Guest post by Grania Brigden. Grania is the TB advisor to the MSF Campaign for Access to Essential Medicines.
There is currently a worldwide shortage of quality-assured capreomycin, a key drug in any regimen to treat multidrug resistant (MDR) TB. This shortage has occurred because Akorn—a US manufacturer and the only supplier of capreomycin to the Global Drug Facility—has had a problem with the supply of the active pharmaceutical ingredient. This situation is not unique to capreomycin: in 2010 there was a global shortage of kanamycin, similarly as a result of having only a single manufacturer producing quality-assured injections and a problem with the active pharmaceutical ingredient. The current shortage of capreomycin could result at a country level in MDR-TB patients not completing the required length of treatment or delay patients starting treatment, with the associated increase in morbidity and mortality.
Of the 9.4 million new tuberculosis (TB) cases diagnosed each year, approximately 5% are multidrug resistant (MDR). MDR-TB treatment is demanding for patients, requiring a complex treatment course lasting 18–24 months, and using a minimum of five different antibiotics that often add up to more than 20 tablets a day.
One of the group of drugs required are injectable antibiotics that must be given for a minimum of 8 months. These drugs—kanamycin, amikacin, and capreomycin—are key to any treatment regimen for MDR-TB. There are a limited number of manufacturers globally who produce quality-assured formulations of these drugs, and changes in the producers in the MDR-TB market has resulted in single manufacturers supplying the global demands. The MDR-TB treatment regimen has been plagued with drug shortages for many years due to this situation .
MSF currently supports TB care for over 25,000 patients in 29 countries, and is providing treatment to over 1000 patients with MDR-TB in 15 countries. The number of patients enrolling in MDR-TB programmes is increasing each year. MSF is using its emergency stock to bridge the shortfall and are advising their projects on ways to prevent patients’ treatment being compromised by the low stock levels.
Prior to the increase in the rate of MDR-TB, the use of some of these antibiotics was declining, so their production capacity decreased accordingly. This has led to the limited availability and high cost of quality assured second line medicines to treat MDF-TB.
There are manufacturers in China, India, South Africa and the former Soviet Union who provude injectable antibiotics for MDR-TB treatment but their compliance with World Health Organization (WHO) quality assurance standards is unknown. All manufacturers of these drugs need to meet internationally recognised quality standards to ensure efficacious treatment and prevention of further resistance.
One mechanism to ensure the quality of drugs is the WHO Prequalification Programme, which evaluates both the product and manufacturer. Today, there are two main mechanisms that are internationally recognised to ensure the quality assurance of a medicine: WHO prequalification and the approval of a stringent regulatory authority.
The lack of quality-assured manufacturers involved in MDR-TB drug production, combined with growing demand, has contributed to the increased price of these drugs. The average price of treating a patient with MDR-TB is approximately US$9000, compared with $19 for drug-sensitive TB. Capreomycin significantly contributes to this increase in cost (as well as moxifloxacin, para-aminosalycilic acid, and cycloserine). The price of capreomycin has risen from $4 to $8 a unit, after manufacturer Eli Lilly, which had been subsidising the cost, ceased production. The new quality-assured manufacturer for capreomycin was not able to offer the same prices, although they are still offering some subsidies. The other major injectable agent, amikacin, has increased in price by 991% since 2001.3 This and other cost increases could be attributed to monopoly situations for some drugs and manufacturers who were subsidising the supply of certain drugs leaving the TB market.
WHO and other partners created the Green Light Committee (GLC) in 2000 to respond to the need for affordable second-line drugs. It has been largely unsuccessful in providing a large market force to drive down prices. The GLC is currently undergoing a restructuring to try and increase access to quality-assured products and encourage the scale up of DR-TB programmes. Some countries and projects not currently in GLC programmes are purchasing these important drugs from either pharmaceutical companies with non-approved products or at increased cost from approved companies, and in some cases not starting MDR-TB patients on the appropriate treatment. MSF has recently published, in collaboration with the Treatment Action Group (TAG) and Partners in Health (PIH), a report into these global initiatives and the extent of certain countries’ scale up of MDR-TB programmes.
With the improvements in TB diagnostics, especially with the new Xpert MTB/RIF test, MDR-TB is becoming faster and easier to diagnose, and the numbers requiring treatment is expected to grow exponentially as a result. Even without this expected increase in diagnosis, only 10% of the current estimated MDR-TB cases in the high burden MDR-TB countries, and 11% globally, have been started on treatment.2 This could mean that there are, at least, more than half a million potential patients needing second-line treatment now, even before the expected increase with new diagnostics.
The current stock rupture of capreomycin should be seen as a wake-up call to everyone involved in the management of MDR-TB. There is an urgent need to develop novel funding mechanisms to incentivise new manufacturers to enter, and to retain current manufacturers’ engagement, in the global TB market, to ensure uninterrupted supply of quality assured medicines. While this key debate is left unaddressed, we will continue to see severe shortages of critical MDR-TB drugs, and with a likely greater frequency as the demand increases. This will have devastating implications for both the individual and the public health of the community.
WHO. Towards universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis by 2015: WHO progress report 2011. http://www.who.int/tb/publications/2011/mdr_report_2011/en/index.html