Premarket Testing and Validation 2.0

1. Premarket Testing and Validation 2.0 Dom Gilson Lindsay Sherer Ruthanne Shaull

2. Overview • General Verification and Validation • FDA Classifications • Subsets of the Biomedical Industry • Medical Devices • Software • Pharmaceuticals

3. Verification and Validation • Verification  Checking to make sure design outputs=inputs • Are we building the product right? • Validation  Checking to make sure user needs are met • Are we building the right product?

4. Verification & Validation • In a nutshell, the process of V&V is the confirmation that design outputs match design inputs (verification) and the device fulfills user needs (validation). • This confirmation is achieved by testing of the product in ways that simulate actual use. • Validation requires that verification is working. • V&V should maximize the assurance of quality, but minimize required testing.

5. Reliability and Risk • Percent confidence and reliability determine the quality of the product. • Reliability refers to failure rate. • Confidence refers to the minimum certainty that the claimed failure rate is accurate. • Ex: 95% confident that 90% of parts are in spec • Target reliability and confidence levels are related to the severity of failure.

6. Verification and Validation Reporting • Test documentation that is generated for a particular product/equipment also depends on life cycle and level of concern. • The verification and validation report summarizes the results of verification and validation activity. • The summary contains: • Description of tasks performed • Number of cycles • Summary of task results • Summary of errors and their resolutions • Description and location • Impact • Criticality • Rational for resolution • Results of re-test

7. Regulatory Bodies • In order to satisfy the requirements of regulatory agencies, international communities, and corporate commitments, an effective systematic approach to medical product software is necessary. • Food & Drug Administration (FDA) – USA • Pharmaceuticals and Medical Devices Agency (PMDA) and/or Ministry of Health, Labor and Welfare ((MHLW) - Japan • European Commission (EC) – European Union

8. FDA Classifications • Amount of testing required is dependent on classification of a particular medical device • Class I, II, III – Class III is the most stringent • Classification is dependent on severity of failure and substantial equivalency. • Based on the classification a company will either need to submit a PMA (Premarket approval), a 510k, or a lesser submission with exemptions. • PMA is the most thorough, followed by a 510k. • “Intended Use” is a very important concept.

9. PMA vs 510k 510k • Class I & II Devices • ~5000 per year • 50-100 pages • ~10% need clinical studies • $4000 Application Fee PMA • Class III Devices • ~50 per year • ~1000 pages • All need clinical studies • $218,000 Application Fee

10. Documents in Submission • Documents should contain the engineering rationale for how certain tests will confirm that the design inputs were met (verification) and that the design is actually useful (validation), as well as the data to back up the claims. • Engineering Document Examples: Design Verification and Validation Master Plans, V&V Protocols and Reports, Test Methods, Data Sheets, etc, etc, etc, etc, etc • All documents should adhere to Good Documenting Practices (GDP)

11. Subsets of the Biomedical Industry • Medical Devices • Pharmaceuticals • Software

12. Medical Devices

13. Testing • Dimensional Characterization • Tensile/Compressive Mechanical Strength • Elasticity or Flexion • Lubricity/Friction Testing • Biocompatibility • Sterility

14. Typical Use Testing • Typical use testing is testing the device as it will be operated in its typical environment. • This testing can help show reliability. • It can also be used to calculate a long term mean time between failures value.

15. Cycle Testing • Cycle testing is conducting tests on individual components. • Or it could consist of passing the state of operation and non-operation of a component or device. • An example being a power supply could be cycled on for 8 hours and off for 16 hours.

16. 10 x 10 Testing • 10 x 10 testing: There are ten samples that tested for a particular parameter at ten different times. • The mean and standard deviation values are then calculated for each of the ten recordings and ten units.

17. Biocompatibility • For devices in contact with the body, biocompatibility testing must be conducted. • The complexity of testing increases as contact with the body increases.

18. Sterility & Age Testing • Due to the function of medical devices all products are required to be sterilized. • The sterility process or aging could affect certain properties of a medical device. • The possibility of these affects causes the need for addition verification testing.

19. Common Testing Equipment

20. Common Testing Equipment

21. Calibration

22. Software

23. Software Testing Process

24. Software Medical companies are faced with validating both products and test/manufacturing equipment. Phases of Software Development • Code and Test – development of the code and debugging the implemented code by the software developers. • Integrate and Test – integration of the software components and the testing of the integrated parts. • Software system testing – verification and validation testing that is performed by the engineers on the fully integrated software and hardware. • Software V&V can become lengthy when performing tests on multiple platforms and different hardware.

25. Pharmaceuticals

26. Pharmaceuticals • Drugs are created in one of three ways: • Trial and error • Computer modeling of the chemical structure • Acquiring/testing unusual fungi, viruses, and molds. • After a drug has made it past test tube stages, tests are done on two relevant animal models. • Primarily rats, mice and other rodents are used. • The validity of a drug is based on a comparison with what is currently available.

27. Clinical Trials • If a drug has been proven to be effective on animal models, the test of the drug may proceed to clinical trials if the FDA believes that the testing has shown potential value for the disease under study. • Before the testing process begins, a committee of medical and lay personnel study the proposed drug’s test and protocol. • Once the committee approves the drug for testing, phase 1 of clinical trials starts.

28. Clinical Trials • Phase 1 of a clinical trial involves 20-100 people, typically healthy volunteers or patients. • This phase is designed to assess the drug for acute adverse effects and examine the size of doses that patients can take safely without a high incidence of side effects. • Phase 1 lasts a few months • ~70% of drugs pass this first test. • Phase 2 of a clinical trial tests several hundred patients to determine short term safety and effectiveness. • Phase 2 takes months to years to perform • ~ 50% of the drugs fail here.

29. ClinicalTrials • Phase 3 tests the drug on several thousand patients with primary questions about drug safety, dosage, and effectiveness are being addressed. • Large samples are usually performed in order to obtain good statistics which will be used in the literature that accompanies the prescription. • About 60-70% of drugs pass this phase. • After phase 3, the FDA is petitioned for a new drug approval. • Which takes an additional two years. • Phase 4 investigates the continued efficacy and long term effects of the drug in use.

30. Questions?