WHAT TO TELL ALZHEIMER'S PATIENTS AFTER A TRIAL GOES AWRY

Dr. Joel Ross, the founder and chief executive of the Memory Enhancement Centers of New Jersey, makes his living enrolling subjects in drug company clinical trials that are testing drugs for Alzheimer's disease, among others.

So when Eli Lilly announced last week that its promising Alzheimer's drug was making patients worse and that it was halting two large clinical trials, it seemed likely that Ross would hear from family members of his patients. Are other experimental Alzheimer's drugs safe? they might ask. Should they get their family members out of those Alzheimer's studies?

Not a single family member called. And Ross is not sure why.

If a study of an experimental breast cancer drug was ended because it made the cancer grow and spread, women in other breast cancer studies of similar drugs would be calling their doctors and asking what to do.

Alzheimer's is different.
'It may reflect the incredible desperation surrounding Alzheimer's disease,' said Baruch Brody, director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine.

There is no treatment and no way to prevent Alzheimer's. It is a leading cause of death, ravaging patients and their families.

'Possibly, the overworked caregiver has precious little time to listen to news or read a paper,' Ross said.

Whatever the reason, the silence of Alzheimer's family members gives rise to an ethical question. Do families now need extra protection or warnings about the Lilly experience when they sign up Alzheimer's patients for studies?

There are no easy answers, ethicists and drug companies say, in part because it is not known what went wrong with the Lilly drug.

When patients enter studies or, in the case of patients with Alzheimer's, when caregivers sign them up for studies, they or their caregivers sign an informed consent document. The forms are reviewed by ethics panels known as institutional review boards.

When the federal government conducts studies, it makes the consent forms public. Drug companies, though, generally insist that their forms be confidential. Investigators conducting studies for companies and institutional review boards must agree not to distribute the forms.

Every form contains a statement that warns patients that a drug might not help, said Angela Bowen of the Western Institutional Review Board, a private group that does ethical reviews of research on human subjects, including studies of Alzheimer drugs. The forms say a clinical trial is aimed at helping future patients. It is not a treatment for a disease.

The forms also say 'there may be side effects that are not known at this time' and 'your condition may not get better or may get worse during this study.'

It is often difficult to convey those ideas, said Dr. John Ennever, Western's vice president for medical affairs.

'We realize drugs can cause side effects and that sometimes they don't work but we don't think they can make conditions worse,' he said. 'We are dealing with humans who have hopes and aspirations. The whole idea of research is a difficult concept. We all forget that if we knew the answer we wouldn't be doing the research.'

The Lilly drug disabled an enzyme needed to make a protein, beta amyloid, that accumulates in plaques in the brains of people with Alzheimer's disease. Other companies are testing different drugs that disable that enzyme, gamma secretase.

Researchers at other companies like Elan and Bristol-Myers Squibb said the Lilly drug, among the first of the gamma secretase inhibitors, took a sledgehammer to the enzyme. As a result, it probably affected levels of many other proteins besides beta amyloid. They say gamma secretase inhibitors now under development are much more selective and may be much safer.

Elan is one of those companies with a newer-generation gamma secretase inhibitor, and its chief scientific officer, Dr. Dale Schenk, said he did not think it necessary to emphasize the Lilly drug result to people taking his company's drug.

'To be fair, this is the first anti-amyloid drug that has demonstrated a negative effect,' Schenk said. 'I'm not worried about the class.'

Ted Yanock, Elan's head of global research, agreed. Telling people taking the Elan drug about the Lilly results 'would almost be misleading,' he said.

Schenk said he awaits further details from Lilly. For example, he said, patients taking the drug could score worse on the scale used to measure cognitive decline if the drug made them feel ill. Alzheimer's patients who do not feel well score low on 'activities of daily living,' which can drag down their overall cognitive score. And the Lilly drug, which may have altered a wide variety of body proteins, could have made people feel ill.

Some Alzheimer's researchers are not so sanguine. They say it remains possible that even those more selective drugs will make Alzheimer's symptoms worse or, like the Lilly drug, make symptoms worse and increase the risk for skin cancer.

There also is a different group of experimental Alzheimer's therapies that use antibodies to attack amyloid plaque. With those drugs, said Dr. Jason Karlawish, a professor of medicine and ethics at the University of Pennsylvania, the Lilly result may be less of an issue.

The antibody therapies are distinctly different from the gamma secretase inhibitors. Warning about the Lilly drug would be like warning someone taking an antibiotic about side effects found with a very different antibiotic.

For gamma secretase inhibitors, Karlawish said, 'you'd have a case about whether this information should be told.'

Dr. Paul Aisen of the University of California, San Diego, agreed. Aisen directs the Alzheimer's Disease Cooperative Study, a program financed by the National Institute on Aging to conduct clinical trials of treatments for Alzheimer's disease. He said that all he knew so far about the Lilly study was what the company said in a press release and that 'the details are important.'

But, he said, 'based on the contents of the press release, I would say that both the risk of skin cancer and the risk of increased cognitive decline should be added to consent forms for gamma secretase inhibitors.'

Most patients entering clinical trials believe they are getting a new treatment that may benefit them, Brody said. Ethicists call that a 'therapeutic misconception,' he said, adding, 'No one should ever assume that in a clinical trial.'

'There are certain clinical conditions like Alzheimer's where people are pretty desperate,' Brody said. 'People say, 'What do I have to lose? Look what I'm facing.''

And so, he said, the Lilly drug result should serve as a caution - no matter how promising an experimental therapy seems, it might turn out to be worse than a placebo.

'The companies and, even more so, the institutional review boards need to take this to heart,' Brody said. 'They need to make sure the consent forms say, 'You may not benefit and may be harmed.'' And, he said, that warning should be prominent, 'not just a side remark.'