It is really a fascinating topic...
There are examples where even spectacular Phase 2 results aren't replicated in larger pivotal Phase 3 studies, which even puzzle researchers and key opinion leaders; here is just one really striking one I found: Pfizer's/Medivation Dimebon in Alzheimer's (2010).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922928/
"Medivation used its financial resources to organize a phase II trial of Dimebon with 183 AD patients (NCT00377715). ...The primary outcome measure was the ADAS-cog (Alzheimer’s Disease Assessment Scale-cognition) scale. ADAS-cog scale is a standard way to evaluate potential AD therapeutics in the USA and acceptable by FDA. Secondary outcome measures included MMSE and Clinician Interview-based Impression of Change plus Caregiver Input (CIBIC-plus).
The results of this trial were spectacular [5]. Dimebon was well tolerated. Common side effects included dry mouth (14% of patients on Dimebon, 1% in placebo group), depression (14% of patients on Dimebon, 5% in placebo group), and insomnia (9% of patients on Dimebon, 4% in placebo group). It was not clear why Dimebon acted as anti-depressant in the previous clinical trial [3], but induced depression in the second trial [5]. At week 26, treatment with Dimebon resulted in significant improvement in the ADAS-cog score compare to placebo (mean drug-placebo difference −4.0, p < 0.0001). Similar efficacy was observed for MMSE (mean drug-placebo difference 2.2, p < 0.0001) and CIBIC-plus (mean drug-placebo difference 0.6, p < 0.0001). Moreover, the ADAS-cog difference between drug and placebo increased substantially during additional 6 months extension phase, indicating that benefits of Dimebon continue to increase over time [5]. The number of patients was relatively small and the trial was designed as a phase II trial. However, results of the trial were so strong that FDA agreed to treat this trial as a first pivotal trial.
A large Phase III clinical trial of Dimebon in AD patients has been recently completed (NCT00838110, CONNECTION trial). This trial was sponsored by Medivation and Pfizer and lasted 26 weeks. The CONNECTION trial was a multi-national, double-blind, placebo-controlled, safety and efficacy trial, involving 598 patients with mild-to-moderate AD, at 63 sites in North America, Europe, and South America. The study director of the trial was Dr Lynn Seely, a Chief Medical Officer of Medivation. More than 40 percent of the patients enrolled were in the United States. In the study, patients were randomized to one of three treatment groups: those receiving Dimebon 20 mg three times a day; those receiving 5 mg Dimebon three times per day; or those receiving placebo. The primary outcome measures were ADAS-cog and CIBIC-plus. The secondary outcome measure was MMSE.
The results of the trial were released by Medivation on March 3, 2010 (http://investors.medivation.com/releasedetail.cfm?ReleaseID=448818). It was reported that no statistically significant improvements for the 20 mg treatment group relative to placebo were achieved on any of the primary endpoints. There was no significant difference for Dimebon-treated patients when compared to the patients receiving placebo on ADAS-cog measure (p=0.86) or CIBIC-plus (p = 0.81). On the MMSE measure, both Dimebon and placebo-treated groups improved significantly over baseline (dimebon 0.7; placebo 1.2). The difference favoring placebo was not significant (p=0.10). Responding to the failure of the CONNECTION trial, Medivation’s CEO Dr Huang stated in the same news release: “The results from the CONNECTION study are unexpected, and we are disappointed for the Alzheimer’s community".
There are examples where even spectacular Phase 2 results aren't replicated in larger pivotal Phase 3 studies, which even puzzle researchers and key opinion leaders; here is just one really striking one I found: Pfizer's/Medivation Dimebon in Alzheimer's (2010).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922928/
"Medivation used its financial resources to organize a phase II trial of Dimebon with 183 AD patients (NCT00377715). ...The primary outcome measure was the ADAS-cog (Alzheimer’s Disease Assessment Scale-cognition) scale. ADAS-cog scale is a standard way to evaluate potential AD therapeutics in the USA and acceptable by FDA. Secondary outcome measures included MMSE and Clinician Interview-based Impression of Change plus Caregiver Input (CIBIC-plus).
The results of this trial were spectacular [5]. Dimebon was well tolerated. Common side effects included dry mouth (14% of patients on Dimebon, 1% in placebo group), depression (14% of patients on Dimebon, 5% in placebo group), and insomnia (9% of patients on Dimebon, 4% in placebo group). It was not clear why Dimebon acted as anti-depressant in the previous clinical trial [3], but induced depression in the second trial [5]. At week 26, treatment with Dimebon resulted in significant improvement in the ADAS-cog score compare to placebo (mean drug-placebo difference −4.0, p < 0.0001). Similar efficacy was observed for MMSE (mean drug-placebo difference 2.2, p < 0.0001) and CIBIC-plus (mean drug-placebo difference 0.6, p < 0.0001). Moreover, the ADAS-cog difference between drug and placebo increased substantially during additional 6 months extension phase, indicating that benefits of Dimebon continue to increase over time [5]. The number of patients was relatively small and the trial was designed as a phase II trial. However, results of the trial were so strong that FDA agreed to treat this trial as a first pivotal trial.
A large Phase III clinical trial of Dimebon in AD patients has been recently completed (NCT00838110, CONNECTION trial). This trial was sponsored by Medivation and Pfizer and lasted 26 weeks. The CONNECTION trial was a multi-national, double-blind, placebo-controlled, safety and efficacy trial, involving 598 patients with mild-to-moderate AD, at 63 sites in North America, Europe, and South America. The study director of the trial was Dr Lynn Seely, a Chief Medical Officer of Medivation. More than 40 percent of the patients enrolled were in the United States. In the study, patients were randomized to one of three treatment groups: those receiving Dimebon 20 mg three times a day; those receiving 5 mg Dimebon three times per day; or those receiving placebo. The primary outcome measures were ADAS-cog and CIBIC-plus. The secondary outcome measure was MMSE.
The results of the trial were released by Medivation on March 3, 2010 (http://investors.medivation.com/releasedetail.cfm?ReleaseID=448818). It was reported that no statistically significant improvements for the 20 mg treatment group relative to placebo were achieved on any of the primary endpoints. There was no significant difference for Dimebon-treated patients when compared to the patients receiving placebo on ADAS-cog measure (p=0.86) or CIBIC-plus (p = 0.81). On the MMSE measure, both Dimebon and placebo-treated groups improved significantly over baseline (dimebon 0.7; placebo 1.2). The difference favoring placebo was not significant (p=0.10). Responding to the failure of the CONNECTION trial, Medivation’s CEO Dr Huang stated in the same news release: “The results from the CONNECTION study are unexpected, and we are disappointed for the Alzheimer’s community".
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