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Sean Milmo is a freelance writer based in Essex, UK.
Greater transparency and reliability of information are needed in the quality assessments of biosimilars.
The size of the European biosimilars market is accelerating rapidly as government-funded healthcare services increase their support for these medicines in an effort to reduce costs. Sales of biosimilars in Europe has tripled in the past five years (1). In 2015-2016, they soared by approximately 50%, according to figures from QuintilesIMS, the US-based international healthcare services company that has been carrying out studies on the European biosimilars market for the European Commission, the European Union executive (1).
By March 2017, 26 EU-approved biosimilars were available in the European market, 10 years after the European Medicines Agency (EMA), the EU’s centralized licensing body, authorized its first biosimilar. In 2016, Europe accounted for 87% of global sales of biosimilars, underlying its world leadership in the development of the medicines, particularly in the regulatory procedures for establishing comparability between biosimilars and the original products. The biosimilars sector in Europe, which is still in its infancy, has now reached a stage where more information about these regulatory procedures needs to be provided to stakeholders, particularly healthcare professionals, if the strong momentum behind biosimilar sales is to be maintained.
Physicians are not greatly concerned anymore about the safety of biosimilars. In the 10 years since they have been on the European market, the EU’s pharmacovigilance monitoring system has not identified any marked differences in the types of adverse effects between biosimilars and their originals. But prescribers are concerned about the challenges of convincing patients about security of treatments by biosimilars for new therapeutic areas such as autoimmune diseases, oncology, and especially chronic conditions.
This necessity for greater transparency is being centred on the way the quality attributes of the manufactured biosimilars are compared with those of the original or reference product. Manufacturers are required to establish that their biosimilars have sufficient levels of similarity in order to be authorized.
These attributes mainly comprise physicochemical and functional properties such as molecular structure, protein modifications, and biological activity. Because the drugs are biological, there are inevitable differences. But for a drug to be “highly” similar so that it can be licensed as a biosimilar, these differences must not result in inferior levels of safety and efficacy to the reference product.
With biologicals in which the active substance is a protein, the biosimilar and reference product must contain the same protein (i.e., amino acid sequence) and the same three-dimensional structure or folding of the protein. In the finished medicine, certain differences, such as excipients used in formulations and in the administration device, are allowed because they have no effect on safety and efficacy.
Quality assessments have become such an essential part of the process for approving biosimilars that in most cases once a biosimilar has proved itself to be highly similar on a quality basis to regulators, investigation of clinical studies to establish safety and efficacy has not been required. “By demonstrating biosimilarity [at the quality level], a biosimilar can rely on the safety and efficacy experience gained with the reference medicine,” says an EU guide to biosimilars for healthcare professionals published jointly in May 2017 by EMA and the European Commission (2). “This avoids unnecessary repetition of clinical trials already carried out with the reference medicine,” it adds.
With quality having such a key position in biosimilars’ authorization, healthcare professional organizations have been urging EMA to increase the transparency of the comparability exercise applied to quality data to show high similarity between biosimilars and their reference products. “Given the role of healthcare professionals on the front line of patient care, it is vital that they have access to reliable information on these medicines: what they are and how they are developed, approved, and monitored,” says Professor Guido Rasi, EMA’s executive director.
When selecting biosimilars for patients, prescribers have tended to rely on the basic details in its summary of product characteristics (SmPC), which focuses on safety and efficacy information. A much more suitable communications vehicle on the quality aspects of biosimilars would be a group of documents known as the European Public Assessment Report (EPAR). In addition to the SmPC information, EPAR documents contain assessment reports on the scientific evaluation of the medicine at the time of approval and on major changes, such as the addition of new indications. Crucially, it integrates the whole comparability exercise covering the quality, safety, and efficacy of the biosimilars. By extending EPAR to give more information on quality aspects, EMA could deal, for example, with concerns about lack of appropriate data when prescribers switch patients from one biosimilar to another.
In a joint position paper (3) on biosimilars switching issued in March 2017, the European Federation of Pharmaceutical Industries & Associations (EFPIA), European Biopharmaceutical Enterprises (EBE), and International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) complained about the lack of comparability data between biosimilars for prescribers. “This type of data may not be available to stakeholders when evaluating a switch between two biosimilars of the same reference product,” the three organizations said (3).
Now EMA has revealed it is testing a scheme for giving more technical information on quality comparability data in the EPAR of an unidentified biosimilar that the agency has recently approved. “This initiative is part of the agency’s efforts to ensure that healthcare professionals have access to reference information on the science and regulation underpinning the use of biosimilars and thereby increase healthcare professionals’ and patients’ confidence in the approval process for biosimilars,” an EMA spokesperson told Pharmaceutical Technology Europe.
“Once the EPAR for the medicine has been published later this year, EMA will conduct a small survey among relevant healthcare professionals to find out whether this additional information is considered helpful.”
At the same time, EMA is making moves to raise the efficiency of analytical methods for the collection and assessment of quality data. In February 2017, it launched a scientific advice pilot project to help biosimilar developers assess existing data. The agency will advise developers on the studies they should conduct on the quality, analytical, and functional data that they already have available. EMA’s scientific advisors usually do not make suggestions on the assessment of existing data. The agency plans to run the pilot until it has undertaken six scientific advice requests, with a maximum of one scientific advice request being accepted per month.
EMA is also considering ways of gaining greater value from the statistics generated by quality assessments in the development of drugs, particularly biosimilars. Conclusions or inferences could be reached from data rather than using the statistics merely in a descriptive manner to make measurements or to detect patterns.
The agency issued in March 2017 a reflection paper (4) on statistical methodology in comparative quality assessment to investigate to what extent the implementation of inferential statistical methods can facilitate comparative evaluations of quality data. The paper highlighted some current difficulties with quality assessments in biosimilars development with some experts being sceptical about what could be achieved with the help of statistics.
“From related discussions between [biosimilar] developers and regulators, it became evident that there is no common understanding what kind of statistical data analyses approaches would be considered suitable, if any, for comparison tasks involving quality attributes data,” EMA said in the paper. Furthermore, the effects of quality differences on safety and efficacy can be difficult to measure. “The impact of differences at the quality level on clinical outcome--efficacy/safety/immunogenicity--is often hard to predict or quantify,” the paper said.
Some of the concerns about quality data stem from the limitations of data sources when biosimilars have been produced in small commercial batch quantities over a relatively short period. “At first sight, it might seem straightforward to apply inferential statistical methods for comparing data from quality attributes,” the paper continues. “But often severe limitations exist regarding practical applicability, given the specific circumstances relating to sampling and data collection. Hence, the question of whether the desired conclusion of similarity of products could indeed be inferred from often limited information from sample data remains difficult to answer on many occasions.”
Meanwhile, physicians in some parts of Europe are coming under growing pressure to prescribe more biosimilars as governments step up their efforts to drive down medicine prices by introducing tendering schemes for mass supplies of biologicals, including both originals and biosimilars. They are also offering incentives for doctors to prescribe lower-cost biosimilars through “gain sharing” projects under which at least some of the money saved is channeled into local healthcare budgets.
Nonetheless, the biosimilars market in areas of Europe remains fragmented. Levels of prescribing are high in Scandinavia but relatively low in Western European countries such as France and Spain and, despite recent rises in the availability of certain biosimilars, in Eastern Europe (5).
There are also huge contrasts in individual countries. In Italy, for example, uptake of biosimilars has reached close to 75% in the north but is as low as 10% in the south (6). Caution among healthcare professionals has been a major factor behind these differences. It remains an open question as to how much greater transparency and reliability in information on quality will help to change their attitude to biosimilars.
1. P. Troein, R.Logendra, Stephen Deitch, QuintilesIMS, “Market development in Europe and Globally-A perspective on biologicals and biosimilars,” presentation at Medicines for Europe’s Biosimilar Medicines Conference ( London, March 2017).
2. EMA and European Commission, Biosimilars in the EU-Information Guide for Healthcare Professionals (London, May 2017).
3. EBE, EFPIA, IFPMA, Considerations for Physicians on Switching Decisions Regarding Biosimilars (Brussels, March 2017).
4. EMA, Reflection Paper on Statistical Methodology for the Comparative Assessment of Quality Attributes in Drug Development, EMA/CHMP/138502/2017 (London, March 2017).
5. IMS Institute for Healthcare Informatics, Delivering on the Potential of Biosimilar Medicines (Parsippany, New Jersey, March 2016).
6. M. Uda, Italian Biosimlars Group, “The New Italian Procurement Law on Off-Patent Biological Medicines,” presentation at Medicines for Europe’s Biosimilar Medicines Conference (London, March 2017).
Pharmaceutical Technology Europe
Vol. 29, No. 7
When referring to this article, please cite it as S. Milmo, “A Question of Quality,” Pharmaceutical Technology Europe 29 (7) 2017.