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Opinion: On the Up and Up

An Amgen executive refutes accusations that the company published misleading results of its mid-90s clinical trial testing an anemia drug.

By | June 20, 2012

image: Opinion: On the Up and Up Wikimedia Commons, MDougM

WIKIMEDIA COMMONS, MDOUGM

Last month, medical professor Daniel Coyne of Washington University School of Medicine in St. Louis discussed the outcomes of a clinical trial that aimed to compare different treatment regimens for epoetin alfa, a drug often used to stimulate blood production in dialysis patients who suffer from anemia, which is characterized by a below-normal red blood cell count. The Normal Hematocrit Trial (NHT) was conducted in the mid-1990s by researchers at Amgen, the biotechnology company that manufactures epoetin alfa under the name-brand EPOGEN, and collaborating nephrologists.

After completing his own analysis of the trial data, which he obtained this March through a Freedom of Information Act request, Coyne claimed to have generated results that were “dramatically different” from those of our original report, published in the New England Journal of Medicine in 1998. He claimed that our report was “incomplete” and that it “misled the medical community about the anemia drug’s risks and benefits” and served the selfish purpose of boosting epoetin sales. We disagree.

Amgen’s actions, and those of the NHT authors, clearly demonstrate an appreciation for the significance of the findings from the trial. Amgen and the academic committee overseeing the trial stopped the NHT early upon learning that targeting higher hemoglobin levels was causing harm rather than benefit; we rapidly initiated a change to the US Food and Drug Administration-approved label, warning health care providers and patients of the risks; and the study authors published the results in the highest-profile medical journal in the country, the New England Journal of Medicine (NEJM), with a clear recommendation to avoid targeting the higher hemoglobin levels studied in the trial.

As is often the case as new information emerges over time, the understanding of the risks and benefits of the drug class now known as erythropoiesis-stimulating agents (ESAs), which includes epoetin alfa, has evolved. In response to new data, Amgen has updated the safety information for ESAs 15 times since the initial approval of EPOGEN and participated in five FDA and two Medicare drug advisory committee meetings where these issues were thoroughly reviewed in public forums led by independent experts.

Coyne also asserted that the workgroup in charge of drafting the National Kidney Foundation’s new anemia (KDOQI) guidelines misread the quality of life benefits reported in the NEJM and that it significantly impacted their recommendation. In reality, the 2006 KDOQI guidelines identified several trials other than NHT that informed their recommendations. The guidelines also clearly acknowledge that two completed trials—the NHT being one of them—demonstrated the risks of hemoglobin targets greater than 13 g/dL, quality of life benefits notwithstanding.

ESAs are widely understood to provide an important benefit to appropriate patients even when balancing those benefits against known risks. Most importantly, the drugs are used to avoid blood transfusions, which carry specific risks for patients on dialysis, namely reducing the success rate of kidney transplants, the optimal treatment option for people with kidney failure.

Coyne’s assertion that Amgen misled the public about the risks and benefits of ESAs is simply wrong. On the contrary, Amgen’s primary concern is for patients, and we have led the efforts to better understand the risks and benefits of these medicines over the past 20 years.

Sean E. Harper, M.D., is the Executive Vice President of Research and Development at Amgen.

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Avatar of: annallen

annallen

Posts: 1

June 20, 2012

My perspective on this issue is quite different.

I saw Amgen actively working to unofficially broaden use of this drug, which turned
out to be very lucrative for both Amgen and the prescribing physicians. At one
point, CMS spent more on EPO than on any other drug.  Much of the research on EPO was targeted towards broadening the indication rather than determining whether it was safe. When FDA requested additional research, the studies were poorly designed.  When CMS cut reimbursement, both Amgen and Johnson & Johnson pressured Congress to ask CMS to reconsider their decision.  I believe that Amgen spent a record amount on lobbyists that year.

Safety concerns were raised about this drug in the early 1990s.  The use of EPO didn’t decrease until CMS and FDA used their regulatory authority to limit the use of EPO.  

So from my perspective, Mr. Harper’s statement that “Amgen’s primary concern is for the patientâ€쳌 is ludicrous.

Avatar of: Bruce Korb

Bruce Korb

Posts: 1

June 20, 2012

Mr. Harper's statement is also fairly vacuous.

Avatar of: Shi V. Liu

Shi V. Liu

Posts: 1457

June 20, 2012

What about the CNS (Cell, Nature, Science)' collective efforts in promoting iPSCs, the so-called induced pluripotent stem cells, as ethical and cancer-free safe replacements for embryonic stem cells (ESCs) and suppression on criticisms against iPSCs because they are in fact some incorrectly programmed stem cells or, in other words, man-made cancer stem cells (mmCSCs)?   

Avatar of: Daniel Coyne

Daniel Coyne

Posts: 1457

June 21, 2012

Sean Harper
joined Amgen in 2002, yet "knows" that Amgen did not mislead the
Nephrology community from 1996 on. He subtitles his article "An Amgen
Executive refutes..." Harper is not using the word “refuteâ€쳌 to mean “to
prove wrongâ€쳌, because he shows nothing I said was wrong.  

To be clear
my "analysis" of the 1996 Amgen NHT trial report was to fairly quote
Amgen's own scientists’ statements of the results of the predefined primary and
major secondary endpoints, and then determine if Amgen gave those same results
in the 1998 NEJM article. Amgen did not. 

Harper
contends addition of some NHT event rates (the primary endpoint of death + MI,
and thrombotic events) to the EPOGEN label sufficiently informed nephrologists,
but those limited results included no statistical testing results, leaving
physicians to look to the 1998 NEJM article and incorrectly conclude there was
only a trend toward harm at hematocrit targets of 39-45%, and to find there was
improved HRQOL.

Harper also
states the 2006 KDOQI guideline group looked at many other trials showing HRQOL
benefits. My Kidney International article showed the results of all five of the
high quality trials they examined. Two trials (78 and 155 patients) found NO
improvement in HRQOL when targeting higher hematocrit. Two other trials (94 and
324 patients) reported some HRQOL improvement when targeting >39% and
>40.5% compared to lower targets, but despite both trials using the same
SF-36 instrument, their results were not consistent. The larger trial also
showed increased strokes (4% vs 1%; p=0.045) when targeting higher hematocrit.  

The fifth
trial KDOQI examined was the giant Normal Hematocrit Trial with 1265 patients,
and based on Amgen’s 1998 NEJM article, they concluded a targeting a hematocrit
of 39-45% gave an impressive 7.2 point improvement in the "Physical
Function" domain of HRQOL! KDOQI also incorrectly concluded based on the
NEJM 1998 publication that the risk of death + MI was insignificantly higher -
“RR 1.3, 95% CI 0.9-1.8, P>0.05â€쳌, the risk of death was not significantly higher:
“29.6% vs. 24.4%, NSâ€쳌, hospitalizations were also “NSâ€쳌, and increased
thrombotic events were not even identified as a problem in the NHT in KDOQI’s
summary adverse events table. Alas, the trial report I received reveals
Amgen knew in 1996 there was no improvement in HRQOL and knew there was
significant harm, though Amgen’s 1998 NEJM article never disclosed those facts.

Amgen could have published more
articles, or shown the predefined results to the Amgen-funded KDOQI in 1997, or
2001, or 2006, or even 2007, or to the new Amgen-funded KDIGO international
guideline group in 2011 which, according to their draft anemia guideline, also is
“misreadingâ€쳌 the results of the Normal Hematocrit Trial.

Avatar of: VladamirPutin

VladamirPutin

Posts: 1

June 22, 2012

Sean Harper has avoided addressing Daniel Coyne's key point - instead he has made a few vacuous assertions - evasive corporate babble. 

So that the scientific community can assess this issue transparently would Amgen please make the clinical study report available for scrutiny - then readers can assess for themselves whether Harper or Dr Coyne are proving the most accurate interpretation? Indeed why not make all the clinical study reports available as suggested in a recent article  http://the-scientist.com/2012/...

If Amgen's primary concern is patient safety then there is no rational reason to not have full and immediate disclosure.

There is an interesting case under review by the Supreme Court not unrelated to this issue - http://www.pharmalot.com/2012/...

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