James Wright1 is mistaken in thinking that postmarketing conduct of a large simple RCT is the best way to resolve controversies associated with the introduction of new drugs. Such trials add more to the controversy than they resolve, as was the case with the ALLHAT study.2
Wright has missed fundamental deficiencies in megatrial methodology. The real-world RCT that he advocates would recruit a large and heterogeneous population, with few inclusion and exclusion criteria. The required simplicity is typically accomplished by not collecting clinical data that would allow analysis of important subgroups. The only outcome variable that can be better assessed in these heterogeneous conditions is eventual mortality, which may be low in some patient groups and of limited relevance in others.
Prior knowledge from both RCT and observational studies is required to select appropriate subjects and to create a protocol that controls for confounding variables. Megatrials should therefore be conducted only at the end of a long process of therapeutic development.3 Paradoxically, megatrials may be superfluous once a significant treatment effect is evident from meta-analysis of existing trials,4 as indicated by studies demonstrating agreement of statistical conclusions among megatrials.5
Observational studies can recruit a broader range of patients and are often cheaper, quicker and less difficult to carry out than RCTs. Moreover, high-quality observational studies and RCTs usually produce similar results.6 Hence, observational studies may be preferable for identifying rare side effects and when RCTs would be impractical.7
Michal R. Pijak Consultant in Rheumatology, Allergy and Clinical Immunology Division of Clinical Immunology Department of Internal Medicine Frantisek Gazdik Associate Professor Institute of Preventive and Clinical Medicine Stefan Hrusovsky Associate Professor of Gastroenterology Head, Department of Internal Medicine Slovak Medical University Bratislava, Slovakia
Footnotes
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Competing interests: Michal Pijak has received speaker fees from local branches of Pharmacia and Fournier.