The Gray Area
There are currently more than 500 compounds with CE properties in the industry pipeline. Virtually all are being developed
as treatments for schizophrenia, Alzheimer's, ADHD, or some other CNS conditions. But disease-based R&D is far from the ideal
setting to develop cosmetic neurology. For example, increasing dopamine levels in the prefrontal cortex looks like the simplest
way to boost attention and learning. But until recently, most dopamine-oriented drug development has focused on schizophrenia,
a disease in which the brain is already producing too much of the neurotransmitter. As a result, researchers have hunted for
dopamine-receptor antagonists that lower dopamine levels. For a CE, you need to flip the switch the other way.
But with "lifestyle enhancement" being a forbidden phrase inside pharma, CE development is set to remain on the disease-only
path. (Neuroscientists at Merck and Roche, who are developing some of pharma's most innovative CEs, refused to comment on
their potential use in healthy people.) It may fall to the aging process, with its many cognitive and memory impairments,
to eventually provide the necessary impetus for regulatory approval.
"When asked about its neglect of age-related brain loss, the drug industry tends to lay the blame on FDA," says Ferris, a
former FDA committee member. "They say, 'We could never get approval for that indication.'" Ferris disagrees. While careful
not to give aid and comfort to the forces of lifestyle drugs, agency officials have been equally careful not to bar the door
to conditions that fall into the gray area between disease treatment and health enhancement. The effects of aging top the
list. "The official line is, 'There are no unique regulatory barriers to this treatment indication,'" says Ferris.
Russell Katz, director of FDA's Division of Neurology Products at the Center for Drug Evaluation and Research, confirmed this
position in a 2009 Journal of Alzheimer's Disease discussion of cognitive enhancement. "There are not any approved treatments for age-associated memory impairment, but only
presumably because industry seems to have abandoned the project. The regulatory requirements were worked out with the sponsors,"
The resistance to treating age-related memory loss extends beyond pharma. "There is a widespread assumption in the entire
medical establishment that aging is 'normal,' and that the profession does not 'treat' normal processes," Ferris says. But
the reverse is plainly true. "We do this for virtually every other age-related problem, from our eyes, ears, and teeth to
our cholesterol, blood pressure, and bone density. We 'treat' all sorts of cosmetic effects of aging, too. But our brain seems
to be off-limits."
By age 65, Ferris explains, the performance of the average human brain has fallen by 50 percent from its optimal point at
around age 20. The real-world consequences are often merely annoying, but sometimes they compromise daily performance. And
with the risk of developing Alzheimer's rising to 50 percent after age 85, a neuroprotective anti-aging agent could slow disease
Yet even Ferris acknowledges that producing age-related smart drugs presents pharma with a triple threat of risk, cost, and
controversy. At a time when firms like AstraZeneca are jettisoning entire drug-discovery capabilities, negotiating this particular
neuroscientific minefield would seem to be a nonstarter. The Phase III clinical trials could prove immensely complex and pricey,
requiring thousands of healthy people representing the general population—with a safety standard exceeding any yet seen. Demonstrating
efficacy would span five years, the length of time it takes to measure the effects of normal aging. As for cognitive enhancement
in healthy people, proving a "therapeutic" effect could be done under specific short-term conditions, such as a transatlantic
flight (at night, from the East Coast to France, in Cephalon's Nuvigil jet-lag trial) or an all-day school exam. But such
data's application to other situations, let alone long term use, will be harder to demonstrate. And after years of being bashed
for producing too many Viagras and too few Avastins, the industry is hardly eager to beat the drum for lifestyle enhancement.
Aversion to risk is not limited to pharma. At the University of Pennsylvania, home to the neuroethics-pioneering Center for
Neuroscience and Society, "it took enormous effort just to start a small study of ADHD drugs for cognitive enhancement," Chatterjee
says. "The investigational review board kept asking us, 'Why is any adverse-event risk worth taking by people who are healthy?'"
The argument that more than a quarter of the school's students already admit to taking that risk finally persuaded them.