The Pipeline for New TB Regimens: Better than Ever Is Not Good Enough
In December 2012, tuberculosis (TB) treatment reached a major milestone with the first approval in over forty years of a new medication from a novel class of TB drugs. The US Food and Drug Administration (FDA) approval of bedaquiline reflects a newly revitalised global effort to develop fresh, more effective treatments for TB after decades of stagnation.
Existing treatment for drug-susceptible TB (DS-TB) is effective, but it takes six months or more and has a high pill burden. The medication causes side-effects that often make patients feel worse than the disease itself does.
The treatment of drug-resistant TB (DR-TB) is even longer. It lasts 9 to 24 months, is very expensive, and involves painful daily injections. The regimen is even harder to tolerate, with side-effects that include hearing loss, heart toxicity, and psychosis.
Most DR-TB drugs have not been validated in clinical trials, and cure rates for the disease are much worse than for DS-TB. People latently infected with TB – particularly DR-TB – also need better, shorter-duration therapies to prevent the onset of active TB disease.
The road to adequate treatment for people with TB remains a long one. Currently the clinical development pipeline contains just six TB drugs (see the table below). This progress is inadequate given the urgency of improving treatment. Bedaquiline, though approved, has not yet begun to reach the thousands who need it. Other drugs lag even farther behind in the development cycle.
Four keys to better TB regimens
1. Governments and donors need to increase funding for TB research at least threefold.
Investment in TB drug studies stands at just a third of what is needed. In 2011 alone, there was a shortfall of nearly $500 million. In the USA, automatic and discretionary cuts to the National Institutes of Health (the leading funder of TB research and development) and the Centers for Disease Control and Prevention are harming already underfunded research programmes.
A recent review also calls on countries with high TB burdens to take a greater share in funding TB research. It recommends that the size of each country’s share should be based on its gross domestic product, TB disease burden, and the size of its treatment programme.
2. Sponsors must commit to developing their drugs and to making them accessible to other research groups and affordable once licensed.
On the research side, this means investing in the development of drug compounds using human and financial resources. It also implies working with other research consortia at an early stage to study drugs in combination. This approach would optimise the use of such drugs and make clinical research more efficient.
On the delivery side, companies must price TB drugs affordably, and manufacturers must work to maintain steady supply. The sponsors of promising candidate drugs must also make their compounds available for urgent cases through responsible pre-approval access programmes.
3. More research is needed in key vulnerable populations.
At present, TB is a disease of the vulnerable and the marginalised. Consequently, there is little economic incentive to develop new drugs. Research into important TB-affected communities is scarce or is done too late.
Sponsors and researchers must commit to studying TB drugs as thoroughly as possible, and as quickly as safety allows, in vulnerable populations. These include children, women, people with HIV, people with Hepatitis B and C, people who use alcohol, and people who inject drugs or use opioid substitution therapy.
Comprehensive drug-drug interaction studies and modelling need to be done with antiretrovirals, with methadone and buprenorphine, and with TB drugs. This is vital because many such medications interact or have overlapping side-effects, such as heart and liver toxicity. Regulatory authorities can also play an important role by appropriately encouraging, and providing incentives for, research in these populations.
4. Regulatory authorities must build their capacity and expertise to appropriately regulate clinical trials, early access, accelerated approval, postmarketing studies, and drug safety for new TB drugs and regimens.
Regulatory agencies – particularly those in high TB burden countries – must increase their ability to rapidly review submissions. This is as important in drug registration as it is in clinical research, where study design and approvals for drug importation can be unnecessarily lengthy and cumbersome. Research and development of new TB drugs is ultimately meaningless if new treatment options are not approved and available to those who need them.
The road ahead
To reach the goal of no TB deaths and no new infections, we must provide people with treatment for TB infection and active TB disease that is effective against their particular strain. Rapid, universal testing for drug susceptibility is therefore vital.
To humanely treat TB, we need shorter, more tolerable regimens. For DR-TB in particular, treatment must also be all-oral, less toxic, and more effective. We need better access to existing and new treatment options, and the auxiliary care and psychosocial support necessary to make TB care patient-centred.
Budget cuts, the spread of DR-TB, and many scientific challenges all threaten progress. But if donors, sponsors, researchers, and regulators commit the necessary resources and will, the potential to improve TB treatment and ultimately to eradicate the disease will be huge.
By Erica Lessem Erica Lessem is Assistant Director of the TB/HIV Project at the Treatment Action Group. This article has been modified from the 2013 Pipeline Report’s TB treatment chapter. To read more, please visit www.PipelineReport.org.
Sources: Jiménez-Levi, E ‘2012 Report on tuberculosis research funding trends, 2005–2011’, New York: Treatment Action Group and Stop TB Partnership (2012). Available from: http://www.treatmentactiongroup.org/tbrd2012 (Accessed 29 April 2013); Walwyn, D ‘Determining quantitative targets for public funding of tuberculosis research and development’, Health Research Policy and Systems. (2013 Mar;11:10). Available from: http://www.health-policy-systems.com/content/11/1/10 (Accessed 29 April 2013)