As patents on biopharmaceuticals start to expire, similar products are being made by other manufacturers. Pharmacists often switch to cheaper generics, but with biosimilars other issues arise
Kingston University London
The number of new biopharmaceuticals gaining marketing authorisations exceeds those for conventional medicines produced by chemical synthesis. In addition, patents on biopharmaceutical products have been expiring and similar products (biosimilars) are being made by other manufacturers. At this point we should define what we mean by “similar”. By their very nature biopharmaceuticals produced from different sources will be different – so they can only be similar, not identical. This is a major difference from chemically synthesised generics.
The European Medicines Evaluation Agency (EMEA) is responsible for licensing in the EU, and for biopharmaceuticals this process must be pan-EU. Within the EMEA, the Committee for Human Medicinal Products (CHMP) evaluates products for human use and defines the rules for submission.
It is tempting to treat biopharmaceuticals as a group, but they are as diverse as conventional medicines or natural products. Biopharmaceuticals are produced, usually within a living cell, by recombinant DNA techniques. The recombinant products are all very different. It is important to remember this heterogeneity because we need different licensing requirements for different product groups. The first “overarching guidelines” on similar biological medicinal products were produced in 2004. It is easy to identify the important groups of biopharmaceuticals, and EMEA legislation currently deals with:
- Growth hormones.
Guidance for other groups such as beta-interferon is in the pipeline. The EMEA has different guidance for each group, which has been fostered by the pharmaceutical industry in discussion with the EMEA. The main concern of the guidelines is to ensure quality, which must be supported by nonclinical and clinical data specific for each product group.
The process is the product
This is a phrase often heard in biotechnology circles. It means that each biotechnology-derived protein is defined by its own production process:
- Equipment, raw materials, process parameters and in-process control contribute to the product characteristics.
- The product may be heterogeneous but has to be consistent (the same kind of heterogeneity for every product batch).
- Any change requires a proof of comparability of the product (product pre-change comparable to the product postchange).
- A marketing authorisation includes the product (specifications), the process (with in-process control specifications) and the facility (with technical and operational specifications).
In January 2006 the EMEA adopted its first positive opinion for a similar biological medicinal product. This was a growth hormone (GH), Omnitrope, produced by Sandoz. This event was not without its difficulties and pitfalls. Omnitrope was compared to genotropin as its reference product. Omnitrope had been marketed in Australia in 2005 as a liquid preparation and later in other countries either as lyophilised product or liquid. The trials therefore had been done on formulations different from the new EU product.
The question then arises as to whether this previous clinical evidence is admissible for the new marketing authorisation.
For growth hormone, the clinical comparability exercise requires data from clinical studies and 12 months’ immunogenicity data. Each product is different, so how much can we extrapolate from previous studies? For growth hormone all known effects involve the same GH receptor, so extrapolation to other indications of the reference product is possible.
The choice of reference product can be crucial. As previously stated, for Omnitrope the reference product was genotropin. Both are produced from modified Escherichia coli. The pharmacokinetics and pharmacodynamics are comparable to those of genotropin.
A nine-month comparability trial showed similar growth rates and safety profile.
In contrast, another growth hormone, Valtropin, was compared with Humatrope as the reference. Valtropin is produced from a modified yeast but Humatrope from E coli. In addition, there was a change in reference product during the pivotal study from EU Humatrope to US Humatrope. So the arguments are more complicated. This was later shown not to influence study results but delayed the time in getting the product to market.
So what lessons have been learned from the first biosimilar somatropins?
- The EMEA guideline is implementable, with realistic requirements.
- All aspects of the comparability exercise are important.
- The use of different host cells is possible in principle.
- The reference product must be approved in the EU.
- There must be no switch of reference product during development.
- Impurities may enhance immune response.
- Indication-related issues are inheritable from the reference product.
Can the indications be extrapolated from the reference product to another where there are two very different patient groups? For example, erythropoietin can be used in renal patients long-term, or for cancer patients short-term. The answer is: indication can be extrapolated only if the treatment is given by the same route. This is important for the latest generation of biosimilar erythropoietins, such as epoetin zeta. For most comparability studies, Eprex has been used as a reference product, but at the time of the trials Eprex only had a marketing authorisation for the intravenous (IV) route. So until further studies are completed biosimilar erythropoetins referenced to Eprex cannot be marketed for subcutaneous (SC) use. It is important to understand that for most EU countries erythropoetin is used IV for renal patients, but not in the UK where the predominant route is SC, because here most patients self-administer at home.
Substitution of biopharmaceuticals in practice
It is important that we define what we mean by substitution and interchange and I offer the following two definitions:
- Substitution: changing from one product to another without referral to the prescriber, for example, ibuprofen marketed as a generic.
- Interchange: switching products after due consideration of the clinical outcome and after discussion with the prescriber, for example, insulin, as blood glucose.
It must be noted that the laws regarding substitution are different across Europe.
For synthesised products we have often switched patients between medicines when a cheaper generic alternative has become available, when there is new competition in the marketplace or the purchasing contract is changed. This allows more patients to be treated for the same amount of money. Sometimes a newer product is produced which has better activity or fewer side-effects. Sometimes national funding and selection systems make the change inevitable – for example, the National Institute for Health and Clinical Excellence in the UK may stipulate a course of action.
Traditionally, there has been an expectation that after patent expiry generics will enter the marketplace. It has been our experience that as soon as a patent expires there are several companies ready to market the discounted product. These generics are discounted by as much as 70% and form part of the health economy, allowing money to be released to buy newer products.
We can expect biosimilars or branded biopharmaceuticals to follow a similar route when patents expire. There is an expectation that these products will be discounted, although because biopharmaceuticals are more expensive and complicated to produce the level of discounting may not be the same as for standard generics. It is also unlikely that these biosimilar products will be substituted, but will be interchanged following consideration of the clinical outcome and after discussion with the prescriber.
The message should be that the biopharmaceuticals we buy and issue to patients are safe.
Adverse drug reactions (ADRs) arise from both chemical and biological pharmaceuticals, but ADRs seldom emerge in clinical trials because the numbers of patients are often too small. So we need pharmacovigilance for all new products: for biosimilars, for original biopharmaceuticals and for chemically synthesised products.
For most conventional medicines it is an accepted principle that the International Nonproprietary Name (INN) implies generic equivalence. Even so, the products may be different in formulation and will be different in their practical use (for instance, film coating of the original product can improve palatability, whereas the generic product may not be coated and cause problems with patient acceptability).
In order to support pharmacovigilance, pharmacists need to be able to name and trace the product that is being used. This may require a unique identifier and this question continues to pose a problem to the regulatory authorities and to the industry. Currently, most prescribing systems use the INN, but is this specific enough? Biopharmaceuticals are mixtures of isoforms, so can a single INN be used? INNs have been used for many years for mixtures, as for antibiotics such as gentamicin, framycetin and neomycin or racemates of active and inactive isomers.
Maintaining correct temperature in the supply chain
It would be remiss not to include a few words about handling and storage of biopharmaceuticals, because improper storage can be a major cause of aggregation leading to an immune response in patients.
The supply chain for biopharmaceuticals, from arrival at the hospital to administration to the patient, consists of many stages, during each of which
temperature-sensitive products must be kept within their recommended temperature – usually 2–8°C – to preserve their biological activity. Biopharmaceutical manufacturers have direct responsibility for and control over correct storage and handling of their products from the start of production to the first point of shipment. Beyond the first point of shipment, manufacturers have only an indirect influence by making recommendations for best practice, the implementation of which depends on professional and personal responsibility.
Proposed strategies for solving these problems include identifying areas of responsibility, providing more information on the hazards of incorrect storage and handling of biopharmaceuticals, improving education at all levels, improving refrigerators and transportation conditions, and implementing regular audits of medication management on the basis of appropriate guidelines.
The era of biopharmaceuticals has taken us into the 21st century and is predicted to dominate the pharmaceutical market for the next few decades.
We can expect follow-on biosimilar products to be cheaper than the originals, and it is important for patient safety that that they are introduced in a controlled manner by pharmacists who are competent to advise prescribers appropriately. ■
Further information can be found on the EMEA website: www.eu.int