Pharmaceutical and Medical Device Development

Pharmaceutical and Medical Device Development, and Public Safety

Andrew HelicherHPA 520

October 7, 2009

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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

4

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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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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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

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Pharmaceutical and Medical Device Development