Frequently Asked Questions about Biosimilar Medicines

1. How is the EGA involved in biosimilar medicines?
2. Why are biosimilar medicines being introduced?
3. Where is Europe now regarding biosimilar medicines?
4. What is the regulatory approval process for biosimilars in Europe?
5. What is the science behind the 'comparability exercise'?
6. What is the meaning of the term 'biosimilar'?
7. How is a biosimilar medicine named?
8. How is quality assured for the manufacture of biopharmaceuticals?
9. How can patients be assured of safety?
10. What measures are needed to ensure access to biosimilar medicines?
11. What cost savings will biosimilar medicines bring to healthcare systems?
12. Why should patients be involved in the biosimilars debate?
13. How is the landscape evolving for biosimilar medicines?

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1. How is the EGA involved in biosimilar medicines? top

The EGA, a European trade association representing the generic and biosimilar medicines industry, takes an active interest in all issues related to medicinal products, including medicines derived from biotechnology. Several member companies of the EGA are biotechnology companies or companies with biotechnology business units. The EGA was particularly involved in the establishment of a legal framework and a regulatory pathway to allow the development and approval of biosimilar medicines in Europe. At present, the EGA continues to support companies developing biosimilar products, by ensuring that full market access is assured, and that the evolving regulatory landscape for biosimilars in Europe remains favourable. This will allow patients to gain access to more affordable high quality biopharmaceuticals[1].

Since biosimilars have now been in use safely in the European Union for several years, we can assert today that EGA members have extensive clinical experience with biosimilars. Our members are the developers of all of the biosimilar products approved and marketed in the EU to date[2], and many also have products approved in other highly regulated markets, including Japan, Canada, Australia and the USA.

2. Why are biosimilar medicines being introduced? top

Medicinal products developed through biotechnology constitute an essential part of medicines available to patients today and many medicines in the development pipeline are biotechnology products. For example 300 therapeutic monoclonal Antibodies (mAbs) are in development in over 200 indications including oncology (cancer treatment), inflammatory disease, autoimmune diseases, metabolic and central nervous system disorders, infectious and cardiovascular disease and transplant rejection.[3]

Some major biotechnology-derived medicines are, or will soon be, no longer protected by patents. As for all other medicines, when their 20-year patent expires, they will become open to development and manufacture by other companies. This introduces competition in the market which ensures continued patient access to safe and effective, and more affordable, biopharmaceuticals. Without competition the prices of the originator biopharmaceuticals would remain artificially high. Similarly, this competition will serve to stimulate research into new originator medicines. This fact is borne out by the situation in the USA where more than 80% of medicines used are generic medicines and where, at the same time, more new originator medicines are developed than anywhere else in the world.

In addition, Europe has a critical need to control healthcare costs. Europe cannot afford not to have competition from biosimilar products. Ageing is accelerating. The EU working age population will be reduced by about 2 million by 2020 and the number of 60+ is increasing twice as fast as before 2007[4]. Since this age group spends on average three to four times more on medicines than when they were 30, the cost of providing adequate access to medicines for this section of the population is exploding. Many biopharmaceuticals are also often used to treat long-term conditions such as diabetes, cancer, chronic kidney failure and multiple sclerosis. On average, biopharmaceuticals cost much more per patient than conventional pharmaceuticals[5], and their use is growing at a much higher growth rate than that of the overall pharmaceutical market.

As already noted, the biologicals pipeline is expanding. Study after study shows that not all patients who could benefit from these medicines have access to them — and with pharmaceutical spending growing more than twice as fast as the gross domestic product (GDP), that situation can only worsen. It is therefore critical that everything possible be done to maximise patient access to cost effective biopharmaceuticals — and this means a rapid introduction of biosimilar medicines as soon as patents expire. For example in the UK, many physicians moved filgrastim back to 1st-line treatment due to a lower biosimilars cost. Filgrastim is known to prevent hospital re-admission due to infection.

Another important reason for introducing biosimilar medicines is, of course, that the scientific basis for biosimilar development and technology exists to obtain approval and bring this important type of medicines to the market. The regulators have built on their very extensive experience with the originator reference products and their manufacturing changes during their life cycle, as well as on experience with many MA applications, approvals and scientific advice procedures for biosimilar medicines.

3. Where is Europe now regarding biosimilar medicines? top

Biosimilar medicines have now been a reality in the European Union for several years. The necessary legal framework for biosimilar medicines was adopted in the EU on 31 March 2004 and the first biosimilar medicines were approved by the European Commission in April 2006. All EU approved biosimilars products undergo the same rigorous scientific assessment at the European Medicines Agency (EMA) and its committees like any other biological medicine. The Agency confirms via their web site that each of them "has been compared to and matches the reference medicine [...] in terms of quality (how it is made), safety (for example the side effects that can occur when receiving treatment are similar), and effectiveness."

Guidance on risk management systems, applicable to all medicines, including biopharmaceuticals, has also been developed which assures safe market entry and post-marketing monitoring of these medicines.

The legal framework which has been in force since 30 October 2005, allows the performance of all necessary and appropriate tests and trials in order to obtain a marketing authorisation for a biosimilar medicine in the European Union without breaching the patent law. This facilitates the development of biosimilar medicines on the European territory and strengthens the EU biotechnology sector.

4. What is the regulatory approval process for biosimilars in Europe? top

All biotechnology medicines, including biosimilar biotechnology-derived medicines, are or will be assessed by the European Medicines Agency in London (EMA), which constitutes the scientific body of the European Commission responsible for the evaluation of medicines. They are approved by the European Commission based on the positive scientific opinion issued by the EMA and its main expert committee the CHMP (Committee on Human Medicinal Products).

When the EMA assesses data for a biosimilar medicine, the scientific principles for ensuring product quality, safety and efficacy are identical to those applied to the originator reference medicine with which comparability is demonstrated.

In addition to the quality data required for all biotechnology products, the companies involved in the developing of biosimilar medicines must additionally submit "comparability data", usually described as data from a "full comparability exercise". Indeed, manufacturers must characterise, in parallel, both their biosimilar product and the originator reference product. They must demonstrate, with a high degree of certainty, that the quality of the biosimilar medicine is highly similar to the originator/reference medicinal product. A comparability programme is clearly defined and agreed upon in advance with the EMA, who defines the set of non-clinical and clinical data that are necessary to sufficiently demonstrate biosimilarity. The extent of this data varies according to the type and complexity of the medicine involved. Each individual biosimilar medicine is assessed on a case-by-case basis.

5. What is the science behind the 'comparability exercise'? top

The development of a biosimilar medicine requires a comprehensive product and process development plus comparative testing at all levels, namely at quality, non-clinical and clinical stages. The aim of the "comparability exercise" is to generate data to provide assurance that the biosimilar product matches its reference product in terms of quality, safety and efficacy. The development of a biosimilar is consequently a target-directed development which means that the manufacturing process for a biosimilar is modified until the product generated has a profile that matches the profile of the reference product.

The underlying scientific principles of comparability were first developed by US regulators at the Food and Drug Administration (FDA) in the 1980s when the manufacturers of original biotechnology products began changing their processes from those in use when their products were first authorised. In these circumstances comparability data were used to provide information so that a newer version of these products could be used interchangeably with the prior versions. A recent scientific publication[6] showed data from analyses of multiple batches of originator biopharmaceuticals currently on the EU market. The data revealed substantial alterations of the quality attributes of the tested products which are most probably caused by changes in the manufacturing process. All tested originator biopharmaceuticals remained on the market with the same product information, indicating that the observed changes did not affect the clinical profile and are therefore acceptable by the health authorities.

The same scientific comparability approach is used in the EU biosimilars review process, based on all relevant data, including considerable data from highly sophisticated characterisation methods often not available, or not fully developed, at the time of the approval of the reference product.

6. What is the meaning of the term 'biosimilar'? top

The term 'biosimilar', 'biosimilar medicine' or 'similar biological medicinal product' (official legal term) is a term derived from the nature of the medicine and from the EU regulatory and legal route for approving these medicines. 'Biosimilar' denotes a biological medicine which is highly similar to an already authorised reference biological medicine. This term should only be used to describe follow-on biological medicines that have been approved following a rigorous comparability exercise as is required in the EU and other non-EU highly regulated markets.

All biopharmaceuticals are inherently variable due to the fact that they are produced from living organisms. This variability exists within batches, from batch to batch, and when production processes are improved or changed or differ between manufacturers. The variability of biopharmaceuticals is greater than that typically observed for conventional pharmaceuticals and applies to originator reference products as well as biosimilars.

7. How is a biosimilar medicine named? top

By law, every biosimilar medicine, like any other medicine, will either have an invented (brand) name, or the name of the active substance together with the company name. All biosimilars are consequently clearly identifiable by their unique name, which has to be formally agreed by the European Medicines Agency as part of the approval process. The name of a medicine is very important for clear identification, safe prescription and dispensing, as well as for monitoring the safe use of the medicine during the whole life-cycle.

8. How is quality assured for the manufacture of biopharmaceuticals? top

Both originator reference products and biosimilar medicines are made under carefully controlled conditions to ensure the products are consistent and of the required quality. This is known as Good Manufacturing Practice (GMP).

In the European Union, GMP inspections for all biopharmaceuticals — originator reference products and biosimilar medicines — are coordinated by the EMA and performed by the National Regulatory Agencies.

Biosimilar medicines are manufactured according to the latest state-of-the-art technology, ensuring the highest quality standards available. It requires a high degree of specialised expertise and the establishment of an expensive technological background.

Biosimilar medicines are usually better characterised than their reference products were characterised at the time of their approval 10 or 20 years earlier.

9. How can patients be assured of safety? top

The development of a biosimilar medicine requires a comprehensive product and process development plus comparative testing at quality, non-clinical and clinical level. This approach ensures that the biosimilar product matches its reference product in terms of quality, efficacy and safety.

Once the medicines are prescribed and dispensed, all European pharmaceutical companies are legally required to monitor their use and effects. They must have systems in place to detect, assess, understand and endeavour to communicate any adverse reactions (sometimes known as "side-effects") or any other medicine-related problem. The science and activities of these processes are known as "Pharmacovigilance". As is the case with every medicine, each manufacturer must submit a Risk Management Plan (RMP) which is a detailed description of the company's pharmacovigilance system. This Risk Management Plan (RMP) must be agreed by the EMA and is an integral part of the marketing authorisation. The RMP describes what is known about the safety of the medicine and outlines how the manufacturer will further monitor and fill any potential or known gaps in knowledge as well as any measures needed to prevent or minimise any potential risk from the medicine. This plan must be regularly updated throughout the entire time the medicine is marketed and used and is published on the Agency web site.

Once marketed, pharmaceutical companies must also continuously evaluate the information on the benefits and risks of their medicines.

All biopharmaceuticals, including biosimilar medicines, follow the same pharmacovigilance rules. Additionally, adverse reaction reports of a biological medicine must contain the name of the medicine and the batch number.

10. What measures are needed to ensure access to biosimilar medicines? top

Strategies to increase the affordability of medicines — and to make them available to more patients — include promoting competition. Biosimilar medicines need to be included in these strategies. Although a solid legal and regulatory environment has been established for biosimilars in the EU, a clear market pathway for biosimilar medicines needs further consideration in each individual Member State to enable full access to these medicines as soon as possible after their marketing approval. Indeed, in some countries the ways and methods by which individual countries determine which medicines are selected and used needs to be adjusted to ensure biosimilar medicines are made fully available. Relevant factors in addition to the initial marketing authorisation approval would include agreement on prices and on how the biosimilar medicines are reimbursed, and ensuring that clinicians and patients fully appreciate the benefits of using biosimilar medicines as part of their practice and treatment. Access for patients to biosimilar medicines is not automatic; it requires that proactive steps be taken by all relevant stakeholders.

11. What cost savings will biosimilar medicines bring to healthcare systems? top

The improved affordability of healthcare that could result from the use of biosimilar medicines is real. As an example, the EPO biosimilar introduction in Germany resulted in EUR 60m annual savings (-17, 3%) in the first year of the market[7]. It has been estimated that biosimilars in Germany alone could contribute to 1 billion EUR annual savings from 2017. By 2020 the savings through biosimilars would be more than 8 billion EUR.[8]

The price differential between a reference product and a biosimilar medicine will depend on the relative development costs. Biosimilar medicines can be expected to be offered at a price below that of the reference product, partly as a result of production process efficiencies, and partly because of the reduced costs of a streamlined development programme as well as a result of competition. The greatest savings are likely to result from the clinical trial programme, since a biosimilar medicine (containing a well-known and well-used substance) would require less clinical data to support its approval. This price differential should lead to a significant and much-needed release of healthcare funds. National governments' should develop measures to stimulate the uptake of biosimilars. Such policies will increase access to biosimilars and contribute to major cost savings for healthcare systems.

12. Why should patients be involved in the biosimilars debate? top

Patients need to contribute their views actively to this debate to ensure that cost effective biotechnology-derived therapies are made available to them as quickly as possible. Patients should discuss the access, cost, safety and efficacy of biosimilar medicines as these are now an emerging source of affordable medicines for more patients with some of the most difficult to treat diseases.

Information about specific biosimilar medicines is available from a number of sources, including the EMA, to enable patients, together with their doctor and pharmacist, to have access to the relevant data on the use of these medicines. The EGA first published a handbook on biosimilar medicines in 2007. A revised second edition of this handbook has been published in 2011.

Patients can have confidence in biosimilar medicines because they are approved by the same regulatory organisation, with the same scientific rigour, and using the same regulatory systems as the comparable originator products.

Healthcare teams also need to live up to their responsibility to contribute to patient awareness of the existence of biosimilar medicines and to communicate their confidence in the scientific assessment performed by the EU regulatory authorities.

13. How is the landscape evolving for biosimilar medicines? top

2012-2017 will see many further developments in relation to biosimilar medicines, and healthcare professionals and healthcare purchasers need to ensure that they are aware of what is happening in this rapidly changing environment. One of the most significant new areas is the potential for the development and approval of biosimilar monoclonal antibodies.  

In 2010 in Europe, 6 out of the top 10 leading pharmaceutical products were monoclonal antibodies. It has been estimated that worldwide over 45 monoclonal antibody products are marketed, with total sales in excess of $40 bn[9].

The patent protection on many originator reference biotech products has expired already, and many more will expire over the next few years. As a result most commentators expect a growing number of biosimilar products on the market in the not too distant future.

Examples of currently licensed monoclonal antibodies active substances with potential for biosimilar products to be developed

 

Trade name

INN of active substance

Clinical use (examples)

Mabthera/Rituxan®

Rituximab

B-cell non-Hodgkin's lymphoma

Rheumatoid arthritis

Avastin®

Bevacizumab

Colorectal cancer, lung cancer

Erbitux®

Cetuximab

Colorectal cancer, head and neck cancer

Vectibix®

Panitumumab

Colorectal cancer

Campath®

Alemtuzumab

B-cell chronic lymphocytic leukaemia (B-CLL)

Herceptin®

Trastuzumab

Breast cancer

Humira®

Adalimumab

Rheumatoid arthritis, Crohn's disease

Remicade®

Infliximab

Rheumatoid arthritis, Crohn's disease, psoriasis

Simulect®

Basiliximab

Transplant rejection

Zenapax®

Daclizumab

Transplant rejection

Xolair®

Omalizumab

Asthma

Tysabri®

Natalizumab

Multiple sclerosis

Lucentis®

Ranibizumab

Macular degeneration

Synagis®

Palivizumab

Respiratory syncytial virus infection

REMEMBER:

For information on a specific medicine or for answers to your own particular health concerns, you should always consult with your doctor or pharmacist for their professional advice.



[1] Biopharmaceuticals are made using, or derived from, living organism using biotechnology

[2] <span >One company that is the license holder to a biosimilar approved with the same dossier is not a full member of EGA, but all of the other companies that sponsor successfully marketed EU biosimilars are EGA members.

[3] Alan Sheppard, Principal, Thought Leadership, Global Generics, IMS Health, EGA biosimilars international symposium, April 14th 2011, London

[4] Presentation of European Commission President J.M. Barroso to the Informal European Council / 11 February 2010

[5]: "A breast cancer patients' annual cost for Herceptin is $37.000. People with rheumatoid arthritis or Crohn's disease spend $50.000 a year on Humira. And those who take Cerezyme to treat Gaucher disease, a rare inherited enzyme deficiency spend a staggering $200.000 a year." Source: New York Times article "Biologics Boondoggle" by Anthony D. SO and Samuel L. Katz published in print on March 8, 2010

[6] Acceptable changes in quality attributes of glycosylated biopharmaceuticals, Martin Schiestl et all, Sandoz Biopharmaceuticals, Nature Biotechnology, Volume 29, Number 4, April 2011

[7] Dr. Paul Cornes, Consultant Oncologist, Bristol Haematology & Oncology Centre, UK at EGA international biosimilars symposium, London, 14th April 2011

[8] Berlin IGES Institut study: B. Häussler, M. Thiede, November 2008

[9] Alan Sheppard, Principal, Thought Leadership, Global Generics, IMS Health



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