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Cellular Therapies for Cardiac Diseases – FDA Questions BRMAC # 37 March 18-19, 2004

Cellular Therapies for Cardiac Diseases – FDA Questions BRMAC # 37 March 18-19, 2004. Stephen M. Grant, M.D. CBER/OCTGT/DCEPT. FDA Mission Statement August 2003.

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Cellular Therapies for Cardiac Diseases – FDA Questions BRMAC # 37 March 18-19, 2004

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  1. Cellular Therapies for Cardiac Diseases – FDA QuestionsBRMAC # 37March 18-19, 2004 Stephen M. Grant, M.D. CBER/OCTGT/DCEPT

  2. FDA Mission StatementAugust 2003 “…The FDA is responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable…”

  3. A Clinical Challenge • 1.1 million acute MI’s per year • Mortality rate from MI declining • Most patients have LV dysfunction after MI • Increasing numbers of patients are surviving acute MI with diminished cardiac reserve • Cellular therapies may benefit the growing number of patients with CHF

  4. Regulatory Requirements • Individual subject safety must be balanced against the potential public health benefits of new therapies • Risk assessment requires sufficiently detailed information regarding: • Product characterization and safety testing • Supportive preclinical or clinical data • Monitoring plan

  5. Common Issues that Delay Initiation of Clinical Trials • Cellular product different from that used in preclinical studies • Insufficiently detailed safety data from published reports • Limited information about compatibility of cellular product and delivery device • Inadequate plan for monitoring of subjects during and after product administration

  6. Advice Sought from Committee • General comments and recommendations • Manufacturing issues • Preclinical testing issues • Pilot clinical study design • With respect to particular issues that need to be addressed to permit safe initiation of clinical development

  7. Question 1 Please discuss the different intrinsic safety concerns for cellular products for the treatment of cardiac diseases, and the testing that should be performed to ensure administration of a safe product. Please consider tissue source, manufacturing process, formulation, storage, route and site of administration, etc.

  8. Question 2 Please comment on the elements of product identity and characterization necessary to generate data demonstrating safety and efficacy. - specific biomarkers - types and relative percentage of cell types - other parameters

  9. Question 3 Please discuss the merits and limitations of various large and small animal species for providing pharmacologic, physiologic, and toxicologic support for cellular products used in the treatment of cardiac diseases. Please consider the following: The intended clinical cellular product The delivery system proposed clinically Extrapolation of study results from animals to humans

  10. Question 4 Please discuss the merits of animal models of ischemic disease with respect to the ability to generate proof of concept (physiologic) data and to generate toxicologic data of relevance to the clinical disease.

  11. Question 5 Please discuss evaluation of potential interactions between cellular products and cardiac catheters: - Adverse effects on the viability / functionality of a specific cell product - Factors other than cell concentration and simple viscosity that can contribute to clogging of catheters - Injection into systemic circulation / pericardial space / thoracic space via needle catheter - Effects of depth or spread of injection into the myocardium on the safety / efficacy

  12. Question 6 Please discuss the appropriate frequency and duration of follow-up. In addition to any other events, please consider the following potential adverse pathological and clinical events in your discussion items: • Scar formation • Left ventricular dysfunction • Ventricular arrhythmias • Neoplasia

  13. Question 7 Please discuss the pros and cons of using control groups in these early clinical studies, including any need for randomization or masking. Within your discussion, please also comment upon the use of placebos in the studies (e.g., transendocardial saline injection into the heart).

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