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Published on 10 July 2009

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Biosimilars under fire … but where is the justification?

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Several biosimilars have been introduced to the market but face significant opposition from medical and pharmaceutical factions. It is time to look at the actual data and open sensible debate

Fritz Sörgel
PhD
Professor/Director
IBMP (Institute for
Biomedical and
Pharmaceutical
Research)
Nurnberg-Heroldsberg
Germany

Ever since biosimilars were developed and finally marketed they have got some pretty harsh reviews and have almost been considered to be “dangerous” drugs. Interestingly, the group of scientific organisations and opinion leaders opposing biosimilars is using the same method of creating fear that was used by the opponents of recombinant technology when it first became available.

In that respect history seems to be repeating itself for biosimilars – at least in part – when one compares them with the early days of small-molecule generics (SMGs), where again there was great mistrust. The development of generics, however, was truly a “wild time”, even including fraud for quite a long period. But opponents of SMGs three decades ago – including myself – have long since had no cause to complain about “bad” generics.

The art of studying bioavailability of drugs is nowadays well established and harmonised to a high degree around the globe. Our attempts, though, to teach physicians what we learned about generics has failed in part, as demonstrated in a recent publication – a metaanalysis of generics of cardiovascular drugs – where the authors conclude that while “evidence does not
support the notion that brand-name drugs used in cardiovascular disease are superior to generic drugs, a substantial number of editorials counsel against the interchangeability of generic drugs.”[1]

Major objections to biosimilars
While the irrational opposition to SMGs in medicine was mostly expressed by “practitioners” and “family doctors”, it is now the “clinician” – usually assumed to be closer to science and the latest research results than a practitioner – who has entered the arena of speculations around the “brothers” of SMGs, the biosimilars. Their irrationality not being any smaller than that of the “family doctor” – at best.

They put biosimilars under fire and use any “weapon” that they have – or think they have – often “on behalf” of a scientific organisation, the latter believed to be obliged to be objective and well considered in their statements and papers. Without claiming completeness of research, I have traced at least 20 papers that oppose biosimilars in the strongest terms. But except for the well-known concerns regarding immunogenicity applicable to any biopharmaceutical product – not only biosimilars – there is little evidence for substantiated concerns about biosimilars.

During phase III studies of EMEA-approved biosimilars, immunogenicity was studied with methods validated to currrent requirements and state-of-theart bioanalytical tools, and there were no findings to present or require a note of caution in the package insert. The intense pharmacovigilance programme during the marketing phase is further aimed at confirming the safety of the product. That is a rational and justifiable procedure – an abbreviated drug approval process based on scientific evidence. Omnitrope®, the first biosimilar approved by the EMEA, has now been dosed in humans for almost eight years, including the clinical development phase. Thus those scientists who mistrust the EMEA over biosimilars in fact mistrust their own research that the EMEA has used in establishing guidelines.

Those who consider EMEA-approved products unsafe should consequently ask the European Parliament to replace or abolish the EMEA. This may be good news for the European taxpayer who pays for EMEA, but it may not be such a good idea in general. The wealth of information centred at the EMEA and the time competent experts can spend in the various countries on reviewing the data seem preferable to “self-installed” and “part-time” regulators and “local committees” that some consider the right place for choosing the “right” recombinant protein.

Pamphlets
The most recent pamphlet on Omnitrope is a good example of how irrational is the discussion taking place.[2] The authors present a physicochemical characterisation of the liquid form of a reference product and a counterfeit with the lyophilisate of Omnitrope. Not using the same forms of somatotropin of the biosimilar certainly represents a flaw in designing such a comparative study. Even more questionable when considering the fact that the fluids are in greater clinical use and will replace the older formulations of somatotropin soon.

Upon request, the manufacturer of Omnitrope stated that if Omnitrope did indeed have the properties and amounts of product-related variants that are postulated in the paper it would never have been released. Indeed, it would never have been approved. With the values published in the paper, the same is also true for Nutropin®.

In Sandoz’s experience, the somatropins that are on the market in the European Union are all of consistent high quality and easily fulfil the requirements of the EP and USP. (Dr Andreas Premstaller, Head, Technical Development, Kundl a.i. Biopharmaceutical Operations, Sandoz GmbH, A-6250 Kundl/Tirol, personal communication). Likewise, the fact that during the development of Omnitrope a manufacturing site failed to provide adequate quality is in my mind a proof that the biosimilar companies know very well what they are doing and which sites they have to exclude.[3]

Problems with manufacturing sites are well known also in the innovator industry, as demonstrated by the recent example with Erbitux® – the failure to show biosimilarity of products manufactured at different production sites in Germany and the USA.[4] In the case of epoetins, it has become popular to raise fears of pure red cell aplasia (PRC A), a truly disastrous adverse event seen with Eprex®, a product made by an originator.[5]

It is not correct to cite a single case of PRC A for a product from India[6] and call that product a “biosimilar”. At present the term “biosimilar” can correctly only be used for products that are approved by the EMEA or a process in another continent where EMEA guidelines are used identically or with additional tests but not less. Also, showing electropherograms of epoetin products from less regulated countries[7] or comparison with counterfeit products[2] is simply misleading.

The often-cited example of rejection of an interferon product by the EMEA[8] in my opinion demonstrates precisely the opposite of what the derogatory papers say. It shows that the EMEA does in fact have the knowledge, experience and willingness to not let the use of biosimilars become a field like the early days of SMGs. The EMEA says “no” when it is necessary and justified. It seems time to encourage a way back to facts and solid science as well as a fair discussion of this new group of important biotechnology products.

EMEA’s role in establishing the “biosimilarity exercise”
The European Drug Agency (EMEA) deserves credit as the first regulatory body worldwide to start several years ago an initiative for cheaper drugs from the biotechnology field – the biosimilars. It published guidelines on how to develop a biosimilar, which include intense analytical work in the laboratory, animal toxicology, in-vitro receptor binding studies, extensive phase I and II studies and at least one phase III study. Following that there should be an intense pharmacovigilance programme once the product is marketed. These guidelines are based on scientific knowledge and well justify an abbreviated drug development.

During the 2006 “Biotechnology week” in Boston a very unusual statement on biosimilars was heard from a US-based official of the US biotech industry: “Europe’s ahead.” That demonstrates how important a drug agency may be for the continent’s pharmaceutical and biotech industry. EMEA’s high international reputation in this field is best reflected by a series of papers by its Committee for Advanced Therapies (CAT) in journals that are among the most respected in science.[9-12]

Food and Drug Administration (FDA)
The fact that the FDA, still considered the most important drug agency, has not introduced guidelines on biosimilars for the American market is simply a matter of protectionism of US industry by former administrations. Even a different term is used in the USA, where the European term “biosimilars” is replaced by “follow-on proteins”. But with the present “Yes, we can” spirit in the USA and the willingness of the new administration to make cheap recombinant drugs available for not only the poor but also middle-class people in the presently underdeveloped social security system, legislation is imminent.[13]

Consequently, the FDA would then have to develop a guideline for approving follow-on proteins. We as European drug researchers and the EMEA can’t wait to see the FDA’s position, which is certainly based on a rich experience with biotechnology products in general and will be to the benefit of the efficacy and safety of biosimilars. Often forgotten is the fact that Omnitrope has been approved in the USA for growth hormone deficiency (GHD).

The need for publicly available data
The EMEA’S Public Assessment Reports (EPARs) on biosimilars provide important information on the approval process. More detailed information is desirable but blocked by companies’ right to protect their research secrets.

The lack of publications on biosimilars in peerreviewed journals is correctly criticised by the scientific organisations and opinion leaders. The biosimilar industry should have nothing to hide and must understand that it should release as much information as possible to allow a fair scientific discussion.

Biosimilars – a case for clinical pharmacology and clinical pharmacy
In my own field of clinical pharmacology and clinical pharmacy “whatever may be the difference between those two fields” I have enjoyed meeting the challenge of comparing the biosimilars mentioned below with their originator products. We have published three papers on a biosimilar, alpha epoetin,[14-16] with more papers, on G-CSF and somatotropin, to come in the very near future.

Clearly, clinical pharmacology and clinical pharmacy methodology provide valid tools to demonstrate or disprove biosimilarity. The data generated by several biosimilar companies that successfully marketed biosimilars may help modify and fine tune the EMEA’s approval process and guidelines – for example, determining how big a deviation from the innovator product’s drug clearance that of a biosimilar may be. Total clearance of a biosimilar being the most important
pharmacokinetic parameter to look at.

And clinical pharmacology/pharmacy can connect to preclinical in-vitro work on receptor binding by applying the most advanced pharmacokinetic/pharmacodynamic modelling techniques for receptor-mediated drug clearance. When measuring concentrations of proteins in plasma during a pharmacokinetic study the bioanalytical technique used is crucial. We validated commercial ELISAs that were never validated before by their manufacturer, assumingly also not during the innovator’s drug development.

Also, the instruments used to count blood cells, such as flow cytometers, have never been truly validated by the manufacturers according to current guidelines but were so in the course of development of biosimilars.

Their role in pharmacodynamics is critical, as is the role of ELISAs in drug concentration measurements. In that way development of biosimilars has made important contributions to understanding the innovator drug better – possibly better in some details than the originator – and testing it with up-to-date bioanalytical technology.

Pharmacokinetics vs pharmacodynamics
Pharmacodynamic measurements are very important in phase I studies and a prerequisite to justify further dosing in humans. If they are not identical between products, further development should be stopped. But such measurement needs to be viewed with caution in the “biosimilarity exercise”, since it may not always be discriminatory enough. It may therefore well be that pharmacokinetic studies are superior to pharmacodynamics to discriminate between agents – for example, by comparing total clearance. It cannot be excluded that there is a correlation between clearance and certain effects of a recombinant protein, including its immunogenic potential. To set goalposts for pharmacodynamics and pharmacokinetics, however, more data and also failures in development of biosimilars are needed. Failures may be even more helpful than successes.

Physicochemical characterisation

From my point of view, the current tools of analytical chemistry, such as peptide mapping by reversed-phase HPLC, MALDI-TOF-MS (matrix assisted laser desorption ionisation time-of-flight mass spectrometry) to determine molecular mass, SDS-PAGE, circular dichroism and many more, allow a complete physicochemical characterisation of an agent, and analytics probably provide the tool to differentiate between agents.

It could well be, and possibly is already the case, that as for SMGs there are biosimilars that are better than the originator product. No one knows quite what differences between products in an electropherogram or a MALDI spectrum really mean clinically. To understand that we have a long way to go and – as stated above – we may need clinical failures or products with severe adverse events.

The phase III study and the pharmacovigilance programme are the least discriminatory of the measures but are – provided that all studies before phase III show biosimilarity – clinically the most important. It cannot be excluded that in two or three decades from now we may approve biosimilars without phase III studies.

Role of scientific organisations and opinion leaders
Recently the European Group for Blood Marrow Transplantation (EBMT)[17] warned against use of the newly EMEA-approved G-CSFs – biosimilars for stem cell mobilisation – and the “Growth Hormone Advisory Group of the Pediatrics Association of the Netherlands”[18] discouraged in very strong words the use of biosimilar somatotropin in their patient population. Other groups, such as in nephrology and oncology, have challenged the use of biosimilars of epoetin. The main arguments across all statements are almost blueprints of each other and are evidence of the malpractice of cross-referencing papers with no real data.

Biosimilars and the missing of clinical experience
In most of the “anti” papers the immunogenic potential and the “missing clinical experience” are used to discourage the use of biosimilars. But how do we define “clinical experience” Clinicians tend to use the term when they are unable to talk about facts and hard data or cannot discriminate rationally between two products. All of us have been at a pharmaceutical company” meeting where a practitioner reported on his “clinical experience” to support the sponsor’s drug.

Most often these presentations are made when there are no hard data. Where was “clinical experience” for almost two decades in the use of epoetin and more than a decade in the use of G-CSF? Did clinicians foresee the problems of thromboembolic risks with epoetin and derivatives when using it? That was as “adverse event” that was published so clearly only recently after many years of use.[19,20] It was certainly well known among professional cyclists, certain of whom knew, when using epoetin for illegal doping, how to use countermeasures such as administering fluid or plasma expanders and monitoring heart rate.[21,22]

Where was “clinical experience” with epoetin and G-CSF to warn of tumour progression[23] and decrease of overall survival following epoetin use. Yes, we appreciate “clinical judgement” from a physician, but in a clinical study and in drug development subjective assessments such as “clinical experience” do not help and blur our view at best.

Ethics of publishing and author responsibility
In a heated debate such as the one on biosimilars it seems a precondition that all authors of scientific communications,
statements and guidances follow the strict rules of ethics in publishing that for quite some time have been a “sine qua non” requirement. Authors and opinion leaders must disclose in detail any relationship or affiliation with companies whose products they write or comment about. Any participation in clinical studies of the product or presentations of it during conferences or similar events and the fact that a honorarium was paid must be disclosed. Several publishers also request that the author of an article also discloses if any “ghostwriter” helped in preparing the article or anybody – other than potential nonpharmaceutical industry co-authors – had the right to review and approve it. The reader of an article has the right to know how the article was developed.

For myself, I hereby confirm that my institution performed contract work and academic research on biosimilars and will do so in the future. The contract work on Binocrit® and Zarzio® was sponsored by Sandoz Pharmaceuticals, Holzkirchen, Germany. I know the database on Omnitrope well and have made paid presentations on Binocrit and Omnitrope at public
conferences and specialised meetings where clinical experts were invited by Sandoz – meetings with no public access. I donate the honoraria to programmes for training young scientists and encouraging schoolchildren to develop an interest in pharmacy.[24]

We also performed and are performing work on interferons for various sponsors that cannot be disclosed at this time due to patent issues. This commentary exclusively represents my personal view and was written completely by myself without any internal or external help, and was not given to any party for “approval” before publishing, except to the publisher.

Conclusions
There is general agreement that approval of a drug should be granted after a certain number of preclinical and clinical studies that are justified by scientific evidence. The very tough, and very costly, pharmacovigilance programmes biosimilar firms have to install and an intelligent abbreviated process leading to drug approval by the EMEA is the right way to allow biosimilars to come onto the market. Biosimilars are here to stay, and may the profession of pharmacists play an important role in monitoring this exciting new era,20 wherever it may lead us to. But stick with facts and findings and listen to but do not blindly believe inaccurate science such as “clinical experience”.

[[HPE.25]]

References
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2. Jiang H, Wu SL, Karger BL, Hancock WS. Mass spectrometric analysis of innovator, counterfeit, and follow-on recombinant human growth hormone. Biotechnol Prog 2009;25:207-18.
3. European Public Assessment Report (EPAR) for Omnitrope® Revision 4 Published 23/04/08. http://www. emea.europa.eu/humandocs/PDFs/EPAR/Omnitrope/060706en6.pdf. Downloaded on May 5th, 2009, 11am.
4. Erbitux-cetuximab receives FDA approval to treat irinotecan refractory or intolerant metatastic colorectal cancer. Cancer. http://phx.corporate-ir.net/phoenix.
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Name (INN): interferon alfa-2a. http://www.
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Schneider CK. Nat Rev Drug Discov 2009 Apr;8(4):270. PMID: 19337268 [PubMed indexed for MEDLINE].
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11. Schneider CK, Schaffner-Dallmann G. Typical pitfalls in applications for marketing authorization of biotechnological products in Europe. Nat Rev Drug Discov 2008;7:893-9.
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antibodies. Nat Biotechnol 2008;26:985-90.
13. Hughes B. Gearing up for follow-on biologics. Nat Rev Drug Discov 2009 Mar;8(3):181
14. Sörgel F, Thyroff-Friesinger U, Vetter A, Vens-Cappell B, Kinzig M. Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple subcutaneous administrations. Pharmacology 2009;83:122-30.
15. Sörgel F, Thyroff-Friesinger U, Vetter A, Vens-Cappell B, Kinzig M. Biosimilarity of HX575 (human recombinant epoetin alfa) and epoetin beta after multiple subcutaneous administrations. Int J Clin Pharmacol Ther 2009 in press.
16. Sörgel F, Thyroff-Friesinger U, Vetter A, Vens Cappell B,
Kinzig M. Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple intravenous administrations: an open-label randomised controlled trial. BMC Clin Pharmacol 2009 in press.
17. Niederwieser D, President of the EBMT on behalf of the Executive Committee. Biosimilar granulocyte-colony stimulating factor (G-CSF) for stem cell mobilization in related and unrelated donors. http://www.ebmt.org/Biosimilars_9Jan09.pdf. Downloaded 5 May 2009.
18. Noordam C, Chairperson, on behalf of the Growth Hormone Advisory Group of the PaediatricsAssociation of the Netherlands. Growing safely, biosimilar. Only a paediatric endocrinologist chooses medication. http://medischcontact.artsennet.nl/Home.htm
19. Bohlius J, Weingart O, Trelle S, Engert A. Cancerrelated
anemia and recombinant human erythropoietin – an updated overview. Nat Clin Pract Oncol 2006 Mar;3(3):152-64.
20. Gebara SN, Moubayed H. The role of the pharmacist in optimizing the use of erythropoietin stimulating agents. J Oncol Pharm Pract 2009 Apr 28.
21. Baron D, Martin D, and Abol Magd S. Doping in sports and its spread to at-risk populations: an international review. World Psychiatry 2007;6:118-23.
22. Der Spiegel 2007 July 2. Interview with Jörg Jaksche,
German cyclist, who admitted doping and reported on doping practices with blood and epo.
23. Tigue CC, McKoy JM, Evens AM, Trifilio SM, Tallman MS, Bennett CL. Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project. Bone Marrow Transplant 2007;40:185-92.
24. Robert-Bosch-Stiftung Schule triftt Wissenchaft – Die
Nominierten (Robert-Bosch-Foundation: School students perform science – the nominees). http://www.boschstiftung. de/content/language1/html/23434.asp. Downloaded 5 May 2009



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