MEDICAL DEVICES

THE TRUTH ABOUT MEDICAL DEVICES In today’s BMJ we raise serious concerns A publicly available central register about the regulation of high risk medical of adverse effects would allow early devices and how well they are tested detection of emerging problems, suggest before they come to market. There are Deborah Cohen and Matthew Billingsley thousands of devices on the market, and (p 1124), and Matthew Thompson and the industry worldwide is worth over colleagues try to quantify recalls in the £200bn a year, however, the approval United Kingdom and the lack of information process is far less stringent than for drugs, about safety and effectiveness (p 1131). particularly in Europe, as Professor Nick Carlo Di Mario and colleagues suggest Freemantle says (p 1129). (p 1128) that although there is room Makers may issue voluntary recalls, for improvement, uniformly increasing but they don’t always act on emerging the hurdles in the regulatory process problems, finds Deborah Cohen’s risks raising costs without improving investigation (p 1116). The maker of patient safety, but Alan Fraser and articular surface replacement (ASR) metal colleagues argue (p 1130), despite official hip implants, Depuy, waited till 2010 to fully protestations, that standards for approving recall its hip despite repeated warnings devices are less rigorous in Europe than in from doctors as early as 2007. the United States. The British Orthopaedic Association has In an accompanying editorial (p 1093) recently said that some metal on metal hip Peter Wilmshurst says that the problem replacements should not be performed of competing interests is far worse until more is known about their failure, say for medical devices than it is for drug John Skinner and Peter Kay (p 1123). prescribing.

More on bmj.com Watch supplementary videos on bmj.com to accompany this series of articles, including a clip showing a patient who has received an ASR replacement hip, and an interview with Stephen Graves (pictured top right), orthopaedic surgeon and director of the Australian National Joint Replacement Registry. Read additional commentaries on bmj.com, including one from Stefan James and colleagues on use of registers Research from BMJ Open: Medical device recalls in the UK and device regulation process (doi:10.1136/bmjopen-2011-000155) Respond to these articles at bmj.com

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t is one of the biggest disasters in orthopaedic only would metal be much harder wearing, but history, according to one senior surgeon. advancements in manufacturing meant that the On 24 August 2010, DePuy, a subsidiary metal could be produced with incredibly smooth of American giant Johnson and Johnson, surfaces. Complicated physical phenomena OUT recalled its ASR (articular surface replace- dictate that these smooth bearing surfaces trap Iment) hip prostheses from the market. The a layer of fl uid between them. So in perfect cir- recall followed years of denial by the company cumstances, the metal surfaces do not touch and that the ASR implants had caused pain and dis- the surfaces wear very little. And, in theory, the ability in patients. In a statement to the BMJ , more quickly the patient moves the thicker this DePuy claim that “given the available informa- fl uid layer becomes, ensuring even less wear.6 7 OF tion, we believe we made the appropriate deci- Competition between manufacturers spurred sion to recall at the appropriate time.” DePuy to develop the ASR. A new hip prosthesis Pathologically, the failing prosthesis had sev- called the Birmingham Hip Resurfacing (BHR), eral eff ects. Metal debris from wear of the implant designed by UK surgeon Derek McMinn, had led to a reaction that destroyed the soft tissues entered the European market in 1997 (the FDA JOINT surrounding the joint, leaving some patients approved it in 2006), and was proving popular. with long term disability. Ions of cobalt and Smith and Nephew acquired it, and DePuy had chromium—the metals from which the implant to design a better product so that it didn’t lose Why did it take so long to was made—were also released into the blood and market share. The attempt to prise surgeons cerebral spinal fl uid in some patients.1 away from the BHR led to fractious competition recall from the market a The long term eff ects are uncertain. But the between the companies, which was refl ected in US Food and Drug Administration recommends their marketing campaigns. hip implant after it became that patients should be monitored for systemic apparent that it was causing eff ects, particularly cardiovascular, neurological, Simulator testing for ASR resurfacing renal, and thyroid signs and symptoms. 1 Both forms of the DePuy ASR came on to the pain and disability in patients. With more than 93 000 ASR implants sold and market in Europe in 2003. At the time, resurfac- In an investigation for the ongoing litigation in many countries, the situa- ing prostheses were classed as a class IIb device, tion may prove costly for DePuy. And if lessons which meant they didn’t need to be tested in BMJ , Deborah Cohen are not learnt from this latest episode in the cheq- patients before entering the EU market. uered history of hip implant failures, it may also DePuy followed and met the European stand- describes how companies prove costly for the reputations of the regulators ards. These provide guidance on how to conduct dictate the fate of their own and the orthopaedic community. simulator studies to test how well the implant The ASR is not the first hip implant to be wears. According to DePuy, it conducted labora- devices and exert an unduly recalled—there have been many others. One tory testing “including tests on simulators that strong hold over surgeons such recall in the late 1990s—the 3M Capital evaluate how the device wears over time, the Hip—prompted questions about European materials used in the device and device strength.” device regulation 2 and a parliamentary investi- But exactly what information the company gation by then health minister, Lord Hunt.3 But submitted is not open to public scrutiny—the nor may it be the last—concerns are now being scientifi c rationale is held by the company and raised about the failure rates of other metal on by the notified body—one of several private metal hip implants. 4 organisations that do the premarket approval on behalf of EU governments.8 In this case the Metal on metal notifi ed body was the British company BSI.9 The ASR is a “metal on metal” hip—the head at The UK Medicines and Healthcare Products the top and the lining of the cup it fi ts into are Regulatory Agency (MHRA) says that clinical made of cobalt chrome metal rather than ceramic studies may be too small and short to detect or polyethylene. The devices come in diff erent problems for premarket approval purposes. But sizes according to the existing anatomy, and clinical tests with relatively short follow-up may there are forms for both total hip replacement have picked up problems with the ASR. Accord- (ASR XL) and hip resurfacing (ASR resurfacing). ing to David Langton, a surgical researcher at the The conventional total hip replacement con- University Hospital of North Tees and Newcastle sists of a metal head with a polyethylene cup. University who has been studying the ASR, prob- But these joints don’t last forever. Over time the lems in some patients fi rst emerged about two plastic cup wears away against the hard metal years after implantation. 10 head. Younger, more active people are especially The absence of any clinical studies of implants likely to require early revision surgery to replace in patients before approval remains a cause for the worn out joint. 5 concern—much like it was over 10 years ago with In search of a more durable option, surgeons the 3M Capital hip. 2 turned their attention to the development of “The reason they get on to the market is that joints using a metal head against a metal cup. Not they look and smell like a joint replacement,”

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says Stephen Graves, orthopaedic surgeon and director of the Australian National Joint Replace- TOTAL HIP REPLACEMENT HIP RESURFACING ment Registry. Professor Graves thinks that simu- lator testing should not be relied on entirely to see if a device will function well when you use it in a person. Indeed, a recent Smith and Nephew backed paper suggests that simulators do not really represent the biological environment.11 “Before a hip or knee replacement is placed on to the market it should have been used in a limited number of people who had been monitored very carefully for a number of years,” Professor Graves says, adding, “the outcome of that monitoring would indicate that the device is actually working very satisfactorily in that small group of patients.” Professor Graves thinks this would protect not only patients but also the company. “They [clini- cal studies] may well prevent a situation where they have a device that is not performing any- where near as well as they would have hoped,” he says.

Problems emerge HIP SURGERY Although the ASR resurfacing made it on to the Total hip replacement surgery—The femoral head is removed and replaced with a prosthetic ball European market, it was not approved in the US. made of metal or ceramic, and the acetabulum is replaced with a prosthetic cup. The cup consists Resurfacing was a new technique and so the of one or two components made of metal, ceramic, or plastic. A stem is also placed in the femur to implant had to go through the FDA’s more rigor- support the femoral head ous premarket approval process. This requires Hip resurfacing surgery—The femoral head is trimmed and capped with a metal covering. Any manufacturers to submit their product to clini- damaged bone and cartilage within the acetabulum are removed and replaced with a metal cup cal testing to prove it is both safe and—unlike the European process—effective for its intended use. were women—who typically fared worse with Similar equivalence—a flawed approach The FDA asked DePuy to perform a clinical study the prosthesis.9 The French agency concluded Although the FDA’s premarketing approval called an investigational device exemption (IDE). in 2008 that given the data and the alternatives ­process requiring a clinical study may have pro- Tony Nargol, an orthopaedic surgeon at the it would not fund the ASR resurfacing. But it was tected patients from the widespread uptake of the University Hospital of North Tees, was one of the still being used in the NHS. failing ASR resurfacing prosthesis, the same could surgeons involved in the studies for the ­American DePuy’s response to the FDA questions shows not be said about ASR XL, the total hip replace- market. But not everything was going to plan. its close relationship with the surgeons it chooses ment. This passed through the FDA’s 510(k) As DePuy’s internal emails show in 2007, he to participate in its regulatory studies and the clearance process via the “­similar ­equivalence” reported problems with fractures in some of his hold it believes it has over them. The company route, whereby companies need to show only that patients. The FDA sent detailed questions to the assigned the list of questions to one of its market- their product is similar to ­something else on the company. ing representatives with experience in regulatory market. Even a small change in design can have a “You have not provided any explanation affairs. It asked the representative to formulate substantial effect on long term outcome.13 why this experienced investigator may have the answers and ask Mr Nargol to sign the docu- Critics say that the similar equivalence route had a higher femoral neck fracture rate in this ment if needed. In the end the company with- is not nearly stringent enough.14 Yet this is IDE study. It is concerning that an experienced drew its application and the ASR resurfacing was how 90% of devices gain US approval.15 Com- surgeon who is familiar with patient selection never approved by the FDA. panies say that toughening up the approval criteria and surgical technique would have the But this did not stop US surgeons from using process will be bad for patients—they will be highest neck fracture rate,” it said. it “off label.” Rita Redberg, editor ofArchives in denied access to new improved technologies So problems were being picked up in the pre- Internal Medicine and a cardiologist, has studied that are available elsewhere. But can this be market clinical study—despite some insisting the US device regulatory system and testified to true in a market saturated with hip prostheses? that these studies are too small for this purpose. recent Congressional hearings. Isn’t there an argument that the bar for mar- Surgeons experienced in the resurfacing tech- “Patients have a right to know what the risks ket entry should be raised? According to data nique should not have a fracture rate of more and benefits of any procedure are for them. If from the 2010 Australian Joint Registry report, than 1% a year.12 Yet according to a June 2008 a device is used off label, it generally means there are more than 1539 stem and acetabu- document from the French health agency Haute there are not good data to support its use for lar ­combinations for total hip replacement, Autorité de Santé, this two year follow-up study that indication. That is information that should but only 72 are commonly used (defined as had a 4.9% fracture rate in the ASR resurfacing be discussed in the informed consent process. having been used in more than 400 recorded arm. And the two year survival of the implant These discussions are particularly important ­procedures).16 was 95.9% (95% confidence interval 93.5% to for an implanted device, which cannot easily Yet, companies scarcely let a year go by 99.9%) when only 25.6% of people in the group be removed,” she says. ­without introducing a “new improved” joint

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replacement that “offers undreamt of (and Royalties are legal, as are consultancies, Marketing campaign unproven) advantages over the older designs.”17 research fees, and stock options. But some com- A successful marketing campaign would be The same is true in other fi elds. Alan Fraser, panies have been in trouble for providing other crucial to persuading surgeons to change from an interventional cardiologist at Cardiff Univer- kinds of payment. the BHR to the ASR resurfacing in Europe. Among sity, says: “I think any doctor who is treating Four years ago, four of the major orthopaedic its many strategies, DePuy ran simulator tests on patients is keen to try to stay up to date and use companies in the US were fi ned about $311m its prosthesis and its competitor. The pictures the most recent advances. And indeed, I think for paying doctors to use their products.18 And appeared to show that the ASR produced less there is a tendency for doctors to want to use last month, DePuy was ordered by the UK metal wear debris than the BHR—the ASR fl uid whatever the latest new technology is, and per- court to pay almost £5m for similar unlawful was clear whereas the BHR was sitting in a dark haps not always to be critical as to whether or payments. 19 Johnson and Johnson was fi ned metallic stained fl uid. An accompanying journal not it’s really been thoroughly evaluated.” $21.4m by the US court for making “improper article indicated that the ASR fluid had been The desire to use something newer, smaller, payments to publicly employed health care pro- changed and the pictures of the two devices and shinier might well trump the evidence viders in Greece, Poland and Romania in order had been taken at diff erent time points.21 22 Yet base. Nearly 20 years ago an editorial in the BMJ to induce the purchase of medical devices and these pictures were used by sales representatives warned that this “fashion trade” in joint replace- pharmaceuticals” made by their subsidiaries— for marketing purposes divorced from the ments is costing the health service many millions including DePuy. 20 accompanying article and might have been mis- of pounds each year and, even more importantly, Charles Rosen, professor of orthopaedic surgery leading. 23 When we put this to DePuy, it said that is causing patients unnecessary pain and distress at the University of California, Irvine, School of it would not respond to “speculation.” through early failure of unproven implants. 17 And Medicine, says companies try to fi nd a relation- But in the absence of publicly available data judging from the recent history of joint failures, it ship to keep you using that product. “It could be and no independent assessment of study summa- seems not much has changed. in the form of maybe having you as a consultant ries in Europe, manufacturers are able to interpret with the company for a certain amount per year and promote their studies as they wish. This is Surgeons and the company and then you feel obligated to continue using that in stark contrast to the US, where devices can be Surgeons involved in the design of a device can product. Or have you lead courses in how to use marketed only for a clinical claim that is included make large sums of money. One of the surgeons that drug or that device and reimburse you for that in labelling that has been reviewed by the FDA. involved in the design of the ASR, Thomas and tie you up to become an advocate as well as a Even the MHRA does not routinely collect any Schmalzried, medical director of the Joint user of that product,” he says. premarket clinical data. This means that clinical Replacement Institute in Los Angeles, received At the time of the launch of the ASR in 2003, claims are diffi cult to verify. just under $3m (£1.9m; €2.1m) in royalties dur- DePuy was behind in the sales stakes, and it Tony Nargol was one of the surgeons who was ing 2009-10 alone. In the same period, another would have to turn to its design surgeons. The persuaded to change from the Birmingham hip of the designers, Thomas Vail, University of ASR’s design surgeons located in several dif- after being shown the pictures by DePuy in 2004. California San Francisco professor, received just ferent countries acted as key opinion leaders, As internal emails show, the company targeted over $500 000. Figures are not available for the promoting the new device. They led educational him because he was known to be a big user of other designers—their respective countries do programmes, published papers in journals, spoke the BHR. not have the same legislation about transparency at company dinners, and presented at conferences “They said the ASR would last considerably of company payments as the US. promoting the ASR. longer than a Birmingham [Hip Resurfacing],”

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1993 1997 2002 2005 2007 An editorial in the Birmingham National Joint Registry set Derek McMinn, designer An FDA email shows concern about fractures in a DePuy BMJ warns of the a Hip Resurfacing up following the failure of of the BHR, highlights ASR resurfacing study for its approval process. This “fashion trade” in (BHR)comes on the 3M Capital Hip what he sees as the unpublished study shows a two year survival of the implant joint replacements was 95.9%. to the market in Major litigation against a design flaws of the ASR that is costing the the EU (the FDA hip manufacturer, Sulzer, at a debate. Mr Nargol starts to notice health service many approved it in which results in a payout problems with the ASR XL. millions of pounds 2006). Some of his patients reported of roughly $1bn and a 2006 each year and is major net loss that year for groin pain and difficulty causing patients 1998 An expert advisory the company. walking. “The soft tissues and unnecessary pain and 3M Capital group at the MHRA muscles around the hip were distress through early Hip recalled discusses metal on destroyed.” metal hips. “There is failure of unproved prompting 2003 He raises concerns with DePuy. But company managers evidence to suggest that implants. questions about The BSI gives Depuy’s ASR pass this off as a failure of surgical technique. some metal on metal European device market approval in the EU. One of DePuy’s engineers presents a two year follow-up hip replacements may regulation and study showing 30% of women and 7.5% of men had be associated with a parliamentary 2004 markedly raised metal ion concentrations in their blood. increased DNA-changes, investigation Consultant orthopaedic The Australian National Joint Replacement Registry reports by then health which might result in surgeon Tony Nargol is genotoxicity in patients.” that the ASR had a high revision rate. DePuy sends out a minister Lord persuaded to change from “white paper” by one of the ASR design surgeons, Professor Hunt . the BHR to the ASR on the Vail, explaining how to interpret the Australian data. back of pictures comparing Four of the major orthopaedic companies in the US are the two. fined about $311m for paying doctors to use their products.

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Mr Nargol said. He described the simulator test he clearly illustrates that it is not a device related and it’s been there ever since. DePuy chose not to was shown. “After a while the BHR went all black. complication,” an email said. comment on this allegation. It looked like metal had come off the bearing and Professor Graves says this response is not The company was also aware of raised blood it looked abnormal. And there’s a clear diff erence wholly surprising. “There’s a natural tendency levels of metal ions. At a conference in Dallas between the two and it was very persuasive. And I for companies [to think] it’s probably factors other in 2007 one of DePuy’s engineers gave a pres- know a lot of surgeons round the world were very than a device, because entation, seen by this persuaded by this.” they have invested a “I think there is a tendency investigation, of two lot of time in it . . . It for doctors to want to use year follow-up data that Device failure or surgical technique? does take some time on showed 30% of women A few years later, Mr Nargol started to notice occasions to convince a whatever the latest new and 7.5% of men had problems with the ASR. In early 2007, some of company that there may technology is, and perhaps markedly raised metal his patients reported groin pain and diffi culty be problems with the ion concentrations walking. He got a shock when he opened them device.” not always to be critical as in their blood. Even up to revise their prostheses. “The soft tissues The high revision rate to whether or not it’s really though the procedures and muscles around the hip were destroyed.” He of the ASR XL should not in the study had been noticed a pus-like fl uid coming from the capsule. have come as a surprise been thoroughly evaluated” performed by the design Initially he put it down to infection. But cultures to the company or to the regulators. In 2005, Mr surgeons—who would be expected to position the were negative. “And then we went on to fi nd cases McMinn—designer of the Birmingham Hip Resur- device with the most precision—the presentation where the bone was starting to get destroyed as facing—participated in a debate in Helsinki pitch- concluded that surgical technique was to blame. well,” Mr Nargol said. ing the prosthesis he had created against the ASR. I n 2008, Mr David Langton, who had been Other surgeons also mentioned problems While Mr McMinn’s arguments primarily focused analysing both the ASR and the BHR, gave a pres- with the device. But according to Mr Nargol, on his prosthesis, he described in detail what he entation at the British Orthopaedic Association some of those with ties to DePuy declined perceived to be the ASR’s design fl aws that would conference in Liverpool describing the problems to report what they were seeing and simply later lead to its demise. 11 24 - 29 caused by the shallowness of the ASR cup. This, stopped using the device. He criticised the shallowness and the rim on he said, was leading to increased wear as the He raised his concerns with the company, and the inside of the cup and the manufacturing edge of the cup rubbed against the head. DePuy asked whether anyone else was having prob- processes used, all of which, he said, could lead representatives were at the meeting. lems. As internal emails show, company manag- to increased wear. The design changes, he said, ers hoped to pass this off as a failure of surgical would mean the prosthesis would be less forgiv- Registry data also dismissed technique—even though he was an experienced ing of surgeon technique—something which, In 2007, individual surgeons were not the resurfacing surgeon. “I’m sure that the complica- some argue, should be factored into the design only people noticing problems. The Australian tions that Tony has experienced are wholly related of a successful device. 30 National Joint Replacement Registry reported to interoperative surgical technique compromises Mr McMinn says DePuy were “certainly aware that the ASR had a high revision rate. The registry and I’m sure if managed eff ectively we can ensure of this lecture,” and the “president wrote to me in was set up to spot “outliers”—prostheses that that the published presented data from North a non-friendly tone ‘advising’ me to remove this have twice the rate of revision of others in their Tees draws this conclusion and more critically talk from my website.” He declined to remove it class. All hip prostheses fail in some patients,

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2008 2009 2010 2011 Surgical researcher David Langton (below) gives a The Australian A team from University Hospital of North The British Orthopaedic presentation at the British Orthopaedic Association National Joint Tees directly approaches the MHRA to Association says the conference in Liverpool describing the problems Replacement force it to acknowledge the problems use of large diameter caused by the shallowness of the ASR cup. Registry again associated with the ASR. metal on metal bearings Haute Autorité de Santé in France says that given the reports that the National Joint Registry sees a rapid rise in primary total hip data and the alternatives it would not fund the ASR ASR had a high in the number of revisions. It notifies the replacement should be resurfacing. revision rate. MHRA. “carefully considered The Australian National Joint Replacement Registry Depuy issues a and possibly avoided.” again reports that the ASR had a high revision rate. voluntary recall DePuy is ordered by Mr Langton and Mr Nargol give a presentation in of the ASR in the UK court to pay Norwich reporting the cases of 10 women with soft Australia for almost £5m for unlawful tissue reactions who have significantly increased commercial payments in Greece between 1998 and metal ion concentrations in their blood and high joint reasons. 2006, and Johnson and Johnson are fluid metal ions. Representatives of both DePuy and Depuy issues a “voluntary recall” of the fined $21.4m by the US court for making the MHRA attend. ASR globally. At the time of recall, the “improper payments to publicly employed A paper shows that several of the company tells sales representatives to health care providers.” ASR patients have raised chromium offer other Depuy options—including the Two year follow-up study in 144 patients and cobalt concentrations in their Pinnacle, another cobalt chrome metal shows an incremental increase in metal blood. In some patients, these on metal implant. ion levels over the study period in a range concentrations are 100 times of large head metal on metal implants greater than normal physiological made by manufacturers such as Zimmer, values. Biomet, DePuy, and Smith and Nephew.

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but it is expected that the rate will be about 1% a and their data, as internal emails show. At a ­professional responsibility to advise the patient year. The Australian data showed a 5.16% (95% meeting in Norwich in 2008, they gave a presen- accordingly and to decline the procedure when confidence interval 3.50% to 7.56%) revision tation reporting the cases of 10 women with soft the correct indications are not present,” he said. rate at two years.31 tissue reactions who had significantly increased And rather than advise surgeons not to use The registry uses revision as the primary out- metal ion concentrations in their blood and high the ASR in women, DePuy merely instructed come to identify implants that aren’t performing joint fluid metal ions. Representatives of both surgeons to be careful how they put the cup part as well as they should. Of course, it’s only one DePuy and the MHRA attended. of the implant in—again refusing to believe that measure of how well a joint performs, but accord- Before presenting the data, Mr Langton had it might be the device that was giving rise to the ing to Professor Graves, it’s an “unambiguous sought advice from a senior surgeon—who, large increases in chromium and cobalt concen- end point—nobody can argue about [it].” according to internal emails, had instructed trations. Mr Langton was even told by a DePuy But that’s precisely what DePuy did. Accord- DePuy on promoting the ASR. He advised Mr sales representative that good sources had told ing to Professor Graves, when the registry first Langton to keep quiet. “He told me, ‘you have them that an illegal chromium ship unloaded notified DePuy about the high revision rate, the great data which will allow you to travel the its cargo in the river Tees a couple of years company released a safety warning to surgeons world. But my advice would be not to present earlier and that was the reason for the raised saying that positioning was important. it at the Hip Society. I would go to DePuy and chromium and cobalt levels he was finding in Over the next three years, DePuy used a range suggest a consultancy role with them. You can patients’ blood. DePuy declined to comment on of techniques and arguments to try to assuage earn a lot of money just for doing nothing. I this allegation. fears arising from the evidence generated repeat- have done this a couple of times in the past with But it was the threat of losing a valued sur- edly by the Australian registry and surgeons previous research,’” Mr Langton said he didn’t geon to their rival that made DePuy really start themselves.16 31 32 take the advice. to take note. Panic started to set in in early 2009. According to a presentation Professor Graves In an email written in capitals, a local sales rep- gave at a meeting in Glasgow, the Australian joint Targeting women resentative wrote: “Tony Nargol has said he will registry warned the Australian regulators and One paper—published in mid-2008 and seen by no longer use ASR at Hartlepool and instead will DePuy 17 times about problems with the ASR DePuy before submission—showed that several use BHR.” The company had calculated the value between 2007 and 2009. of the ASR patients had raised chromium and of his custom—over a quarter of a million pounds But, according to internal company docu- cobalt concentrations in their blood. In some in 2008. The representative said they would ments, concerns were explained away and sales patients, these concentrations were 100 times “work as closely as possible with Tony and to representatives were instructed to keep on mar- greater than normal physiological values.34 move him to Silent [another DePuy implant] as keting the product. To counter the Australian It was also clear from these data that patients soon as possible to brickwall the account against registry’s findings, internal documents show implanted with smaller ASRs, used mainly in competitors.” that DePuy sent out a “white paper” by one of the women, were more likely to develop higher metal Later that year, DePuy was still in denial about ASR design surgeons, Professor Vail, explaining ion concentrations—as DePuy’s own presenta- the extent of the problems and was providing a how to interpret the Australian data. tion in Dallas the year before had shown. counter argument to any concerning data. An It said that the Australian data did not account Yet this was the group of patients targeted by internal email from March 2009 reported on for the surgeons’ learning curve with resurfacing. DePuy in an “advertorial” in the Daily ­Telegraph outreach to surgeons. “All major XL users have The Australian rates were almost double those on 21 February 2008. Featuring quotes been seen over recent weeks and are happy with of the “international surgeon design team at two from the UK design surgeon Andrew Cobb their results.” years,” it added. In order to and a young woman, “set the record straight” the “Why is the first Penny Brown, who Reporting adverse events sales representatives were said her life had been But not all surgeons were happy, and their revi- told to tell surgeons about a response not to suspend changed by the ASR, the sion rates were far higher than they ought to paper detailing the Ameri- the implantation [of a ­advertorial “aimed to be. Shouldn’t the regulators have stepped in to can experience with the educate patients on their remove the product from the market and stop BHR, which reported an device] when legitimate ­treatment options and those who were purportedly happy to continue adverse event rate of 4.9%, concerns are raised?” ­demonstrate the unique to implant the ASR? which they claimed was advantages that the In the UK the onus is on manufacturers, higher than for the ASR.33 Their marketing team DePuy ASR can provide to the right patients.” ­doctors, and patients to report problems directly also quibbled with the exact definition of the Unlike prescription drugs, there is no European to the MHRA—and the MHRA itself has been term “revision” used by the Australian registry. legislation preventing direct to consumer adver- critical of the deficiencies in postmarket­clinical Surgeons carrying out a lot of operations tising of devices. follow-up.35 According to the Association of had the same failure rates as those doing only According to John Nolan, orthopaedic ­British Healthcare Industries, manufacturers a few, Professor Graves says. So their findings surgeon at Norfolk and Norwich Hospital, capture and analyse information from a vari- totally contradicted DePuy’s assertion that patients were keen to have resurfacing. They ety of sources—clinical follow-up, registries, surgical experience and patient selection were would see adverts for it on the internet. “The ­published and unpublished literature, expert to blame. “We were quite strong in our conclu- emergence of resurfacing hip surgery coincided meetings, and complaints. sion,” says Professor Graves. “We thought it was with the increased use of the internet to adver- The MHRA told the BMJ that it is the “manu- the device.” tise hip replacement surgery on websites that facturer’s responsibility to monitor the perform- Meanwhile the North Tees team—including were not peer reviewed. As a result, patients ance of their devices, for as long as they are in Mr Nargol and Mr Langton—were keeping DePuy would request resurfacing surgery when it was use, and to ensure these devices continue to be updated about the problems they were finding not appropriate. I believe the surgeon has a safe and suitable for clinical use. If in the light

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David Langton, surgical researcher Stephen Graves, director of Tony Nargol, orthopaedic Alan Fraser, cardiologist at Charles Rosen, a orthopaedic at Newcastle University, was the Australian National Joint surgeon at North Tees, warned Cardiff University, says doctors surgeon from Los Angeles, advised by another surgeon to Replacement Registry, says how Depuy several times that he are not always critical as to says companies try to find a keep quiet about finding high devices come on to the market was experiencing problems with whether a device has been relationship to keep you using levels of metal ions in patients needs to be reconsidered the ASR evaluated that product

of this evaluation, the manufacturer establishes At the end of 2009, DePuy voluntarily recalled Recall of the ASR that products should not be used, the manufac- the ASR in Australia. But, according to Profes- But in the end, DePuy “voluntarily recalled” the turer should take the necessary steps to ensure sor Graves, their registry reports had influenced ASR in August 2010, saying the recall was due to patient safety.” the practice of the Australian surgeons, and the unpublished NJR data showing a 12% revision But, in the case of the ASR, they chose which number implanted had already dropped. rate for resurfacing at five years and an ASR XL evidence to believe. And we have no way of know- But it remained on the market in the rest of revision rate of 13%. “Early revision of poorly ing whether doctors and patients reported adverse the world. Confused by the apparent inaction performing hip replacements that generate events to the regulator or what kind of postmar- of the MHRA, in April 2010 a team from Univer- metal debris should give a better revision out- keting surveillance was required of the company. sity Hospital of North Tees directly approached come,” it added on the field safety notice—the The BMJ and Channel 4’s Dispatches filed the agency to force it to acknowledge the prob- means by which manufacturers alert people that a Freedom of Information request asking lems associated with the ASR. By this time they a product is being recalled. the MHRA for reports of adverse reactions to were seeing a 15% revision rate at five years, But revision of a destroyed joint is not straight- the ASR. This was declined under medical and almost all patients had tissue damage to forward. Not only are patients put at anaesthetic ­directive legislation that keeps all device regu- some extent. risk once again, the revisions have a higher risk latory affairs confidential. Nor could we access Mr Nargol told the investigation that the MHRA of failure.37 documents that would show what kinds of officials stopped the team’s presentation halfway And although DePuy states that it is “com- ­discussions the MHRA or the notified body were through, saying they believed the team and ask- mitted to addressing reasonable and custom- having with the company. ing what they wanted. But when Mr Nargol and ary costs of testing and treatment” for patients Mr Langton said the ASR should be banned, who might need revision after the recall of ASR, Role of MHRA the MHRA officials said they couldn’t do that as “including revision surgery if necessary,” there They knew that there were concerns about the they would be sued. Instead, the MHRA sent out is a cost to the NHS—in some centres primary hip risks of metal debris from wear of orthopaedic a medical device alert warning about all metal procedures are being put back to accommodate metal implants. In March 2006, an expert advi- on metal hip implants. However, a spokesper- urgent revisions. sory group at the MHRA discussed the issue. son for the MHRA said that, “the MHRA would But the delay in the recall might serve as a “There is evidence to suggest that some metal on never be influenced by the threat or­possibility of lesson to other companies. Not only will DePuy metal hip replacements may be associated with legal challenge in not taking ­regulatory action it have to pay for the cost of revision in the NHS, increased DNA-changes, which might result in thought to be appropriate.” there is global litigation that, if successful, may genotoxicity in patients.”36 But it was not known Shortly after, the UK National Joint Registry cost the company many billions of dollars. The whether there were any clinical implications of (NJR) saw a rapid rise in the number of revisions. last major litigation against a hip manufacturer the findings. “The benefits of such implants are Up until this point there had been a rate of 7.5%. was against Sulzer in 2002, which resulted in a real. Whereas the discussed risk is theoretical and But this increased and they notified the MHRA. roughly $1bn payout and a major net loss that unquantifiable, but definitely low,” it said. Internal company documents show that DePuy year for the company.38 But the agency knew it was a sensitive topic. had decided to phase out the ASR globally by But even while DePuy was offering to pay Before the paper was presented, the chairman the end of 2010 for “commercial performance” revision costs, it again used the opportunity to stressed the importance of confidentiality, adding ­reasons. In a statement to the investigation DePuy promote its products. An internal presentation that “anyone who felt they were unable to keep said that this decision “was not related to any the day before the recall went out—seen by the this matter completely confidential was asked to ­concerns about product safety.” BMJ and Channel 4’s Dispatches—said that since leave the room.” “At the time of the decision, data available the ASR system was no longer available, none Despite the raft of data being published in to DePuy indicated that the revision rate of the of the components should be used for revision. both the medical literature and as formal registry ASR Hip System was similar to that reported for However, it said that “DePuy offers a full line reports over a number of years, the ASR was left other large diameter metal on metal monoblock of both revision and primary acetabular and on the market. No one from the MHRA contacted and resurfacing hip devices, ” the company said. femoral implants and instruments to meet indi- Mr Nargol and Mr Langton to follow-up their data “Because the decision was based on business fac- vidual patient needs.” For revision of both ASR despite the MHRA having a group specifically to tors, not safety concerns, the timing to discontinue resurfacing and ASR it recommends a total hip look at metal on metal concerns for several years. sales differed from country to country.” replacement. “DePuy option: ­Pinnacle,” it said—

BMJ | 21 MAY 2011 | VOLUME 342 1121 MEDICAL DEVICES

including the cobalt chrome metal implant. And analogous to that set up for drugs, involving 14 Zuckerman DM, Brown P, Nissen SE. Medical device recalls and the FDA approval process. Arch Intern Med 2011; Feb 14 in a briefing to the sales force it said the ­Pinnacle“ ­clinical trials, a licensing process, and postmar- [epub ahead of print]. is an alternative for the majority of patients.” keting surveillance. Some new products will 15 PricewaterhouseCoopers. Medical technology innovation scorecard. 2011. http://pwchealth.com/cgi-local/hregister. According to Mr Nolan, this probably wasn’t always have rare and unwanted consequences— cgi?link=reg/innovation-scorecard.pdf. the wisest thing to do. “I don’t think it is it’s an inevitable consequence of innovation. The 16 Australian Orthopaedic Association. National Joint ­advisable, in the presence of an adverse soft regulatory imperative is to ensure that these are Replacement Registry, annual report 2010. AOA, 2010. 17 Bulstrode CJ, Murray DW, Carr AJ, Pynsent PB, Carter SR. tissue reaction to a cobalt chrome implant, to limited in scale and picked up early. A good regu- Designer hips. BMJ. 1993;306:732-3. revise the hip replacement by using another latory system will benefit everybody by ensuring 18 Hopkins Tanne J. US makers of joint replacements are fined for paying surgeons to use their devices. BMJ 2007;335:1065. implant made of cobalt chrome. I feel strongly patients are not exposed unnecessarily to risk and 19 Serious Fraud Office. DePuy International Limited ordered that all cobalt chrome should be removed from that manufacturers and others are not exposed to to pay £4.829 million in Civil Recovery Order. www.sfo.gov. the affected joint,” he said. undue liabilities. uk/press-room/latest-press-releases/press-releases-2011/ depuy-international-limited-ordered-to-pay-%C2%A34829- But a much more widespread problem may be But will we learn from the story of the ASR and million-in-civil-recovery-order.aspx. looming involving a range of other makes and large head metal on metal prostheses? “I think we 20 US Department of Justice. Johnson & Johnson agrees to pay $21.4 million criminal penalty to resolve foreign corrupt models. And once again it illustrates the delicate have to rethink the whole system of how devices practices act and oil for food investigations. 2011. www. trade-off between innovation and safety. Like come on to the market and whether we should be justice.gov/opa/pr/2011/April/11-crm-446.html. resurfacing, the use of large head metal on metal doing things a bit differently from what we are 21 Dowson D, Hardaker C, Flett M, Isacc GH. Hip joint simulator study of the performance of metal-on-metal joints. Part I: the total hip implants has followed another surgical now,” Professor Graves says. role of materials. J Arthroplasty 2004;19 (suppl 3). trend. Heads have got larger to make them less 22 Dowson D, Hardaker C, Flett M, Isacc GH. Hip joint simulator Deborah Cohen is investigations editor, BMJ, London study of the performance of metal-on-metal joints. Part likely to dislocate. But with this comes associ- WC1H 9JR, UK II:Design. J Arthroplasty 2004;19 (suppl 3). ated corrosion problems where the head meets [email protected] 23 Finsbury Orthopaedics. ASR marketing and science. Bulletin No 58. 2006. www.finsbury.org/documents/ the stem. “Some cemented, stemmed, metal Competing interests: The author has completed the unified bulletin/058_030506.pdf. on metal implants have shown marked corro- competing interest form at www.icmje.org/coi_disclosure. 24 De Haan R, Pattyn C, Gill HS, Murray DW, Campbell sion of the stem and some large diameter head, pdf (available on request from her) and declares no support PA, De Smet K. Correlation between inclination of the from any organisation for the submitted work; no financial acetabular component and metal ion levels in metal-on- stemmed implants have shown corrosion at the relationships with any organisation that might have an metal hip resurfacing replacement. J Bone Joint Surg Br taper junction of the head/stem,” Mr Nolan says. interest in the submitted work in the previous three years; and 2008;90:1291-7. A two year follow-up study in 144 patients no other relationships or activities that could appear to have 25 Langton DJ, Sprowson AP, Joyce TJ, Reed M, Carluke I, influenced the submitted work. Partington P, et al. Blood metal ion concentrations after hip published at the beginning of May this year resurfacing arthroplasty: a comparative study of articular shows an incremental increase in metal ion Provenance and peer review: Commissioned; externally peer surface replacement and Birmingham Hip Resurfacing reviewed. arthroplasties. J Bone Joint Surg Br 2009;91:1287-95. levels over the study period in a range of large 1 FDA. Concerns about metal-on-metal hip implant 26 Morlock MM, Bishop N, Zustin J, Hahn M, Rüther W, Amling M. head metal on metal implants made by manu- systems. 2011. www.fda.gov/MedicalDevices/ Modes of implant failure after hip resurfacing: morphological ProductsandMedicalProcedures/ImplantsandProsthetics/ and wear analysis of 267 retrieval specimens. J Bone Joint facturers such as Zimmer, Biomet, DePuy, and Surg Am 2008;90(suppl 3):89-95. 39 MetalonMetalHipImplants/ucm241604.htm. Smith and Nephew. A letter from the British 2 Muirhead-Allwood SK. Lessons of a hip failure. BMJ 27 Lee RK, Essner A, Longaray J, Wang A. Metal-on-metal Orthopaedics Association sent out to members 1998;316:644. bearings: the problem is edge-loading wear. Surg Technol Int 2010;20:303-8. at the end of March says the use of large diam- 3 MHRA. Minutes of the committee on the safety of devices meeting 19 July 2001. www.mhra.gov.uk/home/groups/ 28 Kinbrum A, Unsworth A. The wear of high-carbon metal-on- eter metal on metal bearings in primary total es-cb/documents/committeedocument/con003574.pdf. metal bearings after different heat treatments. Proc Inst Mech Eng H 2008;222:887-95. hip replacement should be “carefully consid- 4 British Orthopeadic Association. Large diameter metal on metal bearing total hip replacements. 2011. www.boa. 29 Langton DJ, Joyce TJ, Mangat N, Lord J, Van Orsouw M, Smet ered and possibly avoided.” Data now show a ac.uk/site/showpublications.aspx?id=59. KD, et al. Reducing metal ion release following hip resurfacing higher than expected early failure rate, it said. 5 Schmalzried TP, Shepherd EF, Dorey FJ, Jackson WO, arthroplasty. Orthop Clin North Am 2011;42:169-80. dela Rosa M, Fa’vae F, et al. The John Charnley Award. 30 McMinn Centre. Northern lights debate ASR vs BSR. www. “These range from 21% revision rate at 4 years Wear is a function of use, not time. Clin Orthop Relat Res mcminncentre.co.uk/research-lectures-debate.html. (potentially rising to 35% if all currently known 2000;381:36-46. 31 Australian Orthopaedic Association. National Joint Replacement Registry, annual report 2007. AOA, 2007. painful implants progress to revision) to 49% at 6 Smith SL, Dowson D, Goldsmith AA. The effect of femoral head diameter upon lubrication and wear of metal-on- 32 Australian Orthopaedic Association, National Joint 6 years for the ASR XL device. Other devices have metal total hip replacements. Proc Inst Mech Eng [H] Replacement Registry, annual report 2008. AOA, 2008. a revision or impending revision rate of 12-15% 2001;215:161-70. 33 Della Valle CJ, Nunley R, Raterman S, Barrack RL. Early 7 Smith SL, Dowson D, Goldsmith AAJ. The effect of diametral American experience with hip resurfacing following FDA at 5 years,” it added. clearances, motion and loading cycles upon lubrication of approval. Clin Orthop 2009;467:72-8. And there continues to be debate within the metal-on-metal hip replacements. Proc Inst Mech Eng [C] 34 EU must tackle clinical trials shortfall. Clinica 2010 Jul 26. www.clinica.co.uk/policyregulation/regulation/EU-must- orthopaedic community about what constitutes 2001;215:1-5. 8 Cohen D, Billingsley M. Europeans are left to their own tackle-clinical-trials-shortfall. a large head—one or two centres are seeing prob- devices. BMJ 2011;342:d2748. 35 Langton DJ, Jameson SS, Joyce TJ, Webb J, Nargol AV. The effect of component size and orientation on the concentration of lems that others are not. As Mr Langton asked in 9 Haute Authorite de Sante. Commision d’evaluation des produits et prestations, 24 Jun 2008. www.etsad.fr/etsad/ metal ions after resurfacing arthroplasty of the hip. J Bone a presentation to the British Hip Society this year: afficher_lien.php?id=1696. Joint Surg Br 2008;90:1143-51. “Why is the first response not to suspend the 10 Langton DJ, Jameson SS, Joyce TJ, Hallab NJ, Natu S, 36 MHRA. Minutes of the Committee on the Safety of Devices Meeting, 23 March 2006. implantation [of a device] when legitimate con- Nargol AV. Early failure of metal-on-metal bearings in hip resurfacing and large-diameter total hip replacement: 37 Grammatopolous G, Pandit H, Kwon YM, Gundle R, cerns are raised?” a consequence of excess wear. J Bone Joint Surg Br McLardy-Smith P, Beard DJ, et al. Hip resurfacings revised for 2010;92:38-46. inflammatory pseudotumour have a poor outcome. J Bone 11 Kamali A, Hussain A, Li C, Pamu J, Daniel J, Ziaee H, et al. Joint Surg Br 2009;91:1019-24. Lack of regulator power Tribiological performance of various CoCr microstructures 38 Sulzer Medica. Sales growth of 5 percent—substantial The story of the ASR shows the power that com- in metal-on-metal bearings: the development of a group loss due to US litigation. PR Newswire, 2002. www. more physiological protocol in vitro. J Bone Joint Surg Br prnewswire.co.uk/cgi/news/release?id=83229). panies have in deciding the fate of their devices, 2010;92:717-25. 39 Lavigne M, Belzile EL, Roy A, Morin F, Amzica T, Vendittoli P-A. their hold over surgeons, and the lack of regula- 12 Shimmin AJ, Back D. Femoral neck fractures following Comparison of whole-blood metal ion levels in four types of metal-on-metal large diameter femoral head total hip tory power in Europe. Birmingham hip resurfacing: a national review of 50 cases. J Bone Joint Surg Br 2005;87:463-4. arthroplasty: the potential influence of the adapter sleeve. J The failure of the 3M hip over 12 years ago 13 Learmonth I. The operation of the century: total hip Bone Joint Surg Am 2011;93:128-36. prompted calls for a device regulatory system replacement. Lancet 2007;370:1508-19. Cite this as: BMJ 2011;342:d2905

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COMMENTARY John Skinner, Peter Kay Metal on metal hips Total hip replacement is one of the most successful that patients with levels of cobalt operation was performed and also operations of the 20th century and is currently or chromium ions above 7 parts centrally in the UK on the National performed in 70 000 patients a year in the UK,1 per billion should be investigated Joint Register, which is accessible 250 000 a year in the United States, and one million and ion measurements repeated through the hospital. worldwide. To improve wear and to allow bone as part of closer follow-up.10 But In the absence of pain with conservation through hip resurfacing, metal on metal measurements may also need to be a metal on metal bearing, no bearings were re-introduced in the 1990s.2. These are repeated in asymptomatic patients investigations are needed other made of cobalt chromium alloys, and in some series with levels between 3 and 7 parts than an annual assessment and the hip resurfacing has shown excellent results in younger per billion, particularly in those with prompt reporting of new symptoms. active patients.3 Hip resurfacing became popular with large diameter metal on metal total The MHRA guidelines included four patients through the internet as a younger person’s hip replacements, perhaps at 6-12 situations in which to test blood solution to arthritis that allowed high activity levels. months.11 There is evidence that for metal ions: pain or symptoms SOVEREIGN,ISM/SPL It was used in 10% of hip arthroplasties in the UK levels are higher in the first 6-12 associated with metal on metal between 2006 and 2009 and in 50% of all hip months after insertion of a metal on metal bearing as bearings; radiological features associated with adverse replacements in patients younger than 50 years.1 it beds in and then they fall, in some patients.12 outcomes including component position or small Problems with hip resurfacing that were initially As yet, the level of cobalt or chromium at which component size; concerns of the patient or surgeon reported included raised blood cobalt and chromium revision surgery is advised has not been clearly about the bearing; and concerns about a cohort of ions,4 loosening of components,5 hip fracture,6 and defined.13 Blood metal ion levels are therefore an patients with higher than expected failure rates. soft tissue reactions around the hip.7 In an attempt to adjunct in assessing metal on metal hip function at The MHRA has suggested follow-up for five years overcome the fracture problem and to extend the use present. Revision surgery should be performed in for all metal on metal implants and for the life of the of large diameter metal on metal bearings to those patients with substantial pain, worsening pain, limp, prosthesis in patients with the ASR/ASR XL. Patients not suitable for hip resurfacing, metal resurfacing type or poor function. Similarly, it should be considered in who have painful metal on metal implants should bearings were introduced on total hip replacement those with rising blood metal ions, increasing or large be reviewed by their orthopaedic surgical team as stems.8 These large diameter metal on metal total fluid collections or masses, around the hip.13 above. The decision whether to revise the hip remains hip replacements had a lower theoretical rate of The risk to patients of failing metal on metal a clinical one between the patient and the surgeon, dislocation. In fact, metal on metal bearings were used implants is a progressive inflammatory response guided by the above investigations. in up to 35% of all total hip replacements in the United leading to tissue necrosis around the hip. All joint The British Orthopaedic Association and British Hip States in 2009.9 replacements using conventional bearings of metal on Society advice is that large diameter metal on metal The commonest symptoms of adverse reactions polyethylene, ceramic on polyethylene, or ceramic on total hip replacements should not be performed until to metal debris are pain, swellings around the hip, ceramic will wear and may fail, with debris generating more is known about their mode of failure (13% and loss of function with reduced exercise tolerance different adverse responses. These include metallosis, revision rate by 5 years on the UK NJR), except in and onset of limp. Soft tissue osteolysis, loosening and exceptional circumstances. swellings, fluid collections or Hip resurfacing with dislocation.14 The difference Hip resurfacing with components that have proven “bursas” may be noticed in the components that have proven with metal on metal bearings track records are an effective and safe treatment in groin, buttock, or laterally. Pain track records are an effective seems to be the potential the active under-55 age group, with favourable hip and symptoms in patients with and safe treatment in the to develop necrosis and cell anatomy with component survival rates of 97-98% at metal on metal hips should be active under-55 age group death in tissues around the 10 years in men and slightly less in carefully selected investigated and referred to an hip. They can occur with all women.3However, adverse metal reactions can still be orthopaedic surgeon. Normal causes of pain should metal on metal bearings in both hip resurfacing and seen in this group. be excluded as for any hip replacement (infection, total hip replacements. They are more likely in women, John Skinner is a consultant orthopaedic surgeon and component loosening, lysis/wear, pain referred from with small component sizes (in hip resurfacing), with chair, the British Orthopaedic Association another source). Full clinical assessment should particular implants, with raised blood metal ions, and [email protected] be accompanied by radiographs, full blood count, in components in suboptimal positions. If a painful Peter Kay is a consultant orthopaedic surgeon and erythrocyte sedimentation rate, and C-reactive protein. metal on metal hip is revised before substantial soft president, the British Orthopaedic Association Cross sectional magnetic resonance imaging using tissue damage the outcome is likely to be excellent.15 If Competing interests: All authors have completed the metal artefact reduction sequences or ultrasound substantial tissue damage occurs then revision surgery Unified Competing Interest form at www.icmje.org/coi_ should also be performed to look for fluid collections is associated with poorer function and higher rates of disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for 16 (common) or solid masses (rare) around the implants. complication including limp and dislocation. the submitted work; PK has previously acted as consultant Hip aspiration and injection may be helpful. In 2010, the ASR hip resurfacing and the ASR XL for Johnson and Johnson in the development of a cemented Blood should be taken for cobalt and chromium ion THR were recalled because of higher than expected cross-linked polyethylene acetabular component, for which no royalties are received, nor are any ongoing payments measurements; again this is best done as part of an rates of failure.17 The company has agreed to fund all linked to its use; no other relationships or activities that could orthopaedic assessment. In asymptomatic patients investigations and revision surgery. Not all patients appear to have influenced the submitted work. with well functioning metal on metal implants, levels know whether they have a metal on metal bearing; Provenance and peer-review: Commissioned, not of these ions are low, typically around 2 parts per all patients with a hip resurfacing do and a minority externally peer reviewed. billion (µg/L or ng/mL).4 In the UK, the Medicines and of patients with total hip replacements do. This References can be found on bmj.com Healthcare products Regulatory Agency has suggested information is recorded at the hospital where the Cite this as: BMJ 2011;342:d3009

BMJ | 21 MAY 2011 | VOLUME 342 1123 MEDICAL DEVICES EUROPEANS ARE LEFT TO THEIR OWN DEVICES When it comes to the regulation of medical devices, Europeans seem to get a worse deal than Americans. Deborah Cohen and Matthew Billingsley compare the regulatory systems

lick and efficient or opaque and cerns about the current system, saying that “the on market authorisation of high risk devices are patchy—these are two of the views evidence on safety and efficacy of new devices made by privately run notified bodies rather than about the European medical device and new procedures at the time they are intro- government agencies (box 1). Together with the regulatory system expressed during a duced into UK practice is very variable.” It has manufacturers, they are therefore the most funda- recent US Congress debate. But unlike also suggested that the evidence base for most mental part of devices market approval and moni- Sthe case with, say, consumer drug advertising, the devices was poor.6 toring.9 Notified bodies issue a certificate when a devices industry argues that conditions are more The number of different types of devices on device has been approved. Companies can then favourable in Europe. the market is about 80 0007 in the UK and over affix a CE [Conformité Européenne] mark, the EU “European regs are driven by one key goal: 200 0008 in Europe. Uncertainty surrounds the safety standard. innovation,” one industry report suggests.1 numbers because there is no publicly available In the UK the knowledge problem is com- And another says that the conditions in Europe list of devices being used day to day in health- pounded by the fact that NHS procedures are favour medical technology companies—they can care settings. The MHRA does not know pre- poorly coded12— although in future all medical obtain regulatory approval more quickly, gener- cisely which class III devices (the most risky) devices should have a barcode.6 So, while we can ate ­revenues faster, and “engage patients and have been cleared for use in the UK or Europe. get detailed information about which drugs are providers in the cycle of innovation to advance Such devices include stents, prosthetic heart being used in the NHS, the same does not apply their products and services.”2 valves, hip implants, and pacemakers. to devices. John Wilkinson, chief executive of Eucomed (a One reason for the ignorance is that decisions The MHRA told the BMJ and Channel 4 European medical device industry trade associa- ­Dispatches that a “list of class III devices tion), said in a report: “The current EU regulatory Box 1 | Notified bodies and EU approval would not be helpful or beneficial.” But MHRA system makes innovative medical technology process ­documents suggest otherwise. available to people the fastest in the world while Decisions about marketing a new medical “Once CE marked, devices can enter wide- ensuring the highest safety standards.”3 device are made by notified bodies. These spread use without any organised monitoring of organisations are accredited by national But although the conditions might be more the outcomes of their use. Long term outcomes regulators—eg, the MHRA in the UK—as being favourable to industry, not everyone agrees that competent to make independent judgments of implanted devices are a particular concern,” 6 this is the best for patients—and that includes the about whether a product complies with the it says. director of the US Food and Drug ­Administration’s CE marking directive. Currently, there are 76 The agency told us that it relies on a “statutory centre for devices and ­radiological health, Jeffrey notified bodies in Europe and six in the UK, vigilance or voluntary adverse incident report- Shuren. Responding to a plastic surgeon’s descrip- including BSI, SGS, and Intertek.10 ing system” to regulate—in other words, govern- tion of what happens in the EU, he said, “We don’t A manufacturer must demonstrate to the mental regulation really starts when devices are use our people as guinea pigs in the US.”4 notified body that the safety of the device already on the market. A similar debate is being conducted within complies with the legal requirements in the EU The FDA takes a different tack. Each class III 11 the European Commission—and on some levels medical device directives and submit a precise device that has either been approved or cleared definition of the intended use of a device. the Europeans agree. Medical device regula- through its regulatory mechanisms is on its web- For the highest risk devices (class III), the tion falls under EU directives, which in turn are site together with the scientific rationale for the manufacturer must conduct some human implemented by each member state’s national clinical investigations, but these needn’t device being on the market. In the US, devices regulator. But the EU claimed earlier this year be randomised clinical trials or evaluate can only be marketed for a clinical claim that is that there was a need to “adapt the European effectiveness.8 A manufacturer need do no more included in labelling that has been reviewed by regulatory framework in order to secure patients’ than produce a comparative literature review if the FDA. safety while favouring innovation.”5 However, it they are arguing that their device is similar to an is uncertain how much its proposals will actually existing (predicate) product.8 Variable standards change the current system—financial constraints National regulators are responsible for There are agreed European standards for medical may mean that only tweaks are made. auditing the notified body. If a medical device devices. But there’s concern that these standards needs to be removed from the market, it is the are not uniformly applied. An AMHRA meeting responsibility of the notified body to suspend Unknown quantity noted that there were discrepancies between its certificate and of the notified body and the The UK regulator, the Medicines and Healthcare manufacturer to let the regulator know. the notified bodies: “Although the UK Notified Products Regulatory Agency (MHRA), has con- Bodies are accredited to EN 13485 [conformity

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John Wilkinson, chief executive The UK’s Medicine and Rita Redberg, a cardiologist The European Medicines Jeffrey Shuren, director of the of Eucomed, an industry trade Healthcare Products and editor of Archives of Agency based in Canary US FDA’s centre for devices and association Regulatory Agency Internal Medicine Wharf, London radiological health

to the EU quality and safety standard] by UKAS Office of In Vitro Diagnostics publishes a summary tators argue that manufacturers of devices used [United Kingdom Accreditation Service], there are of the basis for its 510(k) clearance decisions for in in medicine “have the same ethical responsibili- some Notified Bodies in Europe with only two or vitro diagnostic tests. It also publishes a summary ties to the individual patient as those companies three staff, and these may be operating to differ- of safety and effectiveness data for original post- which manufacture and sell drugs.”8 ent standards.”13 In other words, some of the key market approvals. The Office of Device Evaluation, organisations appointed to control what enters the which reviews all other medical devices, is moving Safety questions European market might not be rigorous enough in towards providing the same information Earlier this year, Rita Redberg, editor of Archives checking how safe or well a device works. “We find great value in being as transparent as of Internal Medicine and a cardiologist, told Con- It’s something that concerns the Association possible. It helps patients and health care prac- gress: “I can’t help but wonder why clinical trials of British Healthcare Industries. “We need to titioners use a device safely and correctly, and it are widely accepted by the pharmaceutical indus- improve the performance of the notified bodies builds trust between patients, practitioners, and try as essential to ensure patient safety, but not by so that they are all checking these requirements the government. Clinicians need to be able to the device industry.”17 Drug regulation is a much to the same high level,” it said. evaluate a device’s risks and benefits, how to use older discipline than device regulation—any leg- Manufacturers can choose the notified body it appropriately, and for which patients. It can help islation on device regulation came into being only to which they submit their application. In his clinicians and patients make better informed deci- in the early 1990s. Yet in the past 10-20 years the testimony to Congress, Dr Shuren said that the sions,” Dr Shuren told the BMJ. number and complexity of medical devices has system allows them to pick the notified body that Nor does the same apply to medicines exploded, particularly in cardiology and ortho- they think will put their device through the least approved by the European Medicines Agency. paedics. Dr Redberg added: “In contrast to most stringent checks. The EMA has come under attack for being secre- devices in the 1970s, the newer products pose Despite these concerns, the decision making tive and opaque, but at least scientific rationale substantially greater risks—even life threaten- process is kept behind closed doors. There is no and study summaries are published along with ing risks—to patients. For example, many new publicly available summary describing the basis updates about the evidence detailing clinical medical devices are permanently implanted in a for granting a CE mark and neither is this available claims for a drug. patient’s body and can be moved or changed, if at to genuine clinical academic researchers. Doctors and patients should know what a all, only with great risk to the patient.”17 When we contacted 192 manufacturers device has been approved to do. And here’s the In the US there are currently two ways for a requesting evidence of the clinical data used to rub—in Europe the highest risk devices have to class III device to get on to the market—through approve their devices,14 they denied us access, go through tests to establish their safety and per- the premarket authorisation route (PMA) or the claiming that “clinical data is proprietary informa- formance. They do not have to prove any effect on less stringent 510(k) process (box 2). tion,” that it was “company confidential informa- clinical outcomes, even when a new technology Although 90% of devices in the US are approved tion,” and that they could discuss only “publicly is being introduced. through the 510(k) route,2 Dr Shuren says that the available information.” As Dr Shuren told the US Congress: “If a FDA approach is more protective to the public than Likewise, when we asked the relevant notified manufacturer wishes to market a laser to incise the European one. “The US system has served bodies for the scientific rationale for approval of heart tissue to treat arrhythmia (abnormal heart patients well by preventing EU approved devices various devices that had been recalled, the results rhythm) in the EU, the manufacturer must show that were later shown to be unsafe or ineffective were stark. This information was classed as confi- that the laser incises heart tissue only. In the US, from harming American consumers,” he said in dential because notified bodies were working as however, the manufacturers must show that his testimony to Congress. a client on behalf of the manufacturers—not the the laser incises heart tissue and also treats the The BMJ and Channel 4 Dispatches were sent people who have them implanted in their bodies. arrhythmia.”16 a document listing six devices that were recently But, as Dr Shuren put it: “For the public in the EU, This is also something that the EU has raised. on the market in Europe but were rejected by the there is no transparency. The approval [require- A 2005 report says: “Questions have arisen on FDA after going through the PMA approval pro­ ments] are just what deal is cut between the device the evaluation of the design of a product and, in cess (box 3). company and the private [notified body].”15 particular, the absence of clear rules on design Most of the problems in the US have been with But is this an acceptable situation? It’s not a line evaluation, including verifying the sufficiency devices approved through the 510(k) route. Dur- that the FDA follows. and adequacy of clinical data.”9 ing 2005 to 2009, there were 113 device recalls The FDA publishes information on its web- Again this is unlike the expectations before that the FDA classified as high risk. Eighty (71%) site about the basis for its approval decisions. The drugs gain market approval—and some commen- of these were cleared through the 510(k) route—

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Box 2 | FDA processes patient safety. However, no information is avail- mation obtained in carrying out their tasks.”25 Premarket authorisation (PMA)—The most able to suggest that patient safety in Europe has Recent changes won’t increase transparency: stringent type of approval of devices and been compromised.”24 the European Commission’s database to share similar to processes for drug regulation. The Association of British Healthcare Indus- information about devices among the national Manufacturers must submit their product tries agrees that the lack of transparency leads regulators (Eudamed) came into full operation to extensive testing to prove it is both “safe to misunderstanding and mistrust. “Today it is this month, but the data will not be publicly and effective for its intended use.” It was very hard for anyone, even manufacturers and available. developed as a pathway for the approval of authorities, let alone citizens, to find out what devices that “support or sustain human life, products are approved to be on the market. We Postmarketing problems are of substantial importance in preventing impairment of human health, or which prevent would like to see enhanced transparency and The European system relies more on postmarket- a potential, unreasonable risk of illness or information to patients, citizens, and all EU gov- ing surveillance than it does on premarket testing. injury.”18 ernment authorities.” It proposes a central EU But what does this entail? For drugs, extensive database to avoid 27 national databases dupli- phase IV trials and studies are usually man- 510(k)—This is sometimes referred to as the cating their efforts. dated by the regulators to help identify adverse “substantial equivalence” route for class Even the Freedom of Information Act is of no reactions. And the FDA mandates postmarket- III devices. Initially intended for the likes of use in obtaining information on adverse events. ing surveillance studies for class III devices and surgical gloves and less invasive instruments, The BMJ/Channel 4 Dispatches attempts to get some class II devices as a condition of approval. it is now used to enable manufacturers to access to adverse incident reports for the Pin- In Europe, however, manufacturers of devices are make tweaks to existing products without nacle and ASR hip implants and the HighRes obliged to implement a “medical device vigilance having to go through the extensive PMA 90k cochlear implants from the MHRA through system” to monitor their products once they are route. Companies also use it if there is an the act were thwarted because it is overridden on the market. This is monitored by the notified existing product on the market (known as a by medical device legislation. Article 15 of the bodies and audited by the MHRA in the UK. predicate device). In this case manufacturers EU Medical Devices Directive states: “Member But how manufacturers do this is not man- have only to show that their new product is States shall ensure that all the parties involved dated. Rather than have large postmarketing stud- “substantially equivalent” to the predicate in the application of this Directive are bound to ies, manufacturers may rely simply on feedback device.19 observe confidentiality with regard to all infor- from users. Steve Owen, head of Devices Policy,

although only 13 (12%) were class III devices. Box 3 | FDA rejected devices that were CE marked in\ Europe However, some major devices, such as hip and knee implants, fell into class IIb.23 Covidien PleuraSeal lung sealant system This device went on the EU market in November 2007 and is used during elective pulmonary resection The FDA also maintains a database of reported as an adjunct to standard closure techniques for visceral pleural air leaks. It has been approved for use adverse events and device malfunctions (called on the dura and spine in the US. However, the Investigational Device Exemption (IDE) study (a clinical MAUDE). The reports list the device and its man- study for FDA regulatory purposes) produced unexpected interim results. In October 2010 Covidien ufacturer but no patient details. This database announced a worldwide recall of all PleuraSeal lung sealant systems provides the agency with safety signals, which can provoke further and deeper investigation. Medtronic Chronicle The Chronicle is an implanted system designed to measure and record haemodynamic variables “By publishing device safety and effectiveness continuously. In March 2007, an FDA panel refused to approve the device, citing statistically information, experts, industry and the public insignificant results as “lack of clinical effectiveness.” It was nonetheless approved in Europe, raising can do their own analysis. In fact, it keeps the questions about the cost and necessity of the procedure. FDA in check. Device problems have been high- lighted to us by other people going through the PIP breast implants reports and drawing our attention to an issue,” In 1991, breast implants manufactured by Poly Implant Prosthese (PIP) received a CE mark for its Dr Shuren says. silicone breast implants But in 2001 they changed the gel, so that it was different from the one described in the CE marking file.20 This modification led to rupture rates higher than silicone implants However, in Europe, it’s almost impossible for made by other manufacturers.21 On 30 March 2010, the French regulator—AFSSAPS— issued a recall of independent researchers to assess the extent of all pre-filled silicone breast implants manufactured by PIP, affecting an estimated 35 000-45 000 women 14 the health problems posed by recalled devices. worldwide. In April 2011, the AFSSAPS had found that there is no link between the PIP and genotoxicity Because information is confidential, companies but that “test results have confirmed that the gel inside can bleed through the pocket of the implant.”22 would often not tell us who had issued a device’s CE mark or what class the device was approved Trilucent breast implants First marketed in the UK in 1995 by LipMatrix, Trilucent implants were recalled and withdrawn from the as. Furthermore, neither lists of devices on the market in 1999. The filler of the implants, which was derived from soybean oil, broke down in the body market nor the number of adverse event reports and leaked through the shell, causing ruptures. The breakdown of the filler was significantly different for each device is publicly available, meaning from that predicted during preclinical testing, and many patients had to have implants removed. that rates of safety problems cannot be accu- rately calculated. Conor CoStar drug eluting stent It’s something that companies acknowledge— CoStar is a cobalt, chromium, paclitaxel eluting coronary stent and received EU approval in 2006. In May 2007, Johnson and Johnson announced that a pivotal clinical study of the device had failed to find a although from a slightly different angle. A trade significant difference on the primary end point, possibly because patients got a suboptimal therapeutic group that lobbies for the medical device indus- dose of paclitaxel. The trial did not identify safety issues. As a result of this trial, Conor terminated try said in a report: “The reasonable question has ongoing clinical trials and chose not to conclude the submission of its US premarketing approval. Conor been raised whether greater regulatory efficiency discontinued the sale of the stent in Europe, Asia, and Latin America. in the EU has been achieved at the expense of

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European and Regulatory “some kind of proof of 11 European Commission Enterprise and Industry “I can’t help but wonder Directorate General. Clinical evaluation: a guide for Affairs at the MHRA, has benefit before bringing manufacturers and notified bodies MEDDEV 2.7.1 Rev stated that he finds it “stag- why clinical trials are medtech products onto 3. December 2009. http://ec.europa.eu/consumers/ sectors/medical-devices/files/meddev/2_7_1rev_3_ gering” how many manu- the market, just as for en.pdf facturers fail to fully fulfil widely accepted by the drugs.”28 12 Lyratzopoulos G, Patrick H, Campbell B. Registers their legal responsibility to As Dr Redberg said needed for new interventional procedures. Lancet pharmaceutical industry 2008;371:1734-6. collect product data once about the situation in 13 MHRA Committee on the Safety of Devices. Meeting their device is on the mar- as essential to ensure the US, this needs to be minutes, 19 Nov 2010. www.mhra.gov.uk/home/ 26 groups/clin/documents/committeedocument/ ket. And according to an patient safety, but not through the “proper use con105808.pdf. MHRA report: “Post-market of evidence-based medi- 14 Heneghan C, Thompson M, Billingsley M, Cohen D. Medical device recalls in the UK and the device surveillance has not been by the device industry” cine and well-designed regulation process: retrospective review of safety addressed sufficiently in the clinical tests before the notices and alerts. BMJ Open doi:10.1136/ bmjopen-2011-0155. past, as many manufacturers do not focus on this devices are approved and clinical registries 15 Shuren J. Debate on 510(k)s and recalls reaches area, and it is not ‘policed’ vigorously enough by to track outcomes in real time after they are Capitol Hill. theheart.org 2011 Feb 18. www.theheart. Notified Bodies.”6 approved.”17 org/article/1188437.do 16 Shuren J. Statement before the subcommittee on Company reporting—which is often slow—is Deborah Cohen investigations editor, BMJ, London health. Impact of medical device regulation on jobs supplemented by clinicians and patients report- WC1H 9JR, UK [email protected] and patients. 2011. www.fda.gov/NewsEvents/ Testimony/ucm243716.htm . ing adverse reactions to any devices to the MHRA. Matthew Billingsley editorial intern, BMJ, London 17 Redberg RF. Testimony to subcommittee on health, However, we know that most adverse drug reac- WC1H 9JR, UK House Committee on Energy and Commerce, February 17, 2011. http://republicans.energycommerce. 27 Competing interests: All authors have completed the Unified tions are not reported, although whether that’s house.gov/Media/file/Hearings/Health/021711_ true of devices is unknown. Competing Interest form at www.icmje.org/coi_disclosure. Health/RitaRedberg.pdf. pdf (available on request from the corresponding author) and 18 US Food and Drug Administration. Medical One way to capture problems with devices is to declare no support from any organisation for the submitted devices: premarket approval. www.fda.gov/ use a register. Although registers are not a replace- work; no financial relationships with any organisation that might medicaldevices/deviceregulationandguidance/ ment for clinical trials, they can provide data on have an interest in the submitted work in the previous three howtomarketyourdevice/premarketsubmissions/ years; and no other relationships or activities that could appear premarketapprovalpma/default.htm. long term safety, performance, and reliability and 19 US Food and Drug Administration. Medical devices: to have influenced the submitted work. allow early identification of problems. Registers premarket notification (510k). www.fda.gov/ Provenance and peer review: Commissioned; externally peer medicaldevices/deviceregulationandguidance/ have been crucial in identifying problems with reviewed. howtomarketyourdevice/premarketsubmissions/ premarketnotification510k/default.htm. devices that have not gone through adequate 1 Bylander J. Eucomed Q&A: where do EU regs get it 20 Agence Francaise de Securite Sanitaire des right? An emphasis on innovation. The Gray Sheet premarket clinical testing, such as those occur- Produits de Sante. Silicone filled breast implants 2011;37(Mar 14):1. ring with metal hip implants. manufactured by Poly Implant Prosthese (PIP). 2 PricewaterhouseCoopers. Medical technology Press release, 1 April 2010. www.afssaps.fr/ Although no one wants to slow the pace of innovation scorecard. 2011. http://pwchealth.com/cgi- var/afssaps_site/storage/original/application/ innovation—it has brought dramatic improve- local/hregister.cgi?link=reg/innovation-scorecard.pdf. ff8f7014c6ee1b6674c8fb7dd2835840.pdf. 3 Wilkinson J. EU regulatory system brings Europeans 21 Agence Francaise de Securite Sanitaire des Produits ments to people’s quality of life—the system fastest access to medical technology without de Sante. Silicone filled breast implants from Poly needs fine tuning. Given past problems and compromising safety. Eucomed press release, 28 Implant Prothèse Company. Tests results. 28 Sep Jan 2011. www.eucomed.org/newsroom/8/19/ the rapid pace of innovation over the past 20 2010. www.afssaps.fr/var/afssaps_site/storage/ EU-regulatory-system-brings-Europeans-fastest-access- original/application/38fbe37bdd1897eb09de4f89 years, the EU’s propensity to support innovation to-medical-technology-without-compromising-safety/. 2a317c14.pdf. needs to be balanced with better protection of 4 Richwine L. “Guinea pig” remark spurs US, 22 MHRA. French regulator confirms non-toxicity of EU device spat. Reuters 2011 Feb 24. www. PIP breast implants. Press release, 21 April 2011. the public. reuters.com/article/2011/02/25/us-devices- www.mhra.gov.uk/NewsCentre/Pressreleases/ While an FDA style regulator for Europe has idUSTRE71O0P020110225. CON114614. 5 European Commission. Exploring innovative healthcare 23 Zuckerman DM, Brown P, Nissen SE. Medical device been advocated by some, it’s unlikely to happen. – the role of medical technology innovation and recalls and the FDA approval process. Arch Intern Med But having one agency that regulates devices and regulation. 2011. http://ec.europa.eu/consumers/ 2011; Feb 14 [Epub ahead of press]. sectors/medical-devices/files/exploratory_process/ 24 Makower J, Meer A, Denend L. FDA impact on US drugs has had its benefits in the US—institutional hlc_final_conclusions.pdf. medical technology innovation. 2010. www. memory is collective and experts from both the 6 Campbell B. Report on registers—for the MHRA. advamed.org/NR/rdonlyres/040E6C33-380B-4F6B- device and the drug centres can share exper- 2010. www.mhra.gov.uk/Howweregulate/Devices/ AB58-9AB1C0A7A3CF/0/makowerreportfinal.pdf. Devicesregulatorynews/CON082083 25 European Commission. Article 15. Directive tise and information easily. And data obtained 7 How medical devices are regulated in the UK. Drugs 2007/47/EC Of The European parliament and of the through postmarketing studies, adverse event Ther Bull 2010;48:82-4. council. http://ec.europa.eu/consumers/sectors/ 8 Fraser AG, Daubert JC, van de Werf F, Estes NA, Smith medical-devices/files/revision_docs/2007-47- reporting, and premarket applications from SC Jr. Clinical evaluation of cardiovascular devices— en_en.pdf. other manufacturers can inform the questions principles, problems and proposals for European 26 Maxwell A. EU seriously failing post-market surveillance, says UK regulator. Clinica 2010 May asked about new devices submitted for approval regulatory reform. Eur Heart J 2011 http://eurheartj. oxfordjournals.org/cgi/reprint/ehr171. 19. www.clinica.co.uk/policyregulation/vigilance/ and the decision subsequently made. “It’s much 9 European Commission. Commission staff working EU-seriously-failing-post-market-surveillance-says- harder to learn if you don’t get all the informa- document. Annex to the proposal for a directive of the UK-regulator-289356?autnID=/contentstore/clinica/ European Parliament and of the Council amending codex/c7189da9-6257-11df-bc1e-c5d67941f290. tion,” Dr Shuren says. Council Directives 90/385/EEC and 93/42/EEC and xml. And there are calls for drugs and devices to be Directive 98/8/EC of the European Parliament and 27 Hazell L, Shakir SAW. Under-reporting of adverse drug reactions: a systematic review. Drug Safety put more on an equal footing in terms of evalua- the Council as regards the review of the medical device directives impact assessment. 2005:8. http:// 2006;29:385-96. 28 Yeo A. Windeler of change: medtech must prove its tion. Jürgen Windeler, director of the Institute for ec.europa.eu/consumers/sectors/medical-devices/ worth, insists German HTA chief Clinica 2011 Jan files/revision_docs/entr_pe_dts_ia_md_en.pdf Quality and Efficiency in Health Care in Germany, 6. www.clinica.co.uk/policyregulation/Windeler- 10 European Commission Enterprise and Industry. of-change-medtech-must-prove-its-worth-insists- agrees that the current process of device approval Notified bodies. http://ec.europa.eu/enterprise/ German-HTA-chief-308183?autnID=/contentstore/ does not address the same level of detail as that newapproach/nando/index.cfm?fuseaction=directive. clinica/codex/f964fd9f-083c-11e0-bd26- notifiedbody&dir_id=13&type_dir=NO%20CPD&pro_ b56fabe1b06f.xml. for drugs: “I agree with the CE marking, but it’s id=99999&prc_id=99999&ann_id=99999&prc_ not enough,” he said. He also added that we need anx=99999. Cite this as: BMJ 2011;342:d2748

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COMMENTARY C Di Mario, S James, D Dudek, M Sabate, M Degertekin The risk of over-regulation Regulatory bodies are expected to protect the evidence for the representatives of the cardiology varying requirements of different devices. It is illogi- public from the danger of inappropriately tested and ­cardiothoracic surgical associations to agree cal to have similar requirements for a new thrombec- treatments—a shield against the vested interest of on common guidelines defining the relative merits tomy catheter and for a stent using a new drug and drug and device companies to sell products irre- and indications of the two strategies.2 eluted by a novel fully ­biodegradable polymer. In spective of their safety and effectiveness. The idea New techniques introduced with more stringent the second situation clinical outcome measures of the greedy industrialist focused on short term regulatory processes risk being stopped before pro- are required. Number of patients should not be advantage and endangering lives with low quality gressing to show their full poten- the only qualifying aspect of components used to save manufacturing costs is tial and find their true indications. registration trials. We cannot familiar to the public and seems to justify stringent For a new ­transcatheter device expect that a trial in a selected regulatory processes. But one person is forgotten in to treat mitral ­insufficiency, the subgroup of patients will apply this equation—the doctor. MitraClip, the Food and Drug to the wider population treated The doctor is directly accountable to the patient ­Administration requested a in clinical practice. Allcomers and is expected to have the competency and moti- randomised ­comparison with studies—started as the personal

vation to select appropriate devices and drugs. valve surgery, a mature tech- SOVEREIGN,ISM/SPL initiative of few ­European inves- The personal ethical responsibility of every doctor nique ­benefiting from more Uniformly increasing the tigators4‑7—should become a towards his or her patient may get diluted in the than 30 years of experience. hurdles in the regulatory strict requirement for approval impersonal setting of large hospitals run by gov- The result was not convincing process risks raising of truly new stents. ernments or private health providers. Doctors have enough for the FDA to grant costs without any real If a stringent scrutiny is largely ceased to be independent professionals and approval. In Europe, where increase in patient safety applied to preregistration became employees forced to follow rules aimed at the device received a CE mark, mechanical testing and clini- maximising profit and containment of expenses. The ­doctors have used it not to replace reconstructive cal studies, unforeseen surprises are unlikely with medical industry is the main source of sponsorship mitral valve surgery but to provide alternatives to wider clinical applications. But doctors and regulators for clinical trials and the main supporter of post- the failure of medical therapy in inoperable patients still have a commitment to their patients to ensure graduate medical education. This creates links with and those with severe heart failure and secondary that a sufficiently large and prolonged follow-up industry that have been overemphasised, depict- insufficiency—probably a more logical application is available. The European Society of ­Cardiology’s ing doctors like car dealers with a vested interest for this technique than the comparison with surgery ­EurObservational research programme8 is an ambi- to “sell” products. The net result has been a shift of requested by the FDA. Even though the device is tious project to monitor cardiac interventions, similar power in the decision making process about provid- manufactured in the United States, it is available to the successful initiatives in Sweden.9 Sponsorship ing and regulating healthcare from the medical pro- there only for restrictive compassionate use appli- of such registries for device surveillance and recom- fession to administrative bodies. But have patients cations forcing patients to go abroad for treatment. mendation to the various national health authorities truly benefited from these changes and should we to enforce and police their applications are likely to continue in this direction and strengthen the power Middle Ground be more effective ways of protecting patients than of regulatory bodies policing the introduction and Critics of the current European system argue that doubling the European Medicines Agency’s offices, monitoring of new devices across Europe? the system leads to inconsistency because of the employees, and consultants to extend its compe- variable attitudes of notified bodies and national tency over devices. Lessons from interventional cardiology regulators. Patients should enjoy the same protec- C Di Mario is professor, Royal Brompton Hospital, Interventional cardiology, in which progress is tion everywhere in the world, and the standardi- London SW3 6NP, UK [email protected] strictly linked to technical development, is a gold- sation recommended by Fraser and colleagues S James is associate professor, Uppsala Clinical mine of examples warning against the potential is desirable.3 The number of drug eluting stents Research Centre, Uppsala University, Uppsala, Sweden risks of over-regulation and showing that even the approved in Europe is 10 times greater than D Dudek is professor, Jagiellonian University, Krakow, Poland strictest regulatory process does not offer the full in the US, and many of those approved offer no M Sabate is professor, Hospital Clinic, protection expected. We now know that coronary advantage over bare metal stents for restenosis University of Barcelona, Spain angioplasty saves the lives of patients with acute prevention or have much worse results than other M Degertekin is professor, Yeditepe University Hospital, myocardial infarction and selected patients with drug eluting stents. This can be corrected by doc- Istanbul, Turkey acute coronary syndrome. But when Gruentzig and tors, who can choose only well proved devices for Competing interests: All authors have completed colleagues first described the technique in 1977,1 their patients. Medical societies such as the Euro- the Unified Competing Interest form at www.icmje. org/coi_disclosure.pdf (available on request from the it was not mature enough to be used for these pean Society of Cardiology are also helping in the corresponding author) and declare no support from any challenging indications. Possibly the most widely selection process, producing guidelines that rec- organisation for the submitted work; CdM has received applied “surgical” procedure in the world would ommend only devices with sufficient ­evidence.2 speakers fees from Cordis, Biosensors, and Abbott and trial sponsorship from Medtronic, Biosensors, Biotronik. have died in its infancy if powerful regulatory bod- Unfortunately, stents and other devices are increas- DD has received grants and fees for speaking and writing ies had demanded demonstrations of equivalency ingly selected by hospital managers based on their from numerous drug and device companies. They have no or superiority to the other mechanical revascularisa- cost rather than performance. other relationships or activities that could appear to have influenced the submitted work. tion technique available, coronary bypass surgery. Although there is room for improvement, Provenance and peer review: Commissioned; not It took more than 30 years and numerous trials ­uniformly increasing the hurdles in the ­regulatory externally peer reviewed. of balloon angioplasty, bare metal stents, drug process risks raising costs without improving patient References can be found on bmj.com eluting stents versus surgery to have sufficient safety. The approval process must ­acknowledge the Cite this as: BMJ 2011;342:d3021

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COMMENTARY Nick Freemantle Evaluating and regulating device therapy­ The current European regulatory framework—CE reducing device size rather than increasing bat- generally in the public domain, this raises the risk marking—might provide ­sufficient safeguards for tery life, which would benefit patients and health of inadvertent public sponsorship of commercially electric toasters and kettles, but it is not adequate systems by reducing the frequency of explanting ­organised trials. for treatments that can affect symptoms, health and reimplanting devices. Evolution also raises the Confirmatory trials that aim to establish the related quality of life, serious morbidity, and prospect that a device used in practice may differ effect of a device on serious morbidity and mortal- ­mortality. in some ­important aspect from that evaluated as ity require adequate numbers of participants and There are many kinds of medical devices for part of the regulatory process. sufficiently long follow-up, just as they do for drugs. myriad purposes in healthcare. All require an Although the Medicines and Healthcare Prod- Longer term ­follow-up trials of devices evaluating adequate regulatory framework to ensure that ucts Regulatory Agency (MHRA) provides statistical ­mortality and serious morbidity have often been of patients gain clear benefits and are not placed at guidance for device trials,4 it is less methodologi- poor quality. Describing attempts to interpret one unreasonable and avoidable risk. The so called cally sound than the related guidance available such device trial, a regulator commented that the class III devices have been defined by the US Food for drug trials.5 MHRA guidance states explicitly trial was so challenged methodologically through and Drug Administration as “those that support or that the trial programme for devices will not be loss to follow-up and device implantation in par- sustain human life, are of substantial importance in adequately sized to address questions of safety,4 ticipants randomised to medical therapy alone as preventing impairment of human health, or which a self-fulfilling prophecy that contrasts with drug to be best interpretable as an observational study. present a potential, unreasonable risk of illness regulation, where the randomised trial programme But high quality trials can be conducted. Bardy or injury.”1 Examples include pacemakers, stents, plays a key part in such evaluation.5 and colleagues compared placebo with amiodar- and prostheses. Class III devices share many of the one or an implantable cardioverter-defibrillator challenges of drug treatments, which historically Long term data (ICD) in 2521 patients with a median follow up of have had more regulatory attention and rigour. Regulation is important since it drives the infor- 45.5 months and a primary outcome of all cause The FDA evaluates the safety and effectiveness mation available to inform clinicians and patients mortality.7 Data on the primary outcome were of class III devices in a process parallel to that of about the likely benefits and possible risks of available for all participants at the final planned drugs, although differences treatment options. Cardiac visit. Despite the long follow-up, only 11% of par- exist that some ­people think resynchronisation devices ticipants randomised to placebo or ­amiodarone are inappropriate.2 In Europe, for heart failure became received an ICD during follow-up.7 the process is different from available for use when only Safety of devices must also be examined that for drugs. Market access short term randomised tri- properly in the regulatory process. Thousands of is granted if a device displays als were available; follow- patients receiving ICDs have experienced device a CE mark. It is ultimately the up was 3-6 months, and malfunction,8 with a substantial rate of complica- manufacturer that decides all participants received tions, including death, associated with elective whether to display the mark, devices but they were generator replacement of ICDs known to mal- which indicates that it is satis- switched on according to function.9 It is not clear that those responsible for fied that its product conforms randomisation.6 Such trials regulating devices have dealt adequately with the with the EU’s quality stand- cannot provide adequate challenges associated with device safety. ards and that “it is fit for its evidence on the risks asso- Class III devices share many characteristics intended purpose.”3 Is the CE ciated with implantation with drugs and could be evaluated within a com- mark approach sufficient for a because all ­participants mon framework examining efficacy, effectiveness, sophisticated clinical therapy? received devices, and safety, and quality. Rather than devices being Devices do present some evaluation of benefits was subject to an inferior regulatory model, we should additional challenges to reg- effectively limited to short extend and strengthen the approach taken for

ulatory agencies compared APOGEE/SPL term symptoms and qual- pharmaceuticals. with drugs. Whereas the dose Rather than devices being ity of life. Class III devices Nick Freemantle is professor of clinical epidemiology and formulation of drugs should be evaluated using and biostatistics, Department of Primary Care and is fixed through the regula- subject to an inferior high quality randomised tri- Population Health, University College London, London NW3 2PF, UK tory process, with marketing regulatory model, we should als similar to those to which extend and strengthen [email protected] authorisation given to spe- we aspire for drugs. Competing interests: NF has completed the Unified cific form and usage, devices the approach taken for The manner in which Competing Interest form at www.icmje.org/coi_disclosure. may go through a more con- pharmaceuticals industry sponsors trials of pdf (available on request from him) and declares no tinuous development process CE marked devices also con- support from any organisation for the submitted work; characterised by a series of incremental steps in trasts with the situation for drugs. In drug trials, NF is a member of Data Safety and Monitoring Boards for two trials sponsored by Medtronic Inc; and declares no design and manufacture. Evolution may be help- the investigational drug is paid for by the spon- other relationships or activities that could appear to have ful, although there is the risk that manufacturers sor. However, in trials of devices, the experimental influenced the submitted work. may react to perverse incentives and aim for tar- therapy may be funded indirectly by payments Provenance and peer review: Commissioned; not gets that are not in the best interests of patients per patient (which may depend on the allocated externally peer reviewed. or health systems. For example, manufacturers treatment). This may not always fully cover the cost References can be found on bmj.com of sophisticated pacemakers have emphasised of the device. As contracts are complex and not Cite this as: BMJ 2011;342:d2839

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COMMENTARY Alan G Fraser, Mitchell W Krucoff, Ralph G Brindis, Michel Komajda, Sidney C Smith Jr Standards need international collaboration No implantable medical device is perfectly safe. It turers oft en seek initial approval performance criteria” and is the duty of manufacturers and regulators to mini- for their devices in Europe, where requirements for clinical evalu- mise risks—and the purpose of evaluating and regu- they can recoup some of their ation and postmarketing sur- lating devices is to ensure safety and eff ectiveness. costs while gathering information veillance. This is a task for all The product life cycle of many medical devices about clinical eff ectiveness that professional medical associa- is short—oft en quoted as an average of two years they will submit later to the FDA. tions, the World Health Organi- or less—because of the rapid rate of technologi- As this example shows, diff er- zation, 5 and others. The medical cal change and because of frequent modifi cations ent countries have responded profession should accept some (called iterative changes) to their design, manu- to the common challenges of responsibility for the dearth of facture, or programming. It would be desirable evaluating medical devices detailed clinical standards that for all implantable devices to undergo long term in diff erent ways.3 But it is not regulators can apply. Too few clinical studies—but there is pressure from inter- clear whether one system serves physicians have taken an inter- ventional specialists as well as from industry to patients better than another. est in the regulatory processes base approval on shorter term studies with surro- Although some populations may benefi t earlier governing medical devices. gate rather than clinical end points. This facilitates from new devices, they may also be exposed to If international collaborations can lead to innovation but transfers responsibility for proof of greater risks. This is incompatible with the ethical common standards, it might be possible to safety and clinical effi cacy to follow-up studies. principle that the risks associated with developing negotiate mutual recognition of approval processes Regulatory approval in Europe hinges on the new devices should be equally shared worldwide. between regulatory authorities without undermin- principle that as long as a device has been shown Patients everywhere should be protected by simi- ing essential aspects of individual national jurisdic- to perform its stated task, it can be approved if its lar requirements for medical devices to be safe tions. A device that is evaluated and approved in potential benefi ts outweigh any expected risks. and eff ective. Europe might then also be considered for approval Approval on this basis can mean estimating ben- in the US or Japan, or vice versa. The prospect of efi t before clinical eff ectiveness has been con- Common standards a single application leading to worldwide market- fi rmed, and it means accepting some risk as the To try to overcome these problems, the Global ing authorisation would compensate for increased trade-off for more rapid availability of devices. The Harmonization Task Force (GHTF)—an informal investment in premarket clinical studies. This could system of approval by 74 notifi ed bodies in the collaboration between regulatory authorities in make the regulatory system less cumbersome and European Union (EU) requires manufacturers to Europe, North America, Japan, and Australia— more effi cient, as well as safer for patients. Where evaluate the risks and propose how these should has promoted common principles for evaluating once this vision could have been characterised as a be addressed.1 Offi cial guidance published by the devices, such as when clinical follow-up studies are remote and idealistic dream, current global device European Commission is vague. It relates to gen- indicated. Not all task force members have imple- clinical trials, developing international regula- eral principles, such as which details of a literature mented its recommendations, however, and one tory collaborations, 6 and advances in information search should be included by third of countries still have no technology now make it feasible. Patients everywhere the manufacturer in its clinical regulatory authority for medical Alan G Fraser is reader in cardiology , Wales Heart evaluation of a device, rather should be protected by devices.4 Research Institute, Cardiff University, Cardiff than to specific requirements similar requirements for The European Union is CF14 4XN, UK [email protected] for particular devices, such medical devices to be reviewing its system for approv- Mitchell W Krucoff is professor of medicine/cardiology , as upper limits for complica- ing medical devices. Since the Duke Clinical Research Institute, Duke University safe and effective Medical Center, Durham NC, USA tion rates. It does not mandate EU is a member of the GHTF, it Ralph G Brindis is immediate past president, American when clinical trials are essential. This system would be illogical if the planned recast of the medi- College of Cardiology , Northern California Kaiser means important questions about safety may be cal device directives were to retain important diff er- Permanente, Oakland, California, USA left unanswered. ences from the regulations of other GHTF members. Michel Komajda is president, European Society In the United States, however, implantable Equally, it would be inappropriate for higher levels of Cardiology , Institut de Cardiologie, CHU Pitié Salpêtrière, Paris, France devices are generally expected to undergo bench of evidence to be required in Europe and North Sidney C Smith Jr is president, World Heart Federation , testing, animal studies, and clinical investigations America than in parts of Africa and Asia. There University of North Carolina, Chapel Hill NC, USA before premarket authorisation. The burden of should be no “region of least resistance” where Competing interests: The authors have completed the evidence varies with the category of risk and the devices could be approved more rapidly and on unified competing interest form at www.icmje.org/coi_ degree of novelty, but the emphasis is on clinical the basis of less evidence. Rather, eff orts should be disclosure.pdf (available on request from the corresponding author) and declare no support from any organisation for eff ectiveness rather than the European principle of concentrated on developing a global approach. For the submitted work; no financial relationships with any 1 device performance. each type of high risk device this should include a organisation that might have an interest in the submitted Despite offi cial protestations to the contrary,2 specifi c determination of how safe is “safe enough” work in the previous three years; AGF was chairman of the standards for approving medical devices are less relative to its therapeutic benefi ts. policy conference on medical devices, European Society of Cardiology. MWK is a member of the Global Harmonization rigorous in Europe than in the United States. One The best way to use the limited pool of Task Force. consequence is that devices are approved later in professional expertise concerning medical devices Provenance and peer review: Commissioned; not the US because of the time, work, and expense of would be to develop global clinical standards for externally peer reviewed. providing data on human safety and outcomes for each class of medical device with moderate or References can be found on bmj.com the Food and Drug Administration (FDA). Manufac- high risks (classes II and III), s pecifying “objective Cite this as: BMJ 2011;342:d2952

1130 BMJ | 21 MAY 2011 | VOLUME 342