This news story is a bit too optimistic and accepting of the company line. In truth, Neurochem managers knew in early April that their trial was negative and gave away as much in their April 19 press release by discussing the need for post hoc statistical models. Since then, they have issued carefully parsed public statements, press conferences, investor teleconferences, and a meeting presentation. In my opinion, close observers and certainly statisticians recognize the spin. The company’s statements sound like a distraction to avoid the outright admission that tramiprosate showed no effect compared to placebo. Even the company’s most recent news release does not quite get to this fact, nor does the ARF news story. Wall Street analysts and some investors finally got it, as the stock price tanked.
The company spent over 4 months dredging, sifting, slicing, dicing, and remodeling their database, positing one, another, or several potential “confounding” variables that might have influenced outcomes. All the while, they issued periodic press releases stating that their “external team of statisticians” was hard at work making adjustments to the statistical models “as set out in the statistical plan”; making this sound about as formidable and intellectually challenging an endeavor as decoding the human genome.
At the Alzheimer’s Association’s prevention meeting in June, Neurochem held a press conference and scientific presentation and issued a news release where it spoke about “potential confounding factors,” “numerical differences in favor of tramiprosate,” and “differences between groups on the primary disease modification endpoint as measured by magnetic resonance imaging,” all without providing any data. At the meeting, they presented a slide listing about 19 such factors from which they included from four to six (the slide is ambiguous) in their “adjusted statistical model(s).” Each factor involves an aspect of antidepressant, vitamin E, memantine, or cholinesterase inhibitor use, disuse, and/or dose change. They stated again, “no statistical comparisons can be conducted yet on the preliminary data as the primary statistical model is not reliable…. No conclusions can be drawn presently,” yet they obviously did such statistics.
This level of vagueness has no place in scientific presentations, and arguably no place in drug company communiqués, especially when the presentations can be interpreted as federally required disclosures of information on material changes in the company. It strains the company’s credibility and is virtually impossible to interpret. By withholding data and analysis results while talking around the results, there is really nothing of substance to learn.
The company presentations speak as though some sites may be at fault for site-to-site variability. The significance of this is not apparent, since we expect site variability; it is one reason why we do multicenter trials. They suggest that there was something about the discontinuation of cholinesterase inhibitors (after an average of nearly 2 years’ use) or memantine (average of nearly 1 year’s use), or that antidepressant and vitamin E use suppressed favorable outcomes. The latter is odd because antidepressant use is frequent in AD trials, and vitamin E is not cognitively effective. In the absence of data from the company, one must wonder how strong the potential effect of tramiprosate can be if drugs that have very modest to no cognitive effects are confounders.
Moreover, Neurochem further obfuscates their outcomes by seeming to blame the placebo group for not worsening as expected. ARF quotes that “30 percent of the control group did not decline in cognition,” but this is probably close to what is expected. For example, the ADASc worsens by about 6 to 7 points in other 18-month trials with a standard deviation of about 8 or more. Therefore, about a third of a placebo sample would score the same or better than at baseline.
If any of these “potential confounding factors” really influenced outcomes or suppressed an otherwise significant tramiprosate outcome, then Neurochem would have said as much. No, they would have shouted it, as would their sell-side financial analysts.
The difficulty, of course, is that the company makes assertions without showing supporting data. They imply variously that the trial may have significant outcome elements to it, would have been significant if there had not been “confounders,” or that the trial failed because there was something wrong with the placebo group. Trust us, they seem to say. Better yet, believe our external statisticians, our advisors, or what we say the FDA said in a confidential meeting: “FDA deems…results inconclusive,” or “FDA is encouraging Neurochem to continue working on the U.S. trial data set post hoc.” In effect, they cloak themselves in perceived external authority such that it appears that Neurochem, FDA, and consultants make these statements together.
I doubt that a commission of academics—however capable and well-intentioned—can provide anything additional beyond more breathing space and cover for the company. What can they do with the trial that the company hasn’t already attempted for more than 4 months? Even so, the company has stated that they will hold back outcomes of this trial until July 2008 at ICAD, the next Alzheimer’s Association science meeting.
The company knows well their limited options with regard to both their trials and their business. Neurochem’s development program (and possibly its survival) rests on the European trial that finished enrolling in August and whose last patient would complete about February 2009. The company can increase sample size, tweak the statistical plan, shorten the treatment period, or end the trial and move on. Yet it has only $80 million cash, $45 million in debt, a burn rate of $3 million per month, two other iffy drug programs, and probably some angry investors with leverage. In this context, using an advisory board that won’t produce a report until Christmas strikes me as a play for time while the company does other things and hopes for good luck. Maybe they will get positive opinions from FDA or EMEA about their other, similar drug, eprodisate (branded Kiacta) for amyloid A amyloidosis, or maybe they will reveal phase 2 results from their trial of tramiprosate (here brand named Cerebril) to prevent hemorrhagic stroke in patients with cerebral amyloid angiopathy. I hope so, because good news there would increase the likelihood that the European AD trial is completed.
Neurochem could have made this easier on everyone if they had presented their results in a straightforward manner when they knew them. Then they could have shown any unusual site-to-site variability, confounds, and discussed threats to the trial’s validity. Such forthrightness would have most directly benefited patients in the trials, physicians, other consumers, and stockholders. A straightforward presentation of their results might even gain them new investors. It is not too late for this.
The evolving Neurochem story and its relationship with the Alzheimer’s Association is as much an example of the big business of how little companies finesse research results that have a material impact on their futures, as it is a story of scientific reporting when there are no facts to report. These may be the lessons yet to learn from this trial.
Relevant disclosures: During the last year, I have consulted with the manufacturers of one marketed drug for AD, Forest, Lundbeck, and Merz; consulted with companies developing drugs for AD but without marketed drugs for AD, including AstraZeneca, Elan, GSK, Roche, Sanofi-Aventis, Takeda, Wyeth, Voyager, Myriad, and others. I serve as co-PI of Myriad North American AD trial. I have received a grant from the Alzheimer’s Association and am a member of the NIA ADCS steering committee.
References:
Neurochem news releases and financial statements.
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