US panel endorses WHO's antimalarial artesunate suppository for young children

The US FDA's external experts overwhelmingly endorsed the World Health Organization's NDA for artesunate rectal suppositories for young children with malaria, but recommended against licensing a higher dose for older children and adults.

13 of 15 members of the anti-infective drugs advisory panel said a single 100mg dose was effective in reducing mortality in children under age six years who cannot readily access intravenous antimalarial treatment. The product, which would be administered for emergency parasite control while a patient travels to a clinic or hospital for standard antimalarial therapy, would fill an important gap in early treatment of severe disease in developing countries, the panellists said.

All but one of the committee members voted against approval of a 400mg dose that was studied in children over age six and adults in Bangladesh. The group was swayed by data showing the higher dose was associated with a higher rate of mortality.

The WHO's proposed indication is the initial, single-dose treatment of patients with acute malaria who cannot take oral medicine and for whom injectable treatment is not available. The intent is to reduce mortality and neurological complications by providing antimalarial coverage during the first 24 hours while a patient is being transported to a clinic or hospital, where they would receive intravenous or oral treatment.

The majority of patients targeted by the indication live in malaria endemic areas, particularly Africa, although non-immune travellers or those returning from travel may also benefit.

Although the product is not targeted for use by Americans, several panellists were concerned that an FDA-approved artesunate suppository would be used for off-label indications in the US, such as cytomegalovirus infection and cancer. They also raised fears that subtherapeutic dosing of artesunate monotherapy would lead to development of resistance.

WHO as sponsor

In an unusual situation, the WHO is sponsoring the NDA. The organisation was unable to secure a commercial partner willing to fund a regulatory submission without a guaranteed financial return that would have kept the product affordable for developing countries, said Dr Melba Gomes, product manager with the WHO's Special Programme for Research and Training in Tropical Diseases. The WHO is currently negotiating with several pharmaceutical companies to make the drug available if it receives regulatory approval.

FDA approval would give artesunate rectal suppositories a high level of regulatory credibility for use outside the US, Dr Gomes said. Although there are artemisinin-based suppositories available outside the US, none has gone through a stringent drug regulatory process. "The idea is to raise the bar and make sure there is one that meets stringent standards," Dr Gomes said.

The meeting was the second go-around for the WHO with the anti-infectives panel. In July 2002, the committee unanimously supported accelerated approval based on the results from three pivotal studies that measured the surrogate endpoint of parasite reduction. At the time of the 2002 meeting, Study 13, a large, simple trial designed to look at the efficacy of artesunate under actual-use conditions, was underway.

Although the FDA found sufficient safety and efficacy data based on the surrogate endpoint of parasite clearance at 24 hours, it issued an approvable letter in August 2002 owing to deficiencies in chemistry and manufacturing information.

The WHO responded to the approvable letter in November 2006, but the agency again found the filing deficient and issued a second approvable letter in May 2007. A third approvable action followed in May 2008 due to a higher rate of mortality in artesunate-treated older children and adults in Study 13. These findings, which the FDA called unexpected and unexplained, were included in a summary report, and the agency asked the WHO to provide the complete dataset.

Study 13

The panel meeting focused on Study 13, which was a multicentre, randomised controlled trial that compared single-dose artesunate rectal suppository with placebo in patients with suspected malaria who live in remote areas, were too ill to take oral therapy and did not have access to parenteral antimalarials. The study was designed to evaluate whether there was a survival benefit associated with pre-hospital treatment with rectal artesunate

The study was conducted at four trial sites: one in Ghana; two in Tanzania; and one in Bangladesh. Young children aged six months to 72 months (six years) were enrolled at all four sites. Children over six years and adults were also enrolled in Bangladesh. The artesunate dose was 100mg for young children and 400mg for older children and adults.

Approximately 18,000 patients were randomised. Blood smears subsequently showed that about 5,000 patients had no malaria parasites, so artesunate treatment could have no benefit. Another 10,000 patients either died too rapidly to be helped or reached a clinic within six hours, giving artesunate too little time to be useful.

As reported in The Lancet in 2008, use of rectal artesunate significantly reduced the risk of death or major permanent disability among the 3,000 subjects who did not reach a clinic within six hours after suppository insertion. The mortality rate was 1.9% (29 of 1,568 patients) for artesunate versus 3.8% (57 of 1,519) with placebo (p=0.001) (scripnews.com, 9 December 2008).

The FDA's view of the data, however, was that in three populations analysed (all randomised patients, and two modified intent-to-treat groups), there were consistently favourable mortality results with artesunate for young children overall but unfavourable results for older children and adults.

The mortality benefit for young children appeared to be driven largely by the results at the Bangladesh site, which saw a significant 57% risk reduction in mortality. In contrast, a non-significant reduction of less than 20% was seen for young children across the three African sites. In older children and adults, results in all three analysis populations favoured placebo over artesunate, with the treatment difference being statistically significant for the intent to treat groups.

The agency raised various statistical concerns about the WHO's analysis and asserted that, contrary to the results published in The Lancet, there was not a significant benefit with artesunate among subjects who failed to reach a clinic or hospital within six hours.

The product is also under review in the UK and Switzerland. Margaretha Bindschedler, a senior medical officer at Swissmedic, said that agency's clinical review team had concerns about the increased mortality seen in older children and adults and the post hoc nature of some of the WHO's analysis. She said the Swiss regulator's review team thinks the evidence does not support a positive risk:benefit ratio at this time.

Artesunate is a new molecular entity not approved in the US. The WHO's product, if licensed by the FDA, would nevertheless not qualify for the priority review voucher programme created by the FDA Amendments Act (FDAAA) to spur development of tropical disease treatments. Under the 2007 law, a priority review voucher will not be awarded if a tropical disease product application was submitted prior to the statute's enactment. The WHO's NDA was initially submitted in 2001.