Gaining access to Europe’s pharmaceutical markets has become a multi-stage operation. The licensing of a new drug is only a preliminary step in what can be a lengthy and complex procedure for some pharmaceutical companies, particularly those with innovative biopharmaceuticals. First a drug has to be approved for its quality, safety, and efficacy by one or more regulatory authorities. This approval can be either by the central London-based European Medicines Agency (EMA) for a product to be marketed across the region or by a national licensing authority for one to be sold only in specific European countries.
To be made available, however, in the public sector health services a medicine has to be approved for reimbursement. These reimbursement decisions are increasingly determined by separate investigations of medicines often called Health Technology Assessments (HTAs). While the regulatory agencies deal with benefit-risk aspects of medicines, HTA bodies gauge their effectiveness in relation to existing products, particularly on the basis of cost.
The role of these assessments in European national pharmaceutical markets has become so important that EMA has agreed to collaborate with EUnetHTA, a European Union assessment network, on involving HTA bodies in giving advice to manufacturers in the early stages of a drug’s development.
The move has been welcomed by small- and medium-sized enterprises (SMEs), especially those developing advanced medicines. “SMEs are generally interested in receiving joint EMA/HTA advice, in particular when it comes to advanced therapies,” says Paolo Morgese, chairman of the HTA Topic Group of EuropaBio, a biotechnology trade association. “This is not necessarily linked to the development of new manufacturing processes per se, but more to the need of identifying a common set of data requirements,” he added.
EUnetHTA has been stepping up its efforts to achieve more consistency in the methodology and content of HTAs among the European Union’s 28 member states. The assessments, carried out by a range of public agencies and advisory bodies comprising key opinion leaders (KOLs), mainly comprise appraisals of clinical trial data to ensure that a medicine gives added therapeutic value. But they are also starting to cover types of formulation and manufacturing processes particularly when gauging cost effectiveness. National bodies do not always carry out assessments but they are also conducted by regional clinical and funding organizations within countries. Their support can be necessary for a drug to be put on local formularies.
The Impact of HTAs on Biosimilars
As a result of cuts in healthcare costs due to post-recession austerity programs, favorable HTAs are becoming crucial to the successful market launch of pharmaceuticals in Europe. HTAs backing reimbursement can be vital for new innovative medicines but can also be important to biosimilars.
Despite Europe being a pioneer in the development and commercialization of biosimilars, it has a fragmented market for the products with national health authorities following different policies for their reimbursement and inclusion in formularies. While the EMA has the central responsibility for licensing biosimilars in the EU, many states have been carrying out their own assessment of them.
Biosimilar filgrastim, for the treatment of neutropenia with a granulocyte colony-stimulating factor (G-CSF) analog, had by last year built up market shares ranging from 90–100% in the UK and Sweden and several Eastern European countries. In Belgium, however, the penetration was only 1%, Netherlands 27%, and Switzerland 40%, according to figures from IMS (1).
An European Generic Medicines Association (EGA) survey of national regulators in the EU pinpointed a number of obstacles to the uptake of biosimilars, including a perception of biosimilars being inferior to the originals, with doctors being reluctant to prescribe them because of “hypothetical uncertainties in their safety and effectiveness” (2).
Assessments have done a lot to boost biosimilars prescribing in some countries. “Prior to a pro-biosimilar initiative in Hungary the country had the lowest uptake of biosimilars in Central and Eastern Europe,” Ken Walsh, responsible for global pricing and market access at Sandoz Pharmaceuticals, the leading biosimilars unit of Novartis, said at an EGA biosimilars symposium in 2013 (1). “(Then) payers in Hungary recognized the need to incentivize biosimilars uptake.”
Prominent KOLs were recruited to endorse a pro-biosimilars white paper, which after being submitted to the country’s Ministry of Health, led to a reimbursement agreement for the products. By early 2013, the share of biosimilars in the Hungarian filgrastim market was 99%.
In Denmark, selection of biosimilars available in the country’s health service is based not just on price but quality issues like stability, according to Walsh. This has helped to overcome concerns among Danish patients about production standards with biosimilars. Within less than two years, biosimilar somatropin, the growth hormone, rose from a market share of around 20% in the country to over half.
In Germany, one of Europe’s biggest markets for biosimilars, there have also been worries among patients and doctors about the quality and safety of biosimilars. As a result, doctors’ organizations, and insurers or sickness funds have combined to raise the uptake of biosimilars through assessment work and the introduction of prescription quotas. “In some regions the physicians’ associations together with the sickness funds have been very committed to making sure that doctors are fully aware of the quality and benefits of biosimilars,” says Bork Bretthauser, managing director of Pro Generika, Berlin, the German generic-drug and biosimilars association. There are still big differences in the penetration of biosimilars between German regions. With biosimilar erythropoietin (EPO), for example, in regions like Saxony and Bremen it has shares of over half while in Saarland the proportion is only around 15%, according to Pro Generika. “There is still a concern about variations in product characteristics between batches of the same biosimilar, whereas doctors need to be made aware that there are variations between batches of the original as well,” says Bretthauser.
Across Europe, HTA bodies are taking different approaches to the issue of quality in products like biosimilars and other biopharmaceuticals. “The matter of quality is a new area for HTAs,” says Paul Catchpole, director of values and access at the Association of the British Pharmaceutical Industry (ABPI), London. “Once a product like a biosimilar is assumed to have clinical equivalence to the original, there is a question about what evidence should be assessed for matters like comparative quality.”
The difficulties facing biosimilar producers with reimbursement and market access are those confronting all producers of new medicines in Europe with innovative production processes. Gaining positive HTAs and reimbursement decisions can be especially hard for SMEs with advanced therapy products and orphan medicines. Unlike with large drug companies, they do not have the resources to lobby assessment organizations.
Three years after its cartilage regeneration, biopharmaceutical ChondoCelect was approved by the EMA, TiGenix NV, Leuven,. Belgium, a cell-therapy specialist, has achieved reimbursement deals for the product in only three European countries--Belgium, Netherlands, and Spain, all of which it has facilities in.
“Gaining reimbursement approval has been much slower than expected,” says Maria Pascual Martinez, vice-president, regulatory affairs at TiGenix. “In the current economic conditions, securing access to health service patients is difficult, particularly when your technology can be regarded as being disruptive.”
Uniqure BV (Amsterdam) formed a partnership last summer with Chiesi Farmaceutici SpA (Parma, Italy), a specialist in the development and commercialization of rare disease therapies, to help gain reimbursement approvals for its Glybera medicine, an expensive orphan treatment for lipoprotein lipase deficiency (LPLD). It was the first gene therapy to be approved by the EMA in November 2012. Important to the success of Glybera will be the efficiency of the process at its Amsterdam plant for producing gene cassettes for delivering transgenes into the body’s cells. Chiesi’s strategy is to obtain reimbursement deals this year in the large European markets on a single price, likely to be a six-digit US-dollar figure, for a one-time treatment.
The big challenge for Chiesi and Uniqure is obtaining consistent HTAs on an orphan medicine, particularly on its cost effectiveness when there is little comparative evidence on issues like manufacturing efficiencies.
Producers of new drugs need more uniformity in assessments across Europe if they are to obtain the reimbursement prices they need to recoup their development costs.
1. K. Walsh, “Biosimilars’ utilisation and the role payers do play in driving uptake in Europe: an industry perspective,” Biosimilar Medicines, 11th EGA International Symposium, London, Apr. 25-26, 2013.
2. EGA,Survey to Members States and EEA Countries on Biosimilars (EGA, September 2012), accessed Jan. 16, 2014.