Question of the Month #6: Meeting The Challenges of the Regulatory Maze and Getting Rejuvenation Biotech Into the Clinic
Q: In response to a previous question of the month, you explained why the fact that "aging" is not recognized as a "disease" for which the FDA and other regulatory bodies license therapies should not actually pose a significant hurdle to getting rejuvenation biotechnologies licensed and into widespread use. But there was a lot of discussion at the recent Rejuvenation Biotechnology 2014 Conference about the challenges to rejuvenation biotechnology posed by current regulatory structures and some gestures toward what might be needed to advance the science into the clinic. Would you spell those out?
A: Rejuvenation biotechnologies are a new approach to preventing and treating the diseases and disabilities of aging, based on the repair and maintenance of the cellular and molecular structures that become damaged over time. Degenerative aging processes occur all across our bodies as this damage accumulates in particular tissues; the "diseases" that emerge in our bodies late in life are simply the recognizable impairment of organ-specific function resulting from the gradual build-up of this damage.
This approach is so new that it is not very well-served by current regulatory structures, which mostly assume the presence of an existing disease, and that drugs will either alleviate current symptoms, or will intervene in metabolic pathways that perpetuate aspects of abnormal function without having any effect on the underlying damage that causes it.
Several regulatory changes would help to bring rejuvenation biotechnologies into clinical trials and then into widespread use. One is to reverse the sequence in which rejuvenation biotechnologies are tested.
First, there are several states of ill health driven by the degenerative aging process that are clearly extremely disabling and deadly, but that are not yet recognized as "diseases" by the FDA. The most glaring of these is sarcopenia (or, some have argued, "dynapenia"): the age-related loss of muscular strength that results from the combination of loss of muscle mass, and the degradation of the cellular and molecular integrity of what muscle remains. Sarcopenia is highly disabling, restricts people's ability to take care of themselves, increases the risk of accidents and fractures, and is strongly linked to increased risk of death — but it is not yet a licensed "disease" indication.
Fortunately, the FDA seems to be open to the idea of developing a new indication for therapies that combat sarcopenia, and several pharmaceutical companies are working in the field. There have now been several scientific conferences and high-level summit meetings in which senior FDA officials, sarcopenia researchers, and major pharmaceutical companies have worked toward defining diagnostic criteria and suitable outcomes for licensing anti-sarcopenia drugs. The sooner they succeed, the better.
Second: today, new drugs are usually first tested in patients with existing disease. Regulatory approval depends on the drug showing a clear impact on clearly-defined, hard clinical outcomes such as heart attacks or progression to dialysis. Over time, many therapies initially approved on this basis later come to be used in a more preventive approach in high-risk patients without overt disease, through a mixture of informal practice and clinical trials. This occurred, for example, with statins, antihypertensives, and antidiabetics.
Unfortunately, this progression begins to yield useful data too late in the pathological process to optimally test rejuvenation biotechnologies. Our goal is to develop therapies that will keep people's tissues sufficiently healthy and functional that such late-stage pathologies do not occur. Thus, we will want to test these therapies in patients not yet exhibiting overt disease, with minimal or no symptoms and no near-term risk of death or disability from the disease.
Instead, it would be preferable for regulators to accept the removal, repair, or replacement of cellular and molecular damage itself as an initial goal of clinical trials. The prevention of particular diseases' emergence would then be incorporated in a kind of "conditional licensing" a longer-term goal, perhaps to be monitored in a robust system of postmarket surveillance. This, again, reverses the usual practice in today's regulatory system, where the endpoint is initially a catastrophic patient outcome such as heart attack or stroke, and only later are surrogate outcomes on mediating metabolic factors (such as lowering LDL cholesterol or blood glucose) accepted.
Finally, it would be of tremendous benefit to test rejuvenation biotechnologies in combination with each other from the outset. The normal approval path for a candidate drug entails that it first be tested for effectiveness and safety on its own, or as an add-on to drugs that are already the standard of care. But many specific, diagnosed diseases of aging are actually the clustering together of several forms of aging damage in one or more tissues. Additionally, it is often the case (as with the beta-amyloid protein and aberrant tau species in Alzheimer's disease) that the contributing kinds of aging damage are intertwined with one another in complex causal chains.
In such cases, the removal of only one form of aging damage may not be enough to demonstrate a positive effect on tissue function or disease-related outcomes. If researchers are forced to test individual rejuvenation therapies that each remove only one of these contributing forms of damage in isolation, they may well fail to show any meaningful effect, and be kept out of the hands of doctors and patients — even though they would have indefinitely postponed the disease if tested together.
This potential dilemma could be resolved if complementary rejuvenation biotechnologies — each targeting one of the key lesions driving such a disease state — could be tested in combination from the outset, following the collection of basic safety data, without first having to prove their individual effectiveness in averting catastrophic outcomes.
All of these moves are dramatic departures from the ways that medical therapies are currently tested, approved, and regulated for use. Fortunately, substantial moves in these directions are already afoot in the testing of rejuvenation biotechnologies for Alzheimer's disease and other neurological disorders. We believe that these moves can be supported and normalized, and then used as a template for the testing of rejuvenation biotechnologies generally.