As anyone working in the healthcare products sector can attest to, definitions are vitally important in the regulation of products. Definitions are the difference between a manufactured pharmaceutical product being overseen by US Food and Drug Administration (FDA) regulators and a compounded pharmaceutical product being overseen by state boards of pharmacy; the difference between an in vitro diagnostic test regulated by FDAand a lab-developed test by the Clinical Laboratory Improvements Act (CLIA).
So when the US Department of Health and Human Services (DHHS) proposes changing the definition of the term "human organ" to include stem cells, it's well worth paying attention.
Stem Cells and FDA: A Tortured History
FDA has something of a long and tortured history with the regulation of human cells, tissues and tissue-based products, which includes stem cells, embryos, oocytes, skin, bone, tendons and a long list of other products.
While the agency maintains-and thus far, the courts have as well-that any stem cells that undergo any medical manipulation that exceeds a "minimal" standard places it under its regulation, others have said such actions amount to an attempt to regulate the practice of medicine.
The re-injection of a patient's own stem cells is a medical procedure-not an article like a drug or device, argued Scott Gottlieb, a former FDA associate commissioner, and Coleen Klasmeier, head of FDA practice at Sidley Austin LLP, in a Wall Street Journal editorial in 2012.
"Federal regulators have stretched that definition [of minimal manipulation] to the point where a reasonable limit no longer exists," they wrote, arguing that under FDA's interpretation, the processing of stem cells turned them into a drug.
Whatever the merits of their arguments, FDA has been aggressively going after processors of stem cells. An October 2012 Warning Letter to Texas-based CellTex Therapeutics Corporation argued that manipulation of adipose tissue broke federal regulations since the company had failed to obtain approval for the product.
A March 2012 Warning Letter was sent to IntelliCell Biosciences for similar reasons, citing its processing of adipose tissue without proper agency approval.
Stem Cells as an Organ: From FDA to DHHS
But there's one thing FDA doesn't regulate: Organs. Under federal regulations, organs are the purview of DHHS, which regulates them through a donor and transplant network administered through the Health Resource and Service Administration (HRSA).
Under the terms of the National Organ Transplant Act (NOTA) of 1984, DHHS also bans the sale of organs for monetary gain. It's the reason you can't sell-or buy-a kidney on the free market, much to the dismay of some advocates who believe such a system would incentivize more organs to reach needy patients. Violators of this portion of the law can face a fine of up to $50,000 and five years in prison.
But while one traditionally thinks of an organ as a structural collection of tissue such as a heart or lung, NOTA defines organ much more broadly, including "bone marrow" and "any subpart thereof."
The latter-"any subpart thereof"-was added in 1988, and a subsequent update in 2005 more clearly defined "bone marrow" to include stem cells in the peripheral blood.
A Definitional Run-Around
Now DHHS wants to make clear that paying for hematopoietic stem cells (HSCs) collected from a patient's bone marrow through the process of apheresis is prohibited. The newer apheresis process stimulates the production of HSCs through drugs, which are released into the blood stream and later collected.
The problem, as noted by DHHS in its Federal Register filing on 2 October 2013, is that the US Ninth Circuit Court of Appeals has held that such a ban lacks a "rational basis" under the Fifth Amendment's equal protection clause. A group had sued the government after it was unable to offer scholarships, housing allowances or gifts to charity under NOTA.
Having lost the case, DHHS said it had evaluated its options and determined that it could redefine-and thus regulate-peripheral blood stem cells as organs.
"The effect of exercising this authority through this proposed amendment is to clarify that HSCs are covered by the prohibition on transfers of human organs for valuable consideration found in NOTA section 301(c)(1)," DHHS explained, adding that the potential for exploitation of "those in medical need of HSC transplantation" had led it to make the decision.
Under the proposed rule, DHHS would change the definition of "human organ" under NOTA to specifically include HSCs in peripheral blood under the sub-definition of "bone marrow." This authority to regulate the organs would extend "without regard to the method of their collection" for any hematopoietic stem/progenitor cells," DHHS added.
It remains unclear if this will impact any products now regulated by FDA. At present, most-if not all-of the stem cell products sent Warning Letters have concerned adipose tissue, and not HSCs. FDA does, however, regulate the most common drug used to stimulate the production of HSCs in the apheresis process, Genzyme's Mozobil.
DHHS Federal Register Notice