FDA Stem cell regulation and the English language: switched at birth?

FDA logo.

In January, President Obama ordered federal agencies, such as the FDA, to search their books and strike any overburdensome regulations. Following this queue, in June, the FDA quietly posted a request for comments to any existing regulations that are burdensome or outdated by technology. To quote the FDA’s request to the public:

The “FDA is particularly interested in comments that identify regulations that may be impediments to innovation and suggestions for how they can be improved.”

We saw the request and passed the link on to a friend of ours who teaches healthcare law and has taken great interest in the fate of autologous stem cell therapies. Professor Mary Chirba holds a Ph.D. in Public Health from Harvard and is a Professor of Healthcare Law at BC College. She believes that it’s high time for the FDA to reclassify therapies in which patients use their own stem cells and decided to submit a comment. She’s graciously given us permission to post her comments here on our blog.

Her point is that therapies using your own adult stem cells are being held to the same rigorous regulations as allogeneic stem cell therapies (where tissues from a donor are used), despite each having very different risk profiles for patients. It’s a sentiment we’ve voiced ourselves. Keep in mind that the FDA’s primary mission is to protect the public from transmitted disease by regulating the manufacture and marketing of mass produced drugs or biologic tissue products.

Rather than ‘reinvent the wheel’ of regulatory apparatus, it can simply expand IVF oversight to include a broader category of cell and tissue products.

– Prof Mary Chirba

Autologous therapies pose no public health threat to the general population, as they are your own cells. However, allogeneic (donor) therapies do use cells from other human beings, and it is the proper role of the FDA to regulate those therapies.

In her submission to the FDA, Professor Chirba critiques changes made to the regulations by the FDA without public comment. In 2006, the FDA replaced the wording regarding the use of tissues “into another human” with the wording “into a human.” By doing so, replacing the word another with the word a, the FDA expanded the regulatory overview of allogeneic therapies to include autologous therapies. Although it involved only one tiny word swap, it completely redefined the circumstances which draws the line between practice of medicine, where a physician uses tissues from the patient being treated, and drug therapy, where a physician uses tissues from a separate donor.

Anyone who’s following the case filed in Federal Court, US Justice Department vs. Regenerative Sciences knows exactly what we’re talking about here. This will no doubt be a landmark case which will affect the entire cell therapy world.

Dr. Chirba’s suggestion to the FDA is to treat autologous stem cell therapies not as it treats drug therapies, but rather to treat them in the same capacity as IVF therapies. This would make regulations less burdensome and allow autologous adult stem cell therapies, using stem cells derived from a patient’s own body, to come to market much quicker.

Professor Mary Chirba is simply one of the smartest people we know and we think she’s hit a lot of nails on the head with her commentary. We take great pride in sharing her brilliance with you!

FDA’s Periodic Reviews of Existing Regulations

[Document ID FDA-2011-N-0259-0001]

Cite: 21 CFR 1271
Agency Division: CBER

From: Mary Ann Chirba, J.D., D.Sc., M.P.H.
Boston College Law School, 885 Centre Street, Newton Centre, MA 02459
Date: June 24, 2011

The Problem

In 2005, the FDA stated that autologous cell therapies carried “minimal, if any risk.” See, e.g.,70 Fed. Reg. 29952 (May 25, 2005) (clarifying § 1271.90(b)(3) labeling requirements for autologous cells and tissues). Yet in 2006, the agency departed from the requirements of notice and comment rulemaking when it quietly but dramatically changed the basic definition of HCT/Ps that anchors the FDA’s three-tiered, risk based framework for regulating human cells and tissue products. With no notice and absolutely no opportunity for public comment – and, indeed, with no formal announcement beyond its routine, annual publication of regulations – the FDA substantively redefined autologous HCT/Ps by deleting the critical descriptor of transfer into “another” human from the regulation.

Thus, section 1271.3(d) now states that “[h]uman cells, tissues, or cellular or tissue-based products (HCT/Ps) means articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” 21 C.F.R. § 1271.3(d) (April 1, 2006) (emphasis added). See also, 21 C.F.R. § 1271.3(d)(1) (April 1, 2010).

The White House’s own Cass R. Sunstein, current Administrator of the Office of Information and Regulatory Affairs, has written extensively and testified repeatedly before the U.S. Congress (most recently on June 23, 2011) regarding the need to evaluate the practical impact of regulations, and reject those that yield more costs than benefits. See, e.g., Cass R. Sunstein, Group Judgments: Statistical Means, Deliberation, and Information Markets, 80 N.Y.U.L. Rev. 962, 1042 (2005); Robert H. Frank & Cass R. Sunstein, Cost-Benefit Analysis and Relative Position, 68 U. Chi. L. Rev. 323, 324 (2001) (“The movement toward cost-benefit analysis of regulatory initiatives is generally desirable and . . . most of the conventional criticisms of it are unconvincing.”) And yet, in revising §1271.3(d) without the benefit of public input, the FDA has fashioned a regulation that imposes real and extensive burdens on patients and providers while achieving little if any benefit — at least with regard to low-risk, autologous adult stem cell therapies.

More specifically, the FDA’s CBER merged two previously distinct categories of products, i.e., autologous and allogenic, into one. In doing so, it removed autologous cells from minimal regulatory § 361 oversight and subjected them to § 351’s far more rigorous requirements (including the need to comply with BLA, IND, NDA, cGMP and other FDA premarket review and approval requirements that govern commercial manufacturers of medical drugs and devices).

Obviously, treating autologous and allogeneic HCT/Ps as carrying comparable risks directly contravenes the FDA’s prior stance that autologous cells involve “minimal, if any, risk.” Moreover, making this change in such a covert manner – i.e., without following legally required process of notice and comment rulemaking – unfairly disadvantages the very actors who are most likely to develop and use autologous therapies, i.e., surgeons and physicians engaged in the (state regulated) practice of medicine. And it is no small matter that these actors, on the front lines of therapeutically and economically necessary innovation, are also the least likely to have the legal resources or prior awareness of the need to comb each year’s Code of Federal Regulations for subtle word changes.

As a direct consequence of reclassifying autologous adult stem cells as § 351 products, a physician’s normal ability to develop new therapies is now hampered by the administrative and economic burdens of having to file endless INDs. At a time when patients and the overall economy are desperate for innovation, and the FDA is already so seriously under-resourced, its determination to increase IND filings and to do so exponentially is, to put it mildly, difficult to comprehend.

One adverse, but predictable result is that patients must increasingly leave the country to obtain autologous adult stem cell therapies. Consequently, what should carry “minimal, if any, risk” now varies widely in terms of patient safety due to variability in: (a) the training and skill of the provider; (b) the information available to the patient trying to make informed decisions; and (c) the availability and quality of follow-up care and, if necessary, legal recourse in the event of serious complications or medical error.

In 2001, the FDA promised to regulate HCT/Ps in a manner that would promote consistency, efficiency, safety and “encourage the development of new products.” 66 Fed. Reg. 5447-5448 (Jan. 19, 2001). The FDA initiated its three tiered, risk-based framework for regulating HCT/Ps because it correctly recognized that regulating cellular products as if they were conventional drugs made no sense.

Regulating autologous adult stem cell therapies under section 351 and thereby treating physicians as if they are large, commercial pharmaceutical manufacturers similarly makes no sense. It is neither consistent nor efficient. Erecting regulatory barriers that limit access to existing therapies and impede the development of new ones creates an array of economic inefficiencies. It also compromises what should be the agency’s paramount objective: optimizing patient safety by increasing the availability of low-risk, minimally invasive therapies that harness the power of a patient’s own cells to cure or at least mitigate what ails them.

Physicians take an oath to do no harm to their patients. While not formally bound by the Hippocratic Oath, one would hope that the FDA aspires to the same. However, by surreptitiously changing the substantive content and impact of § 1271.3(d), the FDA did indeed do harm – and did it to patients and providers alike.

Proposed Solution

  1. The FDA should rescind its April 1, 2006 change to the wording of 21 C.F.R. § 1271.3(d) by replacing the current term “transfer into a human” with its predecessor, “transfer into another human….
    • The agency must respect and adhere to federal law concerning notice and comment rulemaking. As explained above, its April 2006 change was substantive and has a significant impact in terms of who is bound by the rule and what their obligations are. Consequently, any change of this kind is invalid and unenforceable unless preceded by giving the public notice of the opportunity to submit comments.
  2. At a minimum, the agency should regulate minimally manipulated autologous adult, freshly isolated, Stromal Vascular Fraction, non-culture expanded stem cells under § 361.
    • This is a necessary first step in relieving the economic costs and administrative log jam of INDs that currently lead too many clinicians to abandon this field or relocate to a more hospitable regulatory climate.
    • Acknowledging that the HCT/P category is not homogenous more properly accommodates the agency’s multiple objectives of maximizing patient safety without unduly burdening economically viable and therapeutically necessary innovation.
  3. Alternatively, the FDA can subject autologous adult stem cells and therapies to the same regulatory oversight currently employed for in vitro fertilization.
    • The FDA presently subjects in vitro fertilization to less rigorous oversight than autologous stem cell therapies even though IVF is typically more invasive, involves more manipulation, and poses higher risks to the patient.
    • Consequently, the agency should acknowledge and correct inconsistencies in its current regulation and enforcement efforts regarding autologous HCT/P therapies, at least with regard to autologous adult stem cells (or subsets thereof). Rather than “reinvent the wheel” of regulatory apparatus, it can simply expand IVF oversight to include a broader category of cell and tissue products.

Thank you for the opportunity to submit these comments.

Mary Ann Chirba

By Dr. Ricardo L. Rodriguez MD Board Certified Plastic Surgeon Cosmeticsurg Baltimore, Maryland Ricardo L. Rodriguez on American Society of Plastic Surgeons.

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