From the earliest days of this blog, in my work, and in my understanding of the world we live in, I have been interested in the dynamic balance between the drive to move forward, progress, and the regressive pull toward the past; the sum total is a homeostasis that has an underlying progressive movement until adulthood and then slowly descends toward individual senescence. We each exist in that dynamic balance and our society has a larger, constantly shifting analogous balance between innovation and risk-avoidance, with an underlying progressive momentum in the West especially evident since the enlightenment.
With the increasing pace of technological innovation moving toward what is now commonly known as the (technological) Singularity, it is not a surprise that the increased rate of change has engendered an opposing increased pressure to stop change. This is visible in such disparate areas as foreign policy, where in response to an unstable and often frightening world, many would like to withdraw from the field and retreat into neo-isolationism and, in my area of greatest concern, biology.
Biology is now in the early stages of moving from an empirical and experimental science toward an information technology. As we understand more and more about the ways in which our proteins interact we will become better able to predict, intervene, and control such interactions. The shape of various treatments is already becoming clear. It is very likely that within a relatively short time, in historical terms, our ability to selectively target all sorts of cancer cells will effectively place a cure for cancer within reach. Other illnesses once thought intractable and refractory to treatment will also became understandable and treatable.
The ultimate disease to which we all succumb eventually is aging. While such thinkers as Aubrey de Grey may be correct that we will one day cure aging, it is inarguable that we will be able to slow aging and cure many, if not most, of the diseases of aging. This is inevitable, but there are serious impediments that arise out of our fears and our inability to accurately evaluate risk.
Reason discussed a milestone in the movement of anti-aging technology from the fringe to the mainstream and noted that the primary impediment to rapid progress resides in our hidebound bureaucracy:
Comments on the Sirtris Acquisition
Notice that the largest problem for the future of longevity medicine in the established research and development community is the FDA and its heavy-duty, risk averse structure of trials after trials after trials. The cost is immense, and in most cases utterly out of proportion to any rational cost-benefit analysis of a new medical technology. So those technologies simply aren't commercialized, joining the vast sea of wasted potential that attends all imposition of regulatory cost.
The simple answer to the questions in the quote above is that you don't run a Phase II trial for life extension strategies. It doesn't make sense to talk about these structures and strategies rigidly applied to this case, but the present weight of regulation doesn't allow for the sort of free competition and innovation under pressure that always produces working, practical answers.
Since the FDA will never approve an intervention into the aging process - as aging is not recognized as a disease, and the FDA only approves treatments for disease - the underlying technologies are not applied to that end. No-one invests in medicine that cannot be sold due to government prohibition. Instead, the promising science is diverted into the same old process of patching up the very end results of age-related damage. It's that simple and that wasteful.
The development of our cumbersome and onerous regulatory environment that will slow the availability of drugs to those who would benefit from it is a sad story of missed opportunities and risk aversion; the FDA started with a horror story and developed under the grow lights of good intentions.
One of the true horror stories that haunts the institutional memories of the FDA and drug companies alike, concerns the drug Thalidomide. The drug was developed at a time when we were somewhat cavalier about safety concerns; from Wikipedia:
Thalidomide, 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione, was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names, including Distaval, Talimol, Nibrol, Sedimide, Quietoplex, Contergan, Neurosedyn, and Softenon. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies.
From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy. In 1962, in reaction to the tragedy, the United States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S. Other countries enacted similar legislation, and thalidomide was not prescribed or sold for decades.
It is hard for people who did not live through those times to appreciate the effect of seeing an infant with phocomelia on the cover of Life Magazine. Recently Thalidomide has become a focus of intense research interest; a number of possible avenues of benefit are being explored:
Serious infections including sepsis and tuberculosis cause the level of Tumor necrosis factor-alpha (TNFα) to rise. TNFα is a chemical mediator in the body, and it may enhance the wasting process in cancer patients as well. Thalidomide may reduce the levels of TNFα, and it is possible that the drug's effect on ENL is caused by this mechanism.
Thalidomide also has potent anti-inflammatory effects that may help ENL patients. In July 1998, the FDA approved the application of Celgene to distribute thalidomide under the brand name Thalomid for treatment of ENL. Pharmion Corporation, who licensed the rights to market Thalidomide in Europe, Australia and various other territories from Celgene, received approval for its use against multiple myeloma in Australia and New Zealand in 2003. Thalomid, in conjunction with dexamethasone, is now standard therapy for multiple myeloma.
Thalidomide also inhibits the growth of new blood vessels (angiogenesis), which may be useful in treating macular degeneration and other diseases. This effect helps AIDS patients with Kaposi's sarcoma, although there are better and cheaper drugs to treat the condition. Thalidomide may be able to fight painful, debilitating aphthous lesions in the mouth and esophagus of AIDS patients which prevent them from eating. The FDA formed a Thalidomide Working Group in 1994 to provide consistency between its divisions, with particular emphasis on safety monitoring. The agency also imposed severe restrictions on the distribution of Thalomid through the System for Thalidomide Education and Prescribing Safety (STEPS) program.[3]
Thalidomide is also being investigated for treating symptoms of prostate cancer, glioblastoma, lymphoma, arachnoiditis, Behçet's disease, and Crohn's disease. In a small trial, Australian researchers found thalidomide sparked a doubling of the number of T cells in patients, allowing the patients' own immune system to attack cancer cells.
After the Thalidomide experience, the FDA was established and set up a framework for approving drugs only after they were shown to be safe and effective. The terrible problem for medicine is that there is no such thing as a drug that can be proven to be completely safe.
Drbuzz0, at Depleted Cranium, in his discussion of the Precautionary Principle: Possibly the biggest sham of our time, suggests the problem for medicine in a period of rapid change:
Precautionary principle sounds logical: When you aren’t sure if something might cause harm, be careful and don’t do anything that could be dangerous, especially to anything really important like human lives, the environment and so on. It also seems like it would not be a new or revolutionary concept. However, Precautionary Principle is really a lot more extreme and a lot less common sense than one might think.
The term actually dates back to 1998, when The Wingspread Conference on the Precautionary Principle was convened by the Science and Environmental Health Network was issued the statement: ”
“When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically.”
And with this one statement, “Precautionary Principle” became the next big thing and was totally the “in” concept for everyone in the enviro-political movement to go to workshops on and state talking about - just to show how up to date they are.
He briefly touches upon its effect in medicine but restricts his comment to reinforcing the need for caution in the use of medications. This is wise, but can go too far. I have written about the Vioxx disaster, in which legal threats caused Merck to withdraw a medication from the market that while increasing the risk of cardiac disease also enabled people who could otherwise find no relief, the ability to live pain-free with arthritis. In that post I suggested that patients should be allowed to make their own, informed choice about whether they were willing to accept a low risk attendant to long term use of the drug versus a life of painful limitation. I might add that the calculation of a medicine allowing a person to exercise who would not otherwise be able to do so and how that might effect cardiac and other diseases, was never considered by Merck or the FDA.
On every level it makes sense for us to develop anti-aging treatments. Losing the abilities of those who are most skilled and experienced on a regular basis is wasteful of human resources. Yet our current regulatory environment not only precludes developing drugs that could slow aging, but makes studies to show their safety and effectiveness impossible to perform.
Within the next 5-10 years, there is likely to be a winner of the Methuselah Prize. Shortly thereafter, there is going to be a tremendous, uncontrolled study performed in real life by millions of elderly people to determine if the drugs and technology involved in the Methuselah Prize can perform the same function in humans. Ideally, the FDA would monitor the treatment to get some baseline of safety in the early adopters, but as in any bureaucracy, the FDA is not going to be able to modify its mandate without a tremendous push from those most likely to be effected by their conservatism. We should be thinking of altering the FDA's mandate now rather than wait for the uncontrolled experiment to take place. If Agent XYZ can add 50% more days of life to a mouse, there will be people, scrupulous and unscrupulous, developing, marketing, and selling Agent XYZ to eager octa- and septa-genarians. A hidebound FDA will assure that such an Agent is developed and manufactures outside of normal quality controls and without anything approaching adequate safety testing. It would be far better were the FDA to enlist that elderly cohort of risk-takers and gather the data that might help all of us lead healthier, longer, and more productive lives.
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