The New Year is five days away. As we near the December 31st the media is full of reminders of events of the year that is passing. Statistics also contributed to the news, and to breakthroughs in science, in politics, and in human progress. Today, and every day this week, we bring you, two each day, 10 of the most noteworthy stories of the year and the statistics that made them possible. Here we look at two health stories that will affect thousands of lives.
1. Breakthroughs in the prevention of HIV. This year, the parallel group, placebo-controlled randomized trial (RCT) was responsible for two major public health successes in the fight against the HIV/AIDS epidemic. Investigators from the Preexposure Prophylaxis Initiative (iPrEx) randomly assigned 1251 men to daily oral pill, Truvada, and 1248 to placebo. Eligible participants were not infected at the beginning of the study but were at-risk for infection because they were sexually active men who have sex with men (MSM). The objective of the study was to determine if a combination of antiretroviral drugs (Truvada) could reduce the risk of infection for MSM who might be exposed to HIV through sexual intercourse (Grant 2010). After a median 1.2 year follow-up, the intent-to-treat Cox proportional hazards analysis found a 44% reduction in the risk of infection for the Truvada group. Intent-to-treat means that the analysis included all participants as assigned, even if some participants stopped using their assigned drug or crossed over to the other experimental group during the study. Among highly compliant subjects--those who took their medication for 90% of the study days--a subgroup analysis showed an even greater prophylactic effect of a 73% reduced rate of HIV infection.
It was doubted whether the first decade of the 21st century would witness the development of a viable HIV prevention strategy for sexually active women. Prospects for such a discovery suffered major setbacks with the first microbicide trials of a nonoxynol-9 gel. The trials were not simply failures; there was alarming evidence that, due to increased inflammation, the intervention designed to prevent HIV and other sexually transmitted infections might actually increase their transmission. But this year, there was cause for renewed hope in the use of microbicides to end the spread of HIV. Researchers at the Centre for the AIDS Program of Research in South Africa reported who had completed an HIV-prevention trial of at-risk women in KwaZulu-Natal, South Africa, reported that participants assigned (n=4445) to receive a 1% vaginal gel formulation of tenofovir had a 39% decreased risk of infection as compared to those given a placebo gel (n=444). As with iPrEx, better adherence conferred greater benefit; the highest adherers had a 54% lower risk of becoming seropositive. Importantly, there was no indication that the safety of women using the tenofivir gel had been compromised.
With randomization, adequately designed placebo, and sufficient power, these trials were able to identify novel and efficacious HIV prevention strategies. The task for future years will be to determine if and how these discoveries can be turned into effective and feasible interventions outside of an experimental setting.
2. Drug regulation: restrictions and retractions. While the RCT was basking in the brillance of the double rainbow achieved by HIV prevention research, it was simultaneously at the center of regulatory storms concerning pharmacological therapies for two of the most burdensome chronic diseases in the developed world: breast cancer and type 2 diabetes. In 2008, the FDA granted accelerated approval to Avastin (bevacizumab) in combination with chemotherapy for the treatment of metastatic HER2-negative breast cancer after the drug's manufacturer, Genentech, reported results of the RCT E2100: compared to women receiving chemotherapy alone, women on the Avastin-chemo regimen had a 50% increase in time without tumor progression or death (progression-free survival (PFS)). Accelerated approval gave Avastin a conditional entrance into the breast cancer treatment market. For full approval, the sponsor would need to confirm the E2100 findings on PFS and overall survival with follow-up trials.
This summer, when the Oncologic Drug Advisory Committee (ODAC) reviewed the evidence from two subsequent Genentech-sponsored confirmatory trials, AVADO and RIBBON-1, they concluded that the combined results had not met the criteria necessary to support permanent market approval. The totality of evidence on the treatment of HER2-negative metastatic breast cancer showed a median increase of PFS of only 1 to 2 months and no benefit to overall survival. Considering that there were signs of an increase in grade 2-5 toxicities with Avastin regimens, the panel returned a 12 to 1 vote in favor of withdrawing the breast cancer indication from Avastin's label. In November, the FDA decided to take the ODAC recommendation and initiated the label revision process. Hoffmann-La Roche, the ownder of Genenteh, can be expected to appeal the decision, most likely with a statistical argument of Avastin's benefit in a restricted patient population based on subgroup analyses of E2100, AVADO and RIBBON-1.
The European Medicines Agency (EMA) took a mixed position after its December review of the experimental data on Avastin's benefit for the treatment of advanced breast cancer; the agency announced its support of the use of Avastin in combination with paclitaxel but not in combination with chemotherapies in general.
It was a tumultuous end-of-year for drug regulators. Coincident with the revisions to the Avastin label, both the FDA and EMA made moves to restrict the use of the thiazolidinedione Avandia (rosiglitazone) for the treatment of type 2 diabetes. Several meta-analyses were key players in statistical evaluations of the association of Avandia and the chance of cardiovascular (CV) risk events, including CV-related death and non-fatal myocardial infarction. Details of this debate were detailed in a November Significance web exclusive. Although the EMA opted to suspend the sell of Avandia in EU nations, the FDA decided that the quantitative review evidence was equivocal and data from the most recent RCT (RECORD)--designed specifically to measure the risk association of CV events and rosigliltazone use--was potentially biased. While the results of RECORD are being adjudicated, Avandia will be on a restricted use program in the US.
The Avandia and Avastin stories of 2010 were dramatic proof that, when used to predict a drug treatment's effects once in general use, the RCT is a fallible crystal ball.