Regulatory Considerations in Drug and Device Development: The Process and the Science

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2. Introduction. Background on U.S. Food and Drug Administration (FDA)mission, goals, and short historycurrent structure of FDAProcess of drug developmentdefinitions of common termsphases of drug developmentProcess of device development. 3. The Scientific Method. Roger Bacon, monk, philosopher and alchemistDescribed scientific method in 13th centuryRepeating cycle of:ObservationHypothesisExperimentationVerification/replicationRegulations are based on GOOD SCIENCENot

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Regulatory Considerations in Drug and Device Development: The Process and the Science

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1. Regulatory Considerations in Drug and Device Development: The Process and the Science John H. Powers, MD Lead Medical Officer Antimicrobial Drug Development and Resistance Initiatives Office of Drug Evaluation IV Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. 2 Introduction Background on U.S. Food and Drug Administration (FDA) mission, goals, and short history current structure of FDA Process of drug development definitions of common terms phases of drug development Process of device development

3. 3 The Scientific Method Roger Bacon, monk, philosopher and alchemist Described scientific method in 13th century Repeating cycle of: Observation Hypothesis Experimentation Verification/replication Regulations are based on GOOD SCIENCE Not “hurdles” Not “just for licensing”

4. 4 The Scientific Method Science can be an expensive (and dangerous!) business George Wilhemm Richmann was killed by lightning in 1753 attempting to replicate the 1752 kite experiment of Benjamin Franklin

5. 5 Mission and Goals The Food and Drug Administration Modernization Act (FDAMA) of 1997 affirmed FDA’s public health protection role and defined the Agency’s mission: “to promote public health by promptly and efficiently reviewing clinical research and taking appropriate action on the marketing of regulated products in a timely manner.”

6. 6 Background U.S. Food and Drug Administration regulates a wide range of products including foods, cosmetics, drugs and medical devices FDA regulated products make up 1 trillion dollars worth of products and account for 25% of consumer spending FDA has approximately 10,000 employees FDA HQ located in Washington, DC, and across DC suburbs but soon to move to White Oak, MD in April 2005

7. 7 Background Regulatory authority comes from Food, Drugs and Cosmetic (FD&C) Act enacted in 1938 after tragedy with Elixir of Sulfanilamide Code of Federal Regulations (CFR) is interpretation of FD&C Act Original act specified drug sponsor only had to demonstrate safety of drug product Kefauver-Harris Amendments in 1962 specified that drug product must be effective as well as safe after issues with thalidomide Medical device regulations enacted in 1976 FDA determines safety and effectiveness of products

8. 8 Background Executive branch of government Department of Health and Human Services (DHHS) U.S. Food and Drug Administration (FDA) Center for Biologics Evaluation and Research Center for Devices and Radiological Health Center for Food Safety and Applied Nutrition Center for Veterinary Medicine National Center for Toxicological Research Center for Drug Evaluation and Research (CDER) Office of New Drugs (OND)

9. Regulation of Drugs

10. 10 Background CDER mission to oversee research, development, manufacture, and marketing of drugs. Review clinical trial evidence of safety and effectiveness of new drugs before approving them for marketing Monitors drugs post-marketing performance for unexpected health risks Ensures that drug labeling, drug information for patients, and drug promotion are truthful, helpful, and not misleading

11. 11 Background Each drug reviewed by a multi-disciplinary team Project Manager/Consumer Safety Officer coordinates team point of contact for drug sponsors Biopharmacologists Chemists Clinicians Microbiologists Pharmacology/toxicologists Statisticians

12. 12 Drug Development Process Definitions Drug - any substance used to diagnose, cure, mitigate, treat or prevent a disease (FD&C Act) Disease defined in the dictionary as “a condition that results in medically significant symptoms” Efficacy/Effectiveness - impact of drug on outcomes clinically relevant to patients, such as how a patient feels, functions, or survives Safety - describing the adverse events associated with administration of drug

13. 13 Drug Development Process Definitions Efficacy/Effectiveness determined in “adequate and well controlled trials” trials of adequate size and design to determine a difference should such a difference exist uncontrolled trials are usually not acceptable testing a hypothesis in a clinical trial, such as “drug X is superior to drug Y by Z%”

14. 14 Drug Development Process Definitions Safety almost a misnomer in that no drug is completely safe implies concept or risks of adverse effects compared to benefits of receiving drug takes into account seriousness of disease and available alternative therapies and seriousness and frequency of adverse effects

15. 15 Drug Development Process Definitions Safety usually NOT testing a hypothesis but providing descriptive statistics only sample size of clinical trial database often too small to determine rare events “Rule of three” - no events in a given sample rules out a risk of denominator divided by three e.g. no events in 3000 patients rules out risk of 1:1000 (compare to risk of hepatotoxicity in general population of 1:1,000,000)

16. 16 Drug Development Process Definitions Safety Important to look at absolute number of patients potentially experiencing adverse event as well as relative risk risk of visual abnormalities: voriconazole 30% of 5000 patients with invasive aspergillisos is 1500 patients and few available therapies telithromycin 1% of 24 million patients with sinusitis is 240,000 patients and 14 other drugs for acute bacterial sinusitis

17. 17 Drug Development Process

18. 18 Drug Development Process Overall Development Plan Overall goal to prove that drug is safe and effective in treatment and/or prevention of diseases under study Decide which indications to pursue and whether drug is to treat or prevent disease Speak with relevant Division at FDA about overall development plan and number of studies required for approval

19. 19 Development Process Phases of Drug Development Pre-clinical data in vitro data showing biological activity carcinogenicity animal toxicology (NOAEL) by going to high enough dose to observe some effect Phase 1 first introduction of investigational new drug in humans usually performed in healthy volunteers used to determine absorption, metabolism, distribution, elimination in humans

20. 20 Development Process Phases of Drug Development Phase 2 early controlled clinical trials preliminary efficacy of drug in patients determine common short term side effects Phase 3 pivotal information on safety and efficacy adequate and well -controlled trials basis for extrapolating results to general population and product labeling Phase 4 - post-marketing

21. 21 Drug Development Process Investigational New Drug (IND) Application needed whenever a sponsor wishes to study a new drug or an approved drug at a new dose, new route of administration in a new population houses all data prior to submission of NDA New Drug Application (NDA) information from IND as well as Phase 3 trials submitted for application to market a drug

22. 22 Drug Development Process

23. 23 Drug Development Process Fast Track Designation products for serious and life threatening diseases products that have potential to address unmet medical need sponsor can request at time of submission of IND or any time thereafter prior to approval schedule of meeting and written correspondence eligibility for priority review or accelerated approval

24. 24 Drug Development Process Accelerated Approval serious and life threatening diseases restricted distribution approval based on surrogate endpoints reasonably likely to predict clinical benefit contingent on follow-up studies to confirm therapeutic benefits to patients Priority review products with significant improvement in safety or effectiveness not limited to serious and life threatening diseases

25. 25 CDRH Organization

26. Office of Device Evaluation The Office of Device Evaluation is responsible for the premarket review of medical devices. There are currently five divisions divided by medical specialty area. Other offices in the Center for Devices and Radiological Health include the Office of Compliance which is responsible for assuring regulatory compliance, the Office of Surveillance and Biometrics which is responsible for postmarket surveillance and the Office of Science and Technology which provides laboratory support and standards development. The Office of Device Evaluation is responsible for the premarket review of medical devices. There are currently five divisions divided by medical specialty area. Other offices in the Center for Devices and Radiological Health include the Office of Compliance which is responsible for assuring regulatory compliance, the Office of Surveillance and Biometrics which is responsible for postmarket surveillance and the Office of Science and Technology which provides laboratory support and standards development.

27. 27 Device Regulations FFD&C Act (21 U.S.C 301 et seq.) Device Defined in Sec 201(h): Intended to diagnose, cure, mitigate, treat, or prevent a disease or condition; or Affects the function or structure of the body; and Does not achieve intended use through chemical action in/on body; and is not metabolized to achieve purpose FDA’s authority to regulate devices is through the Federal Food Drug and Cosmetic Act. The term device is defined in Section 201 H and includes any product intended to treat or diagnose a disease or condition or affect body function. And the last bullet differentiates devices from drugs in that devices are not metabolized in the body to achieve their intended purpose.FDA’s authority to regulate devices is through the Federal Food Drug and Cosmetic Act. The term device is defined in Section 201 H and includes any product intended to treat or diagnose a disease or condition or affect body function. And the last bullet differentiates devices from drugs in that devices are not metabolized in the body to achieve their intended purpose.

28. 28 Center for Devices and Radiological Health Pre-Marketing Review Devices divided into Classes for purposes of review For Class III Devices: Premarket Approval Application (PMA) similar to NDA for new drugs Requires clinical trials For Class I, II and a few Class III Devices (for which a predicate device exists): Premarket Notification (510k) Comparison to previously approved device There are basically two types of applications for marketing clearance of new medical devices. There is the PMA process for new technology devices where predicate devices do not exist. Examples include heart valves, pacemakers, coronary stents, endovascular grafts just to name a few. The PMA process provides details concerning the device materials, testing, and processing. The other process to market clearance is referred to as the premarket notification process or 510K. It provides for a comparative information between the new device and predicate device. Details on the comparative testing and modifications to the predicate are provided in this submission. There are basically two types of applications for marketing clearance of new medical devices. There is the PMA process for new technology devices where predicate devices do not exist. Examples include heart valves, pacemakers, coronary stents, endovascular grafts just to name a few. The PMA process provides details concerning the device materials, testing, and processing. The other process to market clearance is referred to as the premarket notification process or 510K. It provides for a comparative information between the new device and predicate device. Details on the comparative testing and modifications to the predicate are provided in this submission.

29. 29 FDA APPROVES / DISAPPROVES MARKETING CLEARANCE FOR FINISHED PRODUCTS (DRUGS, DEVICES, BIOLOGICS) not technologies not materials not processing techniques not additives FDA reviews and clears products, NOT materials, NOT Technologies, and NOT Processing techniques.FDA reviews and clears products, NOT materials, NOT Technologies, and NOT Processing techniques.

30. 30 Combination Product Combination Product (21 CFR 3.2(e)): a product comprised of two or more regulated components that are physically, chemically or otherwise combined or mixed as a single entity; two or more separate products packaged together (e.g., drug and device products); or provided separately but intended for use together where both are required to achieve the intended use, indication, or effect and where mutually conforming labeling is needed.

31. 31 Office of Combination Products (Established December 24, 2002) Assignment of combination products to “lead center” based on primary mode of action Inter-center consultation/collaboration Ensure timely and effective premarket review Consistent and appropriate postmarket regulation Dispute resolution (timeliness vs. substance) Review/update guidance, agreements, practices

32. 32 Examples: Antimicrobial Agents in Cleared / Approved Devices silver, silver cpds chlorhexidine cpds triclosan nitrofurazone bacitracin zinc minocycline polymyxin B sulfate rifampin methylene blue crystal violet dicloxicillin combinations of these This list shows some examples of the types of antimicrobial agents included in devices that have been cleared or approved. This list shows some examples of the types of antimicrobial agents included in devices that have been cleared or approved.

33. 33 Examples: Device Types Cleared / Approved catheters - intravascular, urological, peritoneal, etc. wound care products - dressings, etc. dental - toothbrush, floss, instrument covers implanted devices - surgical mesh, orthopedic fixation, ear tube, heart valve FDA has been receiving an increasing number of submissions and inquiries on antimicrobial agents used in devices. The list shows the wide variety of device types that have been cleared or approved.FDA has been receiving an increasing number of submissions and inquiries on antimicrobial agents used in devices. The list shows the wide variety of device types that have been cleared or approved.

34. 34 Contact Information – Office of Combination Products Mark D. Kramer Director, Office of Combination Products 15800 Crabbs Branch Way (HFG-3) Rockville, MD 20855 (301) 827-9229 [email protected] http://www.fda.gov/oc/combination/default.htm

35. 35 Contact Information for Devices Bob Gatling Program Operations Center for Devices and Radiological Health 9200 Corporate Boulevard (HFZ-450) Rockville, MD 20850 (301) 594-3055

36. 36 Product Development Process “Critical Path” Initiative released by FDA in 2004 goal to find better tools to streamline drug development process better predict safety and efficacy of products FDA can provide guidance on what tools may be most helpful www.fda.gov/oc/initiatives/criticalpath

37. 37 Conclusions Communication is one of keys to drug development process Take advantage of opportunities to discuss options with FDA “Failing to plan is planning to fail” Develop future tools during current trials

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