I'll make a few brief comments.
I'm a professor emeritus of pharmacology and toxicology, psychiatry and medicine at the University of Toronto. I've been involved in research, teaching, and clinical care, involving psycho-pharmacology—that is drugs that act on the brain—for over 40 years.
I must say, Mr. Chairman, I was somewhat surprised to be invited to meet with the committee because it wasn't entirely evident to me what you expected. I suspect it may have something to do with my very broad background in basic and clinical neuroscience and my involvement in pharmacal kinetics and risk factors for drugs. One area that I have worked in that might of particular use to the committee is the causality assessment of drug-related events. That is the determination of whether a drug has actually caused a particular adverse event.
One of my papers, for which I was the senior and supervising author, is probably particularly relevant to the work of the committee. This paper was called “A method for estimating the probability of adverse drug reactions”. It is a systematic algorithm for looking at all the factors and rating the likelihood that a drug actually caused a reaction and to take into account the relative contribution that the drug might have had in the face of other factors that may bear on a joint risk between the drug and the particular adverse event.
I agree with Professor Quinn's characterization of the evidence that there are acute and chronic, often serious, adverse events of administering mefloquine. I've used this particular algorithm in many settings, from single patients and groups of patients to literature reviews and so forth. Several years ago, I used this particular way of assessing causality to apply to a non-military individual who in error dispensed mefloquine instead of Malarone and had a profound, acute, and chronic, neurotoxic reaction.
Professor Quinn has outlined some of the issues around diagnosis. Of course, it's very tempting to try and fit what happens after a drug is given into a very tight box. You give penicillin; you get a rash, and it seems fairly straightforward.
In the case of chronic neuropsychiatric toxicity, it's not really that simple because a drug that has such reaction interacts with the individual's past history, their concurrent history, if they have mental disorders or are subject to other stresses. It's not surprising that the manifestations are quite diverse. I have heard people sort of argue, “How could a drug cause such a broad kind of effects?” Anyone who's involved in behavioural science and neuroscience doesn't find it surprising, really, because very many different parts of the brain can be affected by drugs that can bind to different receptors in different parts of the brain. The way the adverse event shows up—it's phenotype, as we call it—is determined by antecedent and concurrent factors.
A problem that frequently comes up is that often the information that's available is incomplete. Many of the studies alleging that the neuropsychiatric consequences of mefloquine are very rare are really done from data sets that are very weak. In those that have been designed properly, prospectively or with matched controls—mefloquine has even been given to healthy, normal volunteers—indicate that it has a very narrow margin of safety. You can raise the dose two-fold or three-fold, and you'll have 40% or 50% of the healthy, normal volunteers having acute effects from the drug.
The acute effects sometimes get passed off as if they're not important, but we're talking about a drug that's used for prophylaxis in people who don't have the disease. When you give the drug to normal volunteers and you see vivid dreams, disassociation, and effects on cognition, this is a warning sign that this drug has potentially serious toxicity.
One issue that comes up with mefloquine is that the toxicity doesn't seem to be entirely predictable. Now, it is true that higher dosages give rise to greater frequency of adverse events, and some of them are very unpleasant. However, it's not so clear with the onset of chronic neurotoxicity. Often, an acute event after taking the drug is a warning that the individual has some risk factor, that the drug is interacting and is going to cause a problem.
What we find is that there are other things that must be afoot. For example, we know that mefloquine gets out of the brain by a particular transport protein. There are individuals who lack this transport protein, so mefloquine can reach very high concentrations in their brains, and that puts them at particular risk. It's really the mefloquine in the brain—amount or concentration—that's important.
The final comment I would make is to endorse the systematic approach that Professor Quinn has urged. It is extremely important that individuals who are to receive any drug that has risk be explicitly warned and that there be careful documentation, and that individuals who have the risk factors don't receive certain drugs.
I know that there's been interest in this particular field in drug labelling, but drug labelling is not a good way to inform patients or even physicians about what the problems are. The surgeon general's review identified a lack of proper documentation among military individuals with respect to having even received this drug, and identified individuals who received the drug who had contraindications.
There's something clearly not right, and I think Professor Quinn outlines a very reasonable, systematic and probably long overdue approach.
Having said that, I think that the current practice of not prescribing this drug is entirely appropriate. I noticed in some of the material I looked at before today that somehow patients are given an option that they can indicate they would be prepared to take the drug. I think we're past that. I don't think this is a drug—except in situations where there is extremely careful monitoring and very knowledgeable individuals are prescribing the drug—that somebody can say, “Well, yes, I'd like to take mefloquine”. There's an implication here that is outside of the normal medical world that I work in.
My recommendation is that you take this assessment of causality, this strategy, and apply it systematically to cases that are either emergent ones or retrospectively.... This involves two steps: applying the algorithm to assess causality, and then assessing what information is missing that makes it difficult to make the assessment of causality. Just because it looks like it's not likely the drug doesn't mean there isn't a reaction caused by the drug. It's usually because the information is not available to make the assessment. This is the problem in most of the literature that people point to when they're trying to support that this is a very rare kind of thing, or that it doesn't happen at all and so forth. That's not the real situation.
Thank you.