A shiver went down my spine when I looked through the New England Journal of Medicine on November 13, 1986. There, in typically stodgy medicalese, was the report of a study that claimed to dramatically improve the cognition of patients with moderate to severe Alzheimer’s disease. It was what I, as a recently minted geriatrician, had been fervently wishing for but despaired of ever seeing—a glimmer of hope that we would have a medication to treat patients with Alzheimer’s disease. So I was struck in reading this week’s “Feature” article in the BMJ, “Alzheimer’s disease: still a perplexing problem,” by the author’s observation that the few drugs available for treating Alzheimer’s today are all agents that, like the drug I read about in 1986, target the production of the neurotransmitter, acetylcholine, which is vastly decreased in the brains of people with Alzheimer’s. In fact, most of the existing drugs are “anticholinesterases,” derivatives of the drug reported on in 1986, tetrahydroaminoacridine (ultimately shortened to tacrine). The only available drug for Alzheimer’s that isn’t an anticholinesterase is mementine (Namenda) approved by the FDA in 2003, which also affects acetylcholine but works in a different way. None of these drugs is terribly effective and NICE, the British agency that advises the National Health Service on coverage for drugs and devices, gives them only the most tepid recommendation. So what, I wondered, ever happened to William Summers, the lead author of the original New England Journal study that created such a stir nearly 28 years ago?
I was familiar with the early history of William Summers and tacrine (THA). The New England Journal of Medicine published an editorial along with the article, heralding the drug as a breakthrough, but the community of Alzheimer’s researchers reacted with venom. They commented on the shortcomings of the study: it only involved 17 patients, the patients served as their own controls, and the conclusions rested on the patients’ performance on a handful of tests of cognition, some of which were unfamiliar or of questionable clinical importance, including a “global assessment of cognition” performed by the examining physician. All valid concerns. Nonetheless, the findings were impressive: the difference between treated patients and untreated patients was statistically significant with a p-value of .0003. That is, if THA actually were ineffective, the chance of the investigators observing what they did was about 3 in 10,000. And the authors didn’t claim to have discovered a miracle drug. They said: “These encouraging initial results suggest that THA may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimer’s Disease. We stress that further observations will be required before a clearer assessment of the role of this agent can be made.”
The deeper concern seemed to have nothing to do with the merits—or weaknesses—of the study. Basically, the question was: Who is William Summers? Summers was not part of the established Alzheimer’s research community. He carried out the study on patients in his private practice. He had gone to medical school and completed a residency in Internal medicine and Psychiatry at Washington University in St. Louis, Missouri and had been on the faculty at the University of Pittsburgh, the University of Southern California and, at the time the initial article came out, at UCLA. But he had no funding, let alone facilities or other forms of support, from either a major research university or a drug company. He had little background carrying out research. In short, he wasn’t one of the boys.
The National Institute on Aging and the Alzheimer’s Association agreed to jointly sponsor the Tacrine Collaborative Study Group to evaluate the drug more definitively. But in the course of its review of Summers’ research, a routine step that takes place when a researcher applies for a chemical to be considered as an “investigational drug,” the FDA uncovered a variety of sloppy research methods. For the next 3 ½ years, Summers and the FDA were at war until finally, in 1991, the FDA formally exonerated Summers of all substantive charges. UCLA, the medical school where Summers had an appointment as a Research Associate Professor, also conducted an investigation. Reporting for the LA Times, writer Janny Scott quoted the panel as finding “severe shortcomings in the design, execution, and report of Summers’ study” but concluding that “these limitations did not undermine the conclusion that the drug had helped some of the patients studied.”
The Tacrine Collaborative largely confirmed Summers’ early findings, this time studying 215 patients at multiple different clinical centers. In 1993, the FDA approved tacrine for use in the treatment of Alzheimer’s disease. Tacrine is no longer on the market, but not because it was found to be ineffective. It was simply superseded by another anticholinesterase that is easier to take (dosing is once a day instead of 3 times a day) and that has even fewer side effects than tacrine. The new drug, Aricept, was a blockbuster drug, accounting for $3 billion in sales worldwide in 2010, before it went off patent. Aricept is not a great drug, any more than Tacrine was, nor are the other 2 anticholinesterases on the market, rivastigmine (Exelon) and galantamine (Razadyne). But Aricept, like Tacrine, fills a void. It gives patients and families something to do, some drug to take; and it may confer a modest benefit, at least for a short time. It’s no worse than a great many other drugs we prescribe for patients, many of them far more toxic and far pricier.
And Summers? He dropped out of sight.
Summers didn’t entirely drop out of sight. PubMed, which keeps tabs on all publications in medical journals, lists 13 articles that Summers has authored since the New England Journal paper in 1986, most in minor journals such as the Journal of Alzheimer’s Disease. His most recent paper, published in 2010, is a study of a “complex antioxidant blend” on cognitive function. His website explains that he offers “care not found in modern healthcare system,” and that he uses an “innovative mix” of traditional medicine, supplements, and homeopathic remedies. Clearly, William Summers is way out on the fringe of respectability. But was he always on the fringe, or was he driven out of mainstream medicine, deterred from pursuing an innovative research career, because he was not an insider?
I don’t know the answer. And I recognize the need to adhere to high standards in the research arena. All too many articles are published of studies that use weak if not downright inadequate methodology. But I can’t help wondering: are funding agencies such as NIH as well as private non-for-profit foundations such as the Robert Wood Johnson Foundation stultifying research by limiting funding to very conventional applicants? I wonder, and I worry.