Guidance for review of studies involving HCT/Ps and IND Basics Angela Bain, IRB Administrator abain@uga.edu 706-542-3821

What are HCT/Ps Human Cells, Tissues, and Cellular and Tissue-Based Products: Articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. Examples: bone, ligament, skin, dura mater, heart valve, cornea, semen or other reproductive tissue Examples of articles that are not HTC/Ts: Vascularized human organs for transplantation, whole blood or blood components, or blood derivative products; Secreted or extracted human products such as milk, collagen, and cell factors (except semen); Minimally manipulated bone marrow for homologous use and not combined with another article; Cells, tissues and organs derived from animals; in vitro diagnostic products; Blood vessels recovered with an organ

Sometimes the FDA requires pre-market approval and sometimes they do not How is this determined????? While the sponsor should interpret the regulatory language and make the determination regarding whether an FDA submission is required, the burden is on the reviewing IRB to ensure that the regulatory requirements are being met appropriately.

Requirements The IRB must have certain information in order to assess each of the five requirements in 21 CFR 1271.10(a). If the product meets these five requirements, FDA review of the product is not required. One requirement – manufacturing registration - is easily verified. The other four requirements necessitate significant analysis.

Minimal Manipulation 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 For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues. The first step is to determine whether the main function of the HCT/P in the donor is structural or not. Structural tissue can be composed of both structural components (such as collagen) and cells. If cells are part of the structural tissue included in this criterion, removing of those cells can be considered more than minimal manipulation.

Homologous Use Repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues is being performed with an HCT/P that performs the same basic function in the recipient as in the donor The second requirement is that the product be intended for homologous use only. This can follow from the prior structural/non-structural separation but requires a different analysis as it focuses on the use of the cells. When HCT/Ps are marketed, the limitation to homologous use needs to be reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent. In the research setting, this means that the specific use of the product for the trial must match the same basic function, and the objectives of the research must be for the research to show that the product performs the same basic function. If a study is designed to test of a cellular product does more than perform the same basic function in the recipient, this requirement would not be met.

Manufacture The manufacture of the HCT/P cannot involve the combination of the cells or tissues with another article, such as a drug. The third requirement involves manufacturing Water, crystalloids, or a sterilizing, preserving, or storage agent are allowed provided that the addition of the agent does not raise new clinical safety concerns with respect to the HCT/P.

Registration Unless the HCT/P is manufactured under an IDE or IND, the HCT/P manufacturer must be registered with the FDA. The FDA maintains these registrations I a publically accessible database. Documents included in the IRB submission should clearly identify the manufacturer so that the IRB can confirm if the manufacturer is properly registered. I have already confirmed that Vivex is registered.

Systemic Effects The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function. Autologous use, allogenic use in a first degree or second degree blood relative or, reproductive use. This criterion is more complicated. To meet it, the product must meet either of two sub-requirements. The first requirement is simpler (queue click). From IRB experience and a review of the literature, the vast majority of HCT/P products fall into this category. The conclusion of systemic effect and dependence on metabolic activity might follow from a homologous use analysis, but not necessarily. If the product does not meet the first sub-requirement and its does have a systemic effect, it must fit into one of the following specific use situations (queue click)

If the product /use does not meet those criterion, then pre market approval is required and an IND or IDE should be sought from the FDA

IND Basics The submission of an IND application is required for any clinical research study that proposes the use or evaluation of an unapproved drug

Clinical investigations involving the use or evaluation of an FDA approved drug for the clinical indications specified in the FDA approved product labeling: IND is not required.

Clinical investigation involving the use or evaluation of a FDA approved drug for a clinical indication that is not currently specified in the FDA approved product labeling: May be exempt from the IND requirement If….

The drug is lawfully marketed in the US There is no intent to report the investigation to the FDA to support new labeling or change in labeling Investigation is not intended to support a change in advertising The investigation does not involve a route of administration, dose, patient population or other factor that increases risk 4: Route of administration: a change in the route of administration can introduce a significant new risk (eg: there could be an increase in risk if a marketed drug for oral administration is converted to a dosage from that is to be administered by a parenteral or inhalation route. Dose: Increases in dose, frequency, or duration of administration, compared to labeling can significantly increase risk. Patient population: the acceptability of the known and unknown risks can vary considerably across different treatment populations. . For example, a drug with significant toxicity can be approved for use in a population with a life-threatening or severely debilitating disease because the risk of toxicity is acceptable in that population. Use of that drug in a clinical investigation of a population that is not so ill (e.g., to evaluate the drug for prevention of the disease or symptomatic relief), however, would present a different risk-benefit situation in which the risks would likely not be acceptable. When the acceptability of the risk is significantly decreased, the study would have to be conducted under an IND application

The investigation is conducted in compliance with the requirements for review by an IRB The investigation is conducted in compliance with the requirements of 21 CFR 312.7 which states that the investigation is not intended to promote or commercialize the drug product by charging the research participant (or his/her insurance provider) for the drug under evaluation