22 Case Studies Where Phase 2 and 3 Results Diverge: New FDA Report

Regulatory NewsRegulatory News | 19 January 2017 |  By 

With a growing interest from industry in exploring alternatives to Phase 3 trials (ie. relying on different types of data and unvalidated surrogate endpoints), the US Food and Drug Administration (FDA) on Thursday released a new report documenting 22 different times drugs, vaccines and medical devices since 1999 saw promising Phase 2 clinical trial results that were not confirmed in Phase 3 trials.

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

Of the 22 case examples, Phase 3 studies did not confirm Phase 2 findings of effectiveness in 14 cases, safety in one case, and both safety and effectiveness in seven cases.

“These unexpected results could occur even when the phase 2 study was relatively large and even when the phase 2 trials assessed clinical outcomes,” FDA explains. “In two cases, the phase 3 studies showed that the experimental product increased the frequency of the problem it was intended to prevent.”

The report also discusses the flexibility of clinical trials, with some Phase 1 trials combined with Phase 2 if the drug is expected 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, FDA explains.

But FDA also cautions: “While clinical testing progression and design has become increasingly flexible, and advances in biomedical science and statistics have enabled introduction of non-traditional study designs and data sources into phase 3 testing, a randomized, controlled, clinical trial (RCT) of a size and duration that reflect the product and target condition remains the gold standard for determining whether there is an acceptable benefit/risk profile for drugs and biologics.”

The case studies cover Roche’s bitopertin, Bristol-Myers Squibb’s brivanib, NeurogesX’s capsaicin topical patch, GlaxoSmithKline’s darapladib, Tagacept/AstraZeneca’s dexmecamylamine, Broncus Technologies’ exhale drug-eluting stent, Novartis’ experimental HSV-2 vaccine, Diamyd Medical’s glutamic acid decarboxylase vaccine, 3M’s imiquimod cream, Sanofi’s inparib, King’s College London’s lithium, GlaxoSmithKline’s MAGE-A3 vaccine, Nabi Biopharmaceuticals’ NicVAX vaccine, Vical’s velimogene aliplasmid, Eli Lilly’s olanzapine pamoate, Novartis’ aliskiren, Conor Medsystems’ CoStar drug-eluting stent, Pfizer’s figitumumab, Novo Nordisk’s recombinant factor VIIa (NovoSeven), Eli Lilly’s semagacestat, Pfizer’s torcetrapib and Intracell/Merck’s V710 vaccine.

“These case studies demonstrate that large phase 3 RCTs can generate critical evidence across all types of products, patients, and diseases. Both safety and efficacy failures occurred even when the phase 2 studies were relatively large (e.g., recombinant VIIa), and even when the product was already approved for another condition (e.g., aliskiren). In some cases, the phase 3 study revealed that short-term results found in the phase 2 study were not associated with a long-term benefit (e.g., bitopertin) or that the product had toxicity that was not uncovered in the phase 2 study (e.g., semagacestat),” FDA added.



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