Moving From In Vitro to In Vivo: What Happens Next?

In FDA, Preclinical, Regulatory, Toxicology by Justin Patri

Preclinical testing of an investigational medical device is a necessary step in obtaining market approval from regulatory agencies. The purpose of preclinical testing is to establish the safety of a device before entering into human trials.

The objectives of medical device safety studies are:

  1. To identify undesirable physiologic responses to an investigational medical device that may have relevance to its human safety
  2. To evaluate the incidence and characteristics of adverse effects related to an investigational medical device
  3. To describe any local or systemic pathologies, as well as toxicological responses to an investigational medical device
  4. To monitor and describe the impact of investigational medical devices on activities of daily living

While in vitro testing generally involves the use of test systems such as isolated organs, tissues or cell cultures, in vivo testing involves live models. The specific study designs will vary, based upon the properties of the device and the nature of the targeted disease state. Some factors to consider include:

  1. Adverse effects to look for
    • Effects related to the mechanism of action of the investigational medical device
    • Effects associated with equivalent predicate medical devices, but independent of the primary mechanism of action
    • Results from previous safety and toxicology studies
    • Enrolling the lowest number of subjects possible in accordance with the USDA APHIS regulations.
  2. Choice of test model
    • Responsiveness of the model
    • Type, gender and age of the model
    • Susceptibility, sensitivity, and reproducibility of the model
    • Available background data on the investigational medical device
    • Human data (e.g., in vitro metabolism)
  3. Time points and methods of assessments
    • Physiology of the test model
    • Mechanism of the investigational medical device and targeted disease state
  4. Sample size and duration
    • Incidence of potential adverse effects
    • Time course of potential adverse effects
    • Duration of targeted disease state and intended duration of use of the investigational medical device
      • Durations required by regulatory agencies
        1. Enrolling the lowest number of subjects possible in accordance with the USDA APHIS regulations.

The International Conference on Harmonization Guidelines on Safety Pharmacology Studies for Human Pharmaceuticals S7A provide additional details on safety study design, although the main focus is on pharmaceutical products, not medical devices. Additional guidance for medical devices can be reviewed in International Standards Organization (ISO) 10993.

The US Food and Drug Administration requires that all nonclinical testing in support of premarket submission for medical devices comply with the Good Laboratory Practices described in 21 CFR 58. These requirements are related to study personnel, testing facilities, quality assurance, animal care, storage facilities, study equipment, study protocols and study records.

Appropriate study designs will be easier to determine if data is already available on the nature and incidence of potential adverse effects, either from previous in vitro safety studies or from equivalent predicate medical devices. Therefore, it is necessary to conduct thorough evaluations of the literature available on the investigational medical device, equivalent predicate medical devices, as well as the targeted disease state or condition.

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Resources

International Conference on Harmonization. ICH Harmonised Tripartite Guideline: Safety Pharmacology Studies for Human Pharmaceuticals S7A. November 8, 2000 (Step 4 version). Available at:http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7A/Step4/S7A_Guideline.pdf.

International Standards Organization. ISO/TC 194 – Biological and clinical evaluation of medical devices. Available at:http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_tc_browse.htm?commid=54508.

Code of Federal Regulations. 21 CFR 58. Good Laboratory Practice for Nonclinical Laboratory Studies. Available at: http://www.ecfr.gov/cgi-bin/text-idx?SID=14ff4451de20af7c3d03869b23a88fb5&node=pt21.1.58&rgn=div5.