Will the FDA Bar The Door When Stem Cells Produced From Therapeutic Cloning Come Knocking?

Semos (named after the god in Planet of the Apes) is the rhesus monkey who donated the skin cells used in the therapeutic cloning study.

David Cyranoski summarizes two exciting new studies in his article "Race to Mimic Human Embryonic Stem Cells:"

Two much-anticipated scientific firsts announced this week bring the dream of regenerative medicine a step closer. The production of cloned primate embryonic stem cells and the reprogramming of adult human cells both represent important milestones in the quest to produce 'pluripotent' cells, which can develop into almost any of the body's roughly 200 cell types. Human embryonic stem cells have this property, and those used in research are usually extracted from leftover embryos created during in vitro fertilization. But researchers want to create pluripotent cells that are genetically matched to individual patients. Such cells could then be transplanted to treat disorders such as Parkinson's disease and diabetes, or be used by researchers to model disease progression. Cloning offers one way to create these cells. This week, a team led by Shoukhrat Mitalipov of Oregon Health & Science University in Beaverton report the first creation of embryonic stem cells from cloned monkey embryos .... Until now, cloned embryonic stem cells had been created only in mice.

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But there is another promising route to creating pluripotent cells that does not require eggs or the controversial destruction of embryos. On Tuesday, Shinya Yamanaka of the University of Kyoto in Japan reported that his team had created pluripotent cells from human skin cells and, on the same day, a team of researchers led by James Thomson at the University of Wisconsin, Madison, reported the same. Yamanaka's work builds on his exciting discovery last year that introducing four transcription factors into mouse skin cells 'reprogrammed' the cells into an embryo-like state. Early this summer, Yamanaka and two other groups reported using the same four factors to create cells that seemed to be indistinguishable from embryonic stem cells.

Since the results of these studies were announced, the news is replete with stories covering the ethical issues that swirl around stem cell technologies and the promises that they hold for the treatment of a broad range of medical conditions. Another interesting question that is little discussed but always lurks behind these new advancements is how the FDA will deal with these innovative technologies. Will the method that is used to generate the stem cell technology make a difference to the FDA’s approval of human clinical trials?

The FDA’s new regulatory structure put in place to capture jurisdiction over new technologies like stem cells generally tracks like this:

1. Tissues that are only "minimally manipulated" and are intended for "homologous use" are covered under the FDA’s "good tissue practice" regulations 21 C.F.R. Part 1271 promulgated under Section 361 of the Public Health Service Act authorizing regulation to prevent the spread of communicable diseases. Minimally manipulated tissues will not be considered drugs or devices and will not be subject to the pre-market approval process.

a. "Homologous use" is the "replacement or supplementation of a recipients cells or tissues with a HCT/P [human cells, tissues and cellular and tissue based products] that performs the same basic function or functions in the recipient as in the donor." 21 C.F.R. 1271.3(c).

b. "Minimal manipulation" with respect to cells and nonstructural tissues is defined as "processing that does not alter the relevant biological characteristics of cells or tissues." 21 C.F.R. 1271.3(f)(2).

i. "For purposes of determining whether a structural tissue product is minimally manipulated, a tissue characteristic is ‘original’ if it is present in the tissue of the donor. A tissue characteristic is ‘relevant’ if it could have meaningful bearing on how the tissue performs when utilized for reconstruction, repair, or replacement. A characteristic of structural tissue would be relevant when it could potentially increase or decrease the utility of the original tissue for reconstruction, repair or replacement."

Office of Combination Products and Center for Biologics Evaluation and Research, Guidance for Industry and FDA Staff: Minimal Manipulation of Structural Tissue Jurisdictional Update (2006).

2. If processing has altered an original, relevant characteristic of a structural tissue (the so called "kick-up factors"), it will be considered to have been more than minimally manipulated. In this case, the structural tissue will be regulated as a drug, device and/or biological product and will be subject to the pre-market approval process.

Stem cells that have been created from bone marrow are already being tested in controversial human clinical trials. The FDA has categorized these stem cells as investigational new drugs (INDs) by applying the above kick-up factors. Designation as a new investigational drug means that scientists must file an IND application and obtain the FDA’s approval prior to starting human clinical trials.

Will the method that is used to generate the stem cell technology make a difference in whether the FDA approves the IND application? In light of current questions regarding the role of politics in FDA decision-making, some may wonder.

The FDA’s current position is that it will apply the same procedures that it has long followed for the clinical testing of new drugs. This reliance on pre-existing law, rather than proposing a new regulatory strategy specifically tailored to this new technology based on therapeutic cloning, appears to bar the FDA from playing any role in the broader ethical and moral debate. As such, regardless of whether the stem cells were generated through reprogramming of human skin cells or from cloning a human embryo, the role of the FDA in approving clinical trials is statutorily limited to performing a risk analysis focusing solely on the issue of safety. Moral and ethical issues should be irrelevant to this calculus.

But what if the FDA approves clinical trials of stem cells from reprogrammed skin cells, but not those derived from therapeutic cloning that results in the destruction of human embryos? Would this denial be ‘end game’ for these scientists?

According to an article written by Richard A. Merrill and Bryan J. Rose, entitled FDA Regulation of Human Cloning: Usurptation or Statesmanship, 15 Harv. J.L.Tech. 85 (2001), maybe not. Professor Merrill suggests that the FDA strategy for the regulation of therapeutic cloning technologies may be suspect. Merrill posits that the FDA’s failure to provide notice and comment on its claimed authority to regulate this new technology may place this issue squarely into the realm of cases like Syncor International Corp. v. Shalala, 127 F. 3d 90 (D.C. Cir. 1997) and Northwest Tissue Center v. Shalala, 1 F. 3d 522 (7th Cir. 1993) which confront rule making’s substantive-interpretive distinction. The FDA’s strategy also suffers from vagueness problems with its ‘minimally manipulated’ dichotomy.

Adding to Merrill’s critique, any decision based on the method of production rather than the end product itself would run counter to the general theme of bioequivalency that pervades the FDA’s regulation of all of the products under its aegis.

All this leaves one to wonder whether, in the race to mimic human embryonic stem cells, will crossing the finish line mean a showdown with the FDA over therapeutic cloning? If so, will who wins the race determine whether people with life threatening diseases also become winners?