Metal on Metal Joint Replacement

8/6/2019 Metal on Metal Joint Replacement

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Total Hip Arthroplasty: The Defects, the FDA and how Patients

are HarmedViles & Beckman, LLC

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Katie Korgaokar of Denver is a living example of one of the most common, effective andsometimes, problematic surgical inventions of the 20th century the hip replacement. Acongenital condition, Perthes disease, had prematurely deteriorated the bones in her hipjoint, compelling Korgaokar to seek a total hip replacement.1

The initial hip replacement surgery was a huge success, she testified to the SenateCommittee on Aging. Within three months of the surgery, I was essentially pain free andwas able to engage in activities that had previously been off limits. The surgery trulychanged my life.2

Her surgeon told her that her new, Metal-on-Metal DePuy hip device would last 20 years.Instead, Korgaokar found herself back on the operating table just four years later. Herstate-of-the-art hip had been recalled, and blood tests showed that metal wear particlesfrom the hip had elevated the level of cobalt and chromium in her bloods stream by 1,000percent above normal levels. Her revision surgery was more troublesome, and in April2011, when she testified during a hearing on the U.S. Food and Drug Administrationregulation and oversight of medical devices, she was still in pain and only recovering hermobility slowly.3

Orthopedic surgeons have been performing hip replacement and hip resurfacing

operations for nearly a century. Each year, about 300,000 patients in the U.S. undergo hiparthroplasty, and many consider this procedure to be the major success story inorthopedic surgery in the twentieth century.4 But hip implants have their failures. All hipimplants are plagued by the problem of wearing away of the components caused byfriction. Even normal wear can cause the implant to loosen and release microscopicparticles into the patients body that have a multitude of short-term and long-rangeadverse effects. The patient experiences these problems as pain, diminished movementand another trip to the orthopedic surgeon for a second hip replacement surgery.Excessive wear, created by designs that do not tolerate even a slight misalignment whenimplanted speeds up and multiplies the damage to the patients health.

1 Testimony of Katherine Korgaokar; A Delicate Balance: FDA and the Reform of the Medical Device ApprovalProcess; Senate Committee on Aging; April 13, 20112 Testimony of Katherine Korgaokar; A Delicate Balance: FDA and the Reform of the Medical Device ApprovalProcess; Senate Committee on Aging; April 13, 20113 Testimony of Katherine Korgaokar; A Delicate Balance: FDA and the Reform of the Medical Device ApprovalProcess; Senate Committee on Aging; April 13, 20114 A Comparative Joint Simulator Study Of The Wear Of Metal-on-Metal And Alternative Material Combinations. InHip Replacements; A A J Goldsmith; D Dowson; G H Isaac; J G Lancaster; Proceedings Institution of MechanicalEngineers; Vol 214 Part H; 1999


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A recent return to Metal-on-Metal (MoM) hip replacement devices, after decades ofexperimentation with other materials, has brought about a fresh wave of adverse effectsnecessitating revision surgeries. Microscopic metal particles released from the metalcomponents as a result of friction and wear can raise cobalt and chromium levels in thebloodstream, damage and destroy surrounding tissue and can be genotoxic to patients.

In 2010, surgeons performed 50,000 revisions meaning a surgery to replace an old,defective or non-functioning hip implant accounting for 16.5 percent of hipreplacements each year.5 In the case of defective implants, many of the defects arentdiscovered until well after the device has been in use and implanted in hundreds ofpatients. Although medical devices have been regulated by the U.S. Food and DrugAdministration since 1976, manufacturers have taken advantage of rules streamlining theapproval process to bring bad designs and material combinations into the marketplacewith no clinical testing or proof of efficacy.

Since 2008, three defective hip replacement devices have been recalled, afterimplantation in some 100,000 patients in the U.S.: Since 2008, two manufacturers,DePuy Orthopaedics and Zimmer, have suspended sales of three different MoM devices,after doctors reported high failure rates. The DePuy ASR XL Acetabular System andDePuy ASR Hip Resurfacing System and the Zimmer Durom had been implanted insome 100,000 patients before sales were suspended. And the complaints to the FDAcontinue. In 2011, there were thousands complaints. Since 2005, the patients andsurgeons have lodged more than 800 complaints involving an unrecalled Metal-on-Metaldevice, the DePuy Pinnacle System. From 2008 to 2010, those complaints quadrupled.These reports are not surprising given that DePuy sought FDA approval for the recalledASR system by claiming that its design was substantially similar to the Pinnacle Metal-on-Metal components.

Last year, the FDA began to address the longstanding complaints of consumers, themedical community and Government Accounting Office investigators that the approvalprocess for implantable devices was too lax. But, the FDAs failure to act on the PinnacleMetal-on-Metal system means that the agency still has a way to go. Meanwhile, recentstudies show that the rate of recalls for medical devices that could cause serious injuryand death is much higher for those that were made available for sale through an expeditedFDA review.

Total Hip Arthroplasty Overview

Today two reconstructive procedures performed everyday, worldwide: Total HipArthroplasty (THA) and Hip Resurfacing Arthroplasty (RSA). Developed in the 1920s,RSA involves replacing only the damaged bearing surfaces of the hip joint, rather thanthe entire femoral head.6 Total Hip Arthroplasty, a newer iteration of hip replacement

5 Orthopedic Surgery Advances; Ron Stoker; Infection Prevention in the OR; HealthVIE.com; January 20116 Current Concepts on Metal on Metal Resurfacing; Ian C. Clarke, et al; Orthopedic Clinics of North America; 2005


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surgery, has been performed since 1956.7Current Total Hip Replacements consist ofthree basic components:

The acetabular cup is typically made of metal and can have a liner made ofpolyethylene, ceramic or metal

The ball, which replaces the head of the femur, is typically made of cobaltchromium (CoCr) alloys, stainless steel or ceramic materials (aluminium oxide orzirconium oxide)

The stem, which fits into the femur, is typically made of titanium alloy(Ti6Al4V), CoCr, or stainless steel.

Orthopaedic device manufacturers have been working with hip implants for almost ahundred years. Some have been robust lasting for more than 10 years in patients, butothers have had much shorter life spans than advertised and present serious adverseaffects to patients. The key to a THAs long-term success is the robustness of the bearingsurface: the femoral head and its interaction with the acetabular lining and the anatomical

functionality after implantation. In general, there are four device options for the bearingsurface in total hip replacement:

Hard-on-Soft Combinations:

Metal-on-Polyethylene (MoPE): ball is made of metal and the acetabular lineris polyethylene

Ceramic-on-Polyethylene (CoPE): ball is made of ceramic and the acetabularliner is polyethylene

Hard-on-Hard Combinations

Metal-on-Metal (MoM): The ball and acetabular liner are both made of metal. Ceramic-on-Ceramic (CoCr): The ball and the acetabular liner are both made

of ceramic.

Metal-on-Metal Hip Replacements

In modern Metal-on-Metal hip implants, the bearing surfaces the femoral head andacetabular cup liner are made of cobalt and chromium, which offer high wear resistanceand less debris as measured by volume than metal-on-polyethylene implants. Thesealloys are extremely hard, resistant to corrosion and can be machined to a smooth surface.They are self-polishing, so small defects tend to smooth out over time. The very first

iterations of total hip replacements were Metal-on-Metal designs.

Contemporary Metal-on-Metal hip replacements in the marketplace today include:

ASR XL (DePuy)

Pinnacle Hip System with the Ultamet Liner (DePuy)

7 Current Concepts on Metal on Metal Resurfacing; Ian C. Clarke, et al; Orthopedic Clinics of North America; 2005


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Metasul LDH (Zimmer) M2aMagnum (Biomet) Conserve (Wright Medical) Lubrimet (Smith and Nephew) Durom (Zimmer)

Manufacturers and surgeons have promoted Metal-on-Metal hip implant systems foryounger and physically active patients because the metal is more durable thanpolyethylene and produces less wear debris, as measured by volume. The componentwhich confers the benefits of a Metal-on-Metal implant is the large femoral head, whichcan be used because less room is taken up by the acetabular liner. The large-diameterfemoral heads reduce the risk of dislocation, increase the range of motion, decrease therisk of impingement and reduce wear production. Surgeons and manufacturers havepostulated that this type of bearing is good for patients who will demand more functionfrom the implant, patients at risk for dislocation and younger patients who require animplant that will last longer.

Manufacturers, or researchers sponsored by hip implant manufacturers, have publishedliterature espousing those potential benefits. For example, DePuy Orthopaedics, aWarsaw, Indiana manufacturer makes these claims in a number of brochures. InHighStability, Low Wear Metal-on-Metal Bearings: Benefits, Risks and Alternatives, themanufacturer cites: large diameter bearings have greater stability and, when properlypositioned the wear rate has been documented to be very low in vivo for three decades.8A DePuyBenefits of Metal on Metalbrochure advertises: durability, strength andfracture resistance; resistance to wear; increased range of motion and maximized jumpdistance and stability.9

Mechanical simulation studies have supported manufacturers contention that MoMimplants are effective.1011 These types of studies are conducted under tightly-controlledlaboratory conditions with the implant in the precisely proper orientation. A hip jointsimulator is a machine that moves the femoral component forward and back, or side toside to side movement that simulates walking, running, jumping and other human hipfunctions. A series of simulator studies in 1999 generally showed the Metal-on-Metalimplants produced less wear, as measured by volume, than metal-on-polyethylenedesigns. One compared the friction, lubrication and wear performance of Metal-on-Metalsystems to metal-on polyethylene systems. This study, and others, found that the MoMbearings generated 100 times less wear debris, by volume, than the metal-on-polyethylene systems.12 However, metal particles are much smaller than polyethyleneparticles. The numberof metal particles was 1,000 times greater than those generated by

8 Advancing High Stability and Low Wear; Brochure; DePuy Orthopaedics; 20089 Benefits of Metal On Metal; Brochure; DePuy Orthopaedics; 200810 Wear and Lubrication of Metal-on-Metal Hip Implants; Frank W. Chan, PhD; J.Dennis Bobyn, PhD.; John B.Medley, PhD; Jan J. Krygier, CET and Michael Tanzer, MD; Clinical Orthopaedics and Related Research, 199911 A comparative joint simulator study of the wear of Metal-on-Metal and alternative material combinations in hipreplacements; A.A.J. Goldsmith; D. Dowson; G.H. Isaac and J.G. Lancaster; Proc Instn Mech Engrs, 199912 Metal-on-Metal bearing in hip prosthesis generates 100-fold less wear debris than metalon-polyethylene; H. LucasAnissian; Andre Stark; Allen Gustafson; Victoria Good and Ian C Clarke; Acta Orthop Scand, 1999


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a polyethylene bearing even though the total wear, as measured by volume, was lower.1314

Some randomized clinical trials comparing conventional metal-on-polyethylene total hipreplacements to Metal-on-Metal implants have also demonstrated favorable short to

medium-term results for the MoM.

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Long-term retrospective observations ofpatients with Metal-on-Metal implants have also demonstrated long-term survivorshipand good mechanical performance.

The U.S. Food and Drug Administration estimates that the Metal-on-Metal devicesurvival-range for non-defective, properly implanted devices at 95.5 percent at twelveyears to 93 percent at ten years.19 However, their effectiveness has been highly over-ratedin the literature and by FDA. Even with superior laboratory wear rates, retrieval studiesdocumenting midterm revision rates do not show that second generation MoM systemslast longer than metal-on-polyethylene hip implants.

From 2008 to 2010, the Australian National Joint Registry, which reports the effect of thebearing surface on the early to mid-term outcomes for primary conventional total hipreplacement, has found that the bearing surface with the highest revision rate is Metal-on-Metal.20 Revision rates for Metal-on-Metal systems are statistically worse than metal-on-polyethylene systems for all sized heads. The Australian joint registry data show thatpolyethylene bearing surfaces had the lowest risk of revision compared to all bearingsurface types.21

In March 2011, the British Orthopaedic Association announced at the British Hip SocietyAnnual Conference that large diameter MoM bearing devices show a higher thananticipated early failure rate ranging from 21percent revision rate at 4 years to 12-15percent at 5 years. The association reported that the DePuy ASR XL had 49 percentrevision rate at 6 years.

Toxicity and Metal-on-Metal Bearings

13 Quantitative analysis of wear debris from Mom Hip prostheses tested in a physiological hip joint simulator. Firkins.et al, Proceedings of the 45th Annual Meeting of the ORS, 199914 Quantitative analysis of the wear and wear debris from low and high carbon content cobalt chrome alloys used inMoM THR. Tipper, et al. J Mater SciMater Med, 199915 The Clinical Performance of Metal on Metal as an Articulation Surface in Total Hip Replacement, Long; The Iowa

Orthopaedic Journal, 200516 Cementless Metal-on-Metal Hip Arthroplasty in Patients Less Than 50 Years of Age; H. Migaud, A. Jobin, C.Chantelot, F. Giraud, P. Laffargue, A. Duquennoy; The Journal of Arthroplasty, 200417 Metal-on-Metal Versus Metal-on-Polyethylene Bearings in Total Hip Arthroplasty; D. Naudie, C. P. Roeder, J.Parvizi, D. J. Berry, S. Eggli, A. Busato. The Journal of Arthroplasty, 200418 Three- to Six-Year Results With the Ultima Metal-on-Metal Hip Articulation for Primary Total Hip Arthroplasty;Michael Jacobs, Robert Gorab, David Mattingly, Lorence Trick, Carleton Southworth. The Journal of Arthroplasty,200419 www.fda.gov20 Australian National Joint Registry Annual Reports 2008, 2009, 201021 Australian National Joint Registry Annual Reports 2008, 2009, 2010


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Besides the wear problem, Metal-on-Metal bearings pose a significant health risk topatients even when they are properly implanted and non-defective. In contemporaryMetal-on-Metal hip joint bearings, tiny metal debris particles can be shed from thefemoral head and acetabular cup surfaces and spread through the body and thebloodstream in the form of metal cobalt and chromium ions. While the metallic ions can

be dissolved in the body fluid and eliminated from the patient's body, (polyethylene wearparticles cannot) some patients have developed a range of adverse reactions.22

Metallosis, also known as Adverse Local Tissue Reaction, has been defined by Dr.Schmalzried, who helped develop the DePuy Pinnacle Systems, as Biologic reactivity tometal particles and the presently unknown long-term effects of exposure to cobalt andchromium ions released from MoM articulating surfaces.2324 They are catch-all terms todescribe adverse reactions, which can range from effects in the immediate vicinity of theimplant to those that affect the entire body.

Metal reactivity, from high wear, causes a foreign-body (macrophage) inflammatory

response to excessive metal particles. Metal reactivity can impact the entire body. Metalsensitivity is an allergic response that can occur from normal or high wear. Typically,patients experience extreme pain due to the production of cloudy fluid, expanded andulcerated joint capsule usually encased in fibrous tissue.

Whether caused by reactivity or sensitivity, the metal particles around the implants cancause serious damage to bone and/or tissue surrounding the implant and joint,including:

Necrotic (dead) tissue mass or pseudo-tumor

Fluid in the joint

Osteolysis

Tissue and bone necrosis (bone death) Hypersensitivity to metal

Adverse reactions that affect the entire body include:

Decreased total lymphocyte, which defends against tumors and virally infectedcells

Decreased CD8+T cells, which fight intracellular pathogens and malignancies

DNA changes

Chromosomal aberrations

Long-term toxicity of MoM is unknown, but doctors have expressed concerns about theexposure to high levels of cobalt and chromium ions and there are numerous reportsshowing significant affects on organs away from the articulation. There are isolated case

22 Long-duration MoM THA with low wear of the articulating surfaces. Thomas P. Schmalzried, Paul C. Peters, BrianT. Maurer, Charles R. Bragdon, William H. Harris. J Arthroplasty, 199623 Complications After Metal-on-Metal Hip Resurfacing Arthroplasty; Harlan C. Amstutz; Michel J. Le Duff; PatriciaA. Campbell; Lauren E. Wisk and Karren M. Takamura, Orthopedic Clinics of North America, 201024 Metal-Metal Bearing Surfaces in Hip Arthroplasty. Schmalzried. Orthopedics 2009.


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reports on a small number of patients in which high levels of metal ions in thebloodstream may have caused other types of symptoms or illnesses elsewhere in thebody, including effects on the heart, nervous system, and thyroid gland.

For example, a study published in 2010 documented two cases in which the patient

developed cobaltism in reaction to the metal wear particles generated from a hiparthroplasty, shortly after implantation. The normal cobalt level in the bloodstream is0.19 micrograms per liter. Any level above 1 microgram per liter indicates excessivecobalt exposure. Levels greater than 5 micrograms per liter are considered toxic.25 Inthese cases, one patient had 122 microns/liter after 36 months; the cobalt level in theother patients blood was 23 microns/liter after one year. In excess, cobalt blocks cellularmetabolism and can damage multiple organs. Cobaltism can cause tinnitus, vertigo,deafness, blindness, optic nerve atrophy, convulsions, headaches, peripheral neuropathy,cardiomyopathy, hypothyroidism.26 27 In these patients, high cobalt levels causedreactions to metal debris beyond the tissues surrounding the hip prosthesis.28

In a 2010 report, Britains Medicines and Healthcare products Regulatory Agency(MHRA) Committee on Mutagenicity of Chemicals in Food, Consumer Products and theEnvironment concluded that there was good evidence for an association between hipimplants with metal components and increased genotoxicity in patients.29 Specifically,the committee found evidence of genetic damage in patients with certain metal hipimplants.

Design and Surgical Technique

Design and surgical technique are keys to both the short term and long term success ofhip joint replacements. As clearly demonstrated above, particulate material produced byimplant surface wear is the demon, causing both early failures and long termcomplications. In hip replacement designs, proper orientation and fixation of the femoraland acetabular components are the most important concepts to minimize wear of thedevices. Component orientation becomes even more important with hard-on-hardbearings such as MoM and CoC, much more critical than with MoPE bearings.

In certain designs, such as DePuys ASR and Pinnacle Systems (as well as ZimmersDurom Cup and Smith and Nephews BHR), acetabular cup orientation slightly out of theoptimum range has catastrophic results. While other designs are much more forgiving toalignment issues commonly seen in surgery, DePuys ASR and Pinnacle Systems exhibit

25 Mayo Medical Laboratories interpretive handbook: interpretive data for diagnostic laboratory tests. Rochester, NM:The Laboratories, Leavelle, Ed. 200126 Arthroprosthetic cobaltism: identification of the at-risk patient. Tower, et al., Alaska Medicine, 201027 Trace Metals in the environment. V6: Cobalt. An appraisal of environmental exposure. Smith, et al. Ann Arbor,MI: Ann Arbor Science, 198128 Arthroprosthetic Cobaltism: Neurological and Cardiac Manifestations in Two Patients with Metal-on-MetalArthroplasty; Stephen S. Tower, MD; JBJS Am 201029 2010 MHRA COM Report


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extreme wear under these circumstances that will result in catastrophic failure andextreme danger to the patient.

In these designs, extremely high wear rates result from slight increases in abductionangle, smaller femoral head size and large diametrical clearance. This is exaggerated in

designs such as the ASR and Pinnacle Systems with a low femoral head coverage angle.

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31323334353637383940414243 Implant designs vary in the amount of hemisphericalcoverage of the femoral head provided by the acetabular cup liner usually ranging from165-180 degrees.444546

In these suboptimal designs, the most important preventative measure to take in order tominimize wear is to know the design characteristics and limitations of the componentsand orient the components in an optimal position for these limitations.47 Someresearchers argue that suboptimal acetabular cup placement is preventable with surgeontraining.48 However, if a product repeatedly fails due to slight variations in implantationorientations, the problem is with the design, not the surgeon and re-engineering the

design is necessary.

30 Early failure of MoM bearings in hip resurfacing and large-diameter THR: a consequence of excess wear. Langton,et al. JBJS Br, 201031 Characterization of the running-in period in THRA: an in vivo and in vitro metal ion analysis. Heisel, et al. JBJSAm, 200832 Cup inclination angle of greater than 50 degrees increases whole blood concentrations of cobalt and chromium ionsafter MoM hip resurfacing. Hart, et al. Hip Int, 200833 A hip joint simulator study of the performance of MoM joints. Part II Design. Dowson, et al. J Arthroplasty 200434 Influence of the clearance on in-vitro tribology of large diameter MoM articulations pertaining to resurfacing hipimplants. Rieker, et al. Orthop Clin NA, 200535 Early clinical failure of the Birmingham MoM hip resurfacing is associated with metallosis and soft-tissue necrosis.

Ollivere, et al. JBJS Br, 200936 Correlation between inclination of the acetabular component and metal ion levels in MoM hip resurfacingreplacement. De Haan, et al. JBJS Br, 200837 The effect of component size and orientation on the concentrations of metal ions after resurfacing arthroplasty of thehip. Langton, et al. JBJS Br, 200838 Chromium and Cobalt ion release following the Durom high carbon content, forged MoM surface replacement of thehip. Vendittoli,et al. JBJS Br,. 200739 Clinical and radiographic results of MoM hip resurfacing with minimum ten year follow up. Amstutz, et al. JBJSAm, 201040 Complications After Metal-on-Metal Hip Resurfacing Arthroplasty. Harlan C. Amstutz; Michel J. Le Duff; PatriciaA. Campbell; Lauren E. Wisk and Karren M. Takamura. Orthopedic Clinics of North America, 201141 Tribological analysis of failed resurfacing hip prostheses and comparison with clinical data. T.J Joyce; D.J. Langton;S.S. Jameson and A.V.F Nargo. Proc. IMechE, 2009.42 The effect of component size and orientation on the concentrations of metal ions after resurfacing arthroplasty of thehip. D.J. Langton; S.S. Jameson; T.J. Joyce; J. Webb and A.V.F. Journal of Bone and Joint Surgery, 2008

43 Ceramic-On Metal Bearings In Total Hip Replacement. Isaac, Brockett, Breckon, van der Jagt, Williams, Hardaker,Fisher, Schepers. JBJS Br, 2009.44 Complications After Metal-on-Metal Hip Resurfacing Arthroplasty. Harlan C. Amstutz; Michel J. Le Duff; PatriciaA. Campbell; Lauren E. Wisk and Karren M. Takamura. Orthopedic Clinics of North America, 201145 Correlation between inclination of the acetabular component and metal ion levels in MoM hip resurfacingreplacement. De Haan, et al. JBJS Br 2008; 90(10):129146 Risk factors for inflammatory pseudotumour formation following hip resurfacing. Glyn-Jones, JBJS Br2009;91(12):156647 Complications After Metal-on-Metal Hip Resurfacing Arthroplasty. Harlan C. Amstutz; Michel J. Le Duff; PatriciaA. Campbell; Lauren E. Wisk and Karren M. Takamura. Orthopedic Clinics of North America, 2011.48 Hip Resurfacing arthroplasty. Mont, et. al., J Am Acad Orhtop Surg 2006; 14:454.


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Rather than correct the problems with its designs, DePuy for example, attempts to put theonus on surgeons. Its product literature stresses the importance of proper acetabular cupplacement for its Pinnacle MoM systems. Specifically, the company emphasizes thatacetabular cup abduction greater than 55 degrees and/or excessive combined anteversionpredisposes to edge loading and dangerously high wear rates.4950 Despite this warning,

clinical and simulation studies of DePuy MoM hip implants and studies funded by DePuydocument high wear rates and high patient ion levels associated with acetabular cupinclination angles greater than 50 degrees and anteversion angles greater than 29 degreesin MoM bearing surfaces. 5152535455565758596061626364 This suggests that the designis too unforgiving of slight misalignment either from initial placement or expectedmigration within the joint space unlike other devices, which allow greater tolerance forthe position of the component.

The Data

Complaints

It is very difficult to determine the success or failure rates of a particular hip arthroplastydevice. Unlike Britain or Australia, the U.S. government does not sponsor a joint registry,in which surgeons and hospitals submit data on primary surgeries and revisions. In 2007,

49 DO_Advancing_High_Stability_and_Low_Wear_Brochure_0612-17-508r150 Benefits of Metal On Metal. DuPuy Brochure51 High Cup Angle and Microseparation Increase the Wear of Hip Surface Replacements. Ian J. Leslie PhD; SophieWilliams PhD; Graham Isaac PhD; Eileen Ingham PhD and John Fisher PhD. Clin Orthop Relat Res, 2009.52

Tribological analysis of failed resurfacing hip prostheses and comparison with clinical data. T.J Joyce; D.J. Langton;S.S. Jameson and A.V.F Nargo. Proc. IMechE Vol. 223 Part J: J. Engineering Tribology, 2009.53 Early failure of MoM bearings in hip resurfacing and large-diameter THR: a consequence of excess wear. Langton,et al. JBJS Br 2010:92(1):3854 Characterization of the running-in period in THRA: an in vivo and in vitro metal ion analysis. Heisel, et al. JBJSAm 2008:90 (Suppl 3): 125.55 Cup inclination angle of greater than 50 degrees increases whole blood concentrations of cobalt and chromium ionsafter MoM hip resurfacing. Hart, et al. Hip Int 2008;18(3):212.56 A hip joint simulator study of the performance of MoM joints. Part II Design. Dowson, et al. J Arthroplasty 2004;19 (8 Suppl 3): 124-30.57 Influence of the clearance on in-vitro tribology of large diameter MoM articulations pertaining to resurfacing hipimplants. Rieker, et al. Orthop Clin NA 2005;36 (2):135.58 Correlation between inclination of the acetabular component and metal ion levels in MoM hip resurfacingreplacement. De Haan, et al. JBJS Br 2008;90(10):1291.59 The effect of component size and orientation on the concentrations of metal ions after resurfacing arthroplasty of the

hip. Langton, et al. JBJS Br. 2008;90(9):1143.60 Chromium and Cobalt ion release following the Durom high carbon content, forged MoM surface replacement of thehip. Vendittoli, et al. JBJS Br. 2007;89(4):441.61 Complications After Metal-on-Metal Hip Resurfacing Arthroplasty. Harlan C. Amstutz; Michel J. Le Duff; PatriciaA. Campbell; Lauren E. Wisk and Karren M. Takamura. Orthopedic Clinics of North America, 2011.62 Tribological analysis of failed resurfacing hip prostheses and comparison with clinical data. T.J Joyce; D.J. Langton;S.S. Jameson and A.V.F Nargo. Proc. IMechE Vol. 223 Part J: J. Engineering Tribology, 2009.63 The effect of component size and orientation on the concentrations of metal ions after resurfacing arthroplasty of thehip. D.J. Langton; S.S. Jameson; T.J. Joyce; J. Webb and A.V.F. Nargol. The Journal of Bone and Joint Surgery, 200864 Ceramic-On Metal Bearings In Total Hip Replacement. Isaac, Brockett, Breckon, van der Jagt, Williams, Hardaker,Fisher, Schepers. JBJS Br, 2009.


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health care conglomerate Kaiser Permanente launched its own National Total JointReplacement Registry (TJRR), a database designed as a postmarket surveillance systemfor elective total hip and knee replacement.65 The registry collects uniform data at thepoint of care regarding patient demographics, implant characteristics, surgical techniques,and clinical outcomes, in an effort to identify problems and best practices, contain costs

and improve care. More than 350 surgeons and 50 hospitals contribute to the database.(As of March 31, 2007, the TJRR recorded 16,945 primary total hip arthroplasties and2144 revisions 12.65 percent.)66

Publicly available information, however, is scant. For example, in August 2010, IowaSenator Charles E. Grassley asked Zimmer Holdings and DePuy Othopaedics to disclosehow they tracked the long-term performance of their devices, after reading aNew YorkTimes article which reported on the breakdown in relationships between consultingsurgeons and device manufacturers, when doctors report problems that go unheeded bytheir employers.67

The FDA does operate a web-accessible complaint database. Complaints related to hipprostheses get filed into the Manufacturer and User Facility Device Experience(MAUDE) database. MAUDE data consist of voluntary reports made to the FDA sinceJune 1993, user facility reports since 1991, distributor reports since 1993, andmanufacturer reports since August 1996.68 While MAUDE data are not intended to beused to evaluate rates of adverse events involving medical devices or to compare adverseevent occurrence between products, they are useful for tracking trends in defectsassociated with devices. Further, MAUDE represents the only government repository ofadverse event reports related to medical data.

When a hip device is recalled, the company, or other entities may disclose revision rates.

For a product that has been suspected of or alleged to have defects, MAUDE can shedsome light on complaint trends. For example, DePuy revealed higher than normalrevision rates for two DePuy Metal-on-Metal hip devices that the company recalled lastyear, the DePuy ASR XL Acetabular System and the DePuy ASR Hip ResurfacingSystem. In 2005, DePuy sought and was granted approval for the DePuy ASR ModularAcetabular Cup System by claiming that the design was substantially similar to the

65 The Kaiser Permanente National Joint Replacement Registry; web page;http://xnet.kp.org/permanentejournal/sum08/joint-replacement.html; accessed May 3,201166 The Kaiser Permanente National Joint Replacement Registry; web page;http://xnet.kp.org/permanentejournal/sum08/joint-replacement.html; accessed May 3,201167 Surgeon Vrs. Knee-Maker: Whos Rejecting Whom?; Barry Meier; The New YorkTimes; June 10, 2010.68 Manufacturer and User Facility Device Experience; U.S. Food and DrugAdministration; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm;accessed May 1, 2011


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DePuy Pinnacle Metal-on-Metal Acetabular CupLine.69 In January 2008, the companyagain sought and gained approval for another variation on the ASR metal acetabular cup,the DePuy ASRTM 300 Acetabular Cup System by claiming that the device wassubstantially similar to the DePuy Pinnacle Acetabular Cup System.70Despite thecompanys claims to the FDA that the metal acetabular cups in the ASR and Pinnacle hip

systems are substantially similar, DePuys Pinnacle hip replacement has not beenrecalled. In the meantime, a rising number of complaints about the Pinnacle Metal-on-Metal system continue to be lodged by patients and surgeons in the MAUDE system.

MAUDE data from 2005 to March 2011 were examined for reports of adverse eventsinvolving Pinnacle Metal-on-Metal systems. Records were identified using device codes,keywords, and brand and generic names; see Appendix A for a detailed explanation ofthat process. Adverse event reports have steadily increased since 2005; Table 1 providesa breakdown of the number of event reports by year.

Table 1. Adverse Report Events Reported in MAUDE by Year Involving DePuy

Pinnacle Systems

Calendar YearUnique

Reports2011 1192010 329

2009 148

2008 86

2007 38

2006 25

2005 15

Complaints have risen sharply since 2005 nearly quadrupling between 2008 and 2010.The narratives that accompany these adverse reports attest to the classic symptoms ofdefective Metal-on-Metal implants:

Patient was revised to address excessive cup ante-version resulting in dislocation. Metaldebris was found in the joint.71

Patient had to have revision hip replacement surgery to remove a Metal-on-Metal totalhip implant which had caused significant synovial inflammation and metallosis reaction.The implant was a DePuy pinnacle Metal-on-Metal hip replacement system -not therecalled asr system-. Dates of use: (b)(6) 2003 - (b)(6) 2010. Diagnosis or reason for use:

hip arthritis. Event abated after use: yes. This is to report a significant problem withcomplications due to Metal-on-Metal wear particles leading to a pt necessitating revisionhip surgery and removal of implants due to severe synovitis and perivascular lymphocyticinfiltrate, confirmed with tissue pathology. The relevance is that this is a different product

69 FDA K040627; 510K Summary; DePuy Orthopaedics; August 5, 200570 FDA K073413; 510K Summary; DePuy Orthopaedics; January 30, 200871 MAUDE Report 1836490


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within the same company -DePuy Orthopaedics- which has recently had a differentMetal-on-Metal hip implant recalled by the fda - the asr hip system-. This is to report aproblem with their Pinnacle Metal-on-Metal system. The common factor being the Metal-on-Metal bearing, leading to metal particulate release, and significant synovial reaction,and necessitating revision surgery and implant removal. Patients should be made aware

of the significant risk associated with this system.

72

They also aptly describe the effect on patients:

I had a left hip replacement (DePuy Pinnacle) on (b)(6) 2009 and ever since (b)(6) 2010I have had a problem which keeps getting worse. I have difficulty standing still for anylength of time. If I stand for 10 minutes shaving, I am in severe pain for the rest of theday. I can only sleep on my right side. I cannot sleep on my back or left side at allbecause the pain is too much. I cannot food shop, clothes shop or shop period because Icannot walk for any length of time. Unless my activity includes sitting such as themovies, out to dinner or the doctor's office, I cannot go out. The quality of my life has

deteriorated. I am in worse shape now then I was before I got my hip replaced.

73

Recalls

To date, two Metal-on-Metal total hip replacements and one Metal-on-Metal hipresurfacing system have been recalled in the U.S.: the DePuy ASR XL AcetabularSystem and DePuy ASR Hip Resurfacing System in 2010 and the Zimmer DuromAcetabular Component in 2008. But the problems regarding Metal-on-Metal hip implantsfirst surfaced in Great Britain several years earlier, when orthopaedic surgeons therealerted the regulatory authorities to the problems of metal wear debris.

DePuy ASR XL Acetabular System and DePuy ASR Hip Resurfacing System

Recalls

The roots of the DePuy recalls go back to September 2005, when the British OrthopaedicAssociation (BOA) contacted the Medicines and Healthcare products Regulatory Agency(MHRA) to express concerns about the ill-effects of metal-wear debris in MoM hipimplants. 74 Researchers had been documenting evidence that the MoM implants may begenotoxic to their hosts meaning that the microscopic shreds of chromium and titaniumreleased into the bloodstream was causing genetic damage. The MHRA presented thegenotoxicity issue to the Committee on the Safety of Devices (CSD), which, turned to the

Department of Healths independent expert advisory committee, the Committee on

72 MAUDE Report 193262773 MAUDE Report 193794374 Minutes of the Committee on the Safety of Devices Expert Advisory Group on metal wear debris from hip implants;Meeting minutes; October 23, 2006


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Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM) forfurther review.75

After discussing the possible biological and clinical effects produced by metal weardebris generated from hip implants, the COM concluded in July 2006 that there was

there was good evidence for an association between CoCr-on-CoCr and CoCr orTiAlVon- polyethylene hip replacement devices and increased genotoxicity in patients.76The COM was less certain about how that genetic damage might impact the health ofpatients particularly in the form of an increased risk of cancer. Based on the researchcurrent at the time, the COM asserted that it was not possible to make any definiteconclusions as to which metal ions, or interactions between metal ions or particulatemetals might be responsible for the observed genotoxicity.77 The MHRA seconded thosesentiments in a companion statement. Although there is currently no information tosuggest that the identified genotoxicity poses a significant health risk, this finding clearlyrequires further investigation. 78

The Committee on the Safety of Devices decided to set up an Expert Advisory Group,consisting of orthopaedic surgeons, pathologists, toxicologists, immunologists, materialscientists, manufacturers, a lay member of the CSD, and relevant MHRA members ofstaff to assess the clinical significance of the COM findings and to put these into a risk-benefit context. The Expert Advisory Group continued to meet, issuing a final report inMarch 2010.

In March 2010, DePuy Orthopaedics issued a Field Safety Notice after receiving newdata from the UK that demonstrated the ASR System had a higher than expectedrevision rate at 8-9 percent at three years when used with smaller head sizes (less than 50mm diameter).

On August 24, 2010, the Johnson & Johnson subsidiary, announced a voluntary recall ofthe DePuy ASR total hip system after unpublished data from the National JointRegistry of England and Wales indicated that the revision rate for that total hipreplacement system was 13 percent (one in eight patients) within five years ofimplantation and about 12 percent for its hip resurfacing system.79 The DePuy ASRHip Resurfacing System was only approved for use outside the U.S. and the ASR XLAcetabular System was available worldwide.80

75 Minutes of the Committee on the Safety of Devices Expert Advisory Group on metal wear debris from hip implants;Meeting minutes; October 23, 200676Statement On Biological Effects Of Wear Debris Generated From Metal On Metal Bearing Surfaces: Evidence ForGenotoxicity; Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment; July 200677 Statement On Biological Effects Of Wear Debris Generated From Metal On Metal Bearing Surfaces: Evidence ForGenotoxicity; Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment; July 200678 Biological Effects Of Metal Wear Debris Generated From Hip Implants: Genotoxicity; Medicines and Healthcare

products Regulatory Agency; July 200679 DePuy April 15, 201180 Large Diameter Metal on Metal Bearing Total Hip Replacements; Statement, John Hodgkinson; John Skinner; PeterKay; British Orthopaedic Association; March 9, 2011


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However, more recently, British surgeons have reported a much higher revision rate thannoted in the recalls. On March 9, British Orthopaedic Association, the British Hip Societyand the Expert Advisory Group on Metal Bearing Hips issued a statement on researchpresented at a professional conference showing a much higher early failure rate for theASR XL device. Four sets of unpublished data showed rates ranging from 21 percent

after four years, and potentially rising to 35 [percent] if all currently known painfulimplants progress to revision, to 49 percent after six years. The warning, issued by JohnHodgkinson, president of the British Hip Society, John Skinner Chair of the advisorygroup and Peter Kay,president British Orthopaedic Association, also noted that otherdevices have a revision or impending revision rate of 12 15 [percent] at 5 years. 81

British surgeons maintained that the potential failure points included the trunnion at theMorse taper where the large diameter Metal head attaches to the stem, wear on thebearing surface or corrosion on the stem, if uncemented. The failure modes includeloosening of the acetabular component, loosening of the femoral component or metalreaction with necrosis and soft tissue damage as previously seen in a small number of

metal on metal hip resurfacing (HR) devices. Failures seem to be more frequent infemales.82

Symptoms of a failed hip replacement included pain and radiographic changes as seenon plain films, including loosening and lysis. Blood Cobalt and Chromium ions are often,but not always elevated. Ultrasound and MRI scans may show fluid collections, cysticand/or solid masses.83

Zimmer Durom Acetabular Component Recall

On July 22, 2008, Zimmer voluntarily and briefly withdrew the Durom Acetabular

Component , known as the Durom Cup, from the marketplace, after one of the companysconsulting surgeons, Dr. Lawrence Dorr, publicly warned other orthopedists about cupfailures his patients were experiencing.84 Dorr and three colleagues later presented theirexperiences with the Durom Cup failures at the February 2009 meeting of the AmericanAcademy of Orthopedic Surgeons.85 The surgeons maintained that the cup loosened in 25percent of patients, leading to revision surgeries in 20 percent. In their abstract, thesurgeons attributed the failures to the cup geometry and sharp peripheral fins whichresult in peripheral fixation without contact of fixation surface to acetabular bone in somehips. Because we cannot predict in which patients this will occur we no longer use theDurom cup.86

81 Large Diameter Metal on Metal Bearing Total Hip Replacements; Statement, John Hodgkinson; John Skinner; PeterKay; British Orthopaedic Association; March 9, 201182 Large Diameter Metal on Metal Bearing Total Hip Replacements; Statement, John Hodgkinson; John Skinner; PeterKay; British Orthopaedic Association; March 9, 201183 Large Diameter Metal on Metal Bearing Total Hip Replacements; Statement, John Hodgkinson; John Skinner; PeterKay; British Orthopaedic Association; March 9, 201184 Complaints Undermine Hip Device; Barry Meier; New York Times; July 24, 200885 Metal-on-Metal total hip arthroplasty using Durom cup; Lawrence Dorr, et al.; 2009 Annual Meeting PosterPresentations; American Academy of Orthopaedic Surgeons; February86 Metal-on-Metal total hip arthroplasty using Durom cup; Lawrence Dorr, et al.; 2009 Annual Meeting PosterPresentations; American Academy of Orthopaedic Surgeons; February


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Zimmer, however, concluded, after an in-depth investigation, that the Durom cupdesign was not the problem.87 Zimmer said that it studied the patient outcomes at 12clinical sites representing the highest volumes of implants using the Durom Cup, andestimated the likely revision rate of 1.5 percent.

No evidence of a defect in the materials, manufacture, or design of the implant has beenfound.88

Instead, Zimmer said, the instructions for use/surgical technique instructions wereinadequate.89 Zimmer vowed to launch a campaign to offer additional surgicaltechnique instructions and training are necessary in the United States, and we stronglyrecommend that U.S. surgeons stop implanting theDurom Cup until receiving suchtraining.90 It also promised to update the labeling to provide more detailed surgeoninstructions. Meanwhile the Durom cup would continue to be marketed withoutinterruption abroad.91

Three weeks later, Zimmer announced that it had revised its surgical training andinstructions and would resume selling the Durom cup to surgeons who completed thenew courses, offered in a variety of settings.92 Besieged by lawsuits relating to ZimmerDurom Cup hip failures, the company set aside millions to pay legal claims.93

We have paid approximately $45 million and $25 million in 2010 and 2009,respectively, related toDurom Cup product liability claims. We estimate the remainingliability forDurom Cup claims as of December 31, 2010, is $132.8 million.94In 2010, surgeons from the University of Wisconsin Hospital and Clinics Department ofOrthopaedics and Rehabilitation, reported an 11.1 percent failure rate defined bypersistent moderate or severe groin pain or revision among its patients implanted with

the Durom cup, compared to a .002 rate for those implanted with components fromZimmers Trilogy acetabular component.95

We could not identify any patient/surgical-related factors predictive of failure, theresearchers concluded.96

FDA Approval and Surveillance Process

87 Urgent Device Correction; Cheryl Blanchard; Letter to surgeons; DePuy Orthopaedics; July 22, 200888 Urgent Device Correction; Cheryl Blanchard; Letter to surgeons; DePuy Orthopaedics; July 22, 200889 Urgent Device Correction; Cheryl Blanchard; Letter to surgeons; DePuy Orthopaedics; July 22, 2008

90 Urgent Device Correction; Cheryl Blanchard; Letter to surgeons; DePuy Orthopaedics; July 22, 200891 Urgent Device Correction; Cheryl Blanchard; Letter to surgeons; DePuy Orthopaedics; July 22, 200892 Urgent Device Correction-Update; Cheryl Blanchard; Letter to surgeons; DePuy Orthopaedics; August 16, 200893 Zimmer Holdings, Inc.; Form 10K Filing; Dec. 31, 201094 Zimmer Holdings, Inc.; Form 10K Filing; Dec. 31, 201095 Large-Head Metal-on-Metal Total Hip Arthroplasty Using the Durom Acetabular Component at Minimum 1-YearInterval; Richard L. Illgen II; John P. Heiner; Matthew W. Squire; David N. Conrad; The Journal of Arthroplasty Vol.25 No. 6 Suppl. 1; 201096 Large-Head Metal-on-Metal Total Hip Arthroplasty Using the Durom Acetabular Component at Minimum 1-YearInterval; Richard L. Illgen II; John P. Heiner; Matthew W. Squire; David N. Conrad; The Journal of Arthroplasty Vol.25 No. 6 Suppl. 1; 2010


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In 1976, public outcry over failed medical devices, (most prominently, the deaths andinfertility caused by the Dalkon shield, a contraceptive intrauterine device), promptedCongress to amend the Food, Drug and Cosmetics Act. The Medical DeviceAmendments granted the FDA authority to regulate medical devices, and provided twopathways to market.97 The more rigorous schema, pre-market approval (PMA), requires

that the manufacturer to prove that the device is safe and effective. Pre-marketNotification (PMN), known popularly by the sub-section of the regulation 510(k),requires that the device is at least as safe and effective, that is, substantially equivalent,to a legally marketed device.98

The FDA sorted new and existing devices into three basic categories: pre-amendmentdevices, post-amendment devices and substantially equivalent devices new devicesbased on pre-amendment devices or approved post-amendment devices. At the sametime, the agency classified devices according to their level of risk to human health, designcomplexity and use. Class I devices, such as tongue depressors and crutches, posed thelowest risk. Class II devices included those that posed an intermediate risk, such as

contact lens solution and electrocardiographs. Class III devices encompassed those thatcarried the highest risk and supported or sustained human life, or prevented theimpairment of health, such as HIV diagnostic tests and implantable devices, such aspacemakers.

Pre-Market Approvals invoke the most stringent FDA scientific and regulatory review,which includes an in-depth scientific and quality system review; a review andrecommendation by an advisory committee; and final deliberations by the FDS before adecision is made.99 Manufacturers seeking a PMA must submit data from a clinicalcontrolled trial and be subject to a manufacturing inspection. Most Class III devices aresubject to the PMA process.

Pre-Market Notification or 510k was established to streamline the process for newmedical devices that were substantially equivalent to devices called predicates inthe approval process that were already on the market by 1976. Many new versions ofolder Class III devices, grandfathered by the Medical Device Amendments, are regulatedunder the 510k process until the FDA can provide an effective date for the devices PMA.In 2002, the aggressive deregulation of the George W. Bush presidency resulted in afurther loosening of the 510k process. The FDA was directed to take the leastburdensome approach to medical device regulation,100 and the definition ofsubstantially equivalent now included products made using different materials andmechanics than the predicate device. Predicates no longer had to be in the marketplace in1976; any device already cleared either by 510k or PMA applied. In result, 510kbecame the de facto route to FDA approval, with 99 percent of all devices approved

97 Medical Devices Amendment; PL 94-295; May 28, 197698 Premarket Notification 510k; accessed from www.fda.gov; Food and Drug Administration; 2011040899 Eventually all Class III devices will require a PMA. However, preamendment Class III devices require a PMA onlyafter FDA publishes a regulation calling for PMA submissions. The preamendment devices must have a PMA filed forthe device by the effective date published in the regulation in order to continue marketing the device.100 Medical Device Recalls and the FDA Approval Process; Diana M. Zuckerman, PhD; Paul Brown, BS; Steven E.

Nissen, MD; Archives of Internal Medicine; February 14, 2011


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under this scheme. The regulations now allowed patients to be exposed to devices thathad never been subjected to clinical trials, testing or any standards.101

Today, the FDA considers a device marketable under 501k if the new device:

Has the same intended use as the predicate; and has the same technological

characteristics as the predicate; orhas the same intended use as the predicate; andhas different technological characteristics and the information submitted to FDA

Does not raise new questions of safety and effectiveness; anddemonstrates thatthe device is at least as safe and effective as the legally marketed device.102

Manufacturers can claim substantial equivalence based on intended use, design, energyused or delivered, materials, chemical composition, manufacturing process, performance,safety, effectiveness, labeling, biocompatibility, standards, and other characteristics, asapplicable.103

The FDA gives wide latitude to what may be considered substantially equivalent. A

medical device manufacturer could submit a 510k if the device has a different intendeduse than the predicate. It can seek approval under 510k if there is a change ormodification of a legally marketed device and that change could significantly affect itssafety or effectiveness.

The 510k process is much quicker and cheaper than a premarket approval. The FDA has90 days to assess a manufacturers declaration of substantial equivalence. Once approved,the device may be marketed to the public.

Many clinicians, public health advocates have been highly critical of the 510k process,and have documented the increased risk of patient harm created by the release of

problematic health devices. This April, the Senate Special Committee on Aging

held ahearing on the safety of medical devices.104 In addition to Korgaokar, the Committeeheard from the Government Accountability Office, which is in the midst of an ongoinginvestigation on the FDAs medical device approval process, post-market monitoring andrecalls, and Dr. Diana Zuckerman, who recently published a study of medical devicerecalls. The committee also heard from manufacturers representatives who expressedfears that the FDA process was slowing the pace of medical device innovation. Themajority of the witnesses, however, raised concerns that the 501K process is not effectivein ensuring the safety of new devices. U.S. Senator Herb Kohl, chairman of the SpecialCommittee on Aging, vowed to advocate for further reforms, and push forward with aneffort to classify high-risk devices now defaulting through the agencys fast track

approval system.

105

101 Medical Device Recalls and the FDA Approval Process; Diana M. Zuckerman, PhD; Paul Brown, BS; Steven E.Nissen, MD; Archives of Internal Medicine; February 14, 2011102 U.S. Food and Drug Administration; April 14, 2011103 U.S. Food and Drug Administration; April 14, 2011104 FDAS Medical Device Review Scrutinized At Senate Hearing; Press release; Special Committee on Aging; April13, 2011105 FDAS Medical Device Review Scrutinized At Senate Hearing; Press release; Special Committee on Aging; April13, 2011


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FDA has had over 20 years to tackle these high risk devices, Kohl said. As wehave seen with the Johnson & Johnson hip implant today, its high time to protectpatient safety and correctly classify these devices.106

In February, The Archives of Internal Medicine published a five-year study of recalls fordevices that that the FDA determined could cause serious health problems or death, andfound that nearly three-quarters were approved via the 510K process.107 Of a total of 113such recalls, from 2005 through 2009, 21 were PMA-approved; 80 entered the stream ofcommerce via 510k and 8 were exempt from any FDA regulations. The authorsconcluded:

Medical devices cleared through the less rigorous 510(k) pathway comprise more thantwo-thirds of the products that are recalled by the FDA because they could seriously harmpatients or result in death. When devices that were intentionally exempt from any FDAreview were added to the 510(k) devices, they comprise more than 3 out of 4 of the high-

risk recalls during the last 5 years. Thus, the standards used to determine whether amedical device is a high-risk or life-sustaining product prior to approval are clearly verydifferent from the standards used to recall a medical device as life threatening. Ourfindings reveal critical flaws in the current FDA device review system and itsimplementation that will require either congressional action or major changes inregulatory policy.108

In the summer of 2009, the General Accounting Office (GAO) issued a report on theFDAs medical devices review processes. It found that between 2003 and 2007, the FDAreviewed 342 submissions for Class III devices through the 510(k) process, clearing 67percent for marketing even though Congress envisioned that all Class III devices wouldbe subject to the more rigorous Premarket Approval process.109 It recommended that theFDA expeditiously take steps to issue regulations for each class III device type currentlyallowed to enter the market through the 510(k) process, including (1) reclassifying eachdevice type into a lower class or requiring it to remain in class III and (2) for those devicetypes remaining in class III, requiring approval for marketing through the PMA process.

By September 2009, the FDAs Center for Devices and Radiological Health convenedtwo working groups to address the criticisms directed at the 510k process.110 Industrycomplained that it was too arbitrary and unpredictable, and that the CDRH reviewershad become less responsive and risk adverse.111 Patients, professional healthcare

106 FDAS Medical Device Review Scrutinized At Senate Hearing; Press release; Special Committee on Aging; April13, 2011107 Medical Device Recalls and the FDA Approval Process; Diana M. Zuckerman, PhD; Paul Brown, BS; Steven E.

Nissen, MD; Archives of Internal Medicine; February 14, 2011108 Medical Device Recalls and the FDA Approval Process; Diana M. Zuckerman, PhD; Paul Brown, BS; Steven E.

Nissen, MD; Archives of Internal Medicine; February 14, 2011109 Medical Devices: FDA Should Take Steps to Ensure That High-Risk Device Types Are Approved through the MostStringent Premarket Review Process; Government Accounting Office; January 2009110FDA to improve most common review path for medical devices; Press release; U.S. Food and Drug Administration;January 19, 2011111 510(K) and Science Report Recommendations; August 2010


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groups and insurers countered that 510K didnt do enough to assure safety oreffectiveness. The 510(k) Working Group and the Task Force on the Utilization ofScience in Regulatory Decision Making. CDRH staff had its own problems with 510k.They asserted that a burgeoning workload, along with the increasing complexity ofdevices and the poor quality of 510k submissions made it difficult to make informed

decisions.

In August 2010, the two groups issued 55 recommendations, and in January, the FDAannounced a plan to begin implementation.112 Among the recommended changes was anexplicit requirement that all 510(k) submitters provide a summary of all scientificinformation known or that the submitter should reasonably know regarding the safety andeffectiveness of the device under review; that CDRH develop a guidance document thatclarifies when a device should not be used as a predicate and promulgating a newregulation clarifying the circumstances under which the center would exercise itsauthority to rescind a 510(k) clearance to remove an unsafe device from the market andpreclude its use as a predicate.113

Hip Arthroplasty and FDA Approval and Surveillance

Hip implants should be, by FDA definition, designated as a Class III device. (Under theMedical Device amendments, all Class III devices will require a PMA. However, if aClass III device was in existence before 1976, the manufacturer can continue to marketthe device until the FDA publishes a regulation calling for PMA submissions.)114

Nonetheless, in 1998, to streamline the premarket approval process, the FDA re-classifiedhip arthroplasty as Class II Devices.115 Regardless of risk classification, the vast majorityof hip replacement devices in use have been brought to market under 510K. According to

a 2008 study published in The Open Rheumatology Journal, in 1976, the few hipreplacement devices already on the market were grandfathered under the MDA.116 Theresearchers looked at all total hip replacement approvals granted between 1976 and 1995,and found that 701 devices produced by 74 manufacturers were brought to market via the510k process, compared to 34 such devices, from just four manufacturers, subjected tothe more rigorous PMA process. Up until 1991, 297 prosthetic hip devices wereapproved. The last five years of the study period, all 404 devices representing 60percent of the all approvals in two decades were approved as substantially equivalentdevices.

112 FDA to improve most common review path for medical devices; Press release; U.S. Food and Drug Administration;January 19, 2011113 FDA Issues Assessments of the 510(k) Program and Use of Science in Decision-Making; Press release; U.S. Foodand Drug Administration; August 4, 2010114 U.S. Food and Drug Administration; April 14, 2011115 Improving the Postmarket Surveillance of Total Joint Arthroplasty Devices; Nizar N Mahomed, Khalid Syed,Clement B. Sledge, Troyen A Brennan, and Matthew H Liang; The open Rheumatology Journal; February 25, 2008116 Improving the Postmarket Surveillance of Total Joint Arthroplasty Devices; Nizar N Mahomed, Khalid Syed,Clement B. Sledge, Troyen A Brennan, and Matthew H Liang; The open Rheumatology Journal; February 25, 2008


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By satisfying this requirement, manufacturers were not required to provide clinical dataon the safety and effectiveness of their device, the authors wrote. 117

These researchers also found that the FDA surveillance system did a poor job offollowing the failure rate of these implants. The FDAs Mandatory Device Reporting

requires that any device causing a serious injury, defined as all events necessitating areturn to the operating room related to a medical device failure. By this measure, theyassert, almost all revision arthroplasties should be reported. The researchers mined twoindependent sources of data for hip replacement revision surgeries performed in 1993 the MDR and the National Hospital Discharge Survey and estimated that only threepercent of all such revisions were reported to the FDA; only 15 percent of the approvedhip replacement devices published data on outcomes.

In addition to the technical literature documenting the laxness of the approval andsurveillance process, the Department of Justice has investigated and obtained multi-million-dollar settlements from four of the five major Total Hip Replacement

manufacturers.

118

The investigation, which began in 2005, culminated in charges that themanufacturers used consulting agreements with orthopedic surgeons to induce thepurchase of their devices Zimmer, Inc., Depuy Orthopaedics, Inc., Biomet Inc., andSmith & Nephew, Inc. for $311 million from four manufacturers of hip and kneesurgical implant productsto settle claims that from at least 2002 through 2006 thesecompanies.119 The government's investigation revealed that the firms paid surgeonshundreds of thousands of dollars a year for consulting contracts and lavished them withtrips and other expensive perquisites in exchange for using the companies productsexclusively. In addition to the civil settlements, the four companies executed deferredprosecution agreements requiring new corporate compliance procedures and theappointment of federal monitors to review their compliance with these procedures.120

History of Total Hip Arthroplasty

Surgeons pioneered Metal-on-Metal hip replacement in a series of 26 operationsperformed between 1956 and 1960. The revision rate was about 30-40 percent, andfailures, mostly due to impingement of the acetabular cup on the femoral neck resultingin notching and wear debris, were accompanied by varying amounts of sludgecontaining many metal particles.121

117 Improving the Postmarket Surveillance of Total Joint Arthroplasty Devices; Nizar N Mahomed, Khalid Syed,Clement B. Sledge, Troyen A Brennan, and Matthew H Liang; The open Rheumatology Journal; February 25, 2008118 Five Companies in Hip and Knee Replacement Industry Avoid Prosecution by Agreeing to ComplianceRules and Monitoring; Christopher J. Christie; United States Department of Justice; September 27, 2007119 Five Companies in Hip and Knee Replacement Industry Avoid Prosecution by Agreeing to ComplianceRules and Monitoring; Christopher J. Christie; United States Department of Justice; September 27, 2007

120 Five Companies in Hip and Knee Replacement Industry Avoid Prosecution by Agreeing to ComplianceRules and Monitoring; Christopher J. Christie; United States Department of Justice; September 27, 2007121 Current Concepts on Metal on Metal Resurfacing; Ian C. Clarke, et al; Orthopedic Clinics of North America; 2005


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The 1960s ushered in a wave of Metal-on-Metal Total Hip Replacements made of castCobalt-Chromium-Alloy or stainless steel. Initial products included: McKee-Farrar(Wiles and McKee; UK); Ring (UK); Mueller-Huggler (Switzerland); Sivash (SovietUnion); and Stanmore (Scales and Wilson; England). These early designs were relativelysimple in design and quality. Loosening rates were high and researchers were concerned

about the biological reaction to the alloys, known as metal sensitivity. For example, theMcKee-Farrar design suffered from high loosening rates because of equatorial bearingand impingement of the femoral neck against the rim of the acetabular component.122

When the first-generation Metal-on-Metal implants were revised, doctors discovered avariety of adverse tissue reactions. Macrophages white blood cells that ingest foreignmatter as part of the bodys defense system consumed the metal wear particles anddied, potentially compromising the surrounding tissue and immune system. Doctors alsodiscovered osteolysis (the dissolution of bone tissue) and many tissues were stained withblack debris from the metal particulate. These adverse effects were mostly associatedwith impingement or loose components rather than with functioning implants.

Nonetheless, some evaluations show that some of these designs had low wear rates andlong term success despite their designs.

Sir John Charnley, regarded as the pioneer of modern hip replacement surgery, advancedthe state of the art by introducing Ultra High Molecular Weight Polyethylene(UHMWPE) to arthroplasty in the 1960s. This material has been used for more than 40years and is still the most frequently used bearing surface in all total joint replacements,including hip, knee, and shoulder implants.123 In the early 1960s, Charnley, a Britishorthopedic surgeon, developed a low-friction arthroplasty consisting of a femoral headand an all-polyethylene cup. Since then, metal-on-polyethylene with a metal femoralhead and polyethylene acetabular cup is the most frequently implanted device. (ceramic-on-polyethylene devices are also popular and boast lower wear rates than metal-on-polyethylene.124)

By 1975, surgeons concerned about the adverse effects of metal particulate began tophase-out Metal-on-Metal systems, and metal-on-polyethylene became the implant ofchoice. By the end of that decade, there was a widespread perception that the metal-on-polyethylene systems gave better clinical results,125126 and this became the preferredroute for total hip replacements throughout the 1980s.

The soft-on-hard combinations develop wear on the plastic part of the device the resultof the high activity level of the patient, thin polyethylene liners, excessive abduction

122 Long Duration Metal-on-Metal Total Hip Arthroplasties; Thomas P. Schmalzried; Paul C. Peters; Brian T. Maurer;Charles R. Bragdon; William H. Harris; The Journal of Arthroplasty Vol. 11 No. 3; 1996123 Arthroplasty of the Hip-a new operation. Charnley, et al. Lancet 1:1129, 1961.124 Bearings of the Future for Total Hip Arthroplasty. Michael T. Manley, FRSA, PhD and Kate Sutton, MA, ELS. TheJournal of Arthroplasty, 2008125 THR by low-friction arthroplasty. Charnley, et. al., Clin Orhtop 1970; 72:7.126 The long-term results of low-friction arthroplasty of the hip performed as a primary intervention. Charnley, et. al.JBJS Br 1972;54B:61


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(laterally) of the acetabular cup or the use of modular uncemented cups.127128 Thegenerated debris can cause an adverse reaction in the tissue, so wear remains the biggestproblem of this type of total hip arthroplasty.129 Eventually, the polyethylene wearparticles can cause osteolysis (destruction of the bone) around that implant and lead to theloosening of the cup, the primary reason for revision in the long term total hip

arthroplasty, especially in young and active patients.

130

131

132

133

134

(Despite the problems of polyethylene wear, some surgeons still prefer polyethyleneliners because they provide the patient with better shock absorption and are moreforgiving when misaligned. A less expensive material, polyethylene does not releasemetal wear debris into the bloodstream, squeak or fracture easily.135136137 Althoughhigh-contact stresses in the polymer due to very thin liners or edge loading may lead tocomponent fracture.138)

On a quest to reduce the wear and osteolysis associated with polyethylene components,French physician, Pierre Boutin, pioneered the use of ceramic-on-ceramic bearings for

total hip arthroplasty in the 1970s.

139

Some surgeons favor the use of ceramic femoralhead and polyethylene cup as an alternative to a metal-on-polyethylene device, due to theexcellent mechanical qualities and because the smooth surface finish reduces theproblems of wear. Compared to metallic heads, ceramic femoral heads paired withpolyethylene cups have generally been associated with as much as a 50 percent reductionwear rate compared to metal-on-polyethylene,140 but still more than Metal-on-Metalbearings.141

Ceramic-on-ceramic hip implants offer several advantages. First, the opposing surfaces(the acetabular cup and the femoral head) can be consistently manufactured to minimalsurface roughness and controlled radial clearances. This, combined with very hard

127 3D PE Wear of a Press-Fit Ti prosthesis-Factors influencing generation of PE Debris. Devane, et. al., J Arthroplast12:256, 1997.128 Effect of acetabular modularity on PE Wear and Osteolysis in THA. Young, et.al. JBJS Am 84: 58, 2002.129 Wear and periprosthetic osteolysis: the problem. Harris, et. al. Clin Orthop 393:66-70. 2001130 Fifteen years experience with Charnley low-friction arthroplasty. Hartofilakidis, et. al. Clin Orhtop 246:48. 1989.131 Early and Late Loosening of the acetabular cup after low-friction arthroplasty. Garcia-Cimbrelo, et. al. JBJS74:1119. 1992132 Low-friction arthroplasty in patients younger than 40 years old: 20-25 year results. Garcia-Cimbrelo, et. al. JArthroplast 15: 825, 2000133 THA for primary osteoarthrosis in younger patients in the Finnish arthroplasty register. Eskelinen, et. al. ActaOrthop 76: 28, 2005134 Long-term results of use of the anatomic medullary locking prosthesis in THA. Engh, et. al. JBJS Am 79: 177,1997.135 Levels of metal ions after small and large-diameter MOM Hip Arthroplasty. Clarke, et. al. JBJS Br 85:913, 2003.

136 Preliminary observations on possible premalignant changes in bone marrow adjacent to worn total hip arthroplastyimplants. Case, et. al. Clin Orthop 329;s269, 1996.137 Squeaking in CoC hips-the importance of acetabular component orientation. Walter, et. al. J Arthroplast 22:496,2007138 Bearings of the Future for Total Hip Arthroplasty. Michael T. Manley, FRSA, PhD and Kate Sutton, MA, ELS. TheJournal of Arthroplasty, 2008139 Total arthroplasty of the hip by fitted aluminum prosthesis. Experimental study and 1st clinical applications.Boutin, et.al. Rev Chir Orthop Reparatrice Appar Mot 1972, 58140 Bearing Surface Options for the THR in young patients. Heisel, et. al. JBJS Am 85:1366, 2003.141 A comparative joint simulator study of the wear of the wear of Metal-on-Metal and alternative materialcombinations in hip replacements. Goldsmith, Dowson, Isacc, Lancaster. Proc Instn Meck Engrs, V 214, Part, H, 1999.


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scratch-resistant ceramic materials, provides an excellent surface for lubrication.142143 Inaddition, alumina (the most commonly used ceramic material) wear debris generated by aceramic-on-ceramic implant is chemically inert and does not have a toxic effect on thebody. The damage to surrounding tissues is less, adverse cellular reactions andmacrophage response are considerably fewer compared to the bodys reactions to

metallic or polyethylene debris.

144

145

Ceramic-on-ceramic implants, however, also have their downside. Some patientscomplain of post-operative squeaking related to the orientation of the acetabularcomponent.146 The alumina-on-alumina bearings are sensitive to the position of the cupand edge-loading, increasing their propensity to chip and fracture.147148149Finally,ceramic-on-ceramic implants are relatively expensive and poor implant position canincrease the wear rate.150

In 1988, Bernard C. Weber,151 a Swiss orthopedic surgeon, revived the use of metal onmetal hip implants.152 Securing the support of device manufacturer Sulzer Orthopedics,

Weber developed the Metasul Metal-on-Metal bearing, which is still being used today.The problem of early component loosing seen in the first generation Metal-on-Metalimplants was allegedly corrected by improved component design (tolerance andclearance), improved metallurgy, better manufacturing quality, improved bearinggeometry (sphericity and clearance), and a smoother surface finish to promote naturallubrication. Improved cobalt-chromium alloys such as wrought or cast, high carbon orlower carbon alloys were developed. These materials significantly improved laboratorywear rates compared to initial Metal-on-Metal and especially metal-on-polyethylenebearing surfaces.

Others followed suit. In the 1990s, many patients were implanted with the Metasul hipsystem. One study that followed patients progress five years after surgery found a verylow rate of loosening of 0 to 1.3 percent. 153154155156157

142 A full numerical analysis of hydrodynamic lubrication in artificial hip joint replacement constructed from hardmaterials. Jin, et.al. Proc. Instn Mech. Engers, Part C. J. of Mechanical Eng Sci, 1999, 213(C4), 355.143 Analysis of fluid film lubrication in artificial hip joint replacements with surfaces of high elastic modulus. Jin, et.al. Proc. Instn Mech. Engrs, Part H, J Eng in medicine, 1997, 211 (H3), 247.144 The use of dense alumina-alumina ceramic combination in THR. Buitin, et. al. J Biomed Mater Res. 1988, 22,1203.145 Biocompatability of surgical grade dense polycrystalline alumina. Christel, et. al. Clin Orthop Rel Res, 1992, 282.146 Bearings of the Future for Total Hip Arthroplasty. Michael T. Manley, FRSA, PhD and Kate Sutton, MA, ELS. TheJournal of Arthroplasty, 2008.147 Bearings of the Future for Total Hip Arthroplasty. Michael T. Manley, FRSA, PhD and Kate Sutton, MA, ELS. The

Journal of Arthroplasty, 2008.148 Ceramic Femoral head retrieval data. Willmann, et al. Con Orhtop Relat Res 2000;379149 Two-9 year clinical results of alumina CoC THA. Murphy, et al. Clin ORhtop Rel Res 2006;453150 Bearings of the Future for Total Hip Arthroplasty. Michael T. Manley, FRSA, PhD and Kate Sutton, MA, ELS. TheJournal of Arthroplasty, 2008.151 Experience with the Metasul TH bearing system. Weber, et al. Coin Orhtop 1996;329(Suppl):569.152 THJ Replacement using a CoCrMo M-M sliding pairing. Weber, et al. J Japanese Orthop Assoc 67: 391, 1993.153 Birmingham hip resurfacing arthroplasty. A minimum follow-up of five years. Treacy, JBJS Br 2005;87(2):167.154 Birmingham hip arthroplasty five to eight years of prospective multicenter results. Khan, et al. J Arthroplasty2009;24(7):1044-50155 Five-year results of MoM resurfacing arthroplasty in Asian patients. Nishii, et al. J Arthroplasty 2007;22(2):176


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Conclusions

While total hip arthroplasty is a well-established and often successful implant procedure,many new designs, using Metal-on-Metal components, are prone to early failure and

introduce significant health hazards in patients. The recipients of defective hip devicesare exposed to an array adverse effects ranging from bone loss to tissue death topoisonous levels of metal wear particles, and are subject to pain and unnecessary anddebilitating second surgeries.

Manufacturers have taken advantage of the regulatory agencys attempts to streamlinethe approval process, by claiming that new devices are simply a variation of an existinghip arthroplasty device. This has allowed too many devices that are critical to a patientshealth and well being to be implanted into patients without proving efficacy or safety.

The U.S. Food and Drug Administrations attempts to reform the medical device

approval process have come too late to prevent defective hip arthroplasty designs fromcoming to the marketplace and being implanted at great risk to consumers. While somehave been recalled, others, such as DePuys Pinnacle Metal-on-Metal hip system havenot. In addition to reforms the FDA is currently implementing, the agency shouldimmediately implement a post-market surveillance program to uncover hip replacementsystems with revision rates outside of the norm and press those manufacturers to recallthose devices immediately.

156 The results of primary Birmingham hip resurfacings at a mean of five years. An independent prospective review ofthe first 230 hips. Hing, et al. JBJS Br 2007;89(11):1431.157 The five-year results of the Birmingham hip resurfacing arthroplasty: an independent series. Steffen, et. Al. JBJS Br2008:90(4):436-41.

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Metal on Metal Joint Replacement