The Pharmaceutical Journal
Vol 277 (Supplement) F30
October 2006

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FIP Congress 2006

How biosimilars can affect practice

Managing uncertainty to serve the patient better was the opening theme of Ajaz Hussain, of Sandoz, US. He explained that to compete for market share held by originator products, copies of approved recombinant protein drug products are being developed, manufactured and marketed by companies other than the originators.

These biogeneric copies are called “biosimilars” by the European Medicines Agency (EMEA) and “follow-on protein products” by the US Food and Drug Administration. There is uncertainty because of the complexity of the product, variations in recombination, the manufacturing process, some safety concerns (including immunogenicity) and confusion in terminology.

Spending on specialty pharmaceuticals is growing twice as fast as traditional prescription drugs, with an expected market in 2010 of $67bn, said Dr Hussain. At current rates this will exceed the ability of health care systems to pay for the demand in all countries. There is an unmet need for affordable, high quality biopharmaceuticals.

Dr Hussain said there were two differing points of view: the originator’s and the copier’s. In Europe this has been partially addressed by the EMEA framework on similar biological medicinal products. Uncertainty has also been reduced in the industrial pharmacy setting. The manufacturing process is scientifically designed to achieve a product equivalent to the reference product — quality by design.

Continuous feedback loops, process development and high performance analytical techniques result in the required specific selection of cell line, raw materials, control of critical variables, formulation, primary packing and delivery system.

Dr Hussain said that interchangeability within hospital pharmacy practice must be based on sound science and appropriate clinical demonstration of therapeutic equivalence. Traceability and pharmacovigilance should not raise new concerns within the EMEA approval process because only products of compatible quality can be introduced.

Precepts challenged

Tim Oldham, of Mayne Pharma, UK, presented a paper challenging many of the precepts that currently exist in the biosimilars arena. He said that given modern comparison techniques it is possible to demonstrate that one therapeutic protein is therapeutically equivalent to another.

Regulators now recognise this and so the time has come for pharmacists and other health care practitioners to understand biosimilars better so that they can make sound, science-based clinical and pharmaceutical decisions and so realise the huge health care economic potential of biosimilars.

Our ability to treat major diseases such as diabetes is under threat because globally the increase in incidence is growing beyond our resources, said Mr Oldham. The rate of increase of health care/pharmaceuticals spend is outpacing gross domestic product growth in most developed countries. Evidence shows that biologicals are currently underprescribed because of pressure on medicine budgets. So biosimilars could make a real difference.

Turning to perspectives on bioequivalence, Mr Oldham discussed the importance of immunogenicity, pointing out that the biggest example of immunogenicity is pure red cell aplasia (PRCA), and that this had been the result of a reformulation in an originator product. But despite the wide use of biopharmaceuticals over the past 20 years, immunogenic response was relatively rare. Isoform variability is also inherent in originator products and is not just seen in biosimilars.

From a pharmacovigilance perspective Mr Oldham stated that “known risks should be tested in accordance with existing risk assessment frameworks. Theoretical risks should not.”

From an interchangeability point of view biosimilars are therapeutically equivalent to the reference product and so there is no reason not to interchange, and they should be considered for substitution under the same local rules as generic drugs. In particular, practitioners should not be asked to second guess the regulatory authorities, which are instrumental in setting appropriate standards.

Differences discussed

Jacques Mascaro, Hoffman la Roche, Switzerland, discussed the differences between originator products and biosimilars and took the view that each biotechnology-derived protein is defined by its own production process and that this contributes to the product characteristics. He urged a more cautious approach regarding substitution, quoting examples where small changes in the product can make a big difference in immunological response.

Summarising, Dr Mascaro stated that for biosimilars the amount of clinical data is critical if a comparison is to be made with the innovator product and the risks are to be properly evaluated. There should be risk management plans as part of the approval process and an obligation to identify all biosimilars by the use of individual non-proprietary names and brand names.

“The EMEA guidelines, and the work of the EMEA, have set an important precedent for Europe and the rest of the world,” said Dr Mascaro. “It is vital to balance the state of our existing knowledge with the need to increase access in a safe, legitimate manner and within Europe there is now a more transparent regulatory pathway.”

Hospital pharmacy perspective

Roger Tredree, London, responded from the perspective of a hospital pharmacist and noted that there were fewer chemically derived products entering the market and that the trend was towards biopharmaceuticals. However, biopharmaceuticals are not the same as traditional generics, which contain identical chemical copies.

From a hospital pharmacist viewpoint the issue is that biopharmaceuticals have been used safely for over 20 years. The PRCA problem was the result of a formulation change and is not related to equivalence of biosimilar molecules. So although immunogenicity should not be ignored (the subcutaneous route is the one most likely to initiate immune response) neither should it be seen as a major obstacle.

EMEA guidelines provide a basis for regulating biosimilars in Europe but need to be extended to all products. In countries of the world where no regulation exists hospital pharmacists should encourage their governments to adopt the EMEA guidelines, rather than reinvent the wheel, said Dr Tredree.

Some studies have shown batch-to-batch variability in products from the same manufacturer. This should be a cause for concern where no regulations exist. Other studies have shown unacceptable pyrogen levels in some products marketed in Brazil. This was due to insufficient purification, and is a “good manufacturing practice” issue. These may be a particular problem for biopharmaceuticals but are not a direct consequence of biosimilars or their equivalence.

Pharmacovigilance should not be discounted for any pharmaceuticals whether of chemical or biological origin because recent experience with COX-2 inhibitors shows that lack of data can have serious consequences for patients and manufacturers, and undermine the patient’s confidence in the health care system. The challenge would be to put robust and effective systems in place.

Guidelines for choosing biosimilars have been published and are still relevant for non-EU countries although some of the evidence to support the decision-making process can be difficult to acquire. Within Europe, for those products covered by the EMEA guidelines, it is not appropriate for hospital pharmacists to second guess the regulators.

Finally, therapeutic tenders for these products are the way forward if the health economy is to afford treatment for more patients. This process will need the agreement of all practitioners involved and the willingness to change patients to different products under strict clinical control. For this process it is irrelevant whether the products are originals, branded or copies. The key will be quality and good therapeutic outcomes for the patient, Dr Tredree concluded.