biosimilars

Int J Pharm Med 2007; 21 (3): 199-206LEADING ARTICLE 1364-9027/07/0003-0199/$44.95/0

BiosimilarsCurrent Status

Martin K. Kuhlmann,1 David Goldsmith2 and Adrian Covic3

1 Vivantes Friedrichshain Hospital, Berlin, Germany2 Guy’s Hospital, London, England3 C.I. Parhon University Hospital, Iasi, Romania

Biosimilars, or similar biological medicinal products, are large, complex molecules manufactured usingAbstractliving cells. Unlike their small-molecule counterparts, identical copies of the originator product are nearlyimpossible to manufacture. Biosimilars require an extensive manufacturing process that is open to variation at anumber of stages and as such requires very careful regulation and monitoring. With the patents on a number ofbiologically engineered proteins nearing their end, increased interest has arisen regarding how the developmentof biosimilars should be regulated. The EU is currently adopting guidelines that address a number of issuessurrounding the generation of biosimilars, including the nonclinical and clinical aspects of comparing thebiosimilar with a reference product. However, questions such as the choice of the reference product, the level ofpostmarketing surveillance and even the name of the biosimilar, all have still to be addressed. In contrast, the UShas yet to agree on guidelines for the introduction of biosimilars and it would appear that these are still a littleway off. While some believe that adequate measures are already in place to safeguard against the introduction ofbiosimilars with unproven safety and efficacy profiles, previous experience would suggest otherwise. Data fromvarious interferon preparations have shown that the immunogenic potential, i.e. the ability of the product toinduce the production of neutralising antibodies, varies according to formulation and place of manufacture. Inaddition, the increased incidence of pure red cell aplasia with a certain preparation of epoetin alfa after theformulation was changed has demonstrated that relatively small changes in the preparation of even establishedbiopharmaceuticals can have serious implications for the patient. Therefore, it is vital that regulatory guidelines,as much as is reasonably possible, ensure that biosimilars will be safe and effective in clinical practice.

1. What is a Biosimilar? ty, the same cannot always be said for biosimilars. Due to thecomplexity of their structures and the manufacturing processesrequired for their production, it is nearly impossible to produce1.1 Definitionbiosimilar molecules that are identical to the originator products.

The term ‘biosimilar’ has been coined for follow-on products ofa biopharmaceutical nature manufactured using living cells (bio- 1.2 Why the Interest in Biosimilars?logically engineered therapeutic agents) – products that are similarbiological medicinals. While it is comparatively simple to make As the patents for many biologically engineered drugs reachsmall-molecule generic pharmaceuticals, copying more complex their expiry date, the issue of biosimilars has received additionalbiologically manufactured products is not quite so easy. The key interest. A recent commentary in Nature Biotechnology suggestedreasons for this difficulty include the complex nature of the that biopharmaceutical products are currently responsible for abiological material itself and the manufacturing processes in- total of $US30 billion annual sales in the US and as patentvolved. Therefore, while chemical generics can be made identical protection on some of these products expires, the potential forto their reference products and are equivalent in terms of mecha- generic brand manufacturers is very great.[1] For example, thenism of action, efficacy, safety, route of administration and quali- global market size for epoetin was over $US12 billion at the end of

200 Kuhlmann et al.

Table I. Some biopharmaceutical drug patent expirations[4]

Product Manufacturer Active drug Patent expiration date

Humulin® Eli Lilly Human insulin 2001

Intron® A Schering-Plough Interferon α 2002

Procrit® Amgen/Johnson & Johnson Erythropoietin 2004

Epogen® Amgen Erythropoietin 2004

Neupogen® Amgen Filgrastim (granulocyte-colony stimulating factor) 2006

2005, and is expected to increase to over $US20 billion by 2020.[2] closely related to the final product. A small alteration in any step,Many of these products are marketed for the treatment of diseases be it the cell line or plasmid used, or the processes that make up therelated to lifestyle and aging, such as diabetes mellitus (insulin), large-scale production of the biopharmaceutical, has the potentialcancer (granulocyte-colony stimulating factor, erythropoietin) and to impact greatly on the final product.[7-9]

multiple sclerosis (interferons). The high cost of treatment for Not only can variations between manufacturers affect the finalthese diseases, in combination with the increasing age of the product, even inconsistencies in the completion of any stage of apopulations in developed countries, highlights the need to curb given protocol by a single manufacturer can lead to inter-batchhealthcare spending and decrease the cost of treatments. Biosimi- variability. Proteins demonstrate a high degree of heterogeneitylars could potentially provide more economical treatment alterna- and the level of this heterogeneity is dependent on manufacturingtives, as long as they have been proven as safe and effective as processes. Any number of changes could occur as a result oftheir originator counterparts. The recently approved growth hor- alterations in manufacturing processes, some of which are high-mone biosimilar, Omnitrope® 1, was launched in Germany at an lighted in table III. The stability of the product post-production isapproximately 25% discount to the originator product.[3] However, also critical to avoiding further modification and degradation bybiosimilar cost reductions may be offset by increased oxidation, deamidation, clipping, misfolding, disulfide scram-pharmacovigilance monitoring requirements. Tables I and II list bling, aggregation and deglycosylation.some biopharmaceutical products and their patent expirationdates, as well as some biosimilar products under development. 2.1 Regulating the Manufacture of Biosimilars in Europe

Before biosimilars can be introduced into the market, they mustreceive regulatory authority approval; this is an issue on which

The complexity of the biosimilar manufacturing process meansmany are finding it difficult to agree – what level of regulatory

that tight regulation is required. Full characterisation and valida-scrutiny should be applied to biosimilar agents? While the manu-

tion of every step is necessary, from the production cell line (safetyfacturers of the originator biopharmaceutical consider stringent

of substrate and genetic consistency) to the fermentation, harvest-preclinical and clinical testing an absolute necessity to guarantee

ing and purification (removal of host cell-related impurities andthe safety of any biosimilar, generic manufacturers believe that

container-derived contaminants), the formulation (including ex-regulatory requirements should reflect the fact that the safety of

cipients and preservatives) and the final container for storage.biosimilars can be assured without lengthy and costly clinical

Only by using careful monitoring at each stage of the productiontesting.

process can the quality of the product be assured.

2. Process Makes the Product

Producers of originator biopharmaceuticals each have theirown, closely guarded manufacturing processes. These have under-gone rigorous testing at all stages of development, as required forall new products. No two biopharmaceuticals can be consideredidentical in terms of safety or efficacy, and the same should applyto biosimilars. By their very nature, biological pharmaceuticals arelarge, structurally complex compounds that are manufactured us-ing living cells.[6] Every step of the manufacturing process is

Table II. Some biosimilar products under development[5]

Active biological substance Therapeutic area

Erythropoietin Anaemia

Granulocyte-colony stimulating factor Neutropenia

Insulin Diabetes mellitus

Interferon α Hepatitis C

Interferon β Multiple sclerosis

Somatropin Human growth hormonereplacement

1 The use of trade names is for product identification purposes only and does not imply endorsement.

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However, even if careful monitoring is undertaken, there is stillno guarantee that the final product will demonstrate the sameefficacy and safety as the originator compound. Therefore, clinicaltrials and pharmacovigilance are also necessary to ensure the finalproduct is efficacious and safe.

These requirements have been recognised to some extent by theEuropean Medicines Agency (EMEA), the organisation responsi-ble for providing regulatory guidelines for the EU. In October2005, the EMEA released a series of documents through theiraffiliate, the Committee for Medicinal Products for Human Use(CHMP). The overarching document from these organisationsrecognised the distinction between biosimilars or ‘essentially simi-lar medicinal products’ and ‘generics’.[10] It highlighted that rou-tine procedures for comparing generics to their parent compoundswere often not suitable for demonstrating the similarity of biologi-

Table III. Potential changes that may occur to a protein following altera-tions in the manufacturing process

Area of change Effect

Amino acid Oxidation

Deamidation

Pyroglutamate formation

Side chains Glutathione adducts

Carbamylation

Citraconylation

Tertiary or quaternary structure Denaturation

Aggregation

General: pattern of Methylation

Acetylation

Formylation

Proteolysiscally manufactured drugs and their originator compounds.

As an accompaniment to the general guideline, which focussed next section, they still oscillate between comparability and simi-on key areas such as the definition of a biosimilar and the use of larity.reference products, the CHMP provided guidelines on quality

2.1.1 Comparability Testingcontrol issues as well as nonclinical and clinical aspects on theConsistency of products is a critical issue in manufacturing.comparability of biosimilars.[11,12] In addition, four case-specific

While originator biopharmaceuticals have had years to demon-concept papers for recombinant human insulin,[13] recombinantstrate the consistency of their production, biosimilars will not havehuman granulocyte-colony stimulating factor,[14] recombinantthis guarantee. Despite optimisation of the manufacturing processhuman growth hormone[15] and recombinant human erythropoie-during development, any changes in this process, no matter howtin[16,17] have also been produced.[18] All these documents havesmall, require rigorous quality control testing to ensure a consis-been recently updated and highlight the specific issues surround-tent production of biosimilar product. The CHMP guidelinesing the generation of biosimilars for each of these agents. Interest-recognise that this should be performed against a reference materi-ingly, this list of biosimilars papers is by no means final. Accord-al, namely the initial product made at the end of the final develop-ing to the 2006 work plan for the EMEA’s Biosimilar Productsmental manufacturing run.[10] A justification for any minor struc-Working Party (BMWP), concept papers on biosimilar recombi-tural differences or changes in impurity profile must be given; thisnant α interferons and on immunogenicity assessment are alsojustification may require additional nonclinical and clinical data.imminent.[19] It remains to be seen how local authorities and

physicians respond to the requirements. Continued discussions2.1.2 Similarity Testing

among physicians, academics, hospital pharmacists, patients,Differences in the manufacturing processes between compa-

learning societies and national competent authorities will be inval-nies, such as source material, expression system, culture process,

uable in determining the practical aspects of implementing thepurification procedure and in-process controls, must all be ac-

EMEA recommendations for biosimilars.counted for when performing similarity tests. During the develop-

Of vital importance in the generation of any guidelines is ment of a biosimilar, appropriate endpoints should be defined toterminology. With respect to biosimilars, the terms ‘comparabili- ensure that the similarity between the biosimilar and its originatorty’ and ‘similarity’ can be used as just one example. These are product is proved. In an ideal setting, the use of treatment-naiveoften used interchangeably but in fact have very different mean- patients would provide the most suitable background in which toings. ‘Comparability’ refers to the level of consistency between compare the biosimilar with its originator product.batches of a biosimilar product produced by a single manufacturer,while ‘similarity’ refers to the likeness of a biosimilar to its 2.2 The Current Status of Biosimilar Regulation in the USoriginator product. Although these may seem very subtle differ-ences, the importance becomes more apparent when considering While European guidelines are well and truly under develop-the tests required to demonstrate each. Although the current guide- ment, the same cannot be said for any US guidelines. Indeed, thelines provide information on comparability, as described in the US appears to be lagging behind Europe quite significantly and, as

202 Kuhlmann et al.

yet, do not have any guidelines in place for the approval of 3. Immunogenicitybiosimilars.

The importance of the issue surrounding the approval of bi- ‘Immunogenicity’ is defined as the capacity to evoke an im-osimilars in the US has been only too clearly highlighted by the mune response and every biopharmaceutical product possesseslegal action taken by Sandoz against the US Food and Drug immunogenic potential. While in some cases, this immunogenicityAdministration (FDA).[20] In 2003, Sandoz submitted a marketing may be harmless, in others it can have potentially serious conse-application to the FDA for Omnitrope®, their biosimilar version of quences. It is therefore vital that every precaution be taken to avoidthe human growth hormone. When 2 years had elapsed without immunogenic biopharmaceuticals being administered to patients.any word from the FDA, Sandoz started legal proceedings against For this to take place, stringent clinical testing is required, includ-the FDA and the FDA was ordered to accept or reject Sandoz’s ing pharmacovigilance, a process that demands close clinical co-application. The FDA argued that they were delaying their final operation from healthcare professionals and maximum awarenessdecision until they had finalised guidelines applicable to all types of immunological factors.of biopharmaceuticals. Having lost their battle against Sandoz, theFDA is still currently working on generalised guidelines. In Janua-

3.1 The Basis of Immunogenicityry 2006 the European Commission approved the licence for Omni-trope®[21] and the FDA followed in May 2006.[22] The recentlyintroduced Access to Life-Saving Medicine Act aims to provide a An immunogenic reaction is characterised by the activation ofUS framework for companies to submit abbreviated applications antibody-secreting B cells and the subsequent production andfor biological products..[23] release of antibodies. Reactions to nonself, or foreign, antigens

tend to occur rapidly and persist even after a single injection.[24]

This type of immune response becomes increasingly more likely2.3 The Biosimilars Debate with biopharmaceuticals that show greater structural diversity

from self molecules, such as those derived from bacterial or plantsources. The second type of reaction is to self molecules.[24] InIt is clear that work on guidelines in both the EU and US is stillthese responses, the extended use of human-derived bi-required. However, even after the guidelines have been finalised, itopharmaceuticals that are structurally similar to those found in theis highly likely that the debate surrounding the regulation ofbody can break B-cell tolerance. As a result, antibodies are pro-biosimilars will continue. Indeed, a recent article in Nature Bio-duced to the biopharmaceutical and, in the worst case scenario, totechnology presented cases from both the generics manufacturer’sthe endogenous protein as well.and brand manufacturer’s point of view.[1]An argument for more

lenient regulatory guidelines for the approval of biosimilars camefrom a generic manufacturer. It was suggested that the safety of

3.2 What Factors Affect the Immunogenicitybiosimilars can be guaranteed and that clinical study requirements

of Biopharmaceuticals?should be related to the complexity of the molecule. While for lesscomplex biopharmaceuticals characterisation alone should be suf-

The immunogenicity of a biopharmaceutical is directly linkedficient, moderately complex compounds should be exposed toto a number of factors. For example, product quality (i.e. the levelclinical trials of limited size designed to demonstrate comparabili-of impurities and contaminants), downstream processing and thety. It was also pointed out that, in the US, when a manufacturer ofduration of treatment are all important factors in defining thean originator product moves the location of product manufactureimmunogenic potential of a biopharmaceutical.[25] In addition, theor alters the process of manufacture, detailed clinical trials are notroute of administration of the biopharmaceutical also plays its part,requested and, thus, the same should apply to biosimilars. In thewith immunogenicity increasing progressively from intravenous,counter argument, a manufacturer of an originator product em-to intramuscular, to subcutaneous administration.[26] The charac-phasised the complex nature of biopharmaceuticals and their man-teristics of the patient, such as disease profile (autoimmune condi-ufacturing processes, and expressed caution regarding the over-tion) or genetic background (major histocompatibility type) aresimplification of the biosimilar approval process – the search foralso known to be important. Finally, and not surprisingly, thereless expensive drugs should not be allowed to compromise themay also be as yet unknown factors that influence the immu-safety and efficacy of the final product. It is likely to be some time,nogenicity of biopharmaceuticals.if ever, before this debate is settled.

Biosimilars 203

3.3 Variations in Manufacturing Processes Can neutralising interferon antibodies. Similarly, the manufacture ofAffect Immunogenicity ‘identical’ interferon β at different manufacturing sites has result-

ed in marked differences in the potential to induce neutralisingantibodies (figure 1b). These data highlight the fact that productsWhile a definitive answer to the question ‘can variations infrom different sources cannot be assumed to be equivalent. Vari-manufacturing processes affect immunogenicity?’ cannot be givenous factors, which in some cases may be of unknown origin, makefor every biopharmaceutical, previous experience with establishedit impossible to predict biological behaviours, such as immu-biopharmaceuticals can give an indication of the answer. Fornogenicity, in biopharmaceuticals.example, data obtained from interferons have indicated that

changes in formulation and manufacturing site can both result indiffering levels of antibody titres.[25] As shown in figure 1a, 3.4 Consequences ofchanging the formulation and storage conditions of interferon α-2a Biopharmaceutical Immunogenicityhas led to as much as a 10-fold variation in the generation of

The end result of an immunogenic reaction to a bi-opharmaceutical can differ markedly. For example, specific an-tibodies to growth hormone have been shown to enhance theefficacy of the product.[27] In contrast, antibodies to interferon βused in the treatment of patients with multiple sclerosis have beenshown to result in a loss of efficacy.[28] However, by far the mostserious effect is when the biopharmaceutical induces the produc-tion of antibodies that neutralise not only the biopharmaceutical,but also the endogenous protein, as has been observed with bothmegakaryocyte-derived growth factor[29] and recombinant humanerythropoietin (epoetin) alfa.[30] These latter two resulted in thedevelopment of severe thrombocytopenia and pure red cell aplasia(PRCA), respectively.

In addition, other, more general immune effects can also beinduced, including allergy, anaphylaxis and serum sickness, all ofwhich can have a significant impact on the patient.

3.5 Lessons to Be Learnt from the Epoetin Alfa Experience

Events surrounding epoetin alfa in recent years can providevaluable lessons regarding the use of biopharmaceuticals. Epoe-tins have been successfully used for >2 decades in the treatment ofanaemia in patients with chronic kidney disease,[31] and morerecently in anaemia associated with cancer and chronic heartfailure.[32,33] Until the late 1990s, the use of epoetin in patients withrenal anaemia was well tolerated with very few unforeseen ad-verse reactions. However, in 1998, there was an unexpected in-crease in the number of cases of PRCA, mainly in those patientsreceiving one brand of epoetin alfa (Eprex®, Johnson and John-son).[30] In complying with the EMEA’s request to remove human-derived proteins from the product formulation, the manufacturerreplaced human serum albumin with sorbitol-80 as a stabiliser.[34]

The goal was to minimise the risks from human-borne contami-nants (such as prions and HIV). However, there was a rise in thenumber of PRCA cases following this change in product formula-tion.

18001600140012001000

800600400200

00 1 2 3 4

Time (mo)

A (n = 190)

B (n = 86)

C (n = 110)

D (n = 81)E (n = 74)

UndetectableNeutralising titre <20Neutralising titre ≥20

6 12 6

Product 1b

Product 1a

Time (h)

Fig. 1. Variations in the immunogenicity of interferons. (a) The immu-nogenicity of human interferon α-2a is dependent on the formulation andstorage conditions as shown by the mean-population antibody titre in pa-tients treated with different interferon preparations: A lyophilised powderstored at room temperature; B lyophilised power stored under refrigeration;C human serum albumin (HSA)-containing liquid stored under refrigeration;D ultrapure liquid formulation (HSA-free) stored under refrigeration; and Eultrapure lyophilised powder stored under refrigeration; and (b) interferon βimmunogenicity has been shown to vary significantly when the site ofmanufacture is changed. The cause of this variation in immunogenicity wasnot elucidated. IFN-neutralising units = interferon arbitrary unit of neutral-ising activity; n = number of patients.

204 Kuhlmann et al.

It was established that in the affected patients, neutralising 3.6 How Can Immunogenicity be Avoided?

antibodies resulted in the loss of efficacy not only of the recombi-Immunogenicity is unpredictable but measures can be taken tonant protein but also the native protein;[35] this required the with-

reduce the risk of introducing a potentially immunogenic biosimi-drawal of epoetin therapy and the introduction of additional treat-lar. A prophylactic approach must be encouraged throughout thements including immunosuppression for the affected patients. Thedevelopment process. In vitro assays such as size exclusion, west-manufacturer’s research suggests that the increase in immu-ern blots and enzyme-linked immunosorbent assays (ELISAs)

nogenicity was related to the adjuvant effects of leachates from theshould be performed, accompanied by in vivo tests using animal

rubber syringe stoppers caused by polysorbate 80.[36,37] However,models. While the former will ensure the quality of the product,

these findings are still under debate, and the actual cause(s) of thethe latter will provide a relative indication of the immunogenicity

PRCA cases remain unclear.[38] Another theory is that the presenceof the biosimilar.

of aggregates during product storage may have played a role,Pharmacovigilance will play a critical part in the identification

suggesting that improved maintenance of the cold chain alongof potentially immunogenic biosimilars. Moreover, continuous

with contraindication of the subcutaneous route of administrationimmunogenicity testing, using techniques such as radioimmu-

may have contributed to reducing the incidences of PRCA.[38]

noprecipitation assays and ELISAs, should also be implemented toWhatever the actual cause(s) may be, the key message is clear. If

ensure adequate postmarketing surveillance is maintained. How-apparently small changes in the formulation of an established

ever, it should be remembered that while pharmacovigilance isbiopharmaceutical can result in dangerous consequences for the

important, it varies greatly from country to country and should inpatient, what could happen with the potentially greater changes

no way be considered a substitution for extensive controlledthat might occur when biopharmaceuticals such as epoetin are

clinical trials.copied? It is difficult to predict the implications for the patient butthe consequences could be even more far reaching. 4. Biosimilars: Where Next?

To ensure that such possibilities are minimised with epoetin,Biopharmaceuticals are complex products of intricate manufac-the latest European guideline on similar medicinal products con-

turing processes that require consistent monitoring, even whentaining recombinant erythropoietins has outlined the level of test-these processes are well established. As has been shown by theing the EMEA believes necessary to demonstrate the similarepoetin example, apparently minor changes in formulation cannature of the reference product and biosimilar in terms of safetyimpact heavily on the safety of the final product. It is, therefore,and efficacy.[17] These recommendations are summarised in tablenot surprising that concern exists surrounding inadequate regula-IV.tion of biosimilars.

In Europe, the EMEA is taking steps to ensure that any biosimi-lar produced is tested in both preclinical and clinical trials. How-ever, the guidelines available to date still have some way to gobefore they can be considered final. For example, the currentguidelines provide very little information on the use of referenceproducts throughout the development of biosimilars. Indeed, thedirector-general of the European Generic Medicines Associationhas acknowledged that this is an area that requires further discus-sion.[39]

In addition, given that biosimilars are not identical to theirreference products, measures must be taken to allow any adverseevent to be attributed to a specific biosimilar. In order to generatemeaningful pharmacovigilance data and to minimise the risk oferrors or confusion in the prescription and distribution of biosimi-lar products, proper nomenclature is essential. Individual interna-tional nonproprietary names (INN) for all biopharmaceuticals,including biosimilars, should be implemented in order to decreasethe likelihood of inadvertent substitution and to increase the tracta-bility of product safety. Clear identification of biosimilar products

Table IV. Regulations for the generation of erythropoietin biosimilars inEurope[17]

Phase Studies

Preclinical In vitro and in vivo pharmacodynamic studies

At least one repeat dose toxicology study

Data on local tolerance in at least one species

Pharmacokinetics (vs Crossover study in healthy volunteers (SC andreference product) IV administration)

Clinical (vs reference Two adequately powered, randomised, double-product) blind, parallel-group studies of 6 months

duration (separate SC and IV administration)

Correction phase study (rHuEPO-naive or3-month wash-out)

Maintenance phase study (after 3 months onreference product)

Comparative, 12-month immunogenicity data

Full pharmacovigilance plan

IV = intravenous; rHuEPO = recombinant human erythropoietin; SC =subcutaneous.

Biosimilars 205

5. European Generic Medicines Association. Biosimilars: competition and af-is essential to ensure proper dispensing of drugs prescribed tofordability in biopharmaceuticals [online]. Available from URL: http://www.e-

patients. As such, guidelines should stipulate that biosimilars be gagenerics.com/ega-biosimilars.htm [Accessed 2007 Mar 19]

6. Walsh G, Jefferis R. Post-translational modifications in the context of therapeuticnamed with a unique identifier, such as a brand name, and thatproteins. Nat Biotechnol 2006; 24: 1241-52prescriptions be written according to the unique brand name of the

7. Bendig MM. The production of foreign proteins in mammalian cells. Genet Engproduct. 1988, 127

It is now well recognised that one of the key issues surrounding 8. Wurm FM. Production of recombinant protein therapeutics in cultivated mammali-an cells. Nat Biotechnol 2004; 22: 1393-8the safety of biosimilars is immunogenicity. To avoid the genera-

9. Ramanathan MP, Ayyavoo V, Weiner DB. Choice of expression vector alters thetion of highly immunogenic biosimilars, extensive testinglocalization of a human cellular protein. DNA Cell Biol 2001; 20: 101-5

throughout the development process, as well as continued moni- 10. Committee for Medicinal Products for Human Use. Guideline on similar biologicalmedicinal products. CHMP/437/04; 2005 Oct [online]. Available from URL:toring through pharmacovigilance, is vital. Given the fact thathttp://www.emea.eu.int/pdfs/human/biosimilar/043704en.pdf [Accessed 2007many immunogenic reactions take years to develop, a long-termMar 19]

plan will be necessary to ensure the safety of a biosimilar is 11. Committee for Medicinal Products for Human Use (CHMP). Guidelines on similarbiological medicinal products containing biotechnology-derived proteins asmaintained. The current EMEA guidelines recognise the need foractive substance: quality issues. European Medicines Agency. EMEA/CHMP/‘a suitable pharmacovigilance plan’.[2] However, without more BWP/49348/2005 [online]. Available from URL: http://www.emea.europa.eu/

detailed guidance, it remains unclear as to the level of pdfs/human/biosimilar/4934805en.pdf [Accessed 2007 Mar 19]

12. Committee for Medicinal Products for Human Use (CHMP). Guideline on similarpharmacovigilance necessary and, indeed, who will be responsi-biological medicinal products containing biotechnology-derived proteins as

ble. Again, these issues need to be addressed. active substance: non-clinical and clinical issues. EMEA/CHMP/42832/2005[online]. Available from URL: http://www.emea.eu.int/pdfs/human/biosimilar/4283205en.pdf [Accessed 2007 Mar 19]5. Conclusion

13. Committee for Medicinal Products for Human Use (CHMP). Annex to guideline onsimilar biological medicinal products containing biotechnology-derived pro-The safety and efficacy of any pharmaceutical, be it a small teins as active substance: non-clinical and clinical issues guidance on similar

molecule, generic, originator biopharmaceutical or biosimilar, is medicinal products containing recombinant human soluble insulin. EMEA/CHMP/BMWP/32775/2005 [online]. Available from URL: http://www.of the utmost importance. Patients must be assured that the drugemea.europa.eu/pdfs/human/biosimilar/3277505en.pdf [Accessed 2007 Mar

they receive has a proven safety and efficacy profile. The genera- 30]

14. Committee for Medicinal Products for Human Use (CHMP). Annex to guideline ontion of biosimilars is one that will require constant and carefulsimilar biological medicinal products containing biotechnology-derived pro-monitoring to ensure the safe emergence and continued productionteins as active substance: non-clinical and clinical issues guidance on similar

of these complex compounds. The implementation of clear and medicinal products containing recombinant granulocyte-colony stimulatingfactor [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/extensive guidelines is only the beginning of what must be abiosimilar/3132905en.pdf [Accessed 2007 Mar 30]

continuously tightly regulated area of the pharmaceutical industry.15. Committee for Medicinal Products for Human Use (CHMP). Concept paper:

similar biological medicinal products containing recombinant human growthhormone. Annex to the guideline for the development of similar biologicalAcknowledgementsmedicinal products containing biotechnology derived proteins as active sub-stance – (non)clinical issues. CHMP/Comparability Working Party/146489/Martin K. Kuhlmann has participated in meetings sponsored by F Hoff-2004

man-La Roche Ltd and received honoraria from Roche and Ortho Biotech.16. Committee for Medicinal Products for Human Use (CHMP). Concept paper:

David Goldsmith has received honoraria for speaking from Fujisawa, similar biological medicinal products containing recombinant human erythro-Novartis, Merck, F Hoffman-La Roche Ltd, Amgen, Abbott, Shire, Genzyme poietin. Annex to the guideline for the development of similar biologicaland Nabi, is a member of advisory boards for Nabi, F Hoffman-La Roche Ltd, medicinal products containing biotechnology derived proteins as active sub-

stance – (non)clinical issues. CHMP/Comparability Working Party/146664/Amgen, Abbott, Genzyme and Shire and holds unrestricted educational grants2004from AstraZeneca and Roche.

17. Committee for Medicinal Products for Human Use (CHMP). Annex to guideline onAdrian Covic has received honoraria and participated in meetings spon-similar biological medicinal products containing biotechnology-derived pro-

sored by F Hoffman-La Roche Ltd.teins as active substance: non-clinical and clinical issues – guidance on similarmedicinal products containing recombinant erythropoietins [online]. Availablefrom URL: http://www.emea.europa.eu/pdfs/human/biosimilar/9452605en.pdfReferences [Accessed 2007 Mar 30]

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