Understanding minimally manipulated tissue grafts

Tissue implants are rapidly gaining in popularity as a treatment for many orthopaedic surgical conditions. Orthopaedic surgeons need a fundamental understanding of the efficacy and safety of these products, as well as their characterization, origin, and processing.

Tissue implants may be divided into two broad categories for classification purposes: cellular and structural. US Food and Drug Administration (FDA) regulations dictate that human cell, tissue, and cellular- and tissue-based product (HCT/P) implants must be “minimally manipulated” to exempt them from the premarket review or premarket notification normally mandated by the FDA for devices, drugs, or biologic products. This concept of “minimal manipulation” refers specifically to the type of “processing” or “additions” that HCT/Ps undergo.

What is an MMTG?
FDA regulations (21 Code of Federal Regulations Part 1271, available online at www.accessdata.fda.gov) define the concept of a minimally manipulated tissue graft (MMTG) as follows:

Criteria for an HCT/P to be regulated solely under section 361 of the Public Health Service Act

• minimal manipulation
• intended for homologous use only, as reflected in the labeling, advertising, or other indications of the manufacturer’s objective intent
• not combined with a drug or device, except for water, crystalloids, or a sterilizing, preserving, or storage agent provided that the addition of the water, crystalloids, or sterilizing, preserving agent does not raise new clinical safety concerns with respect to the HCT/P
• not have a systemic effect and not depend on the metabolic activity of living cells for its primary function except if for autologous use, allogeneic use in a first-degree or second-degree blood relative, or reproductive use

“Minimal manipulation” for structural tissue is further defined as “processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement.”

A development priority
These requirements demonstrate the FDA’s distinction between MMTGs and devices, drugs or biologic products, which have a far more rigorous regulatory pathway. FDA does not require that HCT/Ps meet the four criteria above to be evaluated for efficacy. Under these regulations, an MMTG may come to market in a relatively short time, following the more straightforward pathway of traditional musculoskeletal allografts, for example. As a result, these products can appear in the marketplace quite soon after initial conception by the manufacturer.

For structural implants, minimal manipulation requires that the original structural features of the tissue that made it useful for reconstructive purposes remain unchanged. Minimal manipulation of a cellular product means that there was no alteration in biologic features of the cells or nonstructural tissue in development of the product.

Many orthopaedic product companies have targeted development of biologic implants as a priority, often because minimally manipulated tissue products follow a relatively swift regulatory pathway whereby manufacturers need only register and list the product, follow good tissue practices, and adhere to donor suitability requirements. This significantly eases the cost and time burdens of product development.

Ask questions before using
When presented with a new HCT/P that is characterized and regulated as an MMTG (Table 1), an orthopaedist should be discerning and ask the product vendor several questions before employing the product in patient care. The following questions

are among those that should be asked:

• What is the “active” ingredient of the product?

The “active” ingredient of an HCT/P is that feature or substance that makes it unique from a functional standpoint. In essence, most new products should offer some feature that distinguishes them from products currently in use. Biologic implants and products often have some ingredient or feature that the vendors contend makes them unique or special. It is essential that the vendor define this “active ingredient.”

• What studies have been completed to establish the safety and efficacy of the product?

The orthopaedist should hold each company accountable for doing its due diligence to confirm product safety. He or she should also know how this safety profile compares to that of other products used for similar purposes. The vendor should be able to provide references and/or data that establish the utility of the product. If no data or references are presented, both the orthopaedist and his or her patients should be concerned.

• How did the relevant studies, if there are any, prove efficacy of the new product and more specifically, its “active ingredient”?

A company should be able to provide strong support for any contention that their product and its “active ingredient” have proven more efficacious than current products or treatment options that work in similar ways.

• What other existing products, if any, are currently employed for similar purposes?

Vendors are generally reluctant to discuss competing products. They should, however, be aware of competing products so that they can answer the next question.

• How does the new product improve upon current products and what comparison data are available to support replacing former treatments or products with the new product?

If the vendor cannot provide data and/or references to confirm value for the patients, the new product may be a replicate or offshoot of a current product, touted as an improvement (when brought to market) without validation.

Impact on orthopaedic practices
Orthopaedists should understand the concept of minimal manipulation of tissues because structural and cell-based HCT/P implants are becoming more common in the marketplace. The “minimal manipulation” criteria outlined by the FDA leads to a far less rigorous and time-consuming pathway from conception to market than many more familiar orthopaedic implants and products.

Orthopaedists should carefully choose the questions they ask vendors before using a new HCT/P. This brief summary should serve as a general guide to ensure that orthopaedists obtain the knowledge necessary to decide whether using one of these products is in the best interest of their patients.

Michael E. Trice, MD, is a member of the Biological Implants Committee and may be reached at mtrice1@jhmi.edu

William Bugbee, MD, is a member of the Biological Implants Committee and may be reached at Bugbee.willliam@scrippshealth.org

Disclosure information for Drs. Bugbee and Trice may be found online at www.aaos.org/disclosure