Bisphosphonate Cancer Risk Divides FDA Officials

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Elsevier Global Medical News. 2011 Sept 8, M BERMAN-GORVINE

EXPERT COMMENTARY Lee Schwartzberg, MD, Editor-in-Chief

The FDA has increasingly scrutinized drugs for emerging potential danger signals, prompting a label change, often as a “black box” warning. This approach does not necessarily indicate worsening safety of the therapy with the passage of time. More precisely, it reflects a clear shift of thinking by the FDA on where to draw the line in the risk/benefit ratio for any given agent. The current skirmish arises out of reevaluation of the oral bisphosphonates, a class of drugs used to treat osteoporosis, a widely prevalent disease with serious morbidity and mortality. Remarkably, there is intra-agency discordance, with opposing parties either endorsing or disregarding the results of two retrospective studies. One of these studies showed an increased risk of esophageal cancer, and the other showed no increase in the disease after prolonged exposure to oral bisphosphonates. Slapping a black box label on effective drugs—highly likely to discourage use—based on conflicting poor-quality data is a step backward, not forward. A more balanced approach would maintain safety and still promote health.

Food and Drug Administration officials disagree over whether the long-term use of oral bisphosphonates increases the risk of esophageal cancer, background documents released before an advisory committee meeting show.

The FDA added the question of whether long-term use of the drugs increases the risk of esophageal cancer to the agenda of the Sept. 9 joint session of the Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committees only after the agency had already scheduled the meeting.

None of the four approved drugs in this class - Merck's Fosamax (alendronate), Warner Chilcott's Actonel (risedronate), Novartis' Reclast (zoledronic acid), and Roche's Boniva (ibandronate) - currently carries any warning about an esophageal cancer risk, though the labels do warn of the risks of esophagitis and esophageal ulcers.

In reviews attached to the background documents, Judy Staffa, Ph.D., director of the FDA's Division of Epidemiology II, expressed greater concern about the increased cancer risk with long-term use than did Dr. Stephen Voss, a medical reviewer in the agency's Division of Reproductive and Urologic Products.

Dr. Staffa discussed two studies that used the General Practice Research Database as their data source. One of the studies used a retrospective cohort design (Cardwell et al. JAMA 2010;304:657-63), and the other used a nested case-control design (Green et al. BMJ 2010 Sept. 1 [doi:10.1136/bmj.c4444]).

While Dr. Staffa acknowledged that "definitive conclusions about the risk of esophageal cancer associated with the use of OBPs [oral bisphosphonates] cannot be made based on these two published studies alone," she said that "the signal generated by the Green study concerns me, and I am not reassured by the negative findings of the Cardwell study."

Therefore, Dr. Staffa said, "enough evidence exists to support adding this information to product labeling and issuing a drug safety communication to alert practitioners and patients to this signal, and the accompanying uncertainty, to let them know that we continue to investigate it."

That stands in contradiction to Dr. Voss' view. "Although studies are conflicting, it is very clear that there is not a marked increase in esophageal cancer risk with oral BPs," he wrote.

"The evidence at this time does not appear to warrant any changes to BP prescribing or any other aspects of care in any subgroup of patients; thus, it is unclear what benefit may derive from increased awareness of the issue," he wrote.

The FDA listed two other possible risks of long-term BP use for preventing or treating osteoporosis that it wants the advisory committees to discuss: increased risk of developing osteonecrosis of the jaw (ONJ) and increased risk of atypical fractures.

The agency will ask the panels whether restricting duration of use, implementing a "drug holiday," or requiring label changes could help osteoporosis patients who require chronic long-term therapy. Dr. Theresa Kehoe of the FDA's Division of Reproductive and Urologic Products raised the possibility of drug holidays in a conference call with reporters last October.

Evidence is cloudy on all these points, with existing studies having confounding factors, different definitions of atypical fractures, and very small numbers for ONJ.

For example, the FDA contracted with Kaiser Permanente of Northern California to conduct the "Predicting Risk of Osteonecrosis with Bisphosphonate Exposure" (PROBE) study, which found only nine cases of stage 1 or 2 ONJ among 8,572 patients who had taken OBPs for at least 1 year and responded to a mail survey. Of the nine cases, however, seven were in patients who had taken the drugs for more than 4 years.

Perhaps unsurprisingly, the drugs' sponsors all touted the benefits of long-term oral BP use, especially for bone mineral density, and opposed label changes.

Merck and Novartis said that drug holidays could be implemented on an individual patient basis, but Warner Chilcott warned that any drug holiday could lead to "a compromised clinical benefit."

This coverage is provided by "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

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