Alzheimer's Drugs: The Access Debate

Most people facing the progressively debilitating affects of Alzheimer's disease are not allowed to circumvent the Food and Drug Administration's drug-approval process to gain early access to promising therapies, regardless of their prognosis. Should there be more flexibility in the laws that govern access?

The issue was explored in a December 2008 episode of TV's Boston Legal, but it's hardly a fictional fixation. Millions of Americans diagnosed with Alzheimer's, or worried they eventually will get it, might be willing to weigh the risk and waive manufacturer and physician liability in order to try an experimental drug like Dimebon, which has shown exciting promise in improving brain function in Alzheimer's patients.

Dimebon, now entering Phase III clinical trials to test efficacy and safety, has been placed on a fast track, but it could still be several years away from receiving FDA approval. Meanwhile, family members who are caring for loved ones with Alzheimer's, and watching them struggle to do simple tasks, might not be willing to wait for the FDA's benediction. "I don't have any problems with that — if you make an informed decision and waive liability if something happens as a result," said Bill Grabarek, an Illinois attorney who is caring for his wife Ivanka, an Alzheimer's patient.

Since last August, the Grabareks have made several trips to Middleton so that Ivanka can participate in Dimebon's Phase III trial at the Dean Foundation, one of more than 100 Alzheimer's clinical studies now recruiting participants. Ivanka is one of 525 Alzheimer's patients worldwide who are involved in the Phase III trial, which typically take 3-1/2 years to complete.

If successful, the Phase III evaluation, which is conducted in part to identify long-term side effects, would be followed by an FDA review of about 1-1/2 years.

In that time, the disease will continue to progress in Alzheimer's patients, a population between 2.4 million and 4.5 million in the U.S. and projected to grow as the population ages, according to the National Institute on Aging.

Clinical Promise

Laura Douglass, president and CEO of Next Generation Clinical Research, said drugs like Dimebon are tightly restricted to patients involved in clinical trials.

As part of an open-label extension trial, patients in clinical trials are sometimes offered a chance to continue taking a drug until it's approved, but the general public has to wait for the successful completion of Phase III and the FDA review. The overall drug-approval process, from discovery and preclinical testing to FDA approval, typically takes about 15 years.

"It's not a matter of a patient saying to a drug manufacturer, 'I'll relieve you of any legal liability,'" Douglass said. "Companies are restricted by law from offering it."

About the only opportunity for a wider swath of society to take part in a clinical study is when a drug manufacturer voluntarily offers an expanded-access program in either the later stages of clinical development or while awaiting FDA approval.

In an expanded-access program, a study is opened up to patients in the general population. These patients, who generally have an unmet medical need that is not treatable with approved therapeutic options, receive treatment with the experimental drug. At this stage, efficacy and safety have been demonstrated, and the point "is to provide more access to patients," Douglass said.

The Case for Dimebon

Without a change in federal law governing the FDA, most health consumers will remain on the sidelines. Grabarek, a patent attorney whose first academic interest was chemistry, believes Dimebon is a unique case because it already has been used as an antihistamine in Russia, where the first successful study of its potential as an Alzheimer's drug was conducted.

Initial evidence shows that Dimebon is well tolerated and works differently than existing Alzheimer's drugs. Dimebon affects a cell's mitochondria, the membrane-enclosed organelle that energizes the cell, and addresses a defect that kills brain cells.

Citing the drug's well-documented history, Grabarek said there is ample evidence that Dimebon is safe and effective. "As far as I'm concerned, after reading about the Russian study and looking at the chemical structure of that antihistamine, and the years it had been used until more effective antihistamines came in, it's really an extremely low risk," he said. "Now, had this been some exotic, protein-type extraordinary substance, I would have been much more concerned about even suggesting that we engage in a clinical trial."

Dimebon would not be the first medical substance to find a new use, Grabarek noted."It's like aspirin. It was made for headaches, but my goodness, it also helps prevent strokes," he said. "We pretty much know how aspirin is going to react in the human system, and if it's good for helping to prevent strokes because it thins the blood, so much the better."

Grabarek said any enabling legislation should require health consumers who fear they might develop Alzheimer's to express their interest in early access in a Release and Waiver of Liability document.

The same goes for the caregivers of existing patients because Alzheimer's patients would not have the mental capacity to make this decision. In either case, they would have to waive liability for the drug manufacturer, the physician advising them, pharmacies, or any other party that potentially could be liable.

In addition, he said the legislation should require the person waiving liability to consult with the patient's personal physician so that the drug therapy and the various health risks can be explained, and so the patient, caregiver, or guardian can make a fully informed decision.


The Case Against

There is great reluctance to tamper with the FDA process, even among advocacy groups. William Thies, Ph.D. and chief medical and scientific officer for the Alzheimer's Association, said the association believes a drug therapy should not be made available until it has completed the FDA approval process. "The efficacy and safety of an experimental drug needs to be solidly established – that is what the FDA approval process is for," Thies said in a statement released by the association.

Those who argue against circumventing the FDA also point to the rare occasions when serious complications occur even after drugs are approved because side effects don't show up until they are available to larger numbers of patients. Dr. Leslie Taylor, executive director of the Dean Foundation, noted that drugs like Vioxx were approved by the FDA — only to cause problems later on.

"I have to say in all honesty, my bias is that it [early access] shouldn't be allowed," Taylor said. "It behooves us, as a society, to do the testing to make sure that yes, indeed, it is safe and that it is efficacious because otherwise you'll never know."

She predicted, "You would have everybody and his brother signing up to take it."

Taylor is not convinced that waiving legal liability would necessarily protect drug manufacturers and physicians from blame.

"I don't think we have a society that says, 'Sign off here and waive liability,'" she stated. "I think that when push comes to shove, people want to blame someone. They don't want to take responsibility for their own health."

Knock Out Punch?

Dimebon eventually could be used in combination with other Alzheimer's drugs in a "cocktail" that includes investigational therapies like Rember, which has shown the ability to arrest Alzheimer's progression, or existing drugs like Aricept, which attacks the disease in a different way. That would require the combined usage to undergo studies and review, but it would not prolong the time it takes for Dimebon and other therapies to reach the market, Douglass indicated.

She said drugs typically are evaluated on their own merits, and the safe and effective ones are allowed to enter the market while the FDA and drug manufacturers examine the potential impact of drug interactions.

In March, Dean Foundation will begin a study to examine Dimebon taken with Aricept. "So, patients have to be on Aricept, and Dimebon will be added to see what that affect is," Taylor said. "That's not a study that is part of the approval process for Dimebon. That's about collecting more safety and efficacy data."

More Enrollees Sought

As part of its role in the Phase III study, Dean Foundation is interested in enrolling additional Alzheimer's patients. More information can be obtained by visiting the Foundation's Web site at or by calling (608) 827-2333.