Regulatory Science Symposium: Regulatory Aspects of Clinical Trial Design Session 4: Unique Designs for Medical Device Trials (2018)

1. Presentation Title: Unique Designs for Medical Device Trials
2. Presented by Keith Morel, PhD (VP Regulatory Compliance)
3. Outline of Presentation
   1. Differences between Drug and Device development and regulation (US vs. Europe)
      1. Morel’s specialty is European devices and its requirements
      2. 25-year-old directives are being changed (in the middle of 3-year change)
   2. Challenges with Device Clinical Trials
   3. A control for surgical medical devices? “Sham surgery”
   4. Case Study: Renal Denervation
   5. Changing EU requirements with respect to Clinical Data and evaluation
4. Differences between Drugs and Devices
   1. FDA requirements for clinical investigations (“trials”)
      1. Based on the Cooper Committee Findings (1970)
      2. Device
         1. Often a single trial
         2. Based on the risk of the device (Risk-based approach)
         3. Phases: FIM, Pivotal, Post-Market (“PMCF” in EU)
      3. Drug
         1. Replications of clinical findings required (multiple trials are necessary)
         2. Phases: Phase I, II, III, IV
         3. Begins with 1,000 or some number of compounds and is narrowed down as the drug is further developed
   2. Challenges with Device Trials
      1. Devices Primarily used by Healthcare Professionals
         1. Learning curve, training, skill of the user: factors that can hinder the effectiveness of the device
         2. Hard to blind
         3. Life cycle is shorter
         4. Software, radiation, material problems (complex engineering project)
      2. Devices are subject to frequent, incremental changes
      3. Some devices are implanted
         1. Coming with suitable control is difficult
         2. Ethnical concerns with creating the placebo
         3. Creating long “expected life” due to expense, finding individuals who can do so, failure analysis of retrieve devices, bench testing, and formal design reviews
      4. Device companies may be small manufacturers
         1. Device companies may be small manufacturers
5. Sham surgery – a control for surgical device trials?
   1. Sham Surgery: aka placebo surgery; a faked surgical intervention that omits the step thought to be therapeutically necessary
   2. Whereas, clinical trials involving drugs can use an inactive pill
   3. Historical development of surgical procedures
      1. Developed in hierarchical environment
      2. Surgeon’s experience compared to other operations, historical controls, or randomized controls
   4. Sham surgery controls
      1. Shift towards Evidence Based Medicine (EBM) since the 1980s
      2. Ethical Dilemmas – can harm patient partaking in the surgery
   5. Sham Surgery: History and Controversy
      1. Favor: Necessary for rigorous experimental designs needed to exclude false positives
      2. Example: The “Transplant” Case – 5 individuals need transplants for different organs and the doctor can save 5 lives by taking one healthy life
      3. Example: The “Runaway Train” Case
         1. Nothing can stop the train but there is a group of 5 workers and there is a worker on one of the alternative rails that you can divert the train onto (Saving one life vs. saving four lives)
         2. Variations: The “Fat Man” and The “Thrill Seekers”
      4. The Five Criteria Developed for when harming a few to save many could be justified when…
         1. A specific group is at risk from a harm causing event
         2. Setting in which harm/risk is diverted from many to few involves only individuals from the larger “at risk” group
         3. Harm is diverted between large and smaller subsets of the originally “at risk” group
         4. Harm will occur regardless of whether or the outside agent diverts harm from many to few   
         5. There is a reasonable and legitimate means for allocating risk between the few and the many
      5. How these criteria are met for sham surgery
         1. Involving the subjects with the medial condition
      6. Informed Consent
         1. Informed Consent may not be enough
         2. Necessary but not sufficient for justifying sham surgery
6. Sham Surgery Control – permissible or obligatory?
7. Case Study – Renal Denervation
   1. Renal Denervation (RDN): a minimally invasive, endovascular catheter based procedure using radiofrequency ablation/ultrasound ablation aimed at treating “resistant hypertension”
   2. Causing a decrease in fluid retention and hence blood pressure
   3. First Device: SIMPLICITY (in June 2007), second study in June 2009, third study in 2011-2013 (big study); the first two studies showed significant differences but third study did not illustrate the same conclusion during the Sham
      1. What Happened? -  Biases (lack of blinding), fact of being a study alone can be causing an effect, “white coat syndrome”, learning curve (experience vs. “new” users, the nerves vary in location in the tissue, lack of biomarkers to see whether the nerve was affected by the device, medication compliance issue, patients being on different medications, and medical class interventions, placebo/Hawthorne effect
      2. Approved in Europe but not in the USA
8. Changing requirement in the EU for clinical data & evaluation
   1. 2010- Amended the directives
   2. 2013- Responses from politicians due to scandals between 2010 and 2012
   3. Mid 2016- Increased data regulation with audits and outlining requirements
   4. 2017- Three change period ending in 2020
9. A Clinical Development Plan (CDP) is required as part of the CEP (for all classes of device)
10. EU MDR Requirements (and PMCF)
    1. “No grandfathering”; need to produce sufficient data to prove benefit/effectiveness of device
    2. Question: What should the design of those PMCF studies be?

Accompanying text created by Annie Ly | Undergraduate Research Associate and Provost's First Generation Research Fellow | lyannie@usc.edu