As part of my preparations for an upcoming trip to India, my physician prescribed a 6-week prophylactic course of mefloquine to prevent malaria.
The weekly dosing schedule prompted me to review the package insert. As it turns out, mefloquine has an unusually long half-life (2-4 weeks), making it perfect for weekly dosing.
A review of the Wikipedia entry for mefloquine resulted in a few articles describing the history of this drug, and how it was developed.
According to Croft, mefloquine was compound number 142,490 out of over 250,000 chemical derivatives of chloroquine. Resistance to cholorquine was observed in the 1950s, and soldiers participating in the Vietnam War were succumbing to malaria at alarming rates.
This prompted a massive (at least by 1960’s standards) drug discovery program at the Walter Reed Army Institute of Research (WRAIR) to find effective preventatives and treatments for malaria.
WRAIA collaborated with 175 external contractors, an incredible number by 1960’s standards.
This effort also resulted in the discovery of halofantrine, which is chemically related to mefloquine.
The details are sketchy, but according to Croft, Phase I and Phase II clinical data were “transferred” to Roche and Smith Kline Beecham “as a free good.” Lariam (mefloquine) and Halfan (halofantrine) were eventually approved in 1989 and 1992, respectively.
Now the war was obviously long over by the time these two agents were approved, so their main markets were for travel prophylaxis. Yet, prior to FDA approval, no Phase III trials were conducted in healthy volunteers.
It wasn’t until 2001-2003 that randomized controlled trials were conducted in healthy populations, and the studies confirmed what many people already knew; that mefloquine has the potential for causing psychological and neuropsychological adverse effects.
Halofantrine was also unexpectedly (unexpected because it was never properly researched) found to have a number of serious side effects, to the point where it is no longer recommended by WHO for the self-treatment of malaria.
Now if you read the article by Croft, you will note that the article delves into a criticism of the “military-industrial complex” which drove this “natural experiment” post-approval. To quote,
Customers have been unwitting recruits to this longitudinal study, rather than informed partners…The rapid public rejection of Lariam and Halfan could have been anticipated, since users of malaria chemoprophylaxis differ from normal patients in that they are by definition healthy people, and on this account they are unwilling to accept even relatively minor drug-related harms.
Dr. Croft goes on to cite a number of cases where mefloquine might be implicated in a series of adverse drug events, including a series of murders and suicides amongst soldiers who served in Afghanistan.
Dr. Croft does not mention the combination atovaquone-proguanil (Malarone, GSK), which has a better side effect profile and comparable efficacy compared with mefloquine. But, Dr. Croft does note that no manufacturer has the incentive to conduct additional studies. And, since better drugs are emerging, both mefloquine and halofantrine will eventually be “discarded.”
Dr. Croft concludes,
This apparent willingness to casually sideline two undoubtedly lifesaving drugs represents a waste of resources, and a loss also to future travellers and patients. Researchers, policy makers and prescribers must learn from this experience or be condemned to repeat it. Many of the individual medical tragedies detailed in the table need never have occurred. Powerful institutional pressures must never again override the needs and rights of patients.
Would Mefloquine Be Approved Today?
It’s hard to say if a drug like mefloquine would be approved today for any condition, let alone malaria prophylaxis. With 1% of Vietnam soldiers succumbing to malaria per day, it is somewhat understandable that the US government would make the significant effort to screen 250,000 compounds for a treatment.
Interestingly, mefloquine may have some effectiveness against progressive multifocal leukoencephalopathy, a rare viral disease caused by the JC virus. PML occurs in patients who have secondary immune deficiency, such as AIDS, and also in the immunosuppressed (i.e., severe autoimmune disorders, transplant patients, etc.).
Could these represent orphan indications for a drug like mefloquine today? Maybe. Maybe not.
But what is clear is that the days of the FDA approving drugs without Phase III data (and arguably without sufficient Phase II studies) are long gone…at least we hope they are…
Ashley Croft is back, this time with a tirade against the military prescribing mefloquine for malaria prophylaxis:
The UK MoD’s continued use of mefloquine as routine, first-line malaria prophylaxis for soldiers, based on disastrous advice over a 20-year period from successive surgeon generals, is scientifically and ethically indefensible. It must stop, immediately.