BIOE 301

Lecture Twenty-Two

Schedule

• Today, April 10– Lecture 22: FDA Device Regulation & Research

Funding • Thursday, April 12

– Lecture 23: Future of Bioengineering in World Health & Review for Final

• Tuesday, April 17– No class!

• Thursday, April 19– Exam 3, Lectures 16-23

• Tuesday, April 24– Project Presentations

• Final Exam (see syllabus for details)

Reading Assignment for Thursday

• Financial Anatomy of Biomedical Research, JAMA. 2005, Sep 21;294(11):1333-42

• Application of Microchip Assay System for the Measurement of C-reactive Protein in Human Saliva, Lab Chip. 2005, 5, 261-269

• An exam question will draw from these articles

After Today’s Lecture…

• Appreciate why it costs so much in the US (time & money) to develop devices and get them to market

• Speculate on what this means for developing countries that depend on 1st world research

• Understand the importance and magnitude of research funded by the government

NIBIB Grantsmanship Program

U of H, Oct. 31, 2006

Administration forChildren and Families

(ACF)

Administration forChildren and Families

(ACF)

Food and DrugAdministration

(FDA)

Food and DrugAdministration

(FDA)

Health Resourcesand Services

Administration(HRSA)

Health Resourcesand Services

Administration(HRSA)

TheSecretary

Deputy Secretary

TheSecretary

Deputy Secretary

Administration onAging(AoA)

Administration onAging(AoA)

Centers for MedicareAnd Medicaid Services

(CMS)

Centers for MedicareAnd Medicaid Services

(CMS)

Indian HealthServices

(IHS)

Indian HealthServices

(IHS)

National Institutesof Health

(NIH)

National Institutesof Health

(NIH)

Centers for Disease Controland Prevention

(CDC)

Centers for Disease Controland Prevention

(CDC)

Substance Abuse andMental Health Services

Administration(SAMHSA)

Substance Abuse andMental Health Services

Administration(SAMHSA)

Program SupportCenter(PSC)

Program SupportCenter(PSC)

Agency for ToxicSubstances andDisease Registry

(ATSDR)

Agency for ToxicSubstances andDisease Registry

(ATSDR)

Agency for Healthcare Research and Quality

(AHRQ)

Agency for Healthcare Research and Quality

(AHRQ)

U. S. Department of Health & Human Services

http://www.fda.gov/oc/orgcharts/fda.pdf

Workings of the FDA• Responsibility to protect the public and dealing with

technological changes• Regulates anything for diagnosis, cure, mitigation, or

prevention of disease as well as anything intended to affect structure/function of the human body

• 3 Branches– Drugs– Devices– Biologics– Combination products overseen by panel from three

areas• Requires the expertise of many

- Medical technologists - Statisticians - Consumer safety officers and field investigators - Human factors specialists

- Engineers (including biomedical electrical, and materials)- Biologists and microbiologists- Physcians and other clinicians- Chemists, biochemists, and toxicologists

Role of Center for Devices and Radiological Health (CDRH)

• Ensure that products coming to market have more benefit than risk

• Ensure that products are labeled so that practitioners and patients know what to expect from their use

• Regulates 1,700 types of devices• 23,000 registered manufacturers• In 1996 received 20,236 device related

submissions

Regulation of Medical Devices

• FDA did not regulate devices before 1938• 1938:

– FDA could only challenge sale of products it believed were unsafe– Could only remove them from the market after patient injuries

• 1960s:– Rapid innovation in medical technology– Tried to regulate many as drugs, i.e. contact lenses, IUDs– Catastrophic failures of heart valves and pacemakers

• 1970s:– Broad recognition that different rules were needed to regulate devices– No single policy would work for all devices

• Tongue depressor• Artificial heart

• Review commission determined that more than 700 deaths and 10,000 injuries were associated with medical devices

Medical Device Act (1976)

• Amendments to FD&C act allowed for classification of medical devices, device listing, establishment registration, adherence to Good Manufacturing Practices (GMP), and extensive control over market introduction of medical devices

• Major amendments again in ’90, ’97, and ’02

• However, CDRH can not specifically regulate biomaterials; biomaterials are indirectly regulated according to intended use

Class Activity (~5 min)

• Break up into groups of 3 students representing – Policy Maker– Manufacturer– Consumer

• Discuss what you would want to see in a device approval process from each perspective

• Report back

Basic Regulatory Requirements

• Premarket notification 510(k) or Premarket approval (PMA)

• Establishment registration on form FDA-2891

• Medical device listing on form FDA-2892

• Quality system (QS) regulation

• Labeling requirements

• Medical device reporting (MDR)

http://www.fda.gov/cdrh/devadvice/overview.html

Device Approval Process

• Device + intended use considered together• Manufacturer submits request for marketing

approval• Advisory panel

– One consumer representative (non-voting)– One industry representative (non-voting)– Physicians and scientists

• FDA not required to follow recommendations of panel, although they usually do

Steps in Device Approval Process

• Device, drug, biologic, combo?

• If device, Class I, II, or III?

• 510(k) or PMA pathway?

• If PMA passes, get IDE

• 2 phases of clinical trials

• If efficacy shown, submit pre-market notification

• Post-market surveillance

Classes of Devices according to CDRH

• Class I– Pose least risk to patient– Not life sustaining– GMP, proper record keeping required – 30% of devices– X-ray film, tongue depressors, stethoscopes

• Class II – Not life sustaining, but must meet performance standards– Blood pressure monitors, Catheter guide wires– 60% of devices

• Class III – Pose greatest risk to patient – For use in supporting or sustaining human life– 10% of devices– Stents, heart valves, LVADs– Require GMP, failure modes analysis, animal tests, human

clinical studies under IDE

510(k) vs PMA

• Substantially equivalent to a legally marketed product– Before May 28th, 1976– Determined by FDA

• Most Class I exempt, most Class II required

• For description of device classification and database access, visit http://www.fda.gov/cdrh/devadvice/313.html

• 3rd Party review process now available

• Most Class III required

• Requires submission of clinical data

• Actual approval process of device by FDA

510(k) Determination Flow Chart

http://www.fda.gov/cdrh/ode/dd510kse.pdf

Premarket Approval (PMA)

• Device and company name

• Indications

• Device description and schematics

• Description of alternate practices

• Contraindications

• Potential adverse affects

• Summary of all pre-clinical studies

Pre-clinical studies

• Physical and chemical analysis

• Biological testing– Pyrogenicity (LAL assay)– Blood compatibility– Acute/chronic toxicity– Mutagenicity– Validation of sterility

• Animal studies– Inflammatory/immune response– Degradation– Particulate migration– Performance

• How can one know how to perform all these tests?STANDARDS!

Standards• Tripartite Agreement on Biocompatibility: FDA guidelines

regarding techniques for pre-clinical testing• ASTM Committee F-04 on Medical and Surgical Materials and

Devices• Standards for

– Test methods: specimen prep, conditions, number of samples, data analysis

– Materials: chemical and physical properties– Devices: schematics, dimensions, tolerances– Procedures: how to do something besides a test, i.e. sterilization,

• FDA accepts standards such that one can write, “I did X according to Y standard”

• Shift in perspective towards worldwide harmonized system– ISO 10993 document– At least 16 parts describing globally recognized standards for

• Biocompatibility screens• Evaluation for ethylene oxide residues• Toxicity studies (i.e., cyto, systemic, & kinetics)• Many more

IDE and Clinical Trials

• Investigational Device Exemption– Enables experimental use of high risk device– Must have positive engineering and animal data

• Clinical Trials– First give approval for feasibility studies with small

number of patients– Then proceed to multi-center trials – Larger data sets frequently show results from small

sample sets are not true

Humanitarian Use Exemption

• Device designed to treat or diagnose condition that affects <4,000 patients/year

• Device would not otherwise be available without exemption

• No comparable device is available

• Patients will not be exposed to unreasonable or significant risk of injury or illness by device

Medical Device Reporting

• System to detect device related problems in a timely manner

• Serious injuries or deaths that may have been caused by or related to a a medical device must be reported to the manufacturer of the device within 10 days

• Must be reported to the FDA within 10 days

Steps in Device Approval Process

• Device, drug, biologic, combo?

• If device, Class I, II, or III?

• 510(k) or PMA pathway?

• If PMA passes, get IDE

• 2 phases of clinical trials

• If efficacy shown, submit pre-market notification

• Post-market surveillance

Recently Approved Devices

• http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTopic/MDA/mda-list.cfm?list=1

Device Development Costs $$$

• Who funds development?

• What is the typical government grant process?

R&D Funding for Biomedical Research

• Federal government– Funds ~ 35% of all medical research in US

• Mostly funded through NIH– Current NIH budget: ~$28 billion/year– NIH budget doubled from 1998-2003– Last year 0% increase – Focus is on basic research

NIH Congressional AppropriationsFY1997- FY2006

NIBIB Grantsmanship ProgramU of H, Oct. 31, 2006

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The NIH Organization

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NIAAA NIAID NIAMS

NCI

NICHD

NIDCD NIDCR NIDDK NIDA

NEI

NIEHS NIGMS

NHLBINHGRI

NIMH NINDS NINR NCCAM

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NIBIB

NIBIB Grantsmanship ProgramU of H, Oct. 31, 2006

NIH• National Cancer Institute• National Eye Institute• National Heart, Lung, and Blood Institute• National Human Genome Research Institute• National Institute on Aging• National Institute on Alcohol Abuse and Alcoholism• National Institute of Allergy and Infectious Diseases• National Institute of Arthritis and Musculoskeletal and Skin Diseases• National Institute of Biomedical Imaging and Bioengineering• National Institute of Child Health and Human Development• National Institute on Deafness and Other Communication Disorders• National Institute of Dental and Craniofacial Research• National Institute of Diabetes and Digestive and Kidney Diseases• National Institute on Drug Abuse• National Institute of Environmental Health Sciences• National Institute of General Medical Sciences • National Institute of Neurological Disorders and Stroke • National Institute of Nursing Research • National Library of Medicine

The NIBIB Vision

To profoundly change health care by pushing the frontiers of

technology to make the possible a reality.

NIBIB Grantsmanship ProgramU of H, Oct. 31, 2006

A big challenge for the NIBIB is promoting multidisciplinary research

• Clinicians, biologists and engineers speak in different languages

• Clinicians and biologists may not know what is technically possible; engineers may not know the biomedical problems

• Continued, ongoing collaboration essential

NIBIB Grantsmanship ProgramU of H, Oct. 31, 2006

Current NIBIB Grant Portfolio Areas

• Biosensors• Biomaterials• Biomechanics• Biomedical Informatics• Computational Biology• Drug & Gene Delivery Systems• Lab-on-a-Chip

Devices/Microsystems • Medical Devices & Implant

Science• Nanotechnology• Rehabilitation Engineering• Surgical Tools & Techniques• Telemedicine• Tissue Engineering

• Imaging Agents & Molecular Probes

• Image Displays• Image Guided Therapies &

Interventions • Image Perception • Image Processing• Magnetic, Biomagnetic &

Bioelectric Devices• Magnetic Resonance Imaging &

Spectroscopy• Nuclear Medicine• Optical Imaging & Spectroscopy• Ultrasound and Acoustics• X ray, Electron & Ion Beam

NIBIB Grantsmanship ProgramU of H, Oct. 31, 2006

NIH Granting Process

My Applicationxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

$$$$$$

Center for Scientific ReviewDivision of Receipt and Referral

Integrated Review Group (in CSR)

or Review Office (in Awarding IC)Evaluates Scientific Merit

Awarding Institute or Center

Evaluates Relevance

Advisory Council

Recommends Action

Institute DirectorAllocates Funds

PI / Institution submits application

Conduct Research

Revision / Resubmission

NIBIB Grantsmanship ProgramU of H, Oct. 31, 2006

http://www.csr.nih.gov/video/video.asp

Scores and Funding Level

• ~1/3 go unscored (triaged)

• ~2/3 are scored– 100 best score– 500 worst score– Typically need score of 100-170 to be funded– Approximately 10-15% of submitted proposals

are funded

For More Information, See the Following Sources

• http://www.fda.gov/cdrh/devadvice/overview.html

• Biomaterials Science: An Introduction to Materials in Medicine, 2nd Ed. Chap 10. Elsevier Academic Press. Editors: Ratner, Hoffman, Schoen, Lemons.

• Materials from NIBIB Grantsmanship Program, University of Houston, Oct. 31, 2006

Index Cards

• What was the muddiest point of this lecture?

• What was the clearest point in this lecture?

HHMI survey, see you on Thursday!

Design Control Guidance

http://www.fda.gov/cdrh/comp/designgd.html

Types of Universities

• Carnegie Classification– Taxonomy of colleges and universities

• Doctorate-Granting Institutions– Research Universities /Very High Research Activity– Research Universities/ High Research Activity– Doctoral/Research Universities

• Master’s Colleges & Universities• Baccalaureate Colleges

– http://www.carnegieclassification-preview.org/index.aspx

Rice