To Speed the Clinical Availability of Rejuvenation Therapies, Medical Regulation Must be Reformed or Evaded

Here I'll point out a commentary from the SENS Research Foundation on one of the many changes that is needed in medical regulation in order to smooth the path ahead towards clinical availability of the first rejuvenation therapies. It is not a cynical viewpoint, and is focused on working within the system to make incremental beneficial alterations to one of the many regulatory positions that currently hold back progress. Accordingly, I'll follow it with my much more cynical view of the state of regulation, the harm it does, and the prospects for change - that I think must come from outside the system, not within.

Pathway To New Therapies

Substantial regulatory reform is needed to create a pathway for investors and pharma to put the necessary time and money into researching and developing rejuvenation biotechnologies such that licensable therapies can come out the other end. The most important regulatory reform would entail acceptance of novel biomarkers of the removal, repair, replacement, or rendering harmless of specific forms of cellular and molecular aging damage as sufficient basis to grant rejuvenation biotechnologies preliminary licensure. This would then be followed up by further monitoring of patients to ensure that the therapy actually does bend the curve on diseases of aging over the longer term. This standard would mark a break with regulators' usual insistence (which has been getting more entrenched, rather than less, in recent years) that therapies prove an effect on "hard outcomes" to get approval: things like heart attacks, amputations, or blindness. But people should ideally begin to receive rejuvenation biotechnologies well before patients are in near-term danger of such acute threats to life and health, making it extremely expensive and time-consuming to run a trial.

In 2012, it looked as if significant progress had been made on this front and several others during major stakeholder meetings amongst Alzheimer's disease (AD) patient and caregiver advocates, researchers, and FDA regulators. In particular, there was consensus on the need to work toward the development of new clinical trial designs and regulatory reforms to advance previously-untested combination therapies for AD into clinical testing. Draft guidance acknowledged that therapies for AD are unlikely to have substantial effects in "full-blown" dementia, because by that point, the brain has suffered either irreversible damage, or too many kinds of damage for any one therapy to be useful anymore. Then, despite having climbed up to the top of the diving tower, with advocates and scientists cheering at every step, FDA and pharma seemed to hesitate. The same FDA leaders who had previously expressed their openness to bold initiatives instead adopted a more conservative stance on using biomarkers as outcomes for early-stage disease.

This February, however, FDA finally took the plunge with a revised Draft Guidance, which would represent a tremendous step in the right direction if finalized as official FDA policy. The results of imaging tests or relevant biomarkers could then be considered sufficient to identify so-called "Stage 1" Alzheimer's patients as eligible candidates for clinical trials or new therapies, or to test existing therapies that had failed in people with frank AD. These "Stage 1" candidates are described in terms that identify people at an even earlier stage along the insidious path to dementia than the 2013 guidance: outwardly healthy but aging people without very-high-risk mutations or apparent cognitive or functional impairments, but who are nonetheless identified as being at higher risk than most. In short, these individuals would now be eligible to participate in trials of new and old therapies that might prevent them from ever tipping over into major cognitive impairments.

The use of biomarkers and imaging directly reflecting the key cellular and molecular damage driving AD and other neurodegenerative diseases of aging should be extended to testing of therapies in people who are in even greater danger, showing early signs of cognitive problems but still not suffering from full-fledged dementia. Analogously, biomarkers of the cellular and molecular damage that accumulates in our tissues as we age and that drives other age-related illness and debility should also be acknowledged as the best targets for new therapies that would prevent, arrest, and reverse those conditions. And because AD and other diseases of aging involve multiple kinds of cellular and molecular damage, it's critical that regulators allow the testing of combination therapies potentially capable of attacking multiple kinds of cellular and molecular aging damage, without first needing the constituent therapies to be tested individually.

Medical regulation is a huge problem of misaligned incentives. Regulators act as though the most important thing is to avoid bad press, and they thus trample over the freedom of individuals to assess risk and make their own choices. Regulators impose ever greater requirements on groups seeking regulatory approval of new therapies, and approve ever fewer applications, as a way to (a) make bad press go away, and (b) make them look better when the inevitable small number of problems occur. All medicines bear risk. Over the past few decades, the already enormous regulatory cost imposed on medical development has doubled, and the number of approved therapies fallen dramatically. Countless lines of development have not been carried forward to the clinic because the cost has become prohibitive. Rigorous experimentation and exploration has declined. Regulatory agencies, but in particular the FDA, appear to be following the road of eliminating the appearance of risk by minimizing all progress. This causes far greater actual harms, but those costs are invisible, rarely reaching the press: the new medicines that never appeared, the lives that would have been saved, the suffering that would have been eliminated.

This must change. We stand on the verge of the development of real, working rejuvenation therapies, technologies that will bring radical improvement to the health of older individuals, and offer the potential to indefinitely extend healthy life spans. This is too great a gain to let regulators follow the usual playbook for padding their own nests at the expense of everyone else. The system must be changed, or responsible clinical development must take place outside the system. There is nothing magical about clinical trials: any group can run and publish and and replicate and review tests. Existing law on fraud and harm is more than capable of handling fraudulent or harmful behavior. The onerous requirements forced upon development by the FDA are far greater than the activities needed to obtain a useful assessment of risk and results, and medical development worked just fine before those requirements came into being over the past few decades.

Many groups object to the FDA or its present heavy-handed suppression of progress, and are working within the system to change it. They have been doing this with considerable vigor for quite some time, and very little has changed as a result. I'm not optimistic about the near future of such efforts either: if something as self-evidently humanitarian as allowing terminal patients to choose their treatments has struggled to reach its present position, what hope is there for a general reduction in the FDA presence in medicine? The only approach that has proven to work is to move clinical development and availability overseas, into areas with a lesser regulatory burden, as happened for stem cell medicine. The only reason any stem cell therapies are presently approved for use in the US is that they were widely available elsewhere for years, and the FDA was gaining worse publicity for being obstructionist than from approving some of these approaches.

Within the scientific and established medical development community, the public bias of opinion tends to be towards reforming the system from within. One reason for this is that the regulators at the FDA have proven themselves vindictive when it comes to those who rock the boat - which follows from the observed first principle of minimizing bad press. Make a lot of noise about the FDA and expect the result to be increased attention, cost, and risk of rejection when the time comes to put a therapy through regulatory approval. Another reason is that the publicly funded research community is quite hierarchical and conformist; it doesn't select for career scientists who find that irksome, or who see going outside the system as a viable choice. Revolutionaries tend to be thin on the ground. Nonetheless, I'm much more in favor of development outside the present system as a way to force change - it has a better track record of success.

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