Medical Device Evaluation and Validation

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Medical Device Evaluation and Validation

• Harold Alexander, Ph.D.
• Orthogen Corporation
• Springfield, NJ
• Halexander_at_orthogencorp.com

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Introduction

• Vast experiment underway
• 20 million people (1 in 14) in USA with implants
• Vast experiment with no data collection
• With exception of occasional reports of clinical
  failures, little is know about biomaterials
  performance in the human clinical environment

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• No good, long term, systematic studies have been
  performed.
• A registration system for implants and
  biomaterials?
• When we consider issues of long-term survival of
  biomaterials in vivo, the lack of attention to
  epidemiology and physiology are key issues.
  Researchers must become more careful and
  observant of clinical performance.
• A national database of clinical data is essential
  to this effort.

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Materials Selection

• Currently used materials are survivors of a trial
  and error process.
• Materials borrowed from other industries
• Cost prohibitive for development of unique
  biomaterials.
• Industry, until recently, could not afford it
• Less than optimal materials.

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Unique Biomaterials?

• Few new candidate materials waiting for adoption.
• Medical-legal environment argues for unique
  biomaterials.
• Tissue Engineering Efforts.

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Biologic Safety

• ASTM F 981-87 Standard Practice for Assessment
  of Compatibility of Biomaterials
• Tripartite Biocompatibility Guidance

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Animal Functional Tests

• In use simulation
• Safety
• Efficacy

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Clinical Studies

• Initial Studies, Short term safety
• Clinical Protocol
• Prospective, Controlled, Randomized
• Multi-Center
• Assess mid-term safety and efficacy
• Marketing Application
• Long term follow-up (post-market?)

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Regulatory Primer

• Device Law passed in 1976.
• Methods to introduce new medical devices
• Investigational Device Exemption Application
• Clinical trials
• Premarket Approval Application.
• or
• 510(k), substantial equivalency application.

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Device Retrieval Analysis (DRA)

• Devices that fail in service are not routinely
  analyzed
• Studies address device in absence of clinical
  data
• Clinical studies focus on patient, ignoring
  device issues

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DRA (Continued)

• Knowledge from small, non-random sampling.
• Need to study 10 of devices that fail.
• Greater need to study 90 that do not fail!

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Sample Cases

• Manufacturing flaw
• Excess blast material on a total knee replacement
• Manufacturing flaw
• large grain size in ceramic ball
• Design flaw
• Inadequate stress analysis of hip acetabular
  component
• Manufacturing procedure flaw
• Residual machine oil on hip acetabular component

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DePuy LCS Knee

• Manufacturing flaw
• Excess blast material on a total knee replacement

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DePuy LCS KneePolyethylene Tibial Insert
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DePuy LCS KneeTitanium Alloy Tibial Component
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DePuy LCS KneeTitanium Alloy Tibial Component
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DePuy LCS KneeTitanium Alloy Tibial Component
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DePuy LCS KneeCobalt Chrome Femoral Component
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DePuy LCS KneeCobalt Chrome Femoral Component
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Feldmuhle Ceramic Hip Ball

• Manufacturing flaw
• large grain size in ceramic ball

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Feldmuhle Ceramic Hip Ball
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Feldmuhle Ceramic Hip Ball
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Feldmuhle Ceramic Hip Ball
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Feldmuhle Ceramic Hip Ball
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Feldmuhle Ceramic Hip Ball
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DePuy ACS Cup

• Design flaw
• Inadequate stress analysis of hip acetabular
  component

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DePuy ACS CupPolyethylene Insert
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DePuy ACS CupPolyethylene Fragments
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DePuy ACS CupTitanium Alloy Shell
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DePuy ACS CupCobalt Chrome Head
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Sulzer Acetabular Component

• Manufacturing procedure flaw
• Residual machine oil on hip acetabular component

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Ethical Concerns

• Professional Status
• Professional status creates special obligations
  to use one's specialized skill and knowledge to
  promote significant social values (e.g., health),
  to protect the interests of those (clients) who
  will use the products you design and build, and
  to be a loyal employee.

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Professional Obligations

• Professional obligations take many forms,
  including
• a. using care in design to make sure that devices
  are safe and effective (promoting health)
• b. protecting consumer autonomy, the right to
  make informed choices about health problems
• c. promoting and protecting your employer's
  legitimate interests.

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One of the vexing problems of professional ethics
is that these areas of obligation are often in
conflict, requiring ethical judgment about how
best to balance these conflicting demands!
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Sample cases

• Bjork-Shiley artificial heart valve
• Silicone Gel-filled breast implants
• Pedicle Screw Spinal Fixation
• DePuy ACS Acetabular Cup
• Effect of Radiation Sterilization
• Guidant Heart Defibrillator

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Bjork-Shiley artificial heart valve

• unexpected defects in the welding of the valve
  led to catastrophic failure in a small percentage
  of them
• about 2/3 of those experiencing valve failure
  will die
• Shiley failed to warn patients, who were then
  unable to make informed decisions about their
  possibly defective heart valves
• there is evidence of poor manufacturing
  techniques at Shiley what were the obligations
  of those who were aware of them?

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Bjork-Shiley Valve (continued)

• Who should inform patients of possible defects?
  The patient's physician? The manufacturer? The
  Food and Drug Administration
• What should patients be told? Only scientifically
  valid and reliable research? Reports of poor
  manufacturing techniques?
• What if bioengineers are aware of a defective
  design or poor manufacturing techniques but the
  company is not responsive the their concerns?
• What policies should guide these issues
  concerning medical devices and the patients who
  receive them?

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Silicone Gel Breast Implant
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Silicone Gel Breast Implant
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Silicone Gel Breast Implant
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Silicone Gel Breast Implant
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Silicone Gel-filled Breast Implants

• First introduced in 1964.
• Grandfathered as pre-1976 device - 510(k)
  allowance.
• FDA advisory panel recommended IDE - PMA study in
  1978 because of safety concerns (bleed, rupture,
  inflammation, capsular contracture,
  calcification, autoimmune disease).
• Plastic surgery lobby with aid of Ronald and
  Nancy Reagen prevented clinical review!
• Law suits started in 1984. Reached level of 10s
  of thousands of cases by early 1990s.

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Breast Implant (continued)

• Device removed from market because of safety
  concerns in 1992.
• To escape enormous legal liability, Dow Corning
  declared Chapter 11 bankruptcy in 1995.
• Law suits against Baxter, Bristol Meyer Squibb,
  3M and Dow Corning are now settling with an
  estimated total cost of 5 billion dollars.
• Who is at fault? manufacturers, their employees,
  FDA, plaintiff lawyers, surgeons?

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Silicone Gel-filled Breast Implants

• Inamed Corporation and Mentor Corporation have
  done new 4 year clinical trial.
• More than 300,000 women received breast implants
  last year.
• FDA advisory panel recommended approval in
  October 2003 and April 2005 in spite of no good
  long term study.
• Rationale was comparison to saline filled
  implants and economic infeasibility of requiring
  decade long study.

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Pedicle Screw Spinal Fixation
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Pedicle Screw Spinal Fixation

• Adjunct to spinal fusion surgery.
• Old hook and rod systems did not provide rigid
  fixation and required multiple level fixation.
• Pedicle screw fixation, developed in Europe,
  could be used in single spinal unit (one level)
  or more and provided more rigid fixation. It was
  hypothesized that this would result in higher
  fusion rate.
• Application to FDA for 510(k) allowance denied
  for lumbar pedicle fixation because of concerns
  of nerve damage, broken hardware, clinical
  efficacy.
• FDA required IDE-PMA studies. These studies were
  started, but never concluded.
• Manufacturers applied for 510(k) allowance for
  sacral, long bone or anterior screw fixation a
  pre-1976 application. This was allowed by FDA.

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Pedicle Screws (continued)

• Using the argument that the FDA does not regulate
  the practice of medicine, manufacturers
  encouraged surgeons to use devices for posterior
  lumbar fixation, a non approved application.
  This was done. It became standard practice in
  USA.
• Injured patient sued manufacturers, surgeons and
  hospitals claiming the improper promotion and use
  of an unproven, unsafe product.
• 10s of thousands of lawsuits resulted against
  Smith Nephew Richards, Danek Medical, Acromed,
  and a number of smaller companies.

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Pedicle Screws (continued)

• At one time, Danek alone was spending a million
  dollars a week pursuing the defense of
  outstanding lawsuits.
• Acromed settled globally and others are both
  litigating and settling cases. Total cost of
  this litigation will probably be 2 billion
  dollars.
• Who is at fault? FDA, manufacturers, their
  employees, surgeons, hospitals, the law, lawyers?

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DePuy ACS Acetabular Cup

• This is a hip acetabular component where the
  polyethylene insert was designed with a thin lip
  that tended to be over-stressed and fractured in
  some sizes.
• The device was designed by a novice engineer who
  had been a draftsman for the manufacturer and had
  recently earned his BS degree. He had no
  biomedical engineering or biology training and
  was unfamiliar with the research literature on
  the appropriate design characteristics of an
  acetabular insert.
• The acetabular shell was porous coated for bone
  attachment without cement an IDE-PMA product.
  However, the manufacturer applied for, and
  obtained, 510(k) allowance for cemented use a
  pre-1976 application. Consequently, the device
  was never subjected to rigorous clinical testing.

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ACS Cup (continued)

• As failures started to occur (typically 25 have
  failed within four years) the manufacturer
  embarked upon a crash redesign project hoping to
  phase out the old product and phase in the new
  product without publically admitting the
  defective design. However, pressure from
  surgeons using the product prompted a recall
  before the switch was accomplished.
• A letter was written to selected surgeons and
  distributors announcing the recall. However, a
  number of patients were implanted with the
  product during the phase-out, phase-in period and
  even after the recall because of its incomplete
  notification. Additionally, patients with early
  stage failures were not promptly diagnosed
  because of incomplete notification to orthopaedic
  surgeons. Should all implanted patients have
  been informed?

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ACS Cup (continued)

• Thousands of lawsuits resulted, some seeking
  punitive damages for callous disregard by the
  manufacturer of the dangers inherent in this
  product after they were fully aware of the
  problems. To date, all suits have been settled
  out of court.
• Who is to blame? manufacturer, design engineer,
  his supervisors, employees who became aware of
  the problem, surgeons for using an unproven
  product, FDA for allowing the use of an unproven
  product, the law, the hospitals for allowing
  surgeons to use an unproven product, lawyers?

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Effect of Radiation Sterilization

• Radiation in air embrittles polymers.
• This has been known since 1950s.
• Polyethylene components radiated in air.
• Are manufacturers responsible for early implant
  failures from poly damage?

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Guidant Heart Defibrillators

• Ventak Prizm 2 DR and Contak Renewal.
• 28,900 implanted.
• February 2005 - failed at 1/month.
• March to May 2005 - 2 deaths.
• Circuit flaw found, but sold for months after.
• June 2005 - recalled after 45 reported failures.
• JJ to purchase at 76/share.
• November 2005 -Deal renegotiated to 63/share.

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Issues for Discussion

• What can be done to prevent the introduction of
  potentially dangerous products yet not completely
  stop innovation?
• Can FDA be better insulated from political
  pressure?
• Should we change the law? (Tort Reform)
• What is the professional responsibility of the
  employee?
• How do we protect the employee from retribution
  when problems are reported?

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Issues for Discussion

• Should the FDA regulate the practice of medicine?
• Biomaterials Access Assurance Act of 1998.
  Federal pre-emption of state law.
• Weigh decreased cost for manufacturers vs
  protection for patients
• Punitive damages
• Payment by insurance companies for experimental
  procedures
• Long wait for FDA approvals

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Issues for Discussion

• Effect of managed care on innovation
• Competitiveness of the US medical device industry