Battling Alzheimer’s With Correct Answers to the Wrong Questions

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Roughly five million Americans suffer from Alzheimer’s. Approximately, 50 percent of U.S. Citizens Who reach the age of 80 will contract the disease. All these numbers make Alzheimer’s disease mega business for pharmaceutical companies, holding out the promise of billions on billions of dollars. So, any progress that may allow pharmaceutical companies to get their feet in that trough is considered important.

That is why the recent buzz in the financial world over Biogen’s report of an early trial of “Adu” (as Fortune abbreviated the drug’s tongue-twisting name) was impressive. Everybody in the financial world covered it. Stories appeared in Forbes, The WSJ, Fortune, and the NYT.

More recently, Fortune lavished an entire article on Biogen and its “promising discovery.” Drug trials have their own methods and their own criteria for success. Good trials will give one correct answers to the questions asked. The only problem is that sometimes the questions asked are not the correct questions. What has been forgotten in this impressive round robin of corporate back-slapping is what should be the most meaningful test for any medication for Alzheimer’s—What effects might the drug have on relieving suffering in people’s everyday lives?

Biogen’s testing of their drug was truly innovative in some ways. They used scans to assure that those enrolled in the trial had the plaques in their brain associated with Alzheimer’s. They found that their drug reduced the level of those plaques, that those in the trial showed slower rates of decline on standard cognitive and functional tests and those changes were statistically significant (unlikely to be the result of random chance).  They also found a dose-response in their results—the positive effects of the medication increased with higher doses of the medication. All of these factors are positive signs that Adu may have an effect on the Alzheimer’s disease process.

Biogen is so stoked by the results of this trial involving 166 participants that they claim their next step in research, according to the Fortune article, will involve over two thousand people in something approximating real world conditions.

This strategy will certainly be to Biogen’s benefit. The most striking effects of Adu came from the group of study participants receiving the highest doses of the drug. Unfortunately, these same participants also had very high rates of brain swelling and the highest rates of dropping out of the trial due to side-effects

But, lower doses also had an effect, with a more benign side-effect profile. However, the effects in the lower dose groups were smaller and were often not statistically significant and, therefore, could not be considered effects of Adu. With more than a ten or twenty fold increase in the number of study participants, such smaller differences with their reduced side-effect profile will almost undoubtedly be statistically significant. Biogen will be able to attribute these positive effects to Adu.

Biogen will then ascend into a more elevated plane of corporate existence that includes shockingly higher stock values, gold-plated patents, and corporate revenues that zoom upward. After all, the very mixed results of the report of the small trial resulted in an increase of over $40 in Biogen’s share price.

If the results of the larger trial go as predicted, which is not a certainty but is very likely, a number of things will then occur. Adu will be sold by the shovelful to persons with Alzheimer’s. A new industry of costly brain scans to measure plaques will develop. For those with evidence of early brain plaques, Adu will become the much more expensive analog to low dose aspirin therapy to prevent cardiovascular problems.  People may use Adu (a pharmaceutical company wet-dream) as a preventative measure in decades long efforts to avert further plaque development and the onset of the disease.

Families, who provide the bulk of Alzheimer’s care, will also play into the mix. They will form an enormous cheering section for the use of Adu, should the trial results be positive and the drug be marketed. All of this is likely to be terribly expensive.  But, to be fair, so is the bill we currently pay in our society for Alzheimer’s.

Adu will probably have been shown reduced the rate of decline on tests of cognitive function, reduced the levels of plaque, changed rates of decline in tests of functional status (the need for assistance in activities like dressing or going to the toilet). All of these results will, according to highly trained and respected biostatisticians be attributed to the effects of Adu.

Unfortunately, the effects that should be the real test of Adu will not be include in the trail. “The rate of decline on the test of cognitive function, in the early trial, was slowed by 1.98 points when compared to the rate of decline in the placebo group.” Such a statement is the type of thing one hears after drug trials.  The statement may be true, but it is far from meaningful.

I would go so far as to call it meaningless. I would do so because we have no reliable or valid way of translating a change in a score on a standard cognitive test, a functional measure, or a level of brain plaque into what really matters for those with Alzheimer’s and for their caregivers.

  • Will the drug help someone remember to clean themselves and wash their hands after using the toilet?
  • Will those taking Adu make better decisions that keep them safer and reduce time  spent in monitoring them to assure their safety?
  • How much will it really reduce the total time caregiver’s tend to the needs of those in their care?
  • Will Adu reduce the level of repetitive questioning (asking the same question over and over in a short time span) that so frustrates caregivers?
  • Will it ease the fear, anger, and depression that so often accompany early and mid-stage Alzheimer’s?
  • Will it delay nursing home admissions?

What may be the much-touted results of further testing of Adu are not likely to answer any of these questions. Neither will the ongoing trials of other drugs aimed at the disease. We will hear about changes in cognitive scale scores or ADL indexes. Incredible time and effort are invested in clinical trials to assure that researchers determine whether a drug has a “real” effect on outcome measures
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Unfortunately, much less thought and effort have been expended to develop outcome measures for these trials, so that “real” differences are the same as “meaningful” differences. How such medications affect everyday life for those with this haunting disease, and for those who love and care for them, should be the real test of drugs like Adu.

Those who develop these drugs and those who choose how to measure the success of such drugs draw on a long and illustrious academic and medical tradition related to clinical trials and cognitive testing. Those traditions, alas, are not embedded in the real life concerns of the millions who fall victim to this disease and the tens of millions who care for them.

Resolving this problem is not like grappling with global climate change. All that is required is that a few drug companies, clinical trial groups, and academics re-think their protocols. But, the binds of tradition are very strong in pharmaceutical research. Part of this strength comes in the fact that the results provided are not incorrect.  The results are likely to be unassailable on scientific grounds.

Getting it right is the first rule of science. Determining whether what is correct is also meaningful is too often seen as beyond researcher’s ken. It is also beyond the interest of drug companies, whose main concern is getting clearance to sell their drug as quickly and often as possible. The company wants a proven effect. A proven effect that is not meaningful is the one of the last things a drug company wants to consider.

Primary care physicians will not be of much help, should all this come to pass. The drug representatives hawking the drug will tout the trial results and the mild side-effect profile before leaving a boodle of samples. The physician will then be faced with a frightened patient and a horrified family ready to grasp at the thinnest reed of hope, before they sink below the surface of a sea of grief.

The physician will say that there is this new medication that “might…..” That is all he or she will need to say. The family and patient will literally leap at whatever chance there might be. The family will leave with a sample, a prescription, and hope.

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