Center for Global Health R&D Policy Assessment

In thinking about neglected disease technologies, we often overlook the specialized needs of pediatric patients. Advocacy groups have done an excellent job in illuminating the gaps in appropriate pediatric ARVs, but what about other disease areas? And what are the obstacles in developing the right neglected disease technologies for children more broadly? After a little digging, a few important issues came forward.

New Technologies. There is undoubtedly a need for new neglected disease technologies for children, especially in diagnostics. Many undeveloped technologies—like a treatment for guinea worm—would benefit children and adults, but in some cases children have more specific needs. Diagnosing TB, for instance, is more challenging in children than adults. Data regarding the rates of TB in children is weak, but estimates suggest that there are about 1 million children living with TB worldwide, and in high burden countries, children account for 20-40% of the caseload. Traditional testing methods rely on sputum samples, which are difficult to collect from small children, and more often than not, children with TB are smear negative. Children are much more likely than adults to have extra-pulmonary TB, and the pipeline for an appropriate diagnostic is empty. The Gene Xpert, which could be game-changing in adult TB control, has less promise for pediatric uses. Likewise, current HIV DNA tests often require blood samples to be sent away to Central Reference Laboratories, which opens up the possibility for sample contamination, human error and lost opportunities for patient follow up. Moreover, these tests are inaccurate in infants who are already on treatment (which should hopefully increase with the growth of PMTCT programs). Other childhood diseases with overlapping symptoms, such as pneumonia and malaria, pose difficulties in diagnosis as well.

Adapted Technologies. Although children can benefit from many technologies created for adults, they often require products to be appropriately adapted. This could mean creating pills in different dosages, altering the delivery method or matching vaccines to local serotypes. The difficulty in making these adjustments varies between the type of technology and the adjustment needed, but without them children face a greater risk of receiving inferior care. For example, if a medicine is not available in an appropriate child dose, then physicians are forced to split pills intended for adults. This could easily result in an inaccurate dosage, and becomes even more complicated if the children’s dose is not half of the recommended adult dose. A good illustration of this problem is TB treatment. The WHO revised its pediatric TB treatment guidelines, but there are no FDCs or single dose pills that correspond to the new recommendations. In order to follow the new best practices, physicians have to divide adult medicines.

Regulation and Safety Data. One common problem for adopting existing technologies for use in children is the lack of pharmacokinetic and safety data. Clinicians are regularly forced to extrapolate whether a technology is safe and useful for children based on studies conducted in adult populations. Since children’s metabolisms differ from adults, dosing may not be as simple as dividing an adult course in half. An MSF review of TB drugs found that out of the dozen or so drugs used to treat drug resistant TB, only 3 have been licensed for use in children. Similarly, there is little information available about the use of Artemisinin therapies in children under 5 kg. The good news is that the EMEA and FDA have taken strides to prevent this problem for new technologies. In 2007 both agencies started to require that pediatric evaluation plans be included in New Drug Applications (although firms can request a waiver in cases where it is not relevant**). They also provide an extra 6 months of market exclusivity for firms who do conduct studies in children. Tibotec is one of the first firms to include a pediatric evaluation plan in its NDA for TMC207, a TB drug candidate. Requiring evaluation plans is a strong first step in supporting the development of pediatric technologies, but the legislation does not specify how long after an adult treatment is licensed that a pediatric treatment should follow. Another remaining question is who should conduct the necessary studies for technologies that are on the market already. Of all of the barriers to controlling neglected diseases in children, this problem of collecting pharmacokinetic data should be the easiest to solve with the right mix of push funding targeted at firms, PDPs and other global health research groups.

Access. For technologies that are on the market and deemed safe for children it is important to ensure access and a secure supply, particularly at the peripheries of a health system. A study of WHO Essential Medicines for Children in Central Africa found considerable variation in the price and availability of priority medicines throughout public health systems. The question of access is complex, and requires close coordination between governments, manufacturers, supply chain intermediaries and the public health system.

It is important that the need for new and better pediatric technologies doesn’t remain a neglected issue within neglected diseases. In the current policy landscape, considerations about children are left to groups focusing on particular diseases. This may work well in some cases, but it may lead to an incomplete understanding of pediatric needs or inefficiencies in mobilizing support around cross cutting issues. To make sure that existing products are accessible to pediatric patients and that new neglected disease technologies are consistently evaluated in children and effectively adapted, children must receive sustained attention and advocacy. Shedding light on the problem, however, is only one part of the solution.

The challenges described above span the R&D spectrum, but many return to the issue of small and uncertain markets. Firms already face the prospect of low returns for developing neglected disease products, and creating or adapting products for children requires an additional R&D investment for an even smaller share of the patient segment. For products intended for high-income markets, the extra market exclusivity offered by the FDA or EMEA might be enough to convince product developers to take on pediatrics research, but this is inadequate for neglected disease technologies. Gilead is taking one interesting approach by layering incentives to encourage research for pediatric ARV formulations in semi-exclusive licenses for their HIV/AIDS drugs, but other policies should be explored too. Since manufacturers will most likely face a modest volume of demand for pediatric technologies, minimum price thresholds may help ensure that firms can continue to produce high quality products while recouping costs. Unlike technologies that have high global demand (like anti malarials), continued price pressure may not be the best course of action for ensuring access to pediatric products. Given the weak market incentives at play, developing pediatric technologies will require global health advocates to conduct a systematic review of what is still needed, complemented by a strong push from donors to mobilize the necessary innovators and funding to close the gaps.

*A special thanks to Elodie Jambert, Teri Roberts and Karen Day of Medicin Sans Frontieres for useful conversations around pediatric neglected diseases.

**For example, it would be unnecessary to submit a pediatric evaluation plan for a technology intended for older patients such as treatments for Alzheimer’s or prostate cancer.