2004N-0181 - Critical Path Initiative; Establishment of Docket
FDA Comment Number : EC15
Submitter : Mr. Daniel Perry Date & Time: 08/02/2004 06:08:25
Organization : Alliance for Aging Research
Health Care Association
Category :
Issue Areas/Comments
Comment Issues
1. Hurdle Identification. Please describe the product development issue, the nature of the evaluation tool that is out-of-date or absent, how this problem hinders product development, and how a solution would improve the product development process.
1. Hurdle Identification:

Many of the major diseases in the United States are most prevalent in the aged. The common factor in diabetes, cancer, stroke and heart disease is that they all occur most frequently in the elderly. In order to scientifically secure a life full of vigor and independence, we may need a better scientific understanding of the aging process itself in order to avoid the diseases and conditions of old age.

The field of aging research on the molecular and cellular biology of aging is rapidly advancing and new discoveries abound. Consider the following breakthroughs:

? Researchers studying aging in nematodes (roundworms) have found that by altering certain genes, they can substantially extend the normal life of these tiny organisms. This exciting research may lead to the discovery of the genetic and biologic secrets to longevity in humans.

? Scientific research into teleomeres, the tails at the ends of every chromosome that keep them intact, may hold the answer to understanding cell replication and cellular aging. These repetitive DNA sequences that appear to help regulate cellular replication have led researchers to learn more about telomere structure and function as a possible ?clock of aging.? For instance, we now know that women have slightly longer length teleomeres than men, possibly accounting for their extended lifespan.

? Studies of mammalian diets strictly controlled for calories currently underway at the University of Wisconsin, University of Maryland, University of California at San Francisco, and the NIH are showing promising results in extending their lifetime by 30 to 40 percent. These results, described as ?stunning? by gerontologists, have raised hope that further studies of caloric restriction will uncover the mechanisms responsible for disease in old age.

? Scientists are working to determine what ?longevity genes? are and how they work. There may be a group of genes in each species that can extend life beyond what is presently considered the maximum life span. These longevity-enabling genes could open the gateway to understanding the roots of biological aging in humans and provide revolutionary cures in treating age related diseases.

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The goal of the FDA?s Critical Path research ?is to develop new, publicly available scientific and technical tools ?.. that make the development process more efficient and effective and more likely to result in safe products that benefit patients.? Yet, as promising as the above interventions seem to be, none have been tested in humans?and without the identification of biomarkers for aging, these clinical studies may never be done.

The effectiveness of interventions that mimic caloric restriction and similar mechanisms in lengthening healthy life in rodents and rhesus monkeys have been demonstrated. Yet because of the extended life span of humans, such studies are economically infeasible in our society. Clinical studies would last longer than the patent life of the product.

5. Nature of the Solution. For each problem identified, please describe the evaluation tool that would solve the problem and the work necessary to create and implement the tool/solution. For example, would a solution come from scientific research to
5. Nature of the Solution

There is a relatively long history into the identification of biomarkers of aging?dating back to a National Institute on Aging workshop held in 1982. (Reff and Schneider) NIA also invested substantial effort on the topic in the late 1980s through the late 1990s. None of these early efforts have been successful in identifying biomarkers of aging.

More recently, in research undertaken/supported by NIA, there is increasing evidence that such biomarkers can be identified. In a controlled study of caloric restriction in Rhesus monkeys, reduced body temperature, reduced plasma insulin and increased levels of dehydro-epiandrosterone sulfate (DHEAS) was correlated with reduced mortality. Furthermore, these markers are consistent with the survival of healthy men in the Baltimore Longitudinal Study of Aging (though the men in that study are not restricting their calorie intake).

It is our view, and the view of a number of respected scientists, that another biomarker workshop is now appropriate. Further, FDA and private industry should be active participants in this workshop, and that its objective be to identify the best biomarkers of aging available so that clinical research can proceed and products development can continue. Finally, additional workshops should be scheduled every 3 to 5 years to refine these ?intermediate? biomarkers of aging.

6. For each solution identified, please indicate which could be accomplished quickly, in less than 24 months, and which require a long-term approach?
6. Timeframe of Solution

A workshop producing intermediate biomarkers of aging (or at least outline the steps necessary to develop those biomarkers) could be planned, held and reported on well within a 24-month period. Steps would include the following:

? Convene a public/private steering committee
? Identification of a funding source
? Issue a call for papers
? Hold one or more workshops
? Issue a report



7. For each problem identified, what role should FDA play and what role should be played by others?
7. Role of the FDA

The role of the FDA in addressing this issue would depend on the level of priority set for biomarkers of aging and the availability of FDA resources. At the minimum, however, FDA should agree to be a member of the steering committee in order to help create the momentum necessary to find better tools (biomarkers of aging) to facilitate the development of medical products. The participation by the FDA will increase the
likelihood of the participation of leading researchers in the field. Yet it should also be understood that the FDA participation in this endeavor would not guarantee that FDA would automatically adopt the results.

The Alliance would welcome any increased role the FDA would choose to play.

8. What factors should guide FDA in setting priorities among the hurdles and solutions identified?
8. Factors in Setting Priorities

As with much of the priority setting at the FDA, most attention should be directed at those conditions that are the most serious, that affect the most people, where there are no current treatments and that are amenable to solution. We believe that the identification of biomarkers of aging ranks high in each of these criteria.


GENERAL
GENERAL

BIOMARKERS OF AGING
The ability to identify and measure biomarkers of aging would allow researchers to track aging in an individual--and to analyze interventions that might interfere with that process. To prove that a medicine or treatment slows aging, Richard Miller of the University of Michigan says, "you have to be able to measure how rapidly aging is going." Barring such measurements, the only definitive means of testing antiaging medicines is to wait until all the test subjects have died. Researchers would then determine whether the patients receiving the treatment lived longer than those who did not--an approach that obviously holds little appeal for research scientists, their funding agencies, or the individuals who volunteer for such studies.
But with a reliable group of biomarkers, scientists could measure, in real time, how rapidly their patients were aging. They could then assess whether a particular therapy puts the brakes on aging. The process could take a matter of years rather than a lifetime. And it would allow scientists to measure aging on a person-by-person basis, something that is now beyond their reach. To date, the regimens that have been shown to postpone aging have been judged by their effect on populations. Take, for example, calorie restriction. When researchers report that this intervention retards aging in rats, they're talking about a population--not any individual rat, says Edward Masoro, a physiologist and professor emeritus at the University of Texas Health Science Center in San Antonio. Yet to know if a drug has benefited a particular person, doctors will need to put a finger on the pulse of aging in that individual. "If you're going to be able to study aging in the individual, and not aging of a population, you have to have a biomarker," says Masoro.
For Miller, who is examining the mouse immune system as a possible predictor of longevity, the future of biomarker studies comes down to a question of priorities. "Biomarker research, in essence, is a tool development," he says. "Once you have the tool, then you can use it to ask other interesting questions." This particular tool, if discovered--and that's still a big if--would have an immense impact on researchers' ability to study and evaluate antiaging medicines. Those who hold the purse strings in the field of aging research will have to bear this in mind as they try to decide whether biomarker research deserves another shot.
Chris Mooney
SAGE Crossroads
October 20, 2003