July 20, 2014
Last year we wrote:
[Getting] the best drugs to the most people as quickly as possible ... requires that the compounds and combination products be:
One year later, the research, regulatory, and access landscape for people with HIV, hepatitis C virus (HCV), or tuberculosis (TB) remains one of stark contrasts among the three diseases, and between people with access to affordable health care -- whether they live in rich or developing countries -- and those without. The research pipelines described in this year's report show substantial progress in new treatments and preventive interventions against HIV. Revolutionary changes are afoot in the treatment of HCV, which allow -- for the first time -- the prospect of universal cure and disease eradication -- if only cost and access barriers can be overcome. But, in the case of TB, few new diagnostics, even fewer new drugs, poor access, and declining political will create a pipeline woefully underpopulated, slow-moving, and resource-deprived.
Here we highlight the first of the essential requirements outlined above, the requirement that new interventions be "discovered and developed in a high-quality research program."
A quick scan of worldwide trials data maintained by the U.S. National Institutes of Health (NIH) at clinicaltrials.gov reveals many disparities between research and development programs for treatments of HIV, HCV, and TB. Newly approved drugs for the three diseases -- dolutegravir (for HIV), sofosbuvir (for HCV), and delamanid (for TB) -- have respectively 61, 67, and 6 clinical trials registered to investigate their use.
The 61 studies of dolutegravir cover: treatment-naive and -experienced patients (including those with resistance to other integrase inhibitors); comparisons, use, and interactions with the most commonly used antiretrovirals (and a couple of investigative ones); interactions with potential concomitant medicines that include studies with methadone, rifampin, and oral contraceptives; an investigation into how the drug performs in women; use in people with hepatic and renal impairment; pregnancy pharmacokinetics; a pediatric investigation program down to four weeks of age conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) network; and pharmacokinetics of the pediatric granule formulation. This list is not exhaustive. Despite the limitations of the registrational studies, with the usual underrepresentation of women, people with coinfections, etc., by the time all the studies are completed as well as several in the planning stage that are not yet registered, we will have a pretty good idea how the drug will perform across a diverse population (Polly Clayden looks at some of these that will help with our understanding of how the drug will perform in low- and middle-income settings in her chapter on antiretroviral dose optimization).
Registered sofosbuvir trials are also abundant and include patients with varying treatment experience, liver disease stage, and genotypes. But a closer look reveals limited investigations into regimens with other sponsors' drugs, nothing in pregnant women or children, few in HIV coinfection (and nothing in other comorbidities), and just one (not yet recruiting) in people who inject drugs. As yet there are very few trials registered by independent investigators (and notably these are usually HIV networks or centers). Tracy Swan details the shortcomings of HCV trial enrollment in her chapter.
The tally for delamanid trials is a paltry 10 percent of those for the other two recently approved agents. It is at least encouraging that two of these trials will provide information for use in children with multidrug-resistant TB (MDR-TB). However, approval of delamanid by the European Medicines Agency (EMA) was delayed due to confusingly presented results from the phase II program, which included a two-month study, a six-month study, and an open-label study. The sponsor claimed a mortality benefit for those treated for six rather than two months, but neglected to mention that those not surviving or lost to follow-up between the two- and six-month endpoints were excluded from this survival analysis -- producing a biased readout.2 The sponsor's inexperience and the lack of validated treatment options in multidrug-resistant (MDR) TB cannot excuse the poor design and presentation of this phase II program. A phase III study, now fully enrolled, may shed more light on delamanid's use.
The other recently approved drug to treat MDR-TB, Janssen's bedaquiline, had stronger evidence of efficacy at two and six months, but in the "placebo-controlled C208 trial, however, an imbalance of all-cause mortality has been observed with more deaths reported in the bedaquiline group (10/79 versus 2/81 in the placebo group in C208 Stage 2). Causes of death were varied and all but one occurred after the treatment period with bedaquiline."3 The U.S. Food and Drug Administration (FDA) carried out a thorough review of each death in the phase II program and could not rule out an association with bedaquiline,4 resulting in a black box warning on the label and a requirement that Janssen open a U.S. patient registry to monitor safety post-marketing.5 The excess mortality seen in phase II should have induced Janssen to accelerate its confirmatory phase III study, which has not yet even begun. Rather than mounting its own phase III study, Janssen is trying to piggyback onto an ongoing USAID/British Medical Research Council (BMRC) study of a modified so-called Bangladesh regimen compared with standard of care (SOC). Janssen does not want to compare SOC with or without bedaquiline -- which would be the clearest and simplest confirmatory study -- but rather wants to compare a bedaquiline-containing modified Bangladesh regimen to one without. This way lies madness. The low standards for TB clinical trials leading to these accelerated (FDA) and conditional (EMA) approvals must be improved in future licensing efforts.
Throughout this report, the authors will be pointing out the need for better-quality research in order to more clearly define how to use new interventions. We will be writing in more detail on the challenges of improving research quality over the coming year.
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