Pharmaceutical and Medical Device Development, and Public Safety
Andrew HelicherHPA 520
October 7, 2009
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Pharmaceutical and Medical Device Development, and Public Safety
Pharmaceutical Development
Medical Device Development
Comparative Analysis
Pharmaceutical Development
Medical Device Development
Comparative Analysis
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Pharmaceutical Definitions
Drug Type Definition Examples
Pharmaceutical(small molecule)
Chemical compound used in the diagnosis, treatment, or prevention of disease or other abnormal condition1
Antihypertensive
Antidepressant
Antiulcerant
Biopharmaceuticalor Biologic(large molecule)
Protein derived from living material (such as cells or tissues) used to treat or cure disease2
Prophylactic (vaccines)
Therapeutics (antibodies)
Replacement therapy(hormones)
1. http://medical-dictionary.thefreedictionary.com/Pharmaceuticals, 20072. http://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm#ther_biological, 06/08/2009
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Target Identification
DNA (Genes) RNA Proteins
TargetCompound
(Ng, R., 2004, p. 16)
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Small Molecule Drug Discovery
Rational ApproachIrrational Approach1. Understand 3D structure and
amino acid sequence of receptor molecule
2. Use modeling software to design drug that will fit within binding site
Find Needles in Hay Stacks
vs
1. Natural Product Collection2. Extract Compounds for Screening3. Screen compounds for ‘hits’4. Modify/purify to enhance potency5. Select compounds for development
Cut a Key based on a Lock Tumbler
(Ng , Rick, 2004, p.16)
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Large Molecule Drug Discovery
Approach DiscoveryExamine compounds within us to understand how they affect biological processes
How antibodies fight antigens
Study pathogens to derive vaccines
Remove virulence factor from antigen
Copy biological response modifiers and use them as replacement therapy
How hormones keep biological activities in balance
(Ng , Rick, 2004, p.76)
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Drug Development
Category Definition
Pharmacokinetics Drug’s action on target:• Dose – response
Pharmacodynamics Body’s action on drug:• Absorption, distribution, excretion
Toxicity Drug’s safety:• Carcinogenicity, Genotoxicity, Reproductive
Formulation Components added to drug:• Delivery, Manufacturing
(Ng , Rick, 2004, p. 108)
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Clinical Trials
Phase Objective Subjects Approach
0 Obtain Investigational New Drug (IND) approval
In vivo In vitro
Test drug’s effects on animals and cell tissue specimens
1 Assess safety of new drug 10 – 100 Compensate healthy volunteers to participate in study
2 Safety and Effectiveness, Dose and Regimen 50 – 500 Double-blind, randomized study on
targeted disease group
3 Confirm efficacy of drug in large patient group
300 – 3,000
Compare drug to existing treatment, identify target patient groups
Pre-Marketing Approval
4 Post-marketing surveillance NA Monitor drug’s efficacy and side effects
in a uncontrolled setting
(Ng , Rick, 2004, p.144-147)
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Regulatory Overview
• Investigational New Drug (IND)• FDA approval to start clinical trials
• Good Clinical Practice• Protect human subjects, scientific validity, Independent Review Board
• Good Manufacturing Practice• Defined process, quality control, trained operators, distribution, recall
• FDA Pre-Marketing Approval
• Post-Marketing Surveillance – FDA MedWatchhttp://www.fda.gov/downloads/regulatoryinformation/guidances/UCM129515.pdf, 1996http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm090016.htm
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Pharmaceutical and Medical Device Development, and Public Safety
Pharmaceutical Development
Medical Device Development
Comparative Analysis
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Invention Process
1. Identify unmet needsa) Physicians, Patients, Clinical Literature
2. Evaluate market potential
3. Research existing inventions and IP
4. Consider Regulatory and Reimbursement challenge
5. Consider company’s ability to commercialize product
(Pietzsch, J., Shluzas, L., Pate-Cornell, M., Yock, P., & Linehan, J., 2009, p. 6-8)
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Development Process
1. Maintain Design History Filea. Required by FDA Quality Systems Regulation
2. Create and refine prototype
3. Test prototype using computers, animals, and cadavers
4. Design manufacturing processa. Good Manufacturing Process
(Pietzsch, J. et al., 2009, p. 9-10)
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Testing Process
1. Verify device complies with Quality System Regulationa. Biocompatibilityb. Durability/Longevityc. Sterilization
2. Validate device meets user requirements
3. Submit design and test data to the FDA for approval
(Pietzsch, J. et al., 2009, p. 10)
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Regulatory Overview
• 1976 Medical Device Amendment
• Class 1-3 base on device risk (1 being low risk)
• Class 3 – Investigational Device Exception (IDE)
• Pre-Marketing Approval Application (PMAA)
• 510(k) – “substantially equivalent” devices• Notify 90 days before launching product
(Office of Technology Assessment, 1985, p. 8)
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Clinical Trials
• Phases• Pilot: establish safety• Pivotal: establish safety and efficacy for patient populations
• 1000 participants, 1-2 years, 30-50 sites
• Institutional Review Board (IRB)
• Contract Research Organizations
(http://www.circ.ahajournals.org/cgi/content/full/109/25/3068, 2004)
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Pharmaceutical and Medical Device Development, and Public Safety
Pharmaceutical Development
Medical Device Development
Comparative Analysis
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FDA Approvals (2008)
New Drugs
New Devices
510(k) Devices
0 500 1000 1500 2000 2500 3000 3500
20
754
3031
1. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/default.htm2. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/default.htm
2
2
1
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FDA Drug Approvals (2002 - 2008)
http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/default.htm
2002 2003 2004 2005 2006 2007 20080
10
20
30
40
1721
36
1822
1820
50%
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Vioxx Case
• 1999: FDA approves Vioxx
• 2000: NEJM accuses Merck of excluding heart attack data
• 2000: Merck exposes heart attack / stroke data to FDA
• 2002: FDA required Merck to include warning on label
• 2004: Merck recalls Vioxx (27,000 heart attacks linked to Vioxx)
• FDA leadership accused of blocking findings of FDA researcher
Can the FDA both approve and recall drugs and devices?
http://www.usatoday.com/news/health/2004-10-12-vioxx-cover_x.htm, 10/12/2004
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Efforts to Increase Medical Device Safety
• 510(k) may be approving high risk products
• GAO identified 24 products approved without close scrutiny through 510(k) process• Including hip replacement and heart implants
• Institute of Medicine conducting a review of 510(k) process• Publish findings in March 2011
http://www.physorg.com/news172947801.html, 9/3/2009
Questions?
Food and Drug Administration (FDA) definition of Biologic (2009, Jun. 18). Retrieved from http://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm#ther_biological.
FDA. Drug Applications and Current Good Manufacturing Practice (CGMP) Regulations (2009, Apr. 30) Retrieved fromhttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm090016.htm.
FDA. Drug and Biologic Approval Reports (2009, Jul. 15). Retrieved from http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/default.htm
FDA. Device Approvals and Clearances (2009, Jun. 18) Retrieved fromhttp://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/default.htm
FDA. Guidance for Industry: E6 Good Clinical Practice (2006, Apr.) Retrieved from http://www.fda.gov/downloads/regulatoryinformation/guidances/UCM129515.pdf.
Medical Dictionary definition of Pharmaceutical. Retrieved from http://medical- dictionary.thefreedictionary.com/Pharmaceuticals, 2007.
Ng, Rick (2009) Drugs: From Discovery to Approval. Hoboken, New Jersey: John Wiley & Sons, Inc.
Office of Technology Assessment (1985) Federal Policies and the Medical Devices Industry. Oxford: Pergamon Press.
Patsner, Bruce. (2009, Mar.) Wyeth v. Levine: The Supreme Court Gets It Right . Health Perspectives. Retrieved from: http://www.law.uh.edu/healthlaw/perspectives/2009/(BP)%20wyeth.pdf, 2009
Perrone, Matthew. (2009, Sept. 23) FDA medical device approvals get external review. The Associated Press. Retrieved from: http://www.physorg.com/news172947801.html, 9/3/2009.
Pietzsch, J., Shluzas, L., Pate-Cornell, M., Yock, P., & Linehan, J., (2009, Jun.) Stage-Gate Process for theDevelopment of Medical Devices. Journal of Medical Devices. Volume 3. , No. 021004.
Rubin, Rita. (2004, Oct. 12) How did the Vioxx Debacle Happen? USA Today. Retrieved from: http://www.usatoday.com/news/health/2004-10-12-vioxx-cover_x.htm.
References
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Judicial Findings
• 2008: Riegel vs. Medtronic• Cardiac catheter ruptured during surgery• 1976 Medical Device Amendment • FDA Pre-Marketing Approval gives Medtronic
immunity in state courts
• 2009: Levine vs. Wyeth• Musician lost hand after improperly injecting drug • Label warning inadequate• No state immunity (unlike Medical Devices)
http://www.law.uh.edu/healthlaw/perspectives/2009/(BP)%20wyeth.pdf, 2009