The response from Depuy representatives Graham Isaac and Simon Sinclair sidesteps the substantive concerns described in the BMJ feature (1).
The main thrust of the article was the laxity of medical device regulation in Europe as a whole and some aspects of the US system (2). It described a system that allowed a whole class of implant– in this case large diameter metal on metal total hip replacement– to enter the global market without any clinical studies to assess their safety and effectiveness.
We do think it is necessarily alarming rather than “unnecessarily alarmist” that design changes to implants that were already known to release potentially toxic metal ions passed through the regulators without any need for clinical studies. These changes were the shortening of the taper (the part of the stem that meets the head) coupled with the use of large diameter heads and were an industry wide trend. These changes lead to a toggling effect that has been shown to damage the inside of the head causing the release of metal ions into the body.
As pointed out in the article, even the National Joint Registry has described this class of implant as a “cause for concern” long before the feature appeared. Two weeks after the BMJ article appeared, The Lancet published findings of a high failure rate with these prostheses (3).
The article did not suggest, as you imply in the first paragraph of your letter, that the potential for reactions to wear debris from metal on metal hips was unknown. Indeed, we point to the fact that reactions to metal debris have been documented in the medical literature since the 1970s (4).
You also state that the FDA and the MHRA say that adverse effects are rare. We are unsure how anyone can say this with any authority given that no large scale epidemiological studies have been done on the latest generation of metal on metal hip prostheses.
You then go on to say that the article was misleading in implying that DePuy concealed information about raised metal ion levels in patients’ blood. We did not actually allege this in this article. What we did say is that the company has been aware of concerns over the carcinogenic potential of the metal ions for many years. Indeed, in your reply you acknowledge that when metal-on-metal hip implants were introduced, “it was recognized that one of the effects of having metal bearing surfaces would be that constituents of cobalt and chromium would be released locally and systemically”. You also state that patients with metal on metal hip implants—as well as other types— have “raised levels of ions”.
If this is the case, it begs the question why no clinical studies were carried out before the metal-on -metal Pinnacle hip system (called ULTAMET in your letter) was put onto the market. It also is of concern that even though DePuy knew metal ions would be released locally and systemically, they did not try to establish what levels would be considered safe for patients before rushing to market or modifying the design of the implants. As pointed out in the feature, certain valencies of these ions were either known to be carcinogenic (hexavalent chromium) or to possibly have carcinogenic potential (trivalent chromium and cobalt) long before changes to the design of the prostheses in question.
Given this, one would have thought DePuy would carefully follow up a cohort of patients once the implant was on the market measuring ion data and monitoring both local and systemic effects. Before the BMJ article went to press, we asked Depuy specifically—as we did with several other companies— if it had conducted any post-marketing surveillance of the Pinnacle hip prostheses and if it had published the results. DePuy did not respond to the question. A lack of such detailed follow up might be one reason why the reported incidence of such adverse effects in the literature is low.
If, as you appear to concede, metal ions are of concern - that constituents of cobalt and chromium would be released - why does the supporting paper that you cite as evidence of effectiveness and safety of the metal on metal Pinnacle not include metal ion data (5)? Internal DePuy documents obtained by the BMJ suggest investigators were discouraged from publishing ion data. Two of the three authors of the paper earned large sums of money from their relationships with DePuy. Lead author, William Barrett is a DePuy consultant who earned over US$1.6 million in royalties and consultancy payments between 2010 and 2011 and Kirk Kindsfater is a DePuy consultant who had earned close to quarter of a million dollars in the same time period. The third author, James Lesko, is from DePuy. In small print on the paper, it says that conflicts of interest can be found on a different page.
Is it any wonder the regulators have little evidence to draw upon to make their decisions about the effects of metal ions? This lack of data reflects a trend across the literature. Despite the metal on metal Pinnacle having been implanted into between 300 000- 500 000 people worldwide, there are only data for metal ions in under 150 patients with this prosthesis in the literature to date (6,7, 8)If the literature cannot be relied upon to provide rigorous evidence, there is an urgent need for robust regulation in the future featuring both premarket trials and rigorous post-marketing studies.
You say that the BMJ article “focuses” on the potential cancer risk from metal on metal implants. This was not the focus of the article but one aspect of it, and the article clearly stated that there was no evidence of a link. We simply highlighted how little was known about the long term effects of the metal ions, because of a lack of rigorous follow up.
Will companies only do what’s in the best interest of patients and the public if they are mandated to–and penalised if they don’t comply?
You say that the article raised “considerable alarm” about the levels of metal ions associated with the Pinnacle and imply that we failed to quote the proper figures from the literature. In fact the article clearly described the range of 5-20% from the three referenced studies (6, 9, 10).
It is also worth noting that the conclusion of one of these cited papers led the authors to stop using the Pinnacle implant. Importantly these authors are not likely to have been hostile to DePuy. At least one of them is a DePuy consultant who earned about US$400,000 from DePuy in the previous two years.
Depuy’s internal documents also show that in 2009, another DePuy consultant—who earned US$2.5 million in the previous two years in royalty and consultancy payments— emailed DePuy with his concerns about the metal on metal Pinnacle. “In previous discussions that I have had with DePuy regarding my reservations with metal on metal I have not had a receptive ear,” he wrote.
Interestingly, there is nothing in the published literature highlighting these concerns. Nor has there been anything in the published literature following the concerns of another surgeon who wrote to the company to say that he did not feel that “DePuy is doing enough to understand the extent of the Pinnacle metal on metal disease. I believe it borders on unethical to continue to market the product until the issues are elucidated. These products are harming patients.” This surgeon earned around US$70,000 from DePuy between 2010 and 2011.
The metal on metal Pinnacle is still on the market—although one of the stems used with it has been removed because of concerns over the taper. As you point out, Japanese surgeons spotted the problem. You do not say that this was in 2009 and that it took DePuy over two years to advise doctors in Japan not to use these stems.
The fact that these stems were ‘9/10’ rather than ‘12/14’ in the context of this article is not relevant to the point being made (although DePuy declined to answer our question about this taper prior to publication of the BMJ article). We included the concerns from the Japanese surgeons because the patterns of failure they had spotted were the same as those being reported by Virginia, USA and North Tees, UK since 2010.
You say that the BMJ was wrong in claiming that the design changes to the stem took place around 2004. You say the changes started in 2001 and were applied to other stems. According to the FDA website, the Corail stem—the one most commonly used in the Pinnacle hip system—was cleared for use in 2004. It is this that is referred to in the BMJ article. That we cannot say for certain when these design changes took placeis an indictment of the lack of transparency surrounding device regulation and the fact that individual components’ of a hip system can be cleared separately with no clinical testing.
Why DePuy—or indeed other companies—weren’t more cautious in adopting new designs that affect where the head and stem meet is perplexing. Josh Jacobs, now president of the American Academy of Orthopedic Surgery, wrote in the Journal of Bone and Joint Surgery America (the main US orthopaedic journal) in 1998 :
“The predominant source of the disseminated chromium-degradation products is probably the modular head-neck junction and may be a function of the geometry of the coupling.” This head-neck coupling is an important source of metal release that can lead to increased concentrations of chromium in the serum, he added saying: “This is a particularly timely concern because of recent clinical trends, including the reintroduction of metal-on-metal bearing surfaces.” (11)
You say that our article failed to explain the clinical need for the reintroduction of metal on metal implants. This is not the case. The article clearly states:
“The conventional total hip replacement consists of a metal head with a polyethylene cup. But these joints don’t last forever. Over time the plastic cup wears away against the hard metal head. Younger, more active people are especially likely to require early revision surgery to replace the worn out joint.” It also notes that the introduction was gradual, but eventually the commercial need to constantly innovate trumped patient safety.
Lastly, you cite the aforementioned paper by DePuy consultants (5)— published shortly after the BMJ feature came out—as evidence that the five year survival rate of the metal on metal Pinnacle is 97%, in keeping with NICE benchmarks. However, this paper is flawed.
It reports a pooled analysis of four previously unpublished studies. Over half (59.9%) of people included were taken from a non randomised, non controlled study. Only 59% of the total hip implants in this study had a femoral stem with a shortened taper and only 779 (72%) hips had greater than 2 year follow up—even though research suggests that tapers take a mean of four years to fail. Moreover, radiographic evaluation of cup placement—which should be standard for papers reporting research in orthopaedics– was only obtained on 420 (54%) of the 779 patients evaluated. The authors then use all 1076 hips to conduct survival analysis at five years.
Far from providing convincing evidence about the effectiveness of the implant, it only provides convincing evidence about the need for independent evaluation of medical implants.
All in all, we feel that this article was not “unnecessarily alarmist”, but it provided a necessarily alarming portrait of the state of medical device regulation today.
1. Isaac, G and Sinclair, S. Response to feature ‘How safe are metal on metal hip implants?’
2. Cohen, D. How safe are metal on metal hip implants? BMJ 2012;344:e1410
3. Smith AJ, Dieppe P, Vernon K, Porter M, Blom AW; National Joint Registry of England and Wales. Failure rates of stemmed metal-on-metal hip replacements: analysis of data from the National Joint Registry of England and Wales. Lancet. 2012 Mar 31;379(9822):1199-204.
4. Jones DA, Lucas HK, O’Driscoll M, Price CH, Wibberley B. Cobalt toxicity after McKee hip arthroplasty. J Bone Joint Surg Br 1975;57:289-96
5. Barrett WP, Kindsfater KA, Lesko JP, Large-Diameter Modular Metal-on-Metal Total Hip Arthroplasty: Incidence of Revision for Adverse Reaction to Metallic Debris. J Arthroplasty. Mar 14 2012 (Epub ahead of print]
6. Antoniou J, Zukor DJ, Mwale F, Minarik W, Petit A, Huk OL. Metal ion levels in the blood of patients after hip resurfacing: a comparison between twenty-eight and thirty-six-millimeter-head metal-on-metal prostheses J Bone Joint Surg Am 2008;90(suppl3):142-8.
7. Engh CA Jr, MacDonald SJ, Sritulanondha S, Thompson A, Naudie D, Engh CA. 2008 John Charnley award: metal ion levels after metal-on-metal total hip arthroplasty: a randomized trial. Clin Orthop Relat Res. 2009 Jan;467(1):101-11. Epub 2008 Oct 15.
8. Bernstein, M, et al. Femoral Head Size Does Not Affect Ion Values in Metal-on-Metal Total Hips Clin Orthop Relat Res (2011) 469:1642–1650
9. Takamua KM, Langton D, Ghandi JN, Nargol A, Joyce T, Lord J, et al. The main issue of large diameter MoM total hip arthroplasty: the taper junction. Presentation at American Academy of Orthopedic Surgeons annual meeting, San Francisco, 9 Feb 2012.
10. Fricka K, Engh CA, Hamilton WG, Ho H. Survivorship and revision analysis among primary metal on metal total hip arthroplasty using 36 mm diameter heads. Presentation at American Academy of Orthopedic Surgeons annual meeting, San Francisco, 9 Feb 2012.
11. Jacobs JJ, Skipor AK, Patterson LM, Hallab NJ, Paprosky WG, Black J, Galante JO. Metal release in patients who have had a primary total hip arthroplasty. A prospective, controlled, longitudinal study. J Bone Joint Surg Am. 1998 Oct;80(10):1447-58.
Rapid Response:
Re: How safe are metal-on-metal hip implants?
The response from Depuy representatives Graham Isaac and Simon Sinclair sidesteps the substantive concerns described in the BMJ feature (1).
The main thrust of the article was the laxity of medical device regulation in Europe as a whole and some aspects of the US system (2). It described a system that allowed a whole class of implant– in this case large diameter metal on metal total hip replacement– to enter the global market without any clinical studies to assess their safety and effectiveness.
We do think it is necessarily alarming rather than “unnecessarily alarmist” that design changes to implants that were already known to release potentially toxic metal ions passed through the regulators without any need for clinical studies. These changes were the shortening of the taper (the part of the stem that meets the head) coupled with the use of large diameter heads and were an industry wide trend. These changes lead to a toggling effect that has been shown to damage the inside of the head causing the release of metal ions into the body.
As pointed out in the article, even the National Joint Registry has described this class of implant as a “cause for concern” long before the feature appeared. Two weeks after the BMJ article appeared, The Lancet published findings of a high failure rate with these prostheses (3).
The article did not suggest, as you imply in the first paragraph of your letter, that the potential for reactions to wear debris from metal on metal hips was unknown. Indeed, we point to the fact that reactions to metal debris have been documented in the medical literature since the 1970s (4).
You also state that the FDA and the MHRA say that adverse effects are rare. We are unsure how anyone can say this with any authority given that no large scale epidemiological studies have been done on the latest generation of metal on metal hip prostheses.
You then go on to say that the article was misleading in implying that DePuy concealed information about raised metal ion levels in patients’ blood. We did not actually allege this in this article. What we did say is that the company has been aware of concerns over the carcinogenic potential of the metal ions for many years. Indeed, in your reply you acknowledge that when metal-on-metal hip implants were introduced, “it was recognized that one of the effects of having metal bearing surfaces would be that constituents of cobalt and chromium would be released locally and systemically”. You also state that patients with metal on metal hip implants—as well as other types— have “raised levels of ions”.
If this is the case, it begs the question why no clinical studies were carried out before the metal-on -metal Pinnacle hip system (called ULTAMET in your letter) was put onto the market. It also is of concern that even though DePuy knew metal ions would be released locally and systemically, they did not try to establish what levels would be considered safe for patients before rushing to market or modifying the design of the implants. As pointed out in the feature, certain valencies of these ions were either known to be carcinogenic (hexavalent chromium) or to possibly have carcinogenic potential (trivalent chromium and cobalt) long before changes to the design of the prostheses in question.
Given this, one would have thought DePuy would carefully follow up a cohort of patients once the implant was on the market measuring ion data and monitoring both local and systemic effects. Before the BMJ article went to press, we asked Depuy specifically—as we did with several other companies— if it had conducted any post-marketing surveillance of the Pinnacle hip prostheses and if it had published the results. DePuy did not respond to the question. A lack of such detailed follow up might be one reason why the reported incidence of such adverse effects in the literature is low.
If, as you appear to concede, metal ions are of concern - that constituents of cobalt and chromium would be released - why does the supporting paper that you cite as evidence of effectiveness and safety of the metal on metal Pinnacle not include metal ion data (5)? Internal DePuy documents obtained by the BMJ suggest investigators were discouraged from publishing ion data. Two of the three authors of the paper earned large sums of money from their relationships with DePuy. Lead author, William Barrett is a DePuy consultant who earned over US$1.6 million in royalties and consultancy payments between 2010 and 2011 and Kirk Kindsfater is a DePuy consultant who had earned close to quarter of a million dollars in the same time period. The third author, James Lesko, is from DePuy. In small print on the paper, it says that conflicts of interest can be found on a different page.
Is it any wonder the regulators have little evidence to draw upon to make their decisions about the effects of metal ions? This lack of data reflects a trend across the literature. Despite the metal on metal Pinnacle having been implanted into between 300 000- 500 000 people worldwide, there are only data for metal ions in under 150 patients with this prosthesis in the literature to date (6,7, 8)If the literature cannot be relied upon to provide rigorous evidence, there is an urgent need for robust regulation in the future featuring both premarket trials and rigorous post-marketing studies.
You say that the BMJ article “focuses” on the potential cancer risk from metal on metal implants. This was not the focus of the article but one aspect of it, and the article clearly stated that there was no evidence of a link. We simply highlighted how little was known about the long term effects of the metal ions, because of a lack of rigorous follow up.
Will companies only do what’s in the best interest of patients and the public if they are mandated to–and penalised if they don’t comply?
You say that the article raised “considerable alarm” about the levels of metal ions associated with the Pinnacle and imply that we failed to quote the proper figures from the literature. In fact the article clearly described the range of 5-20% from the three referenced studies (6, 9, 10).
It is also worth noting that the conclusion of one of these cited papers led the authors to stop using the Pinnacle implant. Importantly these authors are not likely to have been hostile to DePuy. At least one of them is a DePuy consultant who earned about US$400,000 from DePuy in the previous two years.
Depuy’s internal documents also show that in 2009, another DePuy consultant—who earned US$2.5 million in the previous two years in royalty and consultancy payments— emailed DePuy with his concerns about the metal on metal Pinnacle. “In previous discussions that I have had with DePuy regarding my reservations with metal on metal I have not had a receptive ear,” he wrote.
Interestingly, there is nothing in the published literature highlighting these concerns. Nor has there been anything in the published literature following the concerns of another surgeon who wrote to the company to say that he did not feel that “DePuy is doing enough to understand the extent of the Pinnacle metal on metal disease. I believe it borders on unethical to continue to market the product until the issues are elucidated. These products are harming patients.” This surgeon earned around US$70,000 from DePuy between 2010 and 2011.
The metal on metal Pinnacle is still on the market—although one of the stems used with it has been removed because of concerns over the taper. As you point out, Japanese surgeons spotted the problem. You do not say that this was in 2009 and that it took DePuy over two years to advise doctors in Japan not to use these stems.
The fact that these stems were ‘9/10’ rather than ‘12/14’ in the context of this article is not relevant to the point being made (although DePuy declined to answer our question about this taper prior to publication of the BMJ article). We included the concerns from the Japanese surgeons because the patterns of failure they had spotted were the same as those being reported by Virginia, USA and North Tees, UK since 2010.
You say that the BMJ was wrong in claiming that the design changes to the stem took place around 2004. You say the changes started in 2001 and were applied to other stems. According to the FDA website, the Corail stem—the one most commonly used in the Pinnacle hip system—was cleared for use in 2004. It is this that is referred to in the BMJ article. That we cannot say for certain when these design changes took placeis an indictment of the lack of transparency surrounding device regulation and the fact that individual components’ of a hip system can be cleared separately with no clinical testing.
Why DePuy—or indeed other companies—weren’t more cautious in adopting new designs that affect where the head and stem meet is perplexing. Josh Jacobs, now president of the American Academy of Orthopedic Surgery, wrote in the Journal of Bone and Joint Surgery America (the main US orthopaedic journal) in 1998 :
“The predominant source of the disseminated chromium-degradation products is probably the modular head-neck junction and may be a function of the geometry of the coupling.” This head-neck coupling is an important source of metal release that can lead to increased concentrations of chromium in the serum, he added saying: “This is a particularly timely concern because of recent clinical trends, including the reintroduction of metal-on-metal bearing surfaces.” (11)
You say that our article failed to explain the clinical need for the reintroduction of metal on metal implants. This is not the case. The article clearly states:
“The conventional total hip replacement consists of a metal head with a polyethylene cup. But these joints don’t last forever. Over time the plastic cup wears away against the hard metal head. Younger, more active people are especially likely to require early revision surgery to replace the worn out joint.” It also notes that the introduction was gradual, but eventually the commercial need to constantly innovate trumped patient safety.
Lastly, you cite the aforementioned paper by DePuy consultants (5)— published shortly after the BMJ feature came out—as evidence that the five year survival rate of the metal on metal Pinnacle is 97%, in keeping with NICE benchmarks. However, this paper is flawed.
It reports a pooled analysis of four previously unpublished studies. Over half (59.9%) of people included were taken from a non randomised, non controlled study. Only 59% of the total hip implants in this study had a femoral stem with a shortened taper and only 779 (72%) hips had greater than 2 year follow up—even though research suggests that tapers take a mean of four years to fail. Moreover, radiographic evaluation of cup placement—which should be standard for papers reporting research in orthopaedics– was only obtained on 420 (54%) of the 779 patients evaluated. The authors then use all 1076 hips to conduct survival analysis at five years.
Far from providing convincing evidence about the effectiveness of the implant, it only provides convincing evidence about the need for independent evaluation of medical implants.
All in all, we feel that this article was not “unnecessarily alarmist”, but it provided a necessarily alarming portrait of the state of medical device regulation today.
1. Isaac, G and Sinclair, S. Response to feature ‘How safe are metal on metal hip implants?’
2. Cohen, D. How safe are metal on metal hip implants? BMJ 2012;344:e1410
3. Smith AJ, Dieppe P, Vernon K, Porter M, Blom AW; National Joint Registry of England and Wales. Failure rates of stemmed metal-on-metal hip replacements: analysis of data from the National Joint Registry of England and Wales. Lancet. 2012 Mar 31;379(9822):1199-204.
4. Jones DA, Lucas HK, O’Driscoll M, Price CH, Wibberley B. Cobalt toxicity after McKee hip arthroplasty. J Bone Joint Surg Br 1975;57:289-96
5. Barrett WP, Kindsfater KA, Lesko JP, Large-Diameter Modular Metal-on-Metal Total Hip Arthroplasty: Incidence of Revision for Adverse Reaction to Metallic Debris. J Arthroplasty. Mar 14 2012 (Epub ahead of print]
6. Antoniou J, Zukor DJ, Mwale F, Minarik W, Petit A, Huk OL. Metal ion levels in the blood of patients after hip resurfacing: a comparison between twenty-eight and thirty-six-millimeter-head metal-on-metal prostheses J Bone Joint Surg Am 2008;90(suppl3):142-8.
7. Engh CA Jr, MacDonald SJ, Sritulanondha S, Thompson A, Naudie D, Engh CA. 2008 John Charnley award: metal ion levels after metal-on-metal total hip arthroplasty: a randomized trial. Clin Orthop Relat Res. 2009 Jan;467(1):101-11. Epub 2008 Oct 15.
8. Bernstein, M, et al. Femoral Head Size Does Not Affect Ion Values in Metal-on-Metal Total Hips Clin Orthop Relat Res (2011) 469:1642–1650
9. Takamua KM, Langton D, Ghandi JN, Nargol A, Joyce T, Lord J, et al. The main issue of large diameter MoM total hip arthroplasty: the taper junction. Presentation at American Academy of Orthopedic Surgeons annual meeting, San Francisco, 9 Feb 2012.
10. Fricka K, Engh CA, Hamilton WG, Ho H. Survivorship and revision analysis among primary metal on metal total hip arthroplasty using 36 mm diameter heads. Presentation at American Academy of Orthopedic Surgeons annual meeting, San Francisco, 9 Feb 2012.
11. Jacobs JJ, Skipor AK, Patterson LM, Hallab NJ, Paprosky WG, Black J, Galante JO. Metal release in patients who have had a primary total hip arthroplasty. A prospective, controlled, longitudinal study. J Bone Joint Surg Am. 1998 Oct;80(10):1447-58.
Competing interests: No competing interests