FDA Asked to Clarify Guidance Affecting Regenerative Medicine

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By John T. Aquino

Sept. 13 — The FDA needs to make major changes to its draft guidances on human cell and tissue products to foster innovation in the burgeoning field of regenerative medicine, industry speakers said at a Sept. 12 agency hearing.

The Food and Drug Administration held the public hearing to get comments on four draft guidances that have generated concerns from product developers, manufacturers and nonprofit groups over how they interpret regulations governing human cell, tissue and cell and tissue-derived products (HCT/Ps).

Some speakers requested specific changes in the guidances that would allow their products, including stem cell and tissue regeneration therapies, to be exempted from FDA premarket approval requirements. Others sought clarifications and more detail to give industry a clearer picture of how they can meet regulatory requirements.

Parker H. Petit, chairman and chief executive officer of the MiMedx Group, a provider of human amniotic tissue, said, “Cell and tissue regeneration products are for the benefit of the public health, and FDA's guidances can affect product development.”

Petit continued, “While the FDA might prefer less detailed regulations in order to afford themselves more flexibility, health care executives want rules that are clearly delineated, easily interpreted and uniformly enforced. Nebulous regulations bring disruption to industry innovation.”

Michael Werner, executive director of the industry group Alliance for Regenerative Medicine, added, “How FDA interprets these regulations is critically important to our sector, providing transparency and insight into the approval process and ultimately ensuring safe and efficacious products reach patients as soon as possible.”

Kristin C. Comella, chief science officer for U.S. Stem Cell Inc., spoke not only for developers of stem cell therapies but also for the patients who have benefited from them. “Why would FDA regulate our own body's tissue and consider it a drug? Regenerative medicine is here to stay, and it is continuously growing,” Comella said.

The meeting was held at the National Institutes of Health in Bethesda, Md., and followed a Sept. 8 public workshop on HCT/Ps ( see related story in this issue ).

Term Definitions at Issue

The four FDA draft guidances discussed at the meeting were:

  •  Same Surgical Procedure Exception: Questions and Answers Regarding the Scope of the Exception: Draft Guidance for Industry;
  •  Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products: Draft Guidance for Industry and Food and Drug Administration Staff;
  •  Human Cells, Tissues, and Cellular and Tissue-Based Products from Adipose Tissue: Regulatory Considerations: Draft Guidance for Industry; and
  •  Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products: Draft Guidance for Industry and FDA Staff.

HCT/Ps, as defined in 21 C.F.R. §1271.3(d), are articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion or transfer into a human recipient.

Under the FDA's tiered, risk-based interpretation of Section 1271, some HCT/Ps are regulated only under those regulations and Section 361 of the Public Health Service Act (42 U.S.C. §264), which don't require agency approval for marketing. Other products, considered to be of higher risk, are regulated as drugs, devices and/or biological products under Section 351 of the PHS Act (42 U.S.C. §262) and/or the Federal Food, Drug, and Cosmetic Act and must demonstrate safety and effectiveness to gain FDA approval.

To qualify for exemption from premarket approval requirements, HCT/P products must be “minimally manipulated” and be intended for “homologous use,” meaning they are used for the same basic function in the recipient as in the donor, among other requirements.

However, the interpretation of these terms has generated concern from companies whose products are considered by the FDA not to be exempt, requiring premarket approval, or where it's unclear how their products are regulated.

Formal Regulatory Changes

Petit of MiMedx Group called for more formal regulatory changes to clarify the requirements, rather than relying on unclear interpretations in the draft guidances.

In October 2015, MiMedx's stock price fell when the homologous use guidance was released because the document said that an amniotic membrane, when used for bone tissue replacement to support bone regeneration, “is not a homologous use because bone regeneration is not a basic function of amniotic membrane” (9 LSLR 1284, 11/13/15).

In addition, Petit noted, Surgical Biologics, a MiMedx company, received a letter from the FDA on Aug. 28, 2013, which said that its micronized amniotic/chorionic-based products didn't meet the minimal manipulation exemption criteria.

The health industry recognizes the need to make regulatory changes if safety issues develop or new science dictates that, he said. “But we have great concerns that the minimal manipulation and homologous guidances represent major changes in tissue regulation that can only be lawfully made through formal notice and comment rulemaking, not by agency guidances,” Petit said. He recommended that the FDA formally withdraw the minimal manipulation and homologous use guidances.

A number of speakers noted that some human tissue, such as amniotic membranes, has both structural and non-structural functionality in the donor and asked the FDA to acknowledge this in the guidances for the purpose of determining homologous use.

Same Surgical Procedure, Minimal Manipulation

Jay Siegel, chief biotechnology officer for Johnson & Johnson, asked for a broader interpretation of the “same surgical procedure” exception for HCT/P products to better align it with minimal manipulation standards.

The FDA's same surgical procedure draft guidance says an establishment can qualify for an exception to certain infection control requirements if it removes HCT/Ps from an individual and implants them into the same individual during the same surgical procedure. The draft guidance interprets regulations under 21 C.F.R. Part 1271 designed to prevent spread of communicable diseases.

Siegel said, “The guidance documents create a different standard for same surgical procedure than they do for minimal manipulation. Other forms of minimal manipulation should be subject to the same exception.”

He acknowledged that the FDA through its guidances has enabled innovation and protected public safety. “But J&J feels that the same surgical procedure exception should be applied more broadly.”

Justin Deuerling, staff engineer for product development at Regeneration Technologies Inc., expressed concern that language in the minimal manipulation draft guidance concerning tissue sterilization and decellularization could block access to these processes.

“The guidance doesn't make clear these products qualify as minimal manipulation. We ask FDA to reconsider the list of processes generally considered minimal manipulation and to expand the list to include decellularization and any validated sterilization process.”

Werner of industry group ARM urged the FDA to publish more examples of how the key terms in the guidances, such as minimal manipulation and homologous use, will be applied to various technologies, such as use of adipose, or fat, tissue. He also urged the FDA to provide a detailed rationale for how products will be regulated and flowcharts to clearly demonstrate the agency’s thinking regarding product evaluation.

Some Products Put Patients at Risk

Patrick Bilbo, senior vice president of regulatory and government affairs for Organogenesis Inc., a developer of advanced wound care technologies, expressed concern about products that claim to but don't meet the necessary FDA criteria.

“Many companies are self-designating their products as Section 361 HCT/Ps even though their products do not, in fact, meet the criteria set forth in Section 1271.10. They are processed in ways that are not minimal, are promoted for uses that fall far outside the realm of homologous use and claim comparative or superior efficacy to FDA-approved biologics and devices. This situation puts some of our most vulnerable patients at risk and must not continue,” Bilbo said.

“It is critical for the public health as well as the future of the regenerative medicine industry that FDA finalize the draft guidance documents with all possible speed,” he concluded.

To contact the reporter on this story: John T. Aquino in Washington at jaquino@bna.com

To contact the editor responsible for this story: Randy Kubetin at rkubetin@bna.com

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