November 15, 2012 (Vol. 32, No. 20)

Putting Safety First Will Ultimately Promote, Not Squelch, Innovation

In recent months, a federal court decision in favor of the FDA established that certain cell therapies—including cell therapies that employ one’s own cells, under certain conditions—fall within the Agency’s purview. Opinion pieces in The Wall Street Journal have come out on both sides of this issue, some claiming that this will slow this emerging area of research and others asserting that it is the right and responsibility of the FDA to provide guidance in this area.

As background, it has been the FDA’s position that the line between cell therapeutics that are regulated as drugs versus those that are not is delineated by 21 CFR Part 1271. Those regulations dictate that cells used therapeutically must be only minimally manipulated, intended only for homologous use, not combined with a drug or device that raises new clinical safety concerns, and not have a systemic effect (absent meeting other criteria such as autologous use) if the therapy is to remain outside of the purview of FDA.

It is the evolving definition of “minimal manipulation,” however, that led to a recent court case wherein the plaintiff argued that the therapy in question did not exceed the definition of minimal manipulation and the FDA disagreed.

Contrary to the view that FDA oversight and guidance of regenerative medicine will slow progress, one could cogently argue that an appropriate regulatory framework will actually enhance advancement of the field. Instead of squelching innovation, these steps provide consistency and predictability for medical product developers.

That, in turn, will allow investors to make smarter decisions, doctors and patients to better understand products, and insurance companies to integrate economic analyses into more rapid coverage determinations.

So what do we need from our FDA partners to promote innovation? The public, the media, and Congress are all pushing hard to promote safety, compelling FDA to err on the side of zero risk. But the Agency leaders and scientific staff want to improve public health and promote innovation where innovation can address unmet needs.

It is important to remember, though, that the mandate for the FDA started with promoting safety. Over 100 years ago, the Agency started with a mission exemplified by protecting Americans from snake-oil salesmen. Seventy-five years or so ago, the Agency fought to protect Americans from tainted drugs after the elixir sulfanilamide disaster of 1937.

Even today, the FDA rallies behind a call to control more tightly compounding pharmacies because of a horrific sequence of recent events that, as GEN went to press, lead to 20 deaths (and counting) from tainted medicines. So, with a culture established and reinforced to prevent problems, the Agency’s actions often appear focused on avoiding all risks.

The FDA is not regulating our cells, per se, and articles with provocative titles such as “The FDA Wants to Regulate Your Cells” run the risk of both missing the mark and oversimplifying the issue. FDA is regulating the process by which cells are turned into a therapeutic under certain conditions that they feel may present risks to individuals in order to assure both safety and efficacy for the intended purpose. In this way, the field of regenerative medicine can gain public trust, as have the drug, device, and biologics industries that preceded it.

The cell source, whether autologous, allogeneic, or xenogeneic, is less important in this regard than other considerations, including the process by which the cells are turned into a therapeutic, the conditions under which the cells are manipulated, the various changes that the cells may undergo during the process, the testing of the cells to ensure they are what we think they are when used as a therapeutic, and the conditions under which the cells are collected, transported, and introduced to the body. FDA regulates to provide confidence that conditions are consistently applied and to yield robust, reproducible therapeutics for patients.

FDA has developed a regulatory paradigm to distinguish between types of manipulation, the cell source, the intended use of the cells, and the nature of the mechanism of action. The Agency has attempted to apply this definition to those conditions that it considers to be less prone to safety concerns and where it feels that the use of the cells can be more immediately justified without application of the rigors of classical clinical development. However, by its nature, the line cannot be defined in a black and white manner, and it is in the gray zone where most of the controversy exists.

For therapies that cross that line (i.e., are considered by the Agency to present a potential safety concern), FDA has required that the process, reagents, methods, etc., be evaluated according to a standard—albeit slightly modified—regulatory paradigm for drug development.

There is a group specifically dedicated to this at FDA (the Center for Biologics, Evaluation and Research’s [CBER] Office of Cellular, Tissue and Gene Therapies [OCTGT]) that has, over the years, become particularly skilled in dealing with the nuance of these therapies.

Over time perhaps the line that FDA has drawn may—indeed should—change, and with experience some of the therapies that are today deemed to cross the line may be considered in a different light. Perhaps the entire regulatory paradigm might be re-evaluated on a different risk basis, facilitating the existing regulatory pathway for industry, FDA, and patients, whereby FDA may perform its duty to protect the public health in an enhanced and streamlined way.

But this will only happen if FDA, the public, industry, and government work in concert, and it will only happen over time as the safety of these novel therapeutics is well assured.

For now, the interest of the public overall seems well served by the Agency’s involvement, and it behooves all of us to keep in mind that attempts to move the regulatory line are as legitimate as the Agency’s view to regulate along the current lines.

Stem cell therapy is developing with such promise because the FDA is weighing the needs of Americans for new treatments. In taking an approach that balances potential benefits with potential risks and considers the impact and/or absence of alternate treatments, cell therapies are advancing at a remarkable pace. Yet the Agency must balance that pace with proper safety controls, and we believe that this is an arena where that is happening.

Unfortunately, with pressure exerted on the Agency, this area of progress is at risk. If we want to have hope—and even more importantly, options—for when we develop life-threatening or debilitating diseases, then we need to support these efforts by the FDA and encourage the public, Congress, and the media to imagine the possibilities, and then move along the development path to get to the right scientific conclusion. This is how we will see innovation flourish and experience its transformative impact.

Robin L. Smith, M.D.

Robin L. Smith, M.D. ([email protected]), is chairman and CEO of NeoStem.

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