Despite regulations, litigation, and significant draft guidance, the future of regulation of HCT/Ps remains up in the air. Learn what you need to know quickly with these seven questions and answers.

What do I Need to Know?

1. What is an HTC/P?

Under the Public Health Service Act (PHSA) and implementing regulations, the FDA regulates human cell and tissue products (HCT/Ps), which refers to articles “containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” See 21 CFR Part 1271.3. The HCT/P regulations require manufacturers to register their products, create donor eligibility criteria, and establish procedures, such as current good tissue practices (cGTPs), to prevent the spread of communicable diseases. Certain tissue products and procedures are explicitly exempt from regulation because they constitute a low risk of disease transmission. They are also, by definition, not considered HCT/Ps.

2. Is FDA Approval Required?

Under the HCT/P framework at 21 CFR Section 1271, the FDA classifies different types of human cells, tissues, and cellular and tissue-based products into categories for regulation based on the public health risks they pose: (1) products not subject to HCT/P regulations, (2) HCT/Ps regulated solely under Section 361 of the PHSA – and which do not required approval, and (3) products posing the most risk that are to be regulated as a biological product and require approval under Section 351 as a biological license application (BLA).

The regulations cover products under both Sections 361 and 351 of the PHSA. Procedures involving HCT/Ps qualifying for regulation under Section 361 are subject to minimal oversight and are regulated solely to prevent the spread of communicable diseases. To qualify, a product must (1) be minimally manipulated; (2) be intended for homologous use only; and (3) not involve cells and tissues combined with other articles (subject to certain exceptions). In addition, a product must either not have a systemic effect “or depend on metabolic activity of living cells for its primary function,” or, if it does have an effect or is dependent on the metabolic activities of cells, the product must be for “(a) autologous use, (b) [allogenic] use in at most a second degree blood relative, or (c) reproductive use.” Historically, FDA has construed these terms narrowly, and has brought enforcement action and litigation when challenged.

3. What Constitutes Minimal Manipulation?

Minimal manipulation is defined in the regulations as:

1. For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement; and
2. For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.¹

In December 2014, the FDA issued a Draft Guidance entitled “Minimal Manipulation of Human, Cells, Tissues, and Cellular and Tissue Based Products.” The Draft Guidance distinguishes between structural tissue and cells or nonstructural tissue. The Draft Guidance explains this distinction, stating that “tissues that physically support or serve as a barrier or conduit, or connect, cover, or cushion are generally considered structural tissues.” On the other hand, cells or nonstructural tissues “are generally those that serve predominantly metabolic or other biochemical roles in the body such as hematopoietic, immune, and endocrine functions.”

The Draft Guidance provides a list of structural tissue examples, including “bone, skin, amniotic membrane, blood vessel, adipose cartilage, non-articular cartilage, and tendons or ligaments.” Examples of cell or nonstructural tissue include “reproductive cells or tissue, cord blood, amniotic fluid, bone marrow aspirate, lymph nodes, parathyroid glands, peripheral nerve, and pancreatic tissue.”

4. What Constitutes Homologous Use?

Homologous use means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor, including when such cells or tissues are for autologous use. In October 2015, FDA issued Draft Guidance on Homologous Use. FDA generally consider an HCT/P to be for homologous use when it is used to repair, reconstruct, replace, or supplement:

• Recipient cells or tissues that are identical (e.g., skin for skin) to the donor cells or tissues, and perform one or more of the same basic functions in the recipient as the cells or tissues performed in the donor; or,
• Recipient cells that may not be identical to the donor’s cells, or recipient tissues that may not be identical to the donor’s tissues, but that perform one or more of the same basic functions in the recipient as the cells or tissues performed in the donor.

Examples provided by FDA include:

• A heart valve is transplanted to replace a dysfunctional heart valve. This is homologous use because the donor heart valve performs the same basic function in the donor as in the recipient of ensuring unidirectional blood flow within the heart.
• Pericardium is intended to be used as a wound covering for dura mater defects. This is homologous use because the pericardium is intended to repair or reconstruct the dura mater and serve as a covering in the recipient, which is one of the basic functions it performs in the donor.

Generally, if an HCT/P is intended for use as an unproven treatment for a myriad of diseases or conditions, the HCT/P is likely not intended for homologous use only.

5. Does FDA Intend to Finalize These Guidances?

In September 2016, FDA held a public meeting entitled, “Draft Guidances Relating to the Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products.” FDA sought public comment on the draft guidance documents relating to the regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps) from a broad group of stakeholders, including tissue establishments, biological and device product manufacturers, health care professionals, clinicians, biomedical researchers, and the public. In February 2017, FDA published its 2017 calendar year guidance agenda and none of the HCT/P Draft Guidances were includes which suggests that FDA does not intend to finalize them in 2017. This also raises the possibility that they may be significantly revised.

6. Does the 21^st Century Cures Act Impact HCT/Ps?

Yes, but only those that require approval and are not solely regulated under Section 361. The 21^st Century Cures Act, signed into law in December 2016, amends the Federal Food, Drug, and Cosmetic Act to create a process and requirements for designation of a drug as a regenerative therapy. A drug is eligible for this designation if:

• It meets the definition of a regenerative advanced therapy (“RAT”): “cell therapy, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the [PHS Act] and part 1271 of title 21, Code of Federal Regulations”;
• The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
• Preliminary clinical evidence indicates the drug has the potential to address an unmet medical need.

For products designated as RATs, FDA must take actions to expedite development and review of the drug, including early interactions to discuss the potential for accelerated approval. In addition, a designated drug may be eligible for priority review or accelerated approval under current FDA regulatory standards, and if approved under accelerated approval would be subject to a confirmatory study. This new regulatory pathway would permit a RAT to be approved for marketing based on surrogate or intermediate clinical trial endpoints rather than longer term clinical outcomes. Subsequently, a sponsor would have to conduct confirmatory clinical trials to ensure that the surrogate or intermediate endpoint was in fact predictive of patients’ clinical response to the product, otherwise the accelerated approval could be withdrawn.

7. What is the Enforcement Profile?

FDA’s enforcement in the area of HTC/Ps continues to be limited. In December 2015, FDA issued a Warning Letter to Irvine Stem Cell Treatment Center. This Warning Letter covered three physician-operated stem cell treatment centers in California, Florida and New York, and asserted that the centers had unlawfully recovered and processed adipose (fat) tissue to perform stem cell therapy, deviated from both current good manufacturing practice and current good tissue practice, and were not regulated solely under Section 361 and thus required approval. Many wondered if this would portend a more aggressive enforcement profile for HTC/Ps, but since then, FDA has only issued one other Warning Letter in this area.

In August 2016, FDA issued a Warning Letter to Amniotic Therapies, LLC, a supplier of amniotic products including to stem cell clinics. This alleged the company’s products were unapproved biological drugs that do not meet the minimal manipulation and homologous use criteria. Notably, however, the Company sued FDA on August 19 in the U.S. District Court for Northern Texas, and was granted an emergency motion for a temporary restraining order FDA. Following the court’s order on August 19, 2016 granting Amniotic Therapies’ emergency motion for a temporary restraining order, the court held a hearing on the merits of the motion on August 31, 2016. [Later, pursuant to agreed mediation, the parties ultimately negotiated a settlement agreement under which the company agreed to cease manufacturing the subject products, destroy existing inventory, and conduct testing product to determine the need for future recall.

Thus, FDA’s enforcement in the area continues to be rather limited but nonetheless aggressive in these limited instances. However, there is every reason to believe that a Trump Administration is unlikely to as aggressively pursue such actions.

¹See 21 CFR §1271.3(f).

Note: A version of this article appeared in the March 15, 2017 edition of the Bloomberg BNA’s Life Sciences Law & Industry Report.