There are only two candidates for tuberculosis vaccines currently in phase III trials, but 59 others elsewhere in the development pipeline
The global health community has been abuzz with news that the new malaria vaccine, which has been in the development phase for over two decades, appears to greatly reduce the risk of malaria in children in Africa. Yet this exciting success story is just one of nearly 90 promising new medicines, vaccines, and diagnostic techniques stuck in the tangled clinical trials process. What is more, if the clinical trials process doesn't improve it could be years before many of those drugs ever get through the complicated testing process to reach the one billion people in the developing world who suffer from neglected diseases like TB and Dengue Fever. How many malaria deaths could have been prevented if only the clinical trials process had been improved sooner?
In many cases delays occur because steps in the approval process need to be done in sequence, rather than in parallel.
The many other drug and vaccine candidates for neglected diseases waiting in the pipeline for late stages of clinical development must face lengthy, inefficient review processes or non-existent regulatory capacity in the poorest, least developed countries before these technologies can reach the millions in need. Take, for example, tuberculosis (TB), a neglected disease that remains one of the largest causes of death and illness worldwide. According to a report by BIO Ventures for Global Health, there are only two vaccines and treatments for the disease in phase III trials, compared to 59 in the remainder of the pipeline. So what does it take to get a new treatment through the pipeline and into the hands of a patient who needs it?
Coordinating large multi-center trials for TB isn't easy (or quick for that matter). A 2008 article in the Lancet cited two examples where trials had been delayed by a year or more due to regulatory hurdles for multi-national clinical trials. One of these examples, a trial studying a four-month treatment regimen, needed to obtain approvals from 18 authorities in six different countries, and was stalled for two years before patient recruitment could commence. The primary drug being evaluated in this study, Rifapetine, was approved by the FDA in 1998, but the best dosage for people living in endemic areas is still under investigation as of July 2011.
Unfortunately, this story isn't unique. In many neglected disease-endemic countries, approval of clinical trials can take as long as six-24 months. For products that require multiple trials in different subject populations, subsequent application approvals may take an additional six-24 months or longer. And if you need to amend a trial protocol? Approval for that could take up to four months in a low-income setting. In contrast, regulatory approval for trials in the United States and the European Union can generally be obtained within 30-60 days, and trial protocol amendments take a few weeks.
Not only do these delays prevent access to effective treatments by a growing number of patients (over nine million individuals are newly infected per year by TB), they can lead to unnecessary costs that eat away at already small budgets to find new cures for neglected diseases. According to a recent report (PDF) by the G-FINDER project, in 2009, the global total spending on TB drug development was just $180 million, with 78 percent of all TB funding coming from public funders and philanthropic organizations.
In many cases delays occur because steps in the regulatory and ethical approval process need to be done in sequence, rather than simultaneously and in parallel, so that more than a year can pass between finalizing a trial protocol and completing all governmental and institutional regulatory and ethics processes. To address this, CGD's Clinical Trials and Regulatory Pathways for Neglected Diseases Working Group recommends establishing a regional regulatory pathway that would increase regulatory capacity, reduce inconsistencies, and speed product development and delivery in neglected disease-endemic countries.
The proposed regional pathway (illustrated below), is based on a joint review model in which participating regulators and ethics committees would jointly review the application and perform the ongoing oversight of the trial.
This approach would offer a single review process with definitive timelines and requirements without undermining the sovereignty of the countries involved. Participation is voluntary for regulators and applicants alike, but those that decide to participate must use common documents, deadlines, and standards to assess applications. The pathway would be, at least initially, non-binding, but can be formalized as the trust and confidence of the participants grows. Applied to the example above, instead of the trial needing to coordinate with 18 different authorities, it would submit a single standardized application to the regional Secretariat, which would then be responsible for circulating to various regulatory authorities in parallel, who would then choose whether or not to participate within a pre-specified period of time. This aspect of the clinical trials regulation would move faster than it does currently, because ethical and regulatory standards would be consistent across the region, making it easier for clinical trials researchers to understand and comply with these standards. Following this step, the committees would offer a joint recommendation and participating national regulatory authorities would be identified.
This approach to regulatory cooperation has a track record of success. The European Union's voluntary harmonization procedure and the World Health Organization's African Vaccine Regulatory Forum both involve joint reviews of clinical trials and have been popular, low-cost, and implemented over a few short years. Regulatory bottlenecks extend the duration of clinical development, which the Institute of Medicine has estimated represents as much as half of the cost of conducting clinical research.
Even further, this approach would provide a useful platform for other regulatory initiatives. Regulatory cooperation that achieves more certain review times and reduces inconsistences in oversight of clinical trials could be used later to register and license safe and efficacious products. A regional approach that pools scarce country regulatory resources and provides a sustainable platform for clinical trial oversight capacity building could also do the same for post-market drug and vaccine safety surveillance, or even cost-effectiveness assessments ahead of public sector funding decisions.
Clinical trials produce goods that span entire regions and, as such, they need a system of regulations to match. Reducing inhibitory costs and bureaucratic hold-ups would benefit the estimated one billion people that suffer from neglected diseases -- be it malaria, TB, or other lesser known diseases -- every year.
Image: Carlos Yudicka/Shutterstock; Figure: Courtesy Safer, Faster, Cheaper.
With Tom Bollyky, a former research fellow at the Center for Global Development.
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