Global Insight Perspective | |
Significance | The advisory committee voted 15-2 in favour of strengthening risk warnings for cancer patients receiving EPOs, while the committee also voted unanimously in favour of requiring a large-scale safety study on EPOs. A separate committee meeting later in the year will decide if stronger warnings should be applied to EPO use by kidney disease patients as well. |
Implications | If endorsed by the FDA, the committee recommendations would undermine sales of Amgen's (U.S.) Epogen (epoetin alfa) and Aranesp (darbepoetin alfa), and Johnson & Johnson's (U.S.) Procrit (epoetin alfa). |
Outlook | In its review of EPOs, the FDA is likely to consider not just the clinical evidence, but also the extent of off-label use of these drugs and evidence of promotional efforts to boost use of EPOs in unnecessarily high doses. |
FDA Committee Votes to Boost Warnings …
The FDA advisory committee charged with reviewing the safety of EPOs yesterday voted overwhelmingly (15-2) in favour of strengthening risk warnings for cancer patients. Risk warnings for kidney patients receiving dialysis will be reviewed at a separate FDA advisory meeting later this year. According the Wall Street Journal(WSJ), which had a representative present during the discussion, the FDA's Vinni Juneja told the experts' panel that safety should be considered in perspective. When EPOs were first approved in the early 1990s, they were thought to be beneficial in reducing the need for blood transfusions in cases of chemotherapy-induced or dialysis-induced anaemia. However, the risk of contracting disease from blood transfusions has decreased dramatically now, while there is no evidence that use of EPOs improves patient survival.
The committee unanimously voted in favour of requiring Amgen and J&J to conduct new large-scale studies to examine the safety of EPOs. From what has been said so far, patient survival will be the end-point of these studies. This recommendation has been triggered by recent findings indicating that when EPOs are used off-label (i.e. for an unapproved indication) to treat cancer-related anaemia in patients not undergoing chemotherapy, they can trigger tumour development and could also boost the risk of blood clots and heart attacks.
… but Upper Haemoglobin Threshold Unchanged
The labelling of EPOs was changed in March to reflect the risk of such side effects. The new ”black box” warnings—which are the strongest form of warning on drug labels in the United States—indicate that when EPOs are administered to target haemoglobin levels above 12 g/dL they increase the risk of death and serious cardiovascular events; shorten the time to disease progression of head and neck tumours in patients receiving radiation therapy; shorten survival and increase deaths attributed to disease progression in patients with metastatic breast cancer receiving chemotherapy; and increase the risk of death in cancer patients receiving neither radiation therapy nor chemotherapy.
There was speculation that the FDA advisory committee would recommend changing the label to reflect the higher risk of using EPOs at doses below 12 g/dL. However, the committee decided not to change the upper threshold for haemoglobin levels, according to the WSJ. Nevertheless, it has recommended the inclusion of a base level of haemoglobin on labelling, essentially advising doctors and patients how low haemoglobin levels should fall before EPO treatment is considered.
Outlook and Implications
The fact that the committee did not recommend a reduction in the upper threshold of haemoglobin targets for patients on EPO is a positive development for Amgen and J&J. Initial estimates indicate that the March black box warning—which effectively reduced the haemoglobin target to 12 g/dL—will undermine sales of Epogen, Aranesp and Procrit by about 10% (see United States: 12 March 2007: FDA Orders Black Box Warnings for Anaemia Treatments). Had the haemoglobin target been reduced further, the adverse impact on sales would have been all the more notable. Having said that, the fact that the committee is considering introducing a minimum recommended haemoglobin (Hb) level (above which EPO treatment should not be initiated) in labelling is a dangerous sign. Should the FDA decide to follow the committee's recommendations it could come up with a minimum Hb requirement of 7-8 g/dL (lower than that for healthy people but above what would be deemed low enough to justify a blood transfusion). If this occurs, the adverse effect on EPO sales could be just as dramatic as the effect of imposing an upper Hb limit.
To make matters worse for EPO makers, when the full FDA meets to review the safety of anaemia drugs, it is likely to consider additional factors as well. Top among these is the extent of off-label usage of EPOs. The agency has grown increasingly concerned that use of EPOs may be promoted for cancer patients not receiving chemotherapy as a way of boosting their energy levels. Evidence of marketing practices encouraging doctors to use higher and unapproved (at the time) doses of Procrit are also likely to be taken into account (see United States: 10 May 2007: J&J Gave 24% Price Discount on Procrit to Doctors, Whistleblowers Claim). In the final analysis, the stance that the FDA takes—which might differ from that of its advisory committee—will be eagerly anticipated. EPOs account for nearly half of Amgen's sales and in total, Amgen and J&J's EPO drugs had more than US$7 billion worth of sales in the United States last year.