Ambition vs. Assessment: The Approval-Reimbursement Divide

There’s no doubting the energy and ambition of the European Medicines Agency (EMA). Its own summary of its achievements in 2015 is eloquent testimony. Highlights in its core activity of evaluating human medicines include 93 drugs recommended for approval, including for 39 new active substances. It was, says EMA, “an important year for public health in the European Union”-citing “innovations that have the potential to make a difference to people’s lives” in cancers, cardiovascular diseases, hematology, and neurology.

The EMA summary also notes other aspects of its work-including continuous checking of drug quality and safety (or, as the agency describes it, a new public-friendly choice of language, “monitoring the benefits and risks that patients experience with this medicine in real life”), ensuring the integrity of the  development and manufacturing of medicines, and updated advice for HIV patients.

But EMA’s principal boast relates to its role in promoting healthcare innovation. And not just with the 39 new active substances. The use of an already approved medicine in a new therapeutic indication can also offer new opportunities for patients, the agency stresses, going on to list half a dozen key examples from the past year, including Perjeta for patients with breast cancer undergoing surgery.

Perjeta (pertuzumab) is a Roche/Genentech monoclonal antibody, first authorized in the U.S. and much of Europe two and three years ago as part of a treatment for specific cases of breast cancer, where the protein HER2 is found on the surface of the cancer cells, and where disease has spread to other parts of the body or has come back after treatment. The drug received EMA approval for this indication in 2013, and is increasingly widely used. Perjeta is a rapidly growing element in Roche’s portfolio, with the company’s third-quarter report last year noting: “Sales of the HER2-positive breast cancer medicines, Herceptin, Perjeta, and Kadcyla, grew 19%.”

As the EMA remarks, in 2015 Perjeta’s indications were extended. The new authorized use includes treating earlier stages of breast cancer at high risk of coming back, where it is locally advanced or inflammatory, so as to improve the chances of surgery-neoadjuvant therapy. The EMA evaluation of Perjeta in neoadjuvant therapy indicates the drug “was shown to improve response to treatment.” Despite some side-effects, “the overall safety profile was acceptable.” EMA “decided that Perjeta’s benefits are greater than its risks and recommended that it be given marketing authorization.” The FDA approved use for neoadjuvant treatment in 2013, under the agency’s priority review program, which provides for an expedited review of drugs that may offer major advances in treatment.

But the EMA’s view of these “new opportunities for patients” is not universally shared. At the end of 2015, just six months after this additional indication received its ringing endorsement from Europe’s top scientists, a diametrically different view emerged from Europe’s most important organization advising payers on which drugs merit reimbursement, the Institute for Quality and Efficiency in Health Care (IQWIQ), which does the groundwork for the reimbursement authority in Europe’s biggest market, Germany,  

According to IQWIQ, the supporting data for neoadjuvant use contains a “hint of lesser benefit,” and there is “no proof of positive effects.” Although IQWIQ assessment in 2013 of Perjeta’s initial use found “a survival advantage for certain patients and, hence, a hint of a major added benefit,” the advice it has given for neoadjuvant use is that “the study data presented resulted in a hint that pertuzumab is of lesser benefit than the appropriate comparator therapy.” It also questioned the relevance of the data supplied. There is only “limited transferability of the study’s results to the German healthcare context,” it said.

There may seem to be something odd about such a discrepancy of view to anyone unfamiliar with the arcania of European authorization and reimbursement processes-and even to those who are inured to the complexities. On the face of it, the difference of opinion seems hard to understand. Even the company itself (and Roche is hardly a newcomer to European procedures) observed with scrupulous restraint that this opposition was highly unusual. “It’s the first time that we’ve received such a divergent view by IQWIG in regard to the EMA approval,” the company said in answer to questions-adding that the product was accepted in this usage in the U.S., too. “With the early approval of Perjeta in the neoadjuvant setting, both the FDA and EMA have acknowledged the need to bring new efficacious treatments to patients,” Roche said.

But Europe is Europe, and operates in its own quaint way. The EMA downplayed the issue when questioned on the coherence of European decision-making. “The assessment methodology as well as the purpose of the assessments carried out by EMA and by health technology assessment (HTA) bodies are very different and cannot be compared,” the agency said, providing

an extensive background review of the distinct roles of authorization bodies and HTA organizations. And it neatly sidestepped further queries with the careful disclaimer that “EMA cannot comment on the assessments made by HTA bodies in the member states.”

Within Europe’s industry associations, hard-headed realists also hesitate to draw conclusions from this apparent clash of views. Pär Tellner, regulatory affairs director at the European Federation  of Pharmaceutical Industries and Associations, said the question was not whether IQWIG is or is not scientific, or less scientific than the EMA. “HTA and regulatory agencies have different remits,” he pointed out. While the EMA assesses the safety, efficacy and quality of products, providing for a range of alternatives to patients, HTA agencies “consider the alternatives that are available and, in light of their national priorities, support decisions on which alternatives should be made available/reimbursed for which patient groups, and at what level,” Tellner said. “Therefore, conclusions from the HTA review and EMA review might very well differ.”

But even allowing for the distinct roles of regulators and HTA bodies, disarray in Europe over getting new medicines to patients is certainly provoking interest at high levels of the European Commission. A recent working document bearing the strong imprint of Commission President Jean-Claude Juncker expresses unambiguous concern over “the limited standardization and coordination of the HTA process in Europe.” It underlines that “with currently about 50 HTA agencies in Europe (including national and in some countries regional agencies), fragmentation is very high,” as “multiple stakeholders and systems apply varying requirements.” It says the varying results between countries raise the question of objectivity and accuracy of assessments, and compromise rewards for innovation. “Shortcomings in HTA coordination … can have negative effects by delaying patients’ access to innovative treatments,” the Commission’s document says. 

Pharmaceutical policy theologians can accurately and adequately explain and even justify what look like contradictions. But the question is being examined not solely by theologians. German patients might well come to question why they should be debarred from a benefit flagged up so enthusiastically by the EMA. They may not be so willing to accept that the system must be accepted as it is. They-and many other patients in many other European countries seeking access to many other treatments they are currently debarred from-may wish to see changes, and changes at a pace greater than the current discussions between industry, EMA, and HTA bodies envision.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium