1. Science, politics, culture: the challenges for medical technology and its regulation Kenneth H. Keller School of Advanced International Studies The Johns Hopkins University Bologna, Italy

2. The readings: some themes Regulation: matching institutional structure to the dynamics of technological innovation Cost and benefit: the economist’s challenge Risk and benefit: the media and/or society “Narratives”: symbol versus substance The diminishing deference to expertise in an information age The contrast between drugs and devices

3. EU and US contrasts: I Political organization –EU- Relative trust of government; delegation of authority; executive power –US- Suspicion of experts; populist government; legislative control Social/economic factors –EU- Flatter income distribution; social safety net; identification with “place”; universal health insurance coverage; higher taxes. –US- Enormous wealth variation; non-uniform medical practice system; serious health insurance gaps; high expectations.

4. EU and US contrasts: II Cultural factors –EU- Strong antipathy to genetic manipulation (food more than pharmaceuticals), BUT openness to other medical technologies. –US- More open to genetic manipulation than to medical devices. Religious factors –EU- Primarily secular societies; religion not a strong factor in policy or bioethical arguments. –US- Highly religious society; formal separation of church and state, but major factor in policy debates.

5. EU and US contrasts: III Privacy –EU- a “human dignity” issue; vis-a-vis other private parties, NOT government. Thus, consistent, comprehensive, government-enforced regulation. –US- a liability, “rights” issue; vis-à-vis government. Patchwork of regulations, difficulty of enforcement. Freedom of Information –EU- Very low priority; very limited. A problem in creating “sunshine” environment. –US- Frequently a concern to government and private entities, but a major element in “checks and balances”.

6. Civic Epistemologies* United States Contentious Britain Communitarian Germany Consensus-seeking Styles of public knowledge-making Pluralistic, interest based Embodied, service based Corporatist, institution based Public accountabi- lity (trust basis) Assumptions of distrust; Legal Assumptions of trust; Relational Assumption of trust; Role-based Demonstration (practices) Sociotechnical experiments Empirical scienceExpert rationality ExpertiseProfessional skillsExperienceTraining, skills, experience Visibility of expert bodies TransparentVariableNontransparent *Jasanoff, S. Designs on Nature: Science & Democracy in Europe & the U.S. (Princeton U. Press 2005)

7. Current Medical Technology Policy Issues Regulatory mechanisms for device development (the failure of the drug model). Criteria for clinical adoption of new technologies. Clinical cost control and support of research/training. Promoting multidisciplinary research. Meeting global needs.

8. The changing context  New fields; new interactions  Confluence of research and development  Rising health care costs  Health concerns in the developing world  Effect and affect: the social and human dimensions of medical technology

9. Effect and affect: the social and human dimensions Public policy issues (effect):  Distributional justice and priority setting.  Quality of life and evidence of value.  Privacy.  The threat of adverse selection. Personal values and beliefs (affect):  Human identity and aversion to “technical invasion.”  Technology as symbol; religious beliefs and core values.  Risk assessment vs. risk perception. Personal empowerment.

10. “Rational” societal investment in medical treatment $ People-years of extended life Disease A Disease B

11. What is the criterion for “acceptable” risk? 100%98%96%94% Reliability (% device survival/yr) Patient yrs of extended life/$ Economist ’ s preference Socially tolerable Personally acceptable (depends)

12. 1 Severity of disease Average years of life after transplant Age-based actuarial prediction 0 Without transplant With transplant Effectiveness of organ transplants

13. What a difference a valve makes Graph courtesy of F Schoen Courtesy Dr Fred Schoenfeld, Brigham

14. The price of risk reduction.0001.001.010.1 Probability of device failure 10 100 10 3 Iteration, experience Relative cost

15. What is a medical device? FDA classifications »Pharmaceuticals »Biologics »Medical devices

16. What is a Medical Device? “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent…which: Is recognized in the official National Formulary, or the U.S. Pharmacopoeia, or any supplement to them, Is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or Is intended to affect the structure or any function of the body … and which does not achieve any of its purposes through chemical action within or on the body…and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”

17. Medical Devices

18. Combination products: a challenge to regulation* Def’n: Products that involve some combination of device, drug, and/or “biologic”. Tissue engineering Tissue scaffolds (skin, nerve regeneration) Hybrid artificial organs (pancreas, liver) Cloned organs Drug delivery systems Drug-eluting stents Site-specific chemotherapeutic particles “Intelligent” sensors * Regulators abhor an ambiguity

19. Medical Device Classes Class I - Minimal potential for harm –Subject only to general controls –Exempt from premarket notification –Some exempt from GMP except for record keeping and complaint files. Class II - Held to a higher level of assurance than Class I –Subject to general and special controls (labeling, performance standards, post-market surveillance) –Require 510(k) premarket notification unless exempt Class III - Highest risk, manufacturing controls insufficient to assure safety and effectiveness, the device is life-sustaining, important in preventing impairment of human health, or presents a potential unreasonable risk of illness or injury –Subject to general and special controls and –Require Premarket Approval Application (PMA) unless a pre-amendment device

20. Safe experimentation Premarket safety Premarket effectiveness Research Inspection Truthful promotion Adverse Event Reporting Postmarket studies Manufacturing Inspection Recall Notification FDA Perspective

21. The Gatekeeper Approach Responsible party NIHFDA CMS/Insurers Hospital/Physician Patient ?? Decision Driver Research Development Payment Clinical use Quality of life None Device Status Experimental Clinical Private property ?? Comment Hypothesis/disease driven “Safe and effective” “Reasonable & necessary” Judgment or evidence? Patients, docs, lawyers Losing explant data

22. What do “safety” and “efficacy” mean? Emphasis in U.S. on clinical outcome (the “gold standard”: double-blind statistically significant studies) – In contrast, the CE Mark (Conformité Européen) requires that the device achieve its intended purpose as designated by the manufacturer Distinction between “efficacy” and “effectiveness” How safe is safe? –In Europe, “a ny risks associated with its use are acceptable when weighed against the benefits to the patient.

23. EU Device Regulation & Harmonization The CE Mark (Conformité Européne) requires that device: (i)Does not compromise the clinical condition or safety of the patient; (ii) Achieves its intended purpose as designated by the manufacturer; (iii) Any risks associated with its use are acceptable when weighed against the benefits to the patient. Concept of Competent Authorities (national entities). Concept of Notified Bodies (private entities).

24. Technical feedback: closing the loop Mfrs have legal responsibility for “device vigilance” but physicians are major source of “incident” reporting. Requirement to report incidents to relevant Competent Authority (CA); CA responsible for notifying other CAs. Limited distribution of information: –Dialogue with manufacturer –Notice to users only when serious and necessary –No public availability of data or data base EUDAMED: European Database on Medical Devices

25. Why “drug model” (gatekeeper) regulation fails in medical technology development  Iterative nature of technical systems development  The technology learning curve  Limitations on “drug model” testing protocols:  Limited data collection possibilities  Scaling constraints  Impracticality of double-blind studies  Small size of medical technology companies  Small size of medical technology markets  Sometimes not suitable for general clinical practice

26. Unintended consequences of gatekeeper regulation  Reduced innovation; the siren call of “substantial equivalence”  Sub-optimal designs; avoiding design revision  Failure of small, innovative firms; the “burn rate”  Reduced competition  Absence of clinical monitoring of effectiveness and design improvement

27. Is clinical testing always the “gold standard”?  The strengths of clinical testing: Sensitivity to systems effects Clinical outcome orientation  The weaknesses of clinical testing: Insensitivity as early warning system Lack of information/guidance on mechanisms De-emphasis on extrapolation

28. Registries: Premarket Perspective Potential Applications  Provide data to support development & design of clinical trials  Provide historical comparator data (if rigorous)  Enhance safety assessments via broader analysis of adverse events  Provide access to product (outside of IDE trial)  Expedite approval of device modifications or labeling

29. Registries: Postmarket Perspective Potential Applications –Provide surveillance for “real-world” events –Assess generalizability of new technologies –Expedite time to market with reliable postmarket data –Provide vehicle for Post-approval Studies (PAS) –Promote evidence development for CMS’ national coverage decisions (NCDs)

30. Policy solution directions  Long term: –Recognition that medical devices and technologies can never be entirely experimental nor entirely clinical –De-emphasis on “gatekeeper” approaches in favor of continuous regulation and monitoring that leads to early introduction, but ongoing control of clinical setting and data gathering  Near term: –Pilot programs in conditional coverage –Financing of medical device registries and implant retrieval

31. Some final questions How risk averse should we be? Are we asking the right questions about benefit? How could we alter the system and still protect the public?

32. The International Challenges  Autonomy and bureaucracy  The temptations of trade restriction  Standardizing data collection and evaluation  Institutionalizing scientific consensus  Harmonizing regulatory approaches  Contrasting patterns of litigiousness  Freedom of information and clinical monitoring  Social and religious values

33. Approval Process, Drugs vs Devices DevicesDrugs Cost$50 Million$800 million Time3 years12 years Trial formatOpen label Blinded, randomized Patients in trial(s) ~100~5,000

34. Unique Aspects of Device Events Lack of standard nomenclature for devices Often, these events represent numerators, with no clear denominator available Operator involvement and human factors issues inherent in virtually every event Complex multi-device situations are common leading to complex evaluation Information in reports often limited

35. CDRH Vision - Total Product Life Cycle