22 case studies where phase 2 and 3 results diverge: new report from the FDA

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Posted on January 19, 2017 | Through Zacharie Brennan

With growing industry interest in exploring alternatives to Phase 3 trials (i.e., relying on different types of data and unvalidated surrogates), the Food and Drug Administration (FDA ) from the United States on Thursday released a new report documenting 22 times different drugs, vaccines and medical devices since 1999 have seen promising results from Phase 2 clinical trials that have not been confirmed in Phase 3 trials.

The FDA said the report “is not intended to assess why each of these unexpected results occurred or why additional product development was not pursued,” but to “illustrate how controlled trials of appropriate size and duration contribute to the scientific understanding of medical products. “

Of the 22 case examples, the Phase 3 studies did not confirm the Phase 2 results regarding efficacy in 14 cases, safety in one case, and both safety and efficacy in seven cases.

“These unexpected results could occur even when the Phase 2 study was relatively large and even when the Phase 2 trials were evaluating clinical outcomes,” says the FDA. “In two cases, the Phase 3 studies showed that the investigational product increased the frequency of the problem it was supposed to prevent. “

The report also discusses the flexibility of clinical trials, with some Phase 1 trials being combined with Phase 2 if the drug is believed to be too toxic for healthy volunteers. And if a product’s mechanism of action and safety profile are well characterized, phase 2 trials may even be shortened or skipped altogether, says the FDA.

But the FDA also cautions, “As the progression and design of clinical trials have become increasingly flexible, and advances in biomedical science and statistics have allowed the introduction of study designs and sources. of non-traditional data in phase 3 trials, a randomized controlled clinical trial (RCT) of a size and duration that reflects the product and target condition remains the gold standard for determining if there is a benefit / benefit profile. acceptable risks for drugs and biologicals.

Case studies cover Bitopertin from Roche, brivanib from Bristol-Myers Squibb, topical capsaicin patch from NeurogesX, darapladib from GlaxoSmithKline, dexmecamylamine from Tagacept / AstraZeneca, expired drug-eluting stent from Broncus Technologies, Imiquimod cream from 3M, inparib from Sanofi, lithium from King’s College London, MAGE-A3 vaccine from GlaxoSmithKline, NicVAX vaccine from Nabi Biopharmaceuticals, velimogenic aliplasmid from Vical, olanzapine pamoate from Eli Lilly, aliskiren from Novartis’s Starevotob, the drug Conor’Med Recombinant factor VIIa from Nordisk (NovoSeven), semagacestat from Eli Lilly, torcetrapib from Pfizer and V710 vaccine from Intracell / Merck.

“These case studies demonstrate that large Phase 3 RCTs can generate critical evidence for all types of products, patients and diseases. Safety and efficacy failures have occurred even when Phase 2 studies were relatively large (eg, recombinant VIIa) and even when the product was already approved for another condition (eg, aliskiren ). In some cases, the phase 3 study found that the short-term results found in the phase 2 study were not associated with long-term benefit (eg, semagaceta), ”added the FDA.

22 CASE STUDIES WHERE PHASE 2 AND PHASE 3 TRIALS HAD DIVERGING RESULTS

© 2021 Society of Regulatory Affairs Professionals.



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