Regional pathways for the regulation and ethical review of clinical trials, coupled with new processes for the design and conduct of faster, cheaper and more effective studies, are imperative if the growing pipeline of drugs and vaccines for neglected diseases is to deliver viable products to patients in need, a new report insists. 

According to the report from the US-based Center for Global Development (CGD), the last decade has seen “tremendous” progress in developing products for the prevention, diagnosis and treatment of neglected diseases, bolstered by product development partnerships and research funding from the public and private sector.

There are now nearly 90 new products in the pipeline for conditions such as malaria and tuberculosis, with many of them approaching clinical trials, the CGD says.

Yet funding for global health is contracting while clinical trial costs can run to US$30,000 per patient, it warns. It can take “billions of dollars” to develop a new medicine and bring it to market in impoverished countries, finds the report on Safer, Faster, Cheaper: Improving Clinical Trials and Regulatory Pathways to Fight Neglected Diseases.

Costing lives

“For many neglected diseases, these drug and vaccine candidates would be the first new therapies in a generation, “ notes Thomas Bollyky, a former CGD fellow who led the 22-member working group that prepared the report, drawing on expertise from the fields of medicine, law, ethics, government, industry, public-private partnerships and international development.

 “For others they are the first ever,” Bollyky says. “Delays in approval are literally costing lives.”

Two bottlenecks

The report identifies two “substantial” bottlenecks to getting new products for neglected diseases through the development process and out into the marketplace.

The first is a shortage of clinical research and regulatory – specifically ethics – capacity in a number of neglected disease-endemic settings, which can “undermine the safety of subjects and the validity of clinical data.

The second, even factoring in expected pipeline attrition, is that current levels of financing are insufficient to support the clinical development of pipeline products under current cost assumptions, the CGD working group warns.

“Addressing these related challenges will require not only identifying new sources of funding for large-scale clinical trials and capacity-building”, the report states, “but also devoting more attention to how these trials and their regulatory pathways can be improved to reduce unnecessary costs, delays, and risks to trial subjects.”

Two-pronged strategy

The working group for the CGD report has recommended a two-pronged strategy to bring the costs, risks and finances for clinical trials targeting neglected diseases into “a better, more sustainable balance”:

•    Establishing regional pathways for the regulation and ethical review of clinical trials in neglected disease-endemic settings.

This should entail a centralised procedure/joint review model with the participation of both national regulatory authorities (NRAs) and ethics committees, the working party suggests. The “particular design and adoption of that approach are questions that participating governments and their underlying institutions must decide”, it adds.

Moving to a single integrated process for the approval and oversight of clinical trials occurring in multiple countries and at multiple sites would, the working group contends:

-    improve the co-ordination and pool the capacities of the ethics committees and national regulatory authorities involved;              

-    reduce regulatory inconsistencies and overlap;                   

-    provide a more attractive platform for external assistance and donor support.

•    Creating conditions for better, faster and cheaper clinical trials in the neglected diseases field.

This calls for a focus on the key parameters and objectives of the study in question, on evidence-driven approaches and early engagement among trial sponsors, clinical investigators and NRAs, the working group says. It recommends, for example:

-    Simpler trials for product licensing coupled with more support for policy research in Phase IV studies                           

Pivotal studies “must be conducted according to the most stringent international standards and at the limited number of sites capable of supporting such trials”, the report comments.

Focusing these studies on the research necessary to support licensing would reduce costs as well as site and investigator demands, while expediting product registration, the working group believes.

For the approach to succeed, though, “donors must increase funding for the Phase IV policy and epidemiological studies necessary to support WHO [World Health Organization] recommendations on the use of the product and neglected-disease research”.

-    Early investigator input and independent advisory committees

Local investigator and independent stakeholder input should be solicited early in the study and protocol design to help spot potential problems and keep studies “simple, feasible, and focused”, the working group recommends.

-    Pressure-testing protocols

 It is common practice for many pharmaceutical multinationals to ‘pressure test’ protocols and screening criteria by performing them with dummy subjects and products prior to patient enrolment, the report notes.

A similar approach should be adopted in the development of neglected-disease products, as it “improves the efficiency of trial design and reduces the number of subsequent protocol amendments”.

Regional regulatory authority

One step the CGD would like to see is the African Union working with the WHO and the World Bank to put in place an effective regional regulatory institution that could approve/oversee clinical trials and ensure the swift registration of new products.

“The co-ordination challenges are daunting, to be sure,” acknowledges CGD president Nancy Birdsall. “But experience shows that when there is a strong technical consensus among the experts and a clear path forward, diverse players can come together in support of a fresh approach.”