsinki was composed by the World MedicalAssociation in 1964 to provide a universal guideline for ethicsreview committees to assess the merits of drug trial protocolsbased on patient consent and protection.In the EU, regulation for the supervision of human medi-cines was centralized in 1993 in the European MedicinesAgency. The pharmaceutical industry, in consort with regula-tory agencies, formulated a code of trial conduct (Good Clini-cal Practice) that ascertained methods for selecting patients,measuring and recording the efficacy and safety of treatments,audit trails for controlling data quality, source data verifica-tion, monitoring, etc. Research ethics are now governed bylaw in some countries. Increasingly, to bring about innovativetherapies, the clinician has to cope with a technology that hasdistanced itself from the ordinary world of clinical medicine. Ithas moved into specialized units for drug testing.One aspect in this new environment for clinical drugresearch is that of the ethics of placebo. Following a WMAmeeting at the University of Pretoria, the Declaration of Hel-sinki was revised in 2000, and its 29th paragraph became thesubject of controversy: ‘the benefits, risks, burdens and effec-tiveness of a new method should be tested against those ofthe best current prophylactic, diagnostic and therapeutic meth-ods’. Thoughtful statisticians commented that to show a differ-ence between two active treatments it requires much largersample sizes than those required for valid comparisons withplacebo, thus exposing many more subjects, the nonresponders,to remain ill (Leon and Solomon, 2003). A partial solution tothis dilemma is to randomize more patients to active treat-ments than to placebo. Another solution was proposed byFisher, et al. (2001), estimating the effect of a ‘putative pla-cebo’ by means of odds ratio as if a placebo arm had been ina trial. Following a period of debate, the WMA issued a noteof clarification that placebo can be accepted for a minor condi-tion that does not pose any additional risk of serious or irre-versible harm. Currently, a WMA task force with membersfrom Brazil, Japan, Sweden, South Africa and Germany hasbeen appointed to revise the Declaration for adoption by theWMA general assembly in October 2008.Hence, one of the latest concepts in clinical trial design fordrug regulation is that of noninferiority. In the absence of aplacebo arm, how does one determine whether two active treat-ments are similarly safe and effective or not? It cannot be donewith certainty. The words equivalence and superiority are morepalatable than noninferiority, but noninferiority is the pre-ferred term in reporting trials (Piaggio, et al., 2006). This termfirst appeared on PubMed in 1998, and now has less than 500entries (there are 250,000 entries for the term randomized con-trol trial, 5600 of which are on psychotropic drugs). In 2005, the European Medicines Agency issued a guidelineon the choice of the noninferiority margin stating at the outsetthat ‘a noninferiority trial aims to show that the test product isnot worse than the comparator by more than a prespecified,small amount. This amount is known as the noninferioritymargin, or delta’. This approach to experimental data is furtherexplained in two of the articles in this issue of the journal (All-gulander, et al., 2008; Nutt, ., 2008). One reason why noninferiority has become an issue inrecent years is the increasing number of medicines with similar