COX-2 Inhibitors: Communication of Accumulating Risk Evidence and a Product Withdrawal

Abstract

This chapter reflects on one of the biggest product withdrawals in pharmaceutical history, known as the “Vioxx story”, and explores the discovery of cardiovascular risks with rofecoxib, the active substance in Vioxx^®, and other COX-2 inhibitors, and the way that these risks were communicated to patients and healthcare professionals. It discusses specifically how evidence generation and communication are linked and how communication challenges arising from evidence accumulating over time demanded a need to frequently communicate to the public updated information. Examples from different countries and the impact on the World Health Organization’s Essential Medicines List are presented. The chapter emphasises the link between the experiences of the Vioxx story and subsequent changes in the regulation of medicines in major jurisdictions, including legally mandated transparency of clinical studies. Ultimately, only with increased knowledge and communication about the safety of COX-2 inhibitors, patients can now be treated in the most effective and safe way.

A contribution from the author Sérgio Nishioka is included in this chapter as Appendix 3.1.

Appendix 3.1: Safety Evaluation and Communication About COX-2 Inhibitors—Experiences in Brazil at the Time of the Rofecoxib Withdrawal in 2004

• Sérgio Nishioka 

1. Department of Communicable Disease Surveillance, Ministry of Health of Brazil, Brasilia, Brazil

   Sérgio Nishioka

The withdrawal of rofecoxib (Vioxx^®) from the US market in 2004 made its impact on clinical practice and on media headlines everywhere including in Brazil. As a consequence, the Brazilian medicines regulatory authority Anvisa decided to re-evaluate the safety of all COX-2 inhibitors already marketed in Brazil. By mid-February 2005 Anvisa’s advisory committee CATEME had made general recommendations regarding the safety information in the package inserts in line with what other regulatory authorities were recommending at the time. A few remaining points were to be discussed in an ordinary meeting of that advisory committee scheduled for mid-April. Because it was felt to be an important issue, the local press was following up on this issue.

In early April 2005 the US Food and Drug Administration (US FDA) announced having requested the manufacturer Pfizer to voluntarily withdraw from the US market its COX-2 inhibitor valdecoxib (Bextra^®). The European Medicines Agency and Health Canada took similar steps and Pfizer informed Anvisa accordingly. Anvisa decided to temporarily suspend the marketing of Bextra^® in line with action taken by other authorities, but in Brazil there was an additional issue to deal with, different from elsewhere.

In 2003, the manufacturer Pharmacia, before its merger with Pfizer, had in its portfolio a COX-2 inhibitor, parecoxib, for parenteral use, which is a prodrug metabolised to valdecoxib. In Brazil only, perhaps because of the timing of registration, Pfizer registered parecoxib as Bextra IM/IV^®, in order to support keeping patients who might have been prescribed parecoxib for perioperative pain control on oral valdecoxib thereafter, instead of switching to another analgesic. Parecoxib had been marketed in Europe and elsewhere under a different trade name, Dynastat^®. Because both valdecoxib and parecoxib were marketed as Bextra^® in Brazil, Anvisa decided that the temporary suspension of valdecoxib should also be applicable to parecoxib. Anvisa concluded that it would be difficult to communicate and make understandable to the public why one formulation of the same tradename would be kept on the market whereas the other would be withdrawn, even if only temporarily, considering that this would unnecessarily confuse the public. Five months later the evaluation was finalised; the marketing suspension of parecoxib was withdrawn while it remained valid for valdecoxib.

This is an example where a regulatory decision took into account the possible confusion through communication that might have been created on a very sensitive issue if only scientific rationales and actions by other regulatory authorities had been considered. The manufacturer in Brazil accepted this approach, and Anvisa, supported by CATEME, explained timely on its website every step taken. This facilitated the communication with the press and passed the image that CATEME had full control of the subject. During this time period, there was no major questioning by the Brazilian press of how Anvisa managed the case.