Medical Device Evaluation and Validation Harold Alexander, Ph.D.

Orthogen Corporation Springfield, NJ [email protected]

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

• 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.

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.

Unique Biomaterials?

• Few new candidate materials waiting for adoption.

• Medical-legal environment argues for unique biomaterials.

• Tissue Engineering Efforts.

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

Animal Functional Tests • In use simulation • Safety • Efficacy

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?)

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.

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

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!

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

DePuy LCS Knee • Manufacturing flaw – Excess blast material on a total knee replacement

DePuy LCS Knee Polyethylene Tibial Insert

DePuy LCS Knee Titanium Alloy Tibial Component

DePuy LCS Knee Titanium Alloy Tibial Component

DePuy LCS Knee Titanium Alloy Tibial Component

DePuy LCS Knee Cobalt Chrome Femoral Component

DePuy LCS Knee Cobalt Chrome Femoral Component

Feldmuhle Ceramic Hip Ball • Manufacturing flaw – large grain size in ceramic ball

Feldmuhle Ceramic Hip Ball

Feldmuhle Ceramic Hip Ball

Feldmuhle Ceramic Hip Ball

Feldmuhle Ceramic Hip Ball

Feldmuhle Ceramic Hip Ball

DePuy ACS Cup • Design flaw – Inadequate stress analysis of hip acetabular component

DePuy ACS Cup Polyethylene Insert

DePuy ACS Cup Polyethylene Fragments

DePuy ACS Cup Titanium Alloy Shell

DePuy ACS Cup Cobalt Chrome Head

Sulzer Acetabular Component • Manufacturing procedure flaw – Residual machine oil on hip acetabular component

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.

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 .

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!

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

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?;

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?

Silicone Gel Breast Implant

Silicone Gel Breast Implant

Silicone Gel Breast Implant

Silicone Gel Breast Implant

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.

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?

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.

Pedicle Screw Spinal Fixation

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.

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.

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?

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.

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?

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?

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?

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.

• J&J to purchase at $76/share.

• November 2005 -Deal renegotiated to $63/share.

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?

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

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