Mega-Trials for Blockbusters

THECONDUCTOFVERYLARGE,SIMPLETRIALS(MEGA-TRIALS) isuncommonand faces several challenges, inparticularcostanddifficulty inpatient recruitment.However, thesechallengescanbeovercomewhen interventions are widely used by hundreds of thousands of individuals and when there is a potential profit to accommodate the trial cost. Accordingly,every licensed interventionwithannualsales that exceed $1 billion, ie, a blockbuster, should have at least 1 trial performed with at least 10 000 patients randomized to the intervention of interest and as many randomized either to placebo (if deemed to be a reasonable choice) or to another active intervention that is the least expensive effective intervention available. The comparison drug can be a generic drug with a well-established effectiveness and safety profile. Adata-intensivemega-trialof20 000randomizedparticipants with 4 years of follow-up costs an estimated $420 million, but streamlining the design, monitoring, data collection, and outcomes could save 90% of that cost. For a blockbuster with $2 billion annual sales, 1-month sales ($167 million) would suffice to conduct a mega-trial of 80 000 participants. The one outcome that should routinely be collected is death. For 80% power to detect a 10% relative risk reduction, sufficient follow-up is needed to achieve a 13.2% death rate in the control group with 10 000 participants per study group, or 3.3% with 40 000 participants per group. Furthermore, information also could be collected on major clinical end points that have not been adequately studied in previous trials of the blockbuster. How many interventions would be affected if such a rule were to be applied? In 2011, sixty different drug products had sales exceeding $1 billion in the United States alone; of those, 24 exceeded $2 billion in sales. More than 100 drugs have exceeded $1 billion in US annual sales at least once. The number is substantially larger if global markets are considered. Sales of the top 100 blockbusters globally accounted for $285 billion in 2009, exceeding 35% of the global pharmaceutical market. Because blockbusters typically maintain top sales for almost a decade, less than 1% of profits could fund an efficient mega-trials agenda. Blockbusterdrugsareeventuallyusedbymillionsofpatients. Typically there is evidence from randomized trials suggesting that thesedrugsareeffective—at least for someendpoints (not necessarilythemostseriousones), forsomefollow-up(notnecessarily longenough),and insomespecificcircumstances(not necessarily representing what happens in real life). The supportingrandomizedtrials typically includeonlya fewhundred participants (as in the case of testosterone [AndroGel] or modafinil [Provigil]) or, in the best case, a few thousand participants,oftenwithrelativelyshort-termfollow-upandareconducted among populations selected to avoid patients with comorbid conditions and those who take some other drugs. Of the 24 top blockbusters of 2011, only clopidogrel has had a randomized trial with more than 10 000 participants allocated to the experimental group—COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) randomized 22 961 participants to clopidogrel and 22 891 to placebo. Rosuvastatin also came close to this threshold but not quite— JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized 8901 patients to rosuvastatin and 8901 to placebo. A few other blockbuster drugs have been studied in trials of 5000 to 10 000 patients (eg, tiotropium in the UPLIFT [Understanding Long-term Impacts on Function With Tiotropium] trial [n=5993] and fluticasone salmeterol in the 4-group TORCH [Towards a Revolution in COPD Health] trial [n=6112]), but such sample sizes coupled with modest follow-up cannot offer definitive evidence for risk of death. Fewof therandomizedtrials supporting theevidence legacy ofblockbustershave includeddeathasaprimaryoutcome.Evidenceofother seriousclinical events is alsooften limited, even though the conditions targeted for these therapies are serious, and for most of them death is the most important outcome for decision-making. Both COMMIT and JUPITER documented asignificantreductioninmortality(relativerisks,0.93[P=.03] and0.80[P=.02],respectively).Perhapsthisdocumentedbenefithascontributedtotheeventualmarketsuccessoftheseproducts. The UPLIFT and TORCH trials came close, but did not passnominalstatisticalsignificanceforreducedmortality(relativerisks,0.89[P=.08]and0.83[P=.052],respectively).Conversely, for some popular agents, such as erythropoietin, significantexcesses inmortalityhavebeendocumented inspe-