This issue marks the forth and final issue of the second year’s edition of the GaBI Journal. The journal has grown rapidly through the combined efforts of the publisher and her staff, all of the members of the executive editorial board and the international editorial advisory board, our contributors, advertisers and readers for which I would like to express my sincere appreciation.
Issue 4 begins with two Editorials concerning the possibility that low- to middle-income/limited resource countries could have a less rigorous biosimilar approval pathway. I wrote the first Editorial in response to the Opinion paper by Ms Barbara Milani and Ms Sara Gaspani concerning the use of pegylated interferon alpha products to treat hepatitis C that appears later in this issue and the second Editorial by Dr Armando A Genazzani and Dr Nicola Magrini also discusses the more general aspects of this issue and conclude that the solution proposed by Ms Milani and Ms Gaspani may in fact not suit patients in resource-poor countries.
These Editorials are followed by four Letters to the Editor covering a number of important issues including one from Dr Janet S Wyatt who, based on safety and monitoring concerns argues against legislative efforts underway in the US State of California to limit information provided to patients on which biosimilar product they are given. Dr Edward T Maggio then discusses immunological differences as a reason to continue to give unique names to each follow-on biosimilar product. The third letter from Dr Richard O Dolinar who commends the World Health Organization (WHO) for providing distinct International Nonproprietary Names for each biosimilar product. The naming of all follow-on products, especially biosimilars is the subject of considerable clinical, regulatory and proprietary interest and is of importance to everyone concerned with the development, testing, use, approval and monitoring of follow-on products. The final letter from Dr Brendan Shaw corrects some information published as a Perspective by Professor David A Power in Volume 2/Year 2013/Issue 3 of the Generics and Biosimilars Initiative Journal [1]. The paper is about biosimilars licensing and prescribing in Australia.
A Commentary by Dr Gustavo Grampp and Dr Sundar Ramanan on how the quality of biosimilar manufacturing should be maintained including examples of problems that have occurred. They conclude with an interesting proposal for an ‘active participation in industry consortia where best practices can be shared among peers’. I have never worked directly for a pharmaceutical company but it seems to me that this suggestion while holding great promise for patients and the healthcare industry if adopted would likely face resistance. I would be interested in hearing what our readers think of this suggestion.
The following Original Research paper by Zhang et al. discusses a related issue, the establishment of reference standards for biosimilar studies.
There are two Review Articles, the first by Vogler et al. explains the components of pharmaceutical expenditures and provides an overview of pharmaceutical policies in Europe, and the second by Dr Vera Brinks discusses the immunogenicity of biosimilar monoclonal antibodies.
In the paper that I wrote an Editorial about Gaspani and Milani in an Opinion suggest that the WHO should develop a system for approving non-biosimilar ‘copies’ of pegylated interferon alpha for the treatment of hepatitis C in resource-poor countries. Their suggestion, which is based on their evaluation of the economics of pegylated interferon alpha treatment, suggests that less comparability testing is required in less wealthy than in wealthy countries. We would welcome contributions from our readers on their suggestion as well as my skepticism about the ability of the WHO to do what they suggest as well as my concerns about the outcome of such a second-class approval process.
These papers are followed by a Meeting Report by Professor Mühlebach et al. that summarizes presentations given by an expert panel at an important closed workshop on the clinical and non-clinical aspects of non-biological complex drugs (NBCDs) held at the 2012 FIP (International Pharmaceutical Federation) Centennial Congress. NBCDs, e.g. liposomes, intravenous iron carbohydrate products and glatiramoids; are a relatively new class of drugs. They are very different and much more complex than are traditional small molecule generics and their composition is highly production method dependent. In fact, while not produced in biological systems they are as or even more complex than many biologicals and can even be impossible to completely characterize by their physiochemical properties. These characteristics raise concerns about the approval of follow-on copies, especially since there is as yet no consistent approach to how they are regulated and approved within or between countries. Members of our editorial board and I feel there is a need for professional education concerning NBCDs. GaBI Journal has therefore begun a number of initiatives aimed at developing best practices for approval, use and monitoring NBCDs. This Meeting Report is the first attempt at bringing this issue to the attention of our readers. Future issues will contain additional information on this subject including meeting reports from educational conferences conducted by GaBI Educational Workshops that will focus on NBCDs.
This issue concludes with a paper on the Japanese regulatory approach to biosimilars.
I want to again urge our readers to submit any comments, commentaries or concerns about the material we publish as well as both their original research and reviews.
Professor Philip Walson, MD
Editor-in-Chief, GaBI Journal
Reference 1. Power D. Licensing and prescribing biosimilars in Australia. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013:2(3):152-4. doi:10.5639/gabij.2013.0203.030
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Despite the fact that hepatitis C is a disease of global importance, many countries cannot afford the costly but effective combination treatment of peg-interferon and ribavirin, which was recently included in the World Health Organization Essential Medicines List. Given that peg-interferon is a biotechnological product, should low- to middle-income countries adopt the burdensome biosimilar approval pathway of western countries or should they find a more pragmatic approach, focusing on efficacy and safety to gain access to affordable biotechnological products?
Submitted: 7 November 2013; Revised: 11 November 2013; Accepted: 14 November 2013; Published online first: 27 November 2013
Hepatitis C is a disease of global importance, and although the global burden of morbidity and mortality is hard to estimate, the approximate prevalence of hepatitis C virus (HCV) infection worldwide is 2.2-3% (about 150 million individuals). There are large variations in prevalence [1]: Southern Mediterranean, Central Africa, South America and South East Asia appear to be among the most affected regions [2]. In recent decades, the HIV/AIDS epidemic (with very effective treatments available) has kept HCV infections out of the spotlight, but we are probably on the eve of a similar growth of interest in HCV management given the presence of more effective treatments for HCV.
In high-income countries, most new HCV infections occur as a result of the use of injectable illicit drugs [3], but in low- to medium-income countries nosocomial transmission due to the reuse of contaminated or inadequately sterilized syringes and needles is still high [4]. HCV infection can lead to acute hepatitis and to chronic hepatitis, the former eventually leading to cirrhosis and, in a proportion of patients, to hepatocarcinoma. Given the natural history of the disease, the treatment of chronic hepatitis is generally considered cost-effective [1], although cost-effectiveness should be tailored to local realities, e.g. cost of medicines, healthcare budget and life expectancy.
The golden standard of therapy was, until recently, the combined administration of peg-interferon and ribavirine, with the goal of producing a sustainable virological response (SVR). Pegylated interferon (PEG-IFN) in combination with ribavirin produces SVR rates around 50% for the genotype 1 subtype of HCV, and up to 80% for the genotype 2 and 3 subtypes [5, 6] when used in western countries and in low- and middle-income countries [7].
The cost of PEG-IFN and ribavirin in western countries amounts to US$10,000–US$20,000 per treatment [8]. This is obviously unaffordable for most low- to medium-income countries, which have had to use less effective therapies as a result. Highly-regulated markets, e.g. Europe, Japan, USA; have recently approved drugs such as boceprevir and telaprevir that, in combination with PEG-IFN and ribavirin, have increased the effectiveness of treatment (up to 65–70% of SVR in genotype 1). More effective second-generation protease inhibitors, as well as polymerase inhibitors, are also being approved (simeprevir and sofobuvir).
The presence of these new treatments in western countries increases the HCV treatment gap between the west and low-income countries, widening an unacceptable divide between countries in relation to an infectious disease. The problem arising from this divide is that of social inequality, but it also carries unacceptable implications for global health. A global, equitable, sustainable and fairly priced solution, like that achieved for HIV, should be sought to make world class HCV treatments available worldwide. The World Health Organization (WHO) recently approved the inclusion of PEG-IFN in its Essential Medicines List [9], attempting to reduce the gap between countries.
Milani and Gaspani writing in this issue [8] tackle a crucial issue in this field: given that PEG-IFN is a biotechnological drug, and the scientific community accepts that the generic (non biotechnological) medicine approval pathway is not appropriate for this class of compound, how can affordable PEG-IFN gain access in low- to medium-income countries?
In brief, the structure and physicochemical properties of biotechnological compounds are by definition difficult to fully characterize, and if different producers attempt to generate the same molecule they will come up with distinct molecules. Furthermore, it is accepted that small differences in the structure of biotechnological compounds can lead to large differences in clinical efficacy and safety (it is, however, also accepted that some large differences can lead to no appreciable change in clinical characteristics). To circumvent these issues, the European Medicines Agency (EMA) and other regulatory agencies have decided to approve generic biotech medicinal products (known as biosimilars) based on a comparability exercise aimed at demonstrating superimposable physicochemical, preclinical and clinical characteristics between the originator drug and the biosimilar. It is important to note that the comparability exercise is per se expensive and is not designed to demonstrate efficacy and safety. WHO has also issued guidelines that largely overlap with those of the European Union.
While biosimilar production is more expensive than generic drug production, the presence of biosimilars (epoetins, filgrastim) on the European market has allowed for competition and has reduced the cost of treatment considerably.
The big question is: do low- to middle-income countries need biosimilars, as previously defined? Would they be affordable for the interested countries and profitable for the producers? At present, there is no clear answer.
We contend that a biosimilar drug, as defined by both EMA and WHO, might not suit the actual needs of low- to middle-income countries. The main reason is that biosimilars are in part designed to create competition based on sameness/therapeutic equivalence in countries where the innovator product was present. In countries where the products were scarcely available, this model might not be the best way forward. These countries require safe and effective treatments, and trials should be designed to demonstrate just this. A possible solution, highlighted by Milani and Gaspani [8] and by others in different contexts [10], is that alternative therapeutic products could be developed without undergoing a lengthy and costly clinical comparative trial. In brief, the alternative product could either have a conditional approval (gathering sufficient efficacy and safety data in real-life) or undergo a less-costly demonstration of efficacy and safety (without having to use the reference product). Both strategies could use accepted and validated surrogate markers and use historical data on innovators as a comparison. In this respect, it is important to note that therapeutic alternatives to PEG-IFN are already present in developing markets, as highlighted by Milani and Gaspani [8]. Their careful clinical characterization could pave the way to the rapid introduction of affordable, safe and effective PEG-IFN, verifying the overall results on a surrogate measure such as liver function and/or SVR (depending on available data). In brief, this represents a very pragmatic solution to the problem.
WHO issued ‘Guidelines on Evaluation of Similar Biotherapeutic Products’ in 2009. Although the scientific merit of the guidelines is not in question, we agree with Milani and Gaspani [8] that they should be updated also to include a more pragmatic approach to the problem in countries where the reference product was not widely available due to cost limitations.
Disclosure of financial and competing interests: The authors declare no conflict of interests regarding the issues raised in this paper. Dr Armando A Genazzani has given paid consultancies to Roche Spa Italy (the producer of a peg-interferon in Italy) and to Sandoz, Teva and Hospira (distributors of biosimilars in Europe) on matters unrelated to peg-interferon. Dr Nicola Magrini declares no financial conflict of interest, but was a member of the 19th WHO Expert Committee which included peg-interferons in the WHO Essential Medicines List in April 2013. Dr Nicola Magrini has been actively supporting WHO activities for both the Essential Medicines List and guidelines production.
Provenance and peer review:Commissioned; internally peer reviewed.
Co-authors
Nicola Magrini, MD
Area Valutazione del Farmaco, Agenzia Sanitaria Regionale, 21 Viale Aldo Moro, IT-40126 Bologna, Italy
Drug Evaluation Unit, WHO Collaborating Centre in Evidence-Based Research Synthesis and Guideline Development, Emilia Romagna Health and Social Care Agency
References 1. Lavanchy D. The global burden of hepatitis C. Liver Int. 2009 Jan;29 Suppl 1:74-81. 2. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5(9):558-67. 3. Wasley A, Alter M. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis. 2000;20(1):1-16. 4. Simonsen L, Kane A, Lloyd J, Zaffran M, Kane M. Unsafe injections in the developing world and transmission of bloodborne pathogens: a review. Bull World Health Organ. 1999;77(10):789-800. 5. Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, Sanchez-Tapias J, et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol. 2004;40(6):993-9. 6. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon- alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140(5):346-55. 7. Ford N, Kirby C, Singh K, Mills EJ, Cooke G, Kamarulzaman A, et al. Chronic hepatitis C treatment outcomes in low- and middle-income countries: a systematic review and meta-analysis. Bull World Health Organ. 2012;90(7):540-50. 8. Milani B, Gaspani S. Pathway to affordable, quality-assured sources of pegylated interferon alpha for treating hepatitis C. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(4):194-203. doi:10.5639/gabij.2013.0204.053 9. World Health Organization. 19th Expert Committee on the Selection and Use of Essential Medicines [homepage on the Internet]. 2013 Nov [cited 2014 Nov 7]. Available from: http://www.who.int/selection_medicines/committees/expert/19/en/index.html 10. Shellekens H, Moor EHM. Reply: in support of the European Union biosimilar framework. Nat Biotechnol. 2012;30:748-9.
Author for correspondence: Armando A Genazzani, DPhil, MD, Department of Pharmaceutical Sciences, Università del Piemonte Orientale, 6 Via Bovio, IT-28100 Novara, Italy
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Information about variable immunogenicity arising from formulation differences between competing biosimilars is critical for informed judgments by prescribing physicians. Use of a common INN for biosimilars will obfuscate such differences to the detriment of patients.
Submitted: 31 October 2013; Revised: 12 November 2013; Accepted: 13 November 2013; Published online first: 26 November 2013
Immunogenicity of biotherapeutics is one of the most serious safety concerns of US Food and Drug Administration and European Medicines Agency for obvious reasons. Unwanted immunogenicity can alter or neutralize biological activity of a biotherapeutic in the best case, and in the worst and most well known case, namely erythropoietin, has resulted in patient mortality. Biosimilars and innovator biotherapeutics can differ significantly in the degree of unwanted immunogenicity. Two principal sources of immunogenicity are protein aggregation [1] and oxidative damage caused by the inclusion of polysorbate excipients in many if not most biotherapeutics – innovator products as well as biosimilars alike. Aggregation induced immunogenicity is a function of the extent and nature of the aggregates formed which in turn is determined in large part by differences in the chemical composition of the biotherapeutic. Oxidative damage is caused by reactive peroxides, epoxy acids, and aldehydes, which spontaneously arise and which are found in all lots of polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20) and which vary over a 26-fold concentration range. These reactive species progressively generate neoantigens in situ during product storage by reaction with aminoacyl sidechains – a principal source of unwanted immunogenicity. Since the factors that determine unwanted immunogenicity, namely amino acid sequence/glycosylation and the composition of the reactive components arising from excipients such as polysorbates in the aqueous vehicle, are likely to vary between innovator and biosimilar, as well as between one biosimilar to the next, failure to differentiate each product by enforcing a common INN (International Nonproprietary Name) deprives physicians of essential information in differentiating and understanding differences in the product safety and efficacy profile of each therapeutic alternative. Lastly, differences in the immunogenicity profile of biotherapeutics often only become apparent once the product has been administered over an extended time to a large group of patients. Simply because biotherapeutics, no matter how similar, are not all equal, one or more of the biosimilars may eventually be identified as ‘biosuperior’ with respect to reduced or eliminated immunogenicity compared to the other corresponding products (biosimilars and innovator alike). Use of a common INN [2] will obfuscate these important differences to the prescribing physician to the detriment of patients whose health, and perhaps life, depend upon the physicians informed judgment.
Disclosure of financial and competing interests: Dr Edward T Maggio is the CEO of Aegis Therapeutics LLC. Aegis does not manufacture or sell any biotherapeutics. Neither Dr Maggio, Aegis Therapeutics, or any Aegis officer own any shares of companies that do so.
However, Aegis out-licence formulation technologies for small molecules and biotherapeutics, this may be indirectly related to the issue focused on in the Letters to the Editor (INN naming of biosimilars).
Provenance and peer review: Not commissioned; internally peer reviewed.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Submitted: 31 October 2013; Revised: 6 November 2013; Accepted: 11 November 2013; Published online first: 25 November 2013
To the Editor:
I wanted to bring to your attention the following paper which was published in Volume 2/Year 2013/Issue 3 of the Generics and Biosimilars Initiative Journal.
The Perspective paper titled Licensing and prescribing biosimilars in Australia [1], Professor David Power’s description of the Australian reimbursement system contains a number of factual errors. Left uncorrected those errors lead people to misunderstand the market for biosimilars in Australia.
Professor Power erroneously draws a link between Australia’s policies on substitution at a pharmacy level and Australia’s naming policies for medicines. He states:
‘Where the products have the same INN names, as for filgrastim, and the prescriber uses the generic drug name, the pharmacist is free to choose any of the products with that name.’
And later:
‘Since PBS [Pharmaceutical Benefits Scheme] does not permit automatic substitution of biosimilars with different INN, pharmacists are unable to substitute a glycosylated biosimilar for its (presumably more expensive) comparator drug. Where the drug has the same INN, then the cheapest product can be supplied unless the prescribers stipulate use of a particular brand.’
This is incorrect. While all available filgrastim biosimilars in Australia have identical non-proprietary names as the reference or originator product, i.e filgrastim, none are considered ‘substitutable’ within the context of Australia’s National Health Act.
As Professor Power correctly notes, the Pharmaceutical Benefits Advisory Committee (PBAC) determines which molecules may or may not be substituted at a pharmacy level. Those brands of medicines deemed substitutable at a pharmacy level by the PBAC include a notation in the official Pharmaceutical Benefits Schedule known as an ‘a-flag’. The PBAC generally accepts the Australian regulator’s (Therapeutic Goods Administration) assessment that a molecule is bioequivalent to its reference product as the principal criterion for ‘a-flagging’. The PBAC also considers other factors, including whether medicines have a narrow therapeutic index.
In the case of the filgrastim biosimilar, Nivestim, the PBAC rejected a request from the sponsor for an ‘a-flag’. The PBAC’s publicly available recommendation on the listing of Nivestim states:
‘SBMPs (similar biological medicinal products, aka biosimilars) have some conceptual parallels with generic versions of products containing chemically-derived small molecules as the active substances. However, although small molecule generic products may be approved for marketing on the basis of bioequivalence (or in limited cases, therapeutic equivalence) to a reference product, these concepts may not at this time be extrapolated to SBMPs. Proteins and other biological medicinal products can be more complex than chemically synthesised medicines. This is in part because even highly purified protein products may consist of more than one molecular entity, and are usually mixtures of many closely related molecular species. This within product micro-heterogeneity may be substantial. Thus, even though a SBMP will have the same encoding DNA sequence as the reference product, the two products may differ in other key attributes.
PBS Listing of SBMPs The current practice of ‘a’ flagging in the Schedule of Pharmaceutical Benefits, denoting that brand substitution may be undertaken by pharmacists at the point of dispensing, will not be applied to SBMPs at this time unless a Therapeutic Goods Administration (TGA) issued statement supportive of ‘a’ flagging is available’ [2].
The PBAC concluded:
‘The PBAC recommended listing of the requested filgrastim products, noting that the TGA delegate proposed to register the products as similar biological medicinal products being of ‘comparable efficacy and safety’ and having the same non-proprietary name as its reference product on the basis of an abridged dataset according to the European Union guidelines adopted by the TGA. …
The PBAC recommended that ‘a’ flagging for the purposes of subsection 103(2 A)(b) of the National Health Act 1953 should not be applied across the two sets of filgrastim products, noting the absence of a TGA issued statement, at the time of consideration, that would support ‘a’ flagging’.
Thus, contrary to Professor Power’s statement pharmacists in Australia cannot ‘freely substitute’ biological medicines with the same INN.
Significantly, the recently released TGA guidelines on [evaluation of] biosimilars (http://www.tga.gov.au/industry/pm-argpm-biosimilars-00.htm) reaffirm the Australian regulator’s view about the inappropriateness of pharmacy level substitution for these products. In these guidelines, TGA has indicated that the product information will include words similar to the following:
‘The level of comparability that has been shown is not sufficient to designate this product as a generic version of [Reference product name]. Replacement of [Reference product name] with [Biosimilar product name], or vice versa, should take place only under the supervision of the prescribing medical practitioner.’
TGA has also advised that the accompanying approval letter will include words similar to the following [3]:
‘It is the TGA’s view that it is not currently possible to determine a degree of similarity, between a biosimilar and an already registered biological medicine sufficient to support a designation by the TGA of ‘bioequivalence’.’
On this basis, it is unlikely that the PBAC will permit an ‘a-flagging’ of a biosimilar soon, regardless of whether the biosimilar was registered in Australia with identical INN or a unique non-proprietary name.
The TGA’s new naming convention, requiring distinguishable names for biosimilar medicines, and its policy on substitution are separate and distinct issues, and should be treated as such.
Professor David Power’s reply:
I wish to thank Dr Shaw for his reply and for correcting any misleading statements in my article. It was written very much from the viewpoint of an end-user of the system. In that vein, it is still not clear to me how a pharmacist decides what product to provide when the practitioner prescribes by INN name if there are two or more products available with that name. Perhaps that could also be clarified by Dr Shaw.
Dr Brendan Shaw’s reply:
This is one of the motivations for the Australian regulators move to create a distinguishable naming policy for biosimilars. The pharmacist currently has to rely on brand name prescribing or otherwise contact the prescriber if there are no continuing records. The Australian regulator has issued information for health professionals (copy provided as below) [3] stating clearly that …
‘Biosimilars should be prescribed by name: Unlike generic small-molecule medicines, which can simply be specified using the international nonproprietary name (INN), biosimilars – and indeed all biological medicines – should be clearly distinguishable on any prescription (preferably by using both trade name and non-proprietary name).
Unlike generic medicines, which must demonstrate bioequivalence to the reference product, biosimilars are not bioequivalent to the products they follow and as such pharmacists may not substitute a biosimilar for the original medicine. This is why it is important to specify which product you are proposing for your patient.’
Competing interests: Dr Brendan Shaw is the CEO of Medicines Australia, the peak body representing the innovative pharmaceutical industry in Australia. Dr Shaw declares no other competing interests.
Provenance and peer review: Not commissioned; internally peer reviewed.
References 1. Power D, Licensing and prescribing biosimilars in Australia. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013:2(3):152-4. doi:10.5639/gabij.2013.0203.030 2. Australian Government. The Department of Health. Therapeutic Goods Administration. Public Summary Document. November 2010 PBAC Meeting. Available from: http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-filgrastim-nov10 3. Australian Government. The Department of Health. Therapeutic Goods Administration. Health professional information and education. Biosimilar medicines – information for healthcare professionals. 5 November 2013. Available from: http://www.tga.gov.au/hp/hp-information-biosimilars.htm
Author: Brendan Shaw, PhD, Chief Executive, Medicines Australia Ltd, Level 1, Napier Close, Deakin Act 2600, Australia
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Legislation in support of pharmacist notification to patients and providers of substitution of an interchangeable biologic for the originator biologic was recently vetoed in California. Automatic substitution of approved biosimilars without notifying the patient and physician/healthcare provider circumvents important pharmacovigilance.
Submitted: 21 October 2013; Revised: 22 October 2013; Accepted: 25 October 2013; Published online first: 7 November 2013
On 13 October 2013, Governor Jerry Brown ignored the recommendations of California legislators and caved into the pressure from outside groups to veto a bill that supported and strengthened patient–provider communication. At a time when national efforts are underway to increase public information sharing and transparency in the most complex corners of our government and society, California and many other state governments have now moved in the opposite direction with the promulgation of regulations which will allow pharmacists to exchange a prescribed biological product for a biosimilar product, without notifying the patient or the prescribing provider.
For those of us taking biological products for rheumatoid arthritis (RA) and other autoimmune diseases, this is appalling and scary. For almost 20 years the discovery and development of complex biological products has been a healthcare triumph for millions with RA and a business boon for pharmaceutical manufacturers who gain more than US$140 billion in sales of biologicals annually. Investigation of the processes needed to manufacture biologicals helps to understand these costs. Biologicals products (medications) are a direct result of our growing knowledge of DNA cloning. These complex treatments are genetically engineered proteins, made from animal, or bacteria cells. Biologicals require sophisticated production and purification processes and delicate handling. Today, there are as many as 10 separate biological products, delivered via self-injection or vein infusion that have helped improve the quality of life for people with RA. As patents on the highly expensive original biological therapies are due to expire in 2014, support is growing for the development of biosimilars, products that will be similar to and potentially interchangeable for original biologicals. While it is hoped that biosimilars might eventually reduce patient costs for biological therapy and increase access to safe biological treatments, it is important to recognize that any new biosimilar product will in no way be the same as the original biological. With the advent of genetic engineering that now transforms foreign cellular proteins into break-through treatments, we cannot apply the same assumptions and rules that govern the production and labelling of ‘generic’ medications. Even though the patent for a biosimilar may expire, biological drug manufacturers will not be required to turn over their original cell line or share information about their sophisticated manufacturing process. Essentially biosimilar manufacturers will not have access to an original biological’s genetic engineering process or molecular clone and will not be able to access the original biological’s active drug substance, production, fermentation, purification or delivery process. While the goal of interchangeable biosimilar therapy is to provide the same clinical benefit with no increased risks to patients, all new biosimilars will essentially be new products. Today, the US Food and Drug Administration (FDA) requires most if not all biologicals prescriptions to be accompanied by a detailed Risk Evaluation and Mitigation Strategy (REMS) which outlines specific monitoring and patient education that must be completed to support informed patient consent within the prescribing treatment process. Through REMS programmes, patients and providers engage in the valued concept of pharmacovigilance – monitoring for the benefits as well as the multitude of potential severe adverse reactions that accompany biological therapies. Indeed the importance of shared patient/provider pharmacovigilance was recently reinforced in the February 2013 FDA’s Inspector General report which cited the need for strengthening patient and provider communication to improve monitoring of complex treatments. Thus, allowing substitution without notification will now severely undermine and complicate risk management strategies since patients and their physicians will not know which product(s) were used if/when adverse effects occur or which was responsible if many are used.
The decision to embark on biological therapy has always involved comprehensive communication between patients and providers. This has been particularly true for those of us with other illnesses and health conditions who are also taking other medications or treatments. But we cannot fool ourselves into thinking that biosimilar products are essentially generic versions of original biologicals. So if indeed new biosimilars are different cells, genetically engineered differently, manufactured and purified and produced differently, with potentially different side and adverse effects … why eliminate the need for crucial patient and provider communication and health education?
A law that allows a pharmacist with no direct knowledge of your health conditions to change a biological for an interchangeable biosimilar without notifying the patient or the provider abandons the critical premise for pharmacovigilance defined by FDA – frequent and in-depth patient–provider communication.
With less than 20 years of accumulated patient response data, we are still learning about the benefits as well as the serious health risks of current biological therapies. As a patient with RA who has recently experienced an adverse reaction to a biological it is my hope that new biosimilars might bring new benefits. We do not have a cure for RA and we need all of the help we can get to manage the bone and joint erosion that marches on, despite the disease modifying effect of biologicals. But we cannot accept any regulation that circumvents the therapeutic relationship between patient and provider and abandons the important principles that guide safe, quality health care … shared patient and provider communication.
Competing interests: None. Dr Janet S Wyatt is an independent consultant in health care, health policy and health advocacy. Dr Wyatt serves as a volunteer on the national Board of Directors of the Arthritis Foundation in the US.
Provenance and peer review: Not commissioned; internally peer reviewed.
Author: Janet S Wyatt, RN, PhD, FAANP, 35460 Sassafras Drive, Round Hill, VA 20141, USA
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
The Editor-in-Chief expresses his concerns about the proposal of a WHO run system to approve copy biologicals in the Milani and Gaspani paper [1].
The paper by Milani and Gaspani [1] suggests that the World Health Organization (WHO) sets up a programme to approve follow-on pegylated interferons and similar biological medications, that is biological product meant to mimic approved, effective and tolerated drugs but which are subjected to less restrictive testing that are true biosimilar products. I have problems with this suggestion that require comment and concerns about the ability of WHO to do what is proposed.
The title of their paper suggests that WHO can approve/recommend such products that are ‘quality assured’ yet they offer little to no evidence that such products will be ‘quality assured’. The authors suggest that such products should be approved by a less rigorous approval system than that required by either the European Medicines Agency (EMA) or US Food and Drug Administration (FDA) [1].
WHO is not a regulatory agency. The authors provide no evidence that WHO would be capable of adequately (or even cost-effectively) evaluating, approving or performing post-approval monitoring of such products. They provide some data suggesting that the use of pegylated interferon copies can lower access costs but no data on either comparative efficacy or toxicity. Acquisition costs are only part of overall healthcare costs. The costs associated with the administration, storage, possible differences in efficacy or adverse events from such copies must also be considered.
The authors do not discuss how WHO or any country using such products would monitor the use or efficacy of such products or how they would identify any problems that might occur after approval. There is also no mention of how lower efficacy or adverse events that occur in patients who were given more than one such biological copy could or would be evaluated.
Access of non-wealthy patients in resource-poor countries to expensive medications such as pegylated interferons is certainly an important topic worthy of new solutions. However, there are reasons beyond patent laws and profits that have prevented the marketing of adequate ‘follow-on biologics’. Biological products and non-biological complex drugs are much more complex than small molecule generics. There are many examples of ‘follow-on biologics’ which failed to be marketed because of inadequate efficacy, greater adverse events, or both. Without access to data from both adequate pre-approval testing as well as from post-marketing efficacy and adverse event surveillance data it is impossible to know whether the examples of increased access provided by the authors represent inferior efficacy, more toxicity or even truly decreased healthcare costs.
The authors’ suggestion that a single organization or entity can take on a global regulatory function for a number if not all resource-poor countries definitely has merit, but it is not clear that this should or even could be adequately done by WHO. Perhaps this could be done better by one of the major pharmacopoeas, i.e. United States Pharmacopeia or British Pharmacopoeia.
The authors suggest both that WHO can develop methods to adequately evaluate and approve ‘follow-on biologic’ copies such as those being used in Iran and imply that such copies are the same as biosimilars. Both may be true but data to adequately support these suggestions were in my view not adequately presented.
Professor Philip Walson, MD
Editor-in-Chief, GaBI Journal
Reference 1. Milani B, Gaspani S. Pathway to affordable, quality-assured sources of pegylated interferon alpha for treating hepatitis C. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(4):194-203. doi:10.5639/gabij.2013.0204.053
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal: Professor Stefan Mühlebach, PhD, Professor Arnold Vulto, PharmD, PhD, Jon SB de Vlieger, PhD, Vera Weinstein, PhD, Beat Flühmann, PhD, Vinod P Shah, PhD
Introduction: Besides biologicals, a new class of complex drugs – non-biological complex drugs (NBCDs), e.g. liposomes, iron carbohydrate products and glatiramoids – has emerged. Originator NBCD products have been approved by established regulatory rules. However, their follow-on products comprise a challenge to the regulators, manufacturers, physicians and pharmacists. Methods: An expert panel at a closed workshop during FIP (International Pharmaceutical Federation) Centennial Congress 2012 discussed non-clinical and clinical aspects that distinguish NBCDs from traditional, small molecule drug products as well as new approaches for regulatory evaluation of NBCD follow-on products. Results: The active ‘substance’ of an NBCD is of non-biological origin and comprises a heteromolecular mixture of closely related, often nanoparticulate, structures that cannot be fully characterized physicochemically by state-of-the-art analytical means. The composition, quality, and in vivo performance of NBCDs are highly dependent on the manufacturing processes of both the active ingredient and the formulation. Furthermore, pharmacokinetics and pharmacodynamics can be substantially influenced by underlying diseases (particularly in case of associated inflammation). The abridged pathway for regulatory assessment of small molecule generics is not appropriate for NBCD follow-on products whereas the biosimilar pathway is not applicable to non-biologicals. Conclusions: New regulatory approaches for the approval of NBCD follow-on products that focus on advanced (analytical) technologies for in vitro characterization and on comparability of clinical safety and therapeutic efficacy are emerging. In contrast to generics, automatic interchange and substitution of NBCD follow-on products should be generally discouraged unless demonstration of therapeutic equivalence and similar safety profiles by appropriate studies.
Submitted: 12 August 2013; Revised: 24 September 2013; Accepted: 27 September 2013; Published online first: 11 October 2013
Introduction
The progress in pharmaceutical sciences and manufacturing techniques together with more targeted and better-tolerated pharmaceutical formulations gave rise to a new class of medicinal products with complex macromolecular (nanoparticulate) structures, the so-called non-biological complex drugs (NBCDs) [1, 2]. Amongst others, NBCDs comprise liposomes, iron carbohydrate products and glatiramoids. The complexity of these synthetic NBCDs may even exceed that of biologicals. Originator NBCDs have received regulatory approval based on proven quality, efficacy and safety and have been established for many years. Some NBCDs have already been introduced before the growing awareness about the specific issues related to the production and characterization of nanostructures. Accordingly, regulatory approval of NBCD follow-on products is subject to a lively discussion about the requirements to prove therapeutic equivalence and being eligible as substitute for the reference product.
The Non-Biological Complex Drugs Working Group at Dutch Top Institute Pharma, a public–private partnership in The Netherlands, is a network of scientific and clinical experts from academia, industry, regulatory bodies, and knowledge institutes to discuss specific aspects of the development and evaluation of NBCDs and give its expert opinion. This paper briefly summarizes the key discussion points of a closed workshop at the FIP (International Pharmaceutical Federation) Centennial Congress in 2012, organized by the FIP Board of Pharmaceutical Sciences, in order to assist the understanding of the regulatory challenges associated with NBCD follow-on products such as the definition of science-based policies for interchange and substitution. The closed workshop on invitation only was followed by an open discussion symposium the following day at the FIP Centennial Congress about the proposed terminology and a planned paper on points to consider for regulation [3, 4].
What are NBCDs and what makes them special?
NBCD are defined as a medicinal product of non-biological origin with an active substance that is not a homo-molecular structure, but consists of different closely related and mostly nanoparticulate structures. Accordingly, there is not a single substance that can be isolated, quantitated and fully characterized or described by state-of-the-art physicochemical analytical means [4]. Changes in the composition and morphology of an NBCD can substantially influence the quality, biological properties and therapeutic profile of the medicinal product and result from minute variations in the manufacturing process [1, 2, 5]. However, not all structural changes and mechanisms that affect the therapeutic profile are fully understood. Notably, the complexity of NBCD prevents establishing full proof of pharmaceutical equivalence by state-of-the-art analytical means, which comprises one of the two pillars in the evaluation of a generic medicinal product, see Figure 1.
In contrast to the mainly direct and systemic drug-target interaction of small molecules with defined receptors in a concentration-dependent manner, most NBCDs comprise nanoparticles from which the active ingredient has to be released or formed and then transported to certain biological compartments where the intended activity should be performed. Even a slightly different release or formation rate of the active ingredient, e.g. due to differences in higher order structure of the precursor molecules, can negatively affect the safety and efficacy profile of an NBCD or its follow-on product. For example, in products for intravenous iron therapy such as iron carbohydrate nanoparticles, the highly reactive iron is bound in a polynuclear core, which in turn is stabilized by a carbohydrate shell. After intravenous administration, this complex is first phagocytized by monocytes where the iron is released and transiently stored before it is bound to transferrin and transported to the target tissue where it exerts its action, e.g. incorporation into newly synthesized erythrocytes in the bone marrow; or is stored in an accessible compartment for later physiological use [6, 7]. Hence, the biological activity of an NBCD is not necessarily correlated to its serum pharmacokinetics (central compartment), the generics pathway’s second pillar to show bioequivalence.
In the case of glatiramoids, products that comprise a complex mixture of polypeptides for the treatment of relapsing-remitting multiple sclerosis, even no pharmacokinetic profile and no validated biomarker for efficacy are available. However, although the originator, Copaxone®, and a follow-on product are similar in many physiochemical properties, e.g. size distribution, molar ratio of amino acids; sensitive chemical and biological analyses demonstrated differences between those products, e.g. gene expression patterns of glatiramoid-primed murine splenocytes [8].
Does the generics approach fit for NBCD follow-on products and their manufacturers?
In contrast to follow-on compounds of biologicals that are evaluated according to distinct biosimilar guidelines (originally established in the EU), some NBCD follow-on products are classified as generics although the two prerequisites for the generics approach cannot be fulfilled. As outlined above, the inability to fully characterize an NBCD prevents proof of pharmaceutical equivalence or clinically meaningful differences between a follow-on NBCD and its reference product. Moreover, bioequivalence assessment in healthy volunteers does not necessarily reflect the biological fate of and therapeutic response to an NBCD as outlined by the example of the iron sucrose complex below. Notably, this lack in proof of therapeutic equivalence and potential differences in tolerability or safety of NBCD follow-on products can easily become a concern since these products are often used as chronic treatment and in patients with already poor health states, e.g. iron carbohydrate products for haemodialysis patients, liposomal formulations of cytotoxic agents for cancer patients and glatiramoids for multiple sclerosis patients [1, 9, 10]. In such patients, even slight but clinically meaningful differences between the products may interfere with clinical success and thus the feasibility for interchange with the innovator’s product.
The potential clinical consequences of the above-mentioned differences could be illustrated by comparative clinical and non-clinical studies of a well-established NBCD (iron sucrose, Venofer®) and different follow-on preparations (iron sucrose similars, ISS). One study evaluated the effects of switching iron treatment from the iron sucrose originator to an ISS in 75 consecutive stable, haemodialysis-dependent chronic kidney disease patients who underwent at least 60 dialysis sessions before and after the switch at a French dialysis centre [11]. After the switch to an ISS, haemoglobin levels decreased rapidly and anaemia medication had to be increased to return to targeted haemoglobin levels after quite a lengthy re-adjustment period. In addition to this apparent lack of therapeutic equivalence of an ISS, other ISS were associated with an increased risk of adverse events (658 patients at a South Korean centre who had been treated with the iron sucrose originator or an ISS) [12], even if the originator iron sucrose has been well tolerated before (three case reports in Germany) [13]. Furthermore, non-clinical studies showed not only differences between ISS and the originator product [14] but also among different ISS [15], particularly with respect to off-target iron disposition from ISS and induction of oxidative stress and inflammation.
In many countries generics approval of follow-on products allows automatic substitution at the pharmacy level. Since the International Nonproprietary Names of the innovator’s and follow-on products are the same, clinicians, caregivers and patients are often not aware of the change in medication. In contrast to the substitutability and interchangeability of fully characterized small molecule generics with well-established therapeutic equivalence, approval for substitution or interchange of NBCD products should only be granted on the basis of appropriate non-clinical and/or clinical comparisons. Together with the comparability of physicochemical quality this would allow to exclude clinically meaningful differences between the NBCD follow-on products and the reference product [1, 2]. Lacking information in case of insufficient response or intolerance can lead to unnecessary diagnostic tests and use of potentially more invasive and more expensive treatment options [8, 10]. Overall, drug product replacement that is guided by acquisition cost only may increase other costs and not be cost-effective from the patient’s and payer’s perspective.
Workshop discussions favour a similar approach
At the NBCD workshop in the course of the FIP Centennial Congress 2012, experts from academia, industry, regulatory bodies and knowledge institutes agreed that there is a need for a globally harmonized approach to authorize NBCD follow-on products. This approach should be linked to an accepted common terminology [4]. Also the requirements for an abbreviated procedure showing comparability between different types of NBCD follow-on products and feasible reference products should be clear. In order to approve an NBCD follow-on product that will be interchangeable with the innovator’s product, relevant and comparative clinical and/or non-clinical trials should be performed. Aims of these studies will be an appropriate characterization of the NBCD with up-to-date analytical techniques and to identify the extent of similarity with the originator product. Clinical trials should be sufficiently powered, conducted in patients rather than healthy volunteers to cover for disease-associated changes in pharmacokinetics (PK) and pharmacodynamics (PD). Furthermore, trials should include suitable biological tests to evaluate the similarity of PK, PD and safety/tolerability in populations with similar aetiology of the disease as for the aimed indication. For these means also surrogate efficacy and safety markers may be used. Based on the degree of similarity that could be confirmed by the results of such trials and markers, approval of an NBCD follow-on product can be gradually extended to allow for interchange or even automatic substitution in newly diagnosed patients or those on existing chronic treatment. Such a stepwise similarity approach towards totality of evidence can help manufacturers of follow-on products in the development of safe and effective products and to make a realistic prediction of development costs and timelines.
Furthermore, the expert panel indicated that post-approval pharmacovigilance for NBCD and follow-on products should be based on specific brand names as already proposed earlier [16]. An information exchange among treating healthcare professionals and eventually the patient is mandatory to allow for appropriate treatment and drug product traceability in the individual patient.
Conclusions
An increasing number of NBCDs including nanomedicines become target for development and introduction of follow-on products. Recent clinical data with NBCD follow-on products (iron sucrose) that were approved like small molecule generics revealed significant differences in efficacy and tolerability compared to the originator product. Accordingly, regulators are prompted to establish a global regulatory framework that considers the structural complexity and specific biological properties of NBCD and provides clear guidance for the development and documentation of safe and effective follow-on products. The experts from academia, industry, regulatory bodies and knowledge institutes at the FIP 2012 workshop suggest a stepwise similarity approach that includes appropriate clinical and/or non-clinical studies that evaluate markers of PK, PD (if applicable) and safety/efficacy in relevant patient populations. As long as proof of therapeutic equivalence and similar safety profiles by appropriate studies is missing, interchange and automatic substitution between NBCDs and their follow-on products should be discouraged. Overall, a critical review of the current and emerging regulation of NBCDs and NBCD follow-on products encourage further multidisciplinary research and consensus discussions among all stakeholders to develop guidance towards the definition of an NBCD and the development of NBCD follow-on products [3].
Acknowledgement
Medical writing support was provided by Mr Walter Fürst, SFL Regulatory Affairs and Scientific Communication, Switzerland, and funded by Vifor Pharma Ltd.
Disclosure of financial and competing interests: This manuscript was written within the framework of the Non-Biological Complex Drugs Working Group, hosted at Dutch Top Institute Pharma. The NBCD Working Group is currently supported by Sanofi, Teva Pharmaceutical Industries Ltd and Vifor Pharma International Inc. Professor Stefan Mühlebach is an employee of Vifor Pharma Ltd, Dr Vera Weinstein is an employee of Teva Pharmaceutical Industries, and Dr Beat Flühmann is an employee of Vifor Fresenius Medical Care Renal Pharma.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Professor Stefan Mühlebach1,2, PhD
Professor Arnold Vulto3, PharmD, PhD
Jon SB de Vlieger4, PhD
Vera Weinstein1,5, PhD
Beat Flühmann1,6, PhD
Vinod P Shah1, PhD
1Steering Committee member, NBCD Working Group, TI Pharma, Leiden, The Netherlands 2Vifor Pharma Ltd, Glattbrugg, Switzerland 3Erasmus University Medical Center, Hospital Pharmacy, Rotterdam, The Netherlands 4TI Pharma, PO Box 142, NL-2300 AC Leiden, The Netherlands 5Teva Pharmaceutical Industries, Petach Tikva, Israel 6Vifor Fresenius Medical Care Renal Pharma, St Gallen, Switzerland
References 1. Borchard G, Fluhmann B, Muhlebach S. Nanoparticle iron medicinal products—requirements for approval of intended copies of non-biological complex drugs (NBCD) and the importance of clinical comparative studies. Regul Toxicol Pharmacol. 2012;64(2):324-8. 2. Schellekens H, Klinger E, Mühlebach S, et al. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol. 2011;59(1):176-83. 3. Schellekens H, Stegemann S, Weinstein V, et al. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J. 2013 Sep 25. doi:10.1208/s12248-013-9533-z 4. Crommelin DJ, de Vlieger JS, Weinstein V, et al. Different pharmaceutical products need similar terminology. AAPS J. 2013 Sep 25. doi:10.1208/s12248-013-9532-0 5. Ehmann F, Sakai-Kato K, Duncan R, et al. Next-generation nanomedicines and nanosimilars: EU regulators’ initiatives relating to the development and evaluation of nanomedicines. Nanomedicine (Lond). 2013;8(5):849-56. 6. Evstatiev R, Gasche C. Iron sensing and signalling. Gut. 2012;61(6):933-52. 7. Geisser P, Burckhardt S. The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011;3(1):12-33. 8. Bakshi S, Chalifa-Caspi V, Plaschkes I, et al. Gene expression analysis reveals functional pathways of glatiramer acetate activation. Expert Opin Ther Targets. 2013;17(4):351-62. 9. Mamidi RN, Weng S, Stellar S, et al. Pharmacokinetics, efficacy and toxicity of different pegylated liposomal doxorubicin formulations in preclinical models: is a conventional bioequivalence approach sufficient to ensure therapeutic equivalence of pegylated liposomal doxorubicin products? Cancer Chemother Pharmacol. 2010;66(6):1173-84. 10. Varkony H, Weinstein V, Klinger E, et al. The glatiramoid class of immunomodulator drugs. Expert Opin Pharmacother. 2009;10(4):657-68. 11. Rottembourg J, Kadri A, Leonard E, et al. Do two intravenous iron sucrose preparations have the same efficacy? Nephrol Dial Transplant. 2011;26(10):3262-7. 12. Lee ES, Park BR, Kim JS, et al. Comparison of adverse event profile of intravenous iron sucrose and iron sucrose similar in postpartum and gynecologic operative patients. Curr Med Res Opin. 2013;29(2):141-7. 13. Stein J, Dignass A, Chow KU. Clinical case reports raise doubts about the therapeutic equivalence of an iron sucrose similar preparation compared with iron sucrose originator. Curr Med Res Opin. 2012;28(2):241-3. 14. Toblli JE, Cao G, Oliveri L, et al. Comparison of oxidative stress and inflammation induced by different intravenous iron sucrose similar preparations in a rat model. Inflamm Allergy Drug Targets. 2012;11(1):66-78. 15. Toblli JE, Cao G, Giani J, et al. Different effects of European iron sucrose similar preparations and originator iron sucrose on nitrosative stress, apoptosis, oxidative stress, biochemical and inflammatory markers in rats. NDT Plus 2011;4 [abstract]:SuO028. 16. Wysowski DK, Swartz L, Borders-Hemphill BV, et al. Use of parenteral iron products and serious anaphylactic-type reactions. Am J Hematol. 2010;85(9):650-4.
Author for correspondence: Professor Stefan Mühlebach, PhD, Vifor Pharma Ltd, CH-8152 Glattbrugg, Switzerland
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Biological product quality is susceptible to unexpected manufacturing issues, and the resulting variation may impact the safety or efficacy of these medicines and increase risks to patients. These risks can be managed more effectively by manufacturers’ adoption of the culture and practices of high reliability organizations and by their sharing of quality risk management information.
Submitted: 5 August 2013; Revised: 18 September 2013; Accepted: 19 September 2013; Published online first: 2 October 2013
The manufacture of therapeutic biologicals is constantly evolving science. Early naturally sourced biologicals were extracted and purified from animal tissues, cadavers, or donated blood with attendant risks of unwanted immune responses or infection with source-derived viruses. Early recombinant biologicals contained impurities from the manufacturing process that were sometimes associated with immunogenicity [1].
Many of these risks have been mitigated through modern bioprocessing technology but the manufacture of biologicals today still faces significant challenges: how can we ensure that biological medicines maintain their high quality, from batch to batch, and are supplied without interruptions to patients who may require long-term therapy to manage their medical conditions?
Biologicals are sensitive to manufacturing process conditions, handling and changes
Most biological medicines are manufactured using living cells that have been engineered to produce therapeutic proteins in large quantities. As these proteins are very sensitive to their conditions of synthesis and handling, a series of critical culturing and purification steps is required to produce a consistent, high quality active ingredient. The complexity of this process and the precision of required control require careful design and strict adherence to procedures as any changes introduced in the process can potentially influence the quality of the final product, including the structure, function and purity of the active ingredient [2].
The complexities of manufacturing biologicals also apply to biosimilars, which are approved on the basis of demonstrating highly similar quality, safety and efficacy to originator biologicals. In attempting to copy the originator product biosimilar manufacturers must independently design their own cell cultures and production steps. This is because the source materials, including the cell lines and the processes by which the original biologicals are made are confidential and may be protected by intellectual property laws, making exact replication of the steps extremely difficult, and typically resulting in structural differences between the products [3].
While many structural differences have no clinical relevance, it is possible that differences in protein folding, structural modifications (such as glycosylation), batch composition, and even the product container may have unexpected impact to the safety or efficacy of the product. For example, a product container contributed to a trend in immunogenicity for EPREX/ERYPO (sold in the EU) starting in 1998. The immunogenicity trend manifested as a sharp increase in the incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease and was ultimately traced to the effects of organic compounds leaching into the pre-filled syringes from uncoated rubber stoppers used by the manufacturer of EPREX/ERYPO. Due to the subtlety of the effect and the latency of the onset of PRCA (in some cases up to nine months after initiation of treatment) it took several years to identify and mitigate the effect of the organic leachate by changing to coated rubber stoppers [4]. Despite this discovery, new cases continue to emerge, generally in clusters. It is believed that the clusters were associated with protein aggregates potentially caused by a variety of factors including drug substance stability, improper handling, or interactions with container leachates [5].
The PRCA incident illustrates the importance of managing unexpected manufacturing events because the issue was not detected before patients were exposed to the impacted product. In many cases, manufacturing issues have been detected and investigated before the product was distributed to patients. These successful examples of managing unexpected events are known to individual manufacturers and to regulatory agencies, but are rarely publicized. Some examples that have been published include:
Changes in glycosylation patterns due to altered cell culture conditions [6]
Altered rates of biochemical modifications to the protein backbone after switching raw material supplier [6]
Turbidity in pre-filled syringes due to interaction of metal leachate with the protein product [7]
A hard-to-detect microbial contaminant that managed to evade cell culture medium filtration and testing programmes [8]
Presence of an impurity in the raw material used for a pegylated protein product [9]
Lack of compliance with cGMP (current good manufacturing practices) affects quality and reliable supply
Manufacturing and quality control issues like those just described can potentially impact patient safety and result in a loss of confidence in the quality of biologicals, but they can also impact to other products manufactured in the facility and cause product recalls and drug shortages, any of which can have profound effects on the company, customers, the biotech industry, providers and patients.
Regulatory agencies in the EU and US have recently emphasized the implications of this dynamic [10, 11]. Officials from the US Food and Drug Administration recently published an article describing quality management failures as a factor in sterile injectable drug shortages:
‘… drug shortages are first and foremost driven by the inability of various firms to maintain production because of the failure of quality management in facilities that produce the finished dosage form of the drug …’,
— J Woodcock and M Wosinska, Center for Drug Evaluation and Research for the US Food and Drug Administration [11].
Although FDA authors refer to the relationship of quality management to shortages of sterile injectable drugs, the issues cited are also relevant to the manufacture of biologicals. Biologicals share some of the same quality control issues with sterile injectables in that the final products are filled in facilities subject to similar stringency of control; but biologicals are, if anything, more susceptible to quality issues due to their relatively high sensitivity to multiple manufacturing steps. The rapidly increasing array of innovative biologicals and biosimilars could increase the chances of unexpected quality issues. These risks can be mitigated with investments in process and facility design, quality control systems, and management oversight, all of which can increase manufacturing reliability. While current market forces may not reward investments in quality and reliability, FDA may explore mechanisms to change this dynamic:
‘… FDA could support the buyers and payers in their purchase and reimbursement decisions by providing them with meaningful manufacturing quality metrics. This general approach has been successfully used in many other settings where quality is difficult to observe or quality signals are difficult to interpret. Restaurant grades, HMO scorecards or even a US Pharmacopeia stamp on vitamins are just a few among many tools that utilize this concept …’ [11].
Recognition of high quality operations could also apply to the biologicals industry, and industry can anticipate this with increased investment in quality systems and sharing of best practices among peer manufacturers.
Sharing best practices in manufacturing and quality
The bioprocessing industry currently shares information about manufacturing challenges and product quality risks via congresses and publications. Regulators often contribute to this by sharing anonymous case studies and by encouraging companies to publish novel findings. For example, after learning of a number of examples of unexpected product quality impact from chemicals leaching from primary containers, FDA published a compilation of these case studies along with recommendations for best practices to evaluate such risks [12]. In furtherance of this objective, Amgen published its experience with a tungsten residual during final production that led to rejection of product during visual inspection [13].
To a large extent this type of sharing focuses on phenomenon with an element of scientific novelty, and it is less common for companies to publish manufacturing challenges and investigations that lack such novelty or that could raise legal issues. This void can be partially filled through participation in technical consortia where case studies and best practices can be shared less formally. Such consortia exist. For example, Rx-360 was established in 2009 to share best practices with raw material and component sourcing in an increasingly global supply chain [14]. With regard to competitive concerns, we would draw a clear distinction between best practices that ensure patient safety and other proprietary information that might, for example, speed production, reduce costs and/or improve output.
High reliability organizations offer a model for the industry
Risks to product quality can be managed with focus on traditional GMP compliance and quality management, but manufacturers can also benefit from the practices of high reliability organizations (HROs). HROs invest in and engage well-trained and experienced support staff and advocate for management cultures that reward, ‘… in-depth analysis of unexpected results, robust risk assessments, and timely and effective implementation of mitigation measures’ [6]. HROs exist where high performance is needed despite overwhelming potential for error and disaster. Examples of HROs in other fields include: nuclear power plants, aircraft carriers, emergency rooms, air traffic control stations, first responder protocols, and wilderness firefighters [15]. While regulators increasingly expect biologicals manufacturers to adapt risk management programmes including some of these behaviors, HROs set a standard for integration and prioritization of these practices that, if more widely adapted, could improve the industry’s reliability and reputation – and further protect patients.
In addition to building a high reliability manufacturing culture, organizations can invest in a comprehensive strategy to reduce supply risks. Such a strategy could include multiple components [16, 17]:
Prevention, e.g. compliance with or exceeding cGMP standards
Technology, e.g. ensuring quality of raw materials using latest detection methods
Inventory, e.g. ensuring adequate stock of drug in the event of natural disaster
Diversification, e.g. multiple plants qualified for drug manufacture
In addition, a successful HRO will educate technical support staff to help orient and inform them so they can respond most effectively to unexpected manufacturing issues and incorporate findings into ongoing risk management. Critical background information includes the product’s history, the current manufacturing environment and any analogous situations that may have been encountered within the company or by other manufacturers. The response team should have senior-level support and have access to the external resources they need, e.g. consultants and analyses; and be authorized to examine every component of the manufacturing process, including in-house laboratories and manufacturing facilities and external vendors and suppliers, with the goal of conducting a focused and thorough investigation on the root causes of the unexpected event and identifying corrective actions [6].
Manufacturers that consistently strive to exceed minimum standards, that invest in supply risk mitigation, and that willingly adapt best practices shared by industry peers could benefit from an enhanced reputation as reliable suppliers.
Conclusion
Biosimilars, like all biologicals, are complex medicines produced in living cells and are highly sensitive to their manufacturing and processing conditions. Because of their complexity and sensitivity biologicals are at increased risk of quality issues compared with traditional drugs and generics, and this can affect the efficacy and safety of these treatments. Active participation in industry consortia where best practices can be shared among peers and a corporate focus on reliability of manufacturing can help minimize the risk and impact of unexpected quality issues, to the benefit of patients and companies.
Acknowledgement
Editorial assistance was provided by Mr Alex Brownstein of BioScience Communications, New York, NY, USA, whose work was funded by Amgen Inc.
Competing interests: Dr Gustavo Grampp and Dr Sundar Ramanan are employees of Amgen Inc and own stock in Amgen Inc.
Provenance and peer review: Not commissioned; externally peer reviewed.
Co-author
Sundar Ramanan, PhD, R & D Policy, Amgen Inc, One Amgen Center Drive, Thousand Oaks, CA, USA.
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document/document_detail.jsp?webContentId=WC500135113&mid=WC0b01ac058009a3dc 11. Woodcock J, Wosinska M. Economic and technological drivers of generic sterile injectable drug shortages. Clin Pharmacol Ther. 2013;93(2):170-6. 12. Markovic I. Evaluation of safety and quality impact of extractable and leachable substances in therapeutic biologic protein products: a risk-based perspective. Expert Opin Drug Saf. 2007;6(5):487-91. 13. Jiang Y, Nashed-Samuel Y, Li C, Liu W, Pollastrini J, Mallard D, et al. Tungsten-induced protein aggregation: solution behavior. J Pharm Sci. 2009;98(12):4695-720. 14. Rx-360: an International Pharmaceutical Supply Chain Consortium [homepage on the Internet]. 2013 [cited 2013 Sep 18]. Available from: http://www.rx-360.org/Home/tabid/38/Default.aspx 15. Weick KE, Sutcliffe KM. Managing the unexpected: resilient performance in an age of uncertainty. 2nd ed. San Francisco: Wiley; 2007. 16. Mica A, Green L. Drug availability: considerations for the hospital pharmacist. Eur J Hosp Pharm. 2012;19:160-1. 17. Mica A, et al. Steps to ensure adequate supply of biological medicines: considerations for the healthcare provider. Generics and Biosimilars Initiative Journal (GaBI Journal) 2013;2(3):136-43. doi:10.5639/gabij.2013.0203.038.
Author for correspondence: Gustavo Grampp, PhD, Director, R & D Policy, Amgen Inc, 4000 Nelson Road, MS AC-27-B, Longmont, CO 80503, USA
Disclosure of Conflict of Interest Statement is available upon request.
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Author byline as per print journal: Barbara Milan, Sara Gaspani
Introduction: The current pipeline of promising oral hepatitis C drugs could lead to a revolution in treatment for this disease in both developed and developing countries. At present, the recommended treatment is pegylated interferon alpha (in combination with ribavirin). However, the limited availability and high cost of this medicine is a major barrier to expanding access to treatment in developing countries. Methods: We compiled information on marketed biosimilars and alternative pegylated interferon alpha products and price information on the innovator products in several developing countries. In parallel, we conducted a review of the biosimilars guidance by World Health Organization (WHO) and by selected national drug regulatory agencies. Results: The price of the innovator products ranges from US$200 to US$375 per vial, meaning that a full (48 weeks) treatment course costs US$10,000–US$20,000 per patient in the surveyed countries. So far, only a few countries have carved out exceptions to this high price. By allowing generics competition Egypt lowered the price of the innovator products to around US$40 per week, while Iran used technology transfer to establish local production and ensure availability within its health system. We have indentified six pegylated interferon alphas, which could be evaluated to expand the pool of quality assured products. Conclusion: WHO added pegylated interferon alpha to its Essential Medicines List released in July 2013, but other steps – and more progressive WHO guidance – are needed to ensure more immediate treatment options for patients in developing countries. In particular, WHO should re-examine its 2009 ‘Guidelines on Evaluation of Similar Biotherapeutic Products’ in light of recent international debates about clinical comparative exercises and of accumulated regulatory experience on biosimilars. In parallel, WHO should establish an evaluation scheme of biological drugs to promote product availability and affordability. These considerations also bear on access problems for other essential and lifesaving biological drugs.
Submitted: 12 August 2013; Revised: 21 October 2013; Accepted: 1 November 2013; Published online first: 14 November 2013
Introduction
Hepatitis C virus (HCV) is a growing public health concern. HCV infection affects an estimated 150-180 million people worldwide and kills about 350,000 annually [1, 2]. The disease burden is greatest in developing countries, with the highest reported prevalence in Egypt (22%), Pakistan (4.8%) and China (3.2%) [3]. In 2010, the World Health Assembly (WHA) issued a resolution (the WHA63.18 on viral hepatitis) which, among other actions, urged Member States to provide access to pharmaceutical products and to use national legislative mechanisms that overcome patent barriers for hepatitis C medicines [4].
The current recommended treatment for HCV is pegylated interferon alpha-2a and 2b, a biological product administered by injection once a week, in combination with oral ribavirin [5, 6]. While there has been some skepticism that such a long, injection-requiring treatment is feasible in resource-poor settings, a recent systematic review has documented that treatment with pegylated interferon in low- and middle-income countries is feasible and that outcomes are comparable to those achieved in high income countries [7]. However, the availability and cost of the innovator pegylated interferon alphas are major barriers to access in developing countries, as we will document in this paper.
Since pegylated interferon alpha is, for now, the only effective HCV treatment, in December 2012 Médecins Sans Frontières (MSF) submitted an application for inclusion of this medicine on the WHO Essential Medicines List – a step intended to highlight unmet needs in combatting this epidemic and to trigger policy changes that expand patients’ access to HCV treatment [8]. WHO has included pegylated interferon alpha in the WHO Model List of Essential Medicines released in July 2013 [9], but other steps are needed to secure access to the current recommended treatment – steps that could draw on lessons learned from treatment scale-up in other epidemics, such as HIV [10].
One lesson is that easier-to-use medicines are desperately needed, and these now appear to be on the horizon: over the next few years a promising pipeline of new drugs for hepatitis C should lead to a fully oral treatment [11], which could revolutionize HCV treatment in both developed and developing countries. Another is that, in the interim, expanding access to the current treatment for patients living with the disease is an imperative. A crucial advance towards this goal is that generic versions of pegylated interferon alpha are being developed and/or marketed in several low- and middle-income countries including Cuba, Egypt, India and Iran. However, since competition is blocked in high-income countries by the existence and enforcement of patents [12], none of these products has yet been evaluated by, or gained approval from, a stringent regulatory authority.
This paper summarizes some key findings and approaches in the search for feasible, accessible alternatives to the current out-of-reach price of innovator pegylated interferon alpha in low- and middle-income countries. First, we present our analysis of the landscape of biosimilars regulatory guidance and discuss how the current international guidelines impact access to quality-assured sources of pegylated interferon and potentially to other essential biological drugs. Next, we provide an overview of the market of pegylated interferon alpha products, which could be evaluated for safety and efficacy and then potentially used to expand treatment. We also present price information and analysis on the effectiveness of competition in decreasing prices for innovator medicines and making treatment affordable for patients and their governments. While a comprehensive package of HCV care will also require lowering barriers surrounding diagnostics, laboratory tests and equipment, these issues are beyond the scope of this paper.
Methods
We conducted a review of the biosimilars official guidance documents that have been published by WHO, by stringent regulatory authorities like EMA, FDA, and by drug regulatory authorities in selected middle-income countries. This review also involved retrieving published articles and white papers (from both academic and industry biosimilars experts) on the regulatory pathways and challenges associated with developing and marketing biosimilars. We have limited inclusion of articles and reviewed those which particularly targeted aspects impacting on access to quality-assured biosimilars. In particular, we focused on the need of comparability exercise at the clinical level. This paper is not meant to be an exhaustive review.
In parallel, we compiled information on biosimilars and alternative pegylated interferon alpha products marketed in several developing countries reported in Table 1. The identified pharmaceutical companies authorized the publication of data, which is not included in their product label. In 2012, we sourced price information from official wholesalers/distributors of Roche’s pegylated interferon alpha-2a and Merck’s pegylated interferon alpha-2b in a few selected countries, see Table 2, to provide a snapshot of private sector prices. National currencies were converted into US$ using the exchange rate on the date of data collection. Additional price trend data on the negotiated prices for the two innovator products over time (2006–2011) were obtained directly from the Egyptian Hepatitis C Committee in 2011, see Figure 1, to demonstrate how competition can lead to price decreases for innovator products and impact positively on access to HCV treatment overtime.
Results
Biotechnological drugs and biosimilars: the complexity Biotechnological drugs are large complex molecules and a precise three-dimensional folded structure. They are manufactured by living organisms or cells engineered in highly sophisticated ways, with approximately 90% of all biological products produced from three sources: E. coli, yeast or Chinese Hamster ovary cells [13]. The size and complexity of biological drugs make it almost impossible to manufacture identical replicas, unlike the situation with small molecule drugs, e.g. HIV antiretroviral drugs. Consequently, the scientific community does not define these new products as ‘generic’ versions of innovator ones [14].
However, there is unfortunately no uniform nomenclature; instead, a variety of terms are used inconsistently, leading to confusion and misperceptions that have hindered acceptance of biosimilars among prescribing physicians and patients in high-income countries. In addition to ‘biosimilar’, other terms include ‘similar biotherapeutic product’, ‘follow-on biologic’, ‘similar biological medicinal product’, ‘subsequent entry biologic’, ‘biogeneric’, ‘me-too biologic’, and ‘non-innovator biologic’ [16]. According to the European Medicines Agency (EMA), ‘biosimilar’ is a copy version of an already-approved innovator (reference) product with demonstrated similarity of physicochemical characteristics, efficacy and safety, as determined by a comprehensive comparability study [17]. The same concept of biosimilars is adopted by other entities, although under different terminology – ‘similar biotherapeutic products’ by WHO, ‘follow-on biologics’ in the US (recently switched to ‘biosimilars’) and Japan, and ‘subsequent entry biologics’ in Canada [18]. Biological products that have been structurally and/or functionally altered to achieve an improved or different clinical performance are often referred to as ‘second-generation biologicals’ or even ‘bio-betters’. From a regulatory perspective, the claim of ‘better’ must be substantiated (usually by presenting a full registration dossier) with data showing a clinically relevant advantage over a previous-generation product.
Investments needed to develop biosimilars Developing biosimilar medicinal products requires considerable investment of time and money. The process generally takes about eight years, far longer than the two years typical for developing small molecule generics, see Figure 2.
It is also extremely expensive, requiring a pre-launch investment in the range of US$10–US$140 million for a bacterially-produced biosimilar product such as pegylated interferon alpha, compared to US$1–US$5 million for a small molecule generic drug [15], see Figure 3.
As with other types of medicines, biosimilars can be marketed following the expiry of patents on the innovator product. But that is often precisely the time point when second-generation biological drugs (or bio-betters) are also introduced into the market, and may be preferred due to improved product characteristics such as better stability profiles, less frequent treatment schedules, and/or increased safety. This is exactly what occurred when biosimilar products of non-pegylated interferon alpha were ready to enter the market in Europe, pegylated interferons were launched precisely at the same time and quickly became the first choice for treatment, taking over the market space of biosimilar non-pegylated interferons.
With the requirement for huge financial pre-launch investments usually followed by lucrative business in high-income countries, the biosimilar market has been characterized by partnering between large multinational pharmaceutical companies and other technology giants such as Fuji Film and Samsung [19]. Nevertheless, in low- and middle-income countries, such as Cuba and Iran [20], other business models exist whereby smaller biological drugs producers rely on much lower-scale investment and government-financed technology transfer programmes to meet mainly national treatment demands.
Overview of regulatory guidance on biosimilars The assessment principles used to evaluate biosimilars are more complex than those used for small molecule generics. Due to the complexity of biological drugs, the classical bioequivalence approach used for small molecule pharmaceuticals is not deemed suitable to establish therapeutic equivalence between the biosimilar and the reference (innovator) drug product [21].
EMA: The European Medicines Agency was the first regulatory agency to provide a framework for evaluating biosimilars. Since 2005, it has issued overarching guidelines for biosimilars [22] (undergoing revision [23]), for quality issues relevant to the development of biosimilars [24] (undergoing revision [25]), and for non-clinical and clinical issues [26], (undergoing revision [27]) and immunogenicity [28]. In subsequent years EMA released several product class-specific guidelines as well as draft guidelines or concept papers for product classes, such as human insulin, heparin, somatropin, erythropoietin and monoclonal antibodies [29].
EMA’s comprehensive biosimilar regulatory pathway relies on the principle of comparability exercise at the preclinical and clinical levels, a controversial approach that has triggered a considerable debate. Since 2005, 14 biosimilars of three biological products (somatropin, erythropoietin, and filgrastim) have been approved in the EU [30], several of which were approved with only partial or no direct preclinical and clinical comparison to the corresponding innovator products [31]. Biosimilar producers consider these comparative clinical trials duplicative and responsible for driving up development costs drastically [32]; likewise, some representatives of the scientific community consider preclinical and clinical comparability studies to be ‘surplus’ requirements and have called for them to be dropped [31, 33]. This has a particular relevance considering that additional 75 other products are in development in the European Union [34].
Although EMA reacted strongly to these calls and reiterated the need for comparability exercise at the clinical level [35], the most recent guidance (the 2013 EMA ‘Guideline on non-clinical and clinical development of similar biological medicinal products containing low-molecular-weight-heparins) shows some flexibility on this point [36]. For example, the biosimilars draft guideline [23] appears to challenge the necessity of a full comparability exercise and that the guideline allows some exceptions to this requirement. The guideline states that ‘in specific circumstances, e.g. for structurally more simple biological medicinal products, a comparative clinical efficacy study may not be necessary if similarity of physicochemical characteristics and biological activity/potency of the biosimilar and the reference product can be convincingly shown and similar efficacy and safety can clearly be deduced from these data and comparative pharmacokinetics (PK)
data’ [23].
To facilitate these alternative pathways, i.e. without repetition of clinical trials, EMA created the option of comparing the biosimilar in certain clinical studies and in vivo non-clinical studies (where needed) to an innovator product that was authorized not by EMA but by a regulatory authority with scientific and regulatory standards similar to those of the EMA, i.e. from countries that are members of the International Conference of Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use [23, 37]. Although simple, this change could have profound consequences in terms of easing and shortening the biosimilars approval process. Indeed, trials conducted outside Europe and using other reference products may now be used for EMA filings (unlike in the past, when EMA required repetition of these trials in European patients, using an EMA-approved reference product), thereby leading to significant savings for biosimilar manufacturers [38].
US FDA: In the US, although the Food and Drug Administration (US FDA) pioneered the development and implementation of an abbreviated approval pathway for small molecule generics through the 1984 Hatch-Waxman Act, an abbreviated pathway for licensure of biosimilar products was formally created only in March 2010 [39] under Section 351 of the Public Health Service Act (42 U.S.C. §262) [40].
In February 2012, the US FDA issued three draft documents to guide industry in developing biosimilar products [41–43]. These draft guidelines allow for waivers of preclinical and clinical studies: ‘As a scientific matter, comparative safety and effectiveness data will be necessary to support a demonstration of biosimilarity if there are residual uncertainties about the biosimilarity of the two products based on structural and functional characterization, animal testing, human PK and pharmacodynamics (PD) data, and clinical immunogenicity assessment. A sponsor may provide a scientific justification if it believes that some or all of these comparisons on clinical safety and effectiveness are not necessary’ [41]. However, as underscored by public comments to these documents, the drafts are unclear about which requirements are indispensable for the US FDA and which ones might be discussed on a case-by-case basis [44, 45].
The lack of finalized guidelines discourages biosimilars producers from submitting applications for registration to the US FDA, which has never received a filing for a biosimilars application [46]. US economists estimated that the regulatory approval process will take at least two years, in which case the first biosimilar approved under the new guidance would not enter the US market for at least two years after adoption of US FDA biosimilars guidelines [47].
WHO: In 2009, the World Health Organization published Guidelines on Evaluation of Similar Biotherapeutic Products, defined as a ‘living document’ that should be developed further as scientific knowledge and experience accumulates [48] and that is modelled on the previously published EMA guidelines. Both sets of guidelines advocate a stepwise approach in which licensing a biosimilar depends on demonstrating similarity in terms of quality, non-clinical and clinical parameters, to a reference product (an innovator biological product with the same dosage form and route of administration), that has already been licensed on the basis of a full registration dossier. Under WHO guidelines, the comparability exercise between the biosimilar and the reference product is requested for the quality, non-clinical and clinical parts. If relevant differences between the biosimilar and the reference product are detected at any step, the reasons for these differences must be explored and justified; if this is not possible, a full licensing (stand alone) application should be considered. In a reversal of the usual sequence of events, WHO guidelines on biosimilars actually preceded the WHO draft guidelines on non-clinical and clinical evaluation of the quality, safety and efficacy of biological medicinal products prepared by recombinant DNA technology [49].
Adoption and adaptation of biosimilars/similar biotherapeutic products regulatory guidance in other countries EMA and WHO guidelines have a strong influence on the biosimilars regulatory framework around the world. Some stringent regulatory authorities, such as that in Australia, adopted the European guidelines [50]. Others, including Canada in 2010 [51], and Japan in 2009, issued new guidelines based on the current EMA guidelines. Since the WHO guideline was released in 2009, 11 National Drug Regulatory Agencies (NDRAs) have published their own guidelines for registering biosimilars/similar biotherapeutic products [13], these NDRAs are from Brazil, Iran, Jordan, Malaysia, Mexico, Singapore, Republic of South Korea, Saudi Arabia, South Africa, Turkey [52], and India [53]. There are differences among criteria adopted by different countries [54]. Indeed some NDRAs such as in Brazil, Mexico, South Korea, India and Iran adapted the general WHO guidance to their specific country context, generally with lower barriers in terms of clinical trial requirements [55].
For example, the Brazilian 2010 guidelines foresee two pathways for similar biotherapeutic products approval [56]: the comparative pathway, based on the principles outlined by WHO; and an individual development pathway with a reduced dossier comprising a full package of data on quality but reduced non-clinical and clinical studies [57].
The 2009 South Korea biosimilar guidelines are also flexible: ‘if the comparability can be demonstrated by confirmatory PK/PD data, an efficacy study may be omitted’ [58]. Similarly, the Indian ‘similar biologic’ guidelines published in August 2012 allow waiving of the comparative clinical trial under certain conditions [53]. Likewise, the Iranian NDRA does not require comprehensive new preclinical or clinical data to prove similarity between locally produced biological drugs and innovator products [59].
A number of countries allow yet another approach to defining the reference product, given that the innovator product may have not been (and may never be) registered in a country. For example, Iran allows evaluation of a domestically produced biological drug against a US FDA or EMA approved biosimilar product [52]. In India, if the reference biological drug is not licensed domestically, it is permitted to use a reference product that is licensed in another country with a well-established regulatory framework and that has been widely marketed for at least four years (or less in cases of a national healthcare emergency) [53, 60].
Innovator and alternative pegylated interferon alpha products Pegylated interferon alpha-2b (PEG-Intron, Merck) was registered by EMA in May 2000 [61] and by US FDA in January 2001 [62]. Pegylated interferon alpha-2a (Pegasys, Hoffmann-La Roche) was registered by EMA in June 2002 [63] and by US FDA in October 2002 [64].
PEG-Intron, Merck, pegylated interferon alpha-2b is a covalent conjugate of recombinant alpha-2b interferon (approximate molecular weight [MW] 19,271 daltons) with monomethoxy polyethylene glycol (PEG, MW = 12,000 daltons). The average molecular weight of the PEG-Intron molecule is approximately 31,000 daltons. Interferon alpha-2b is produced by recombinant DNA techniques from the fermentation of an E. coli strain that harbours a genetically engineered plasmid with an interferon gene from human leukocytes [65].
Pegasys, Hoffmann-La Roche, pegylated interferon alpha-2a, is a covalent conjugate of recombinant alpha-2a interferon (approximate MW 20,000 daltons) with a single branched bis-monomethoxy polyethylene glycol (PEG) chain (approximate MW 40,000 daltons). The PEG moiety is linked at a single site to the interferon alpha moiety via a stable amide bond to lysine. Pegylated interferon alpha-2a has an approximate MW of 60,000 daltons. Interferon alpha-2a is produced using an engineered E. coli strain containing a cloned human leukocyte interferon gene [66].
Pegylated interferon alpha products are being developed and marketed in several low- and middle-income countries, including Cuba, Egypt, India and Iran. Table 1 lists the products we identified during our search for alternatives to the innovator products. A few products seem to have been developed as copies of Pegasys, or PEG-Intron in terms of molecular structure and in certain instances also using the same excipients in the same proportions. Other products represent a different size and form of PEG branches and different attachment sites between the PEG moiety and the molecule of interferon alpha-2a or 2b.
Whether or not the innovator products are patented, has in turn, influenced the ways that producers in low- and middle-income countries have approached development of their products. While the total absence of patents on pharmaceuticals in Iran has made it possible to develop and scale up production of a replica of Roche’s pegylated interferon alpha-2a, in India this molecule was under patent. As a result, the Indian ‘similar biologic’ market has focused on replicas of Merck’s pegylated interferon alpha-2b, due to the absence of patents on the molecule. However, a patent on the innovator’s formulation of pegylated interferon alpha-2b drove development in India towards an alternative formulation, in this case with different excipients, to avoid patent infringement.
Some manufacturers have opted to use a host cell other than E. coli. According to the WHO 2009 guidance [48], ‘the host cell type for manufacture of the [biosimilar] should only be changed if the manufacturer can demonstrate convincingly that the structure of the molecule is not affected or that the clinical profile of the product will not change’. Similarly, a change of excipients is permitted under the EMA guidelines provided that this change makes the formulation suitable for stability, compatibility, integrity, and activity and that its potential impact on safety and efficacy is appropriately justified [25]. For example, the Indian company Zydus Cadila has opted to develop pegylated interferon alpha-2b using a different host cell system (Pichia pastoris yeast instead of E. coli) to simplify the process, and to change excipients as a way of circumventing patent protection. Another Indian company, Virchow, has developed a pegylated interferon version that is reportedly similar in profile to PEG-Intron, which has led to litigation with Merck over the use of certain excipients in the formulation [12]; Virchow has also developed alternative formulations with different excipients.
Pricing trends of the originators products and why competition is important In 2012, the range of product prices from the two innovator companies at wholesaler/distributor level range from US$200 to US$375 per vial or pre-filled syringe in Eastern Europe, Central Asia and India, see Table 2. Prices increase further at the level of private retail pharmacies and therefore out of reach to most patients in the private sector. This further confirms previous survey findings [11], with the two innovator companies selling the originator medicines at similar prices in the same countries.
The countries surveyed here have no governmental HCV treatment programme, so treatment is available only within the private sector. Average patient income in these countries does not allow spending the sums needed to buy these medicines, even excluding diagnostic and laboratory monitoring costs.
In 2013, Roche started marketing pegylated interferon alpha-2a in India under the new brand name Exxura and has decreased its price by more than 50% in one year, to US$125/vial. Similarly Merck’s product is now available for roughly the same price. The presence of alternative products, such as those from Virchow and Zydus Cadilla has also led private sector prices to drop over the last year, but still does not make them an affordable treatment option.
Egypt, one of the countries hit hardest by the hepatitis C epidemic, stands as an exception. Since its establishment in 2006, the National Hepatitis C Committee has managed to progressively reduce the price of pegylated interferon alpha and ribavirin combination therapy, see Figure 1. The Egyptian Ministry of Health has succeeded in negotiating progressive price reductions with both Roche and Merck, from US$79 for pegylated interferon alpha alone in 2006 to US$41 for one vial of pegylated interferon plus weekly supply of ribavirin in 2011 – bringing the 48-week treatment cost to about US$2,000 per patient. This decrease was triggered by the introduction in the Egyptian market of an alternative pegylated interferon alpha, which has reduced the country’s dependence on the multinational companies Roche and Merck and created a more competitive environment [67, 68].
Discussion
The two innovator companies of pegylated interferon alpha have been marketing their products at very similar prices in both developed and developing countries. The collected data shown here indicate the very high prices charged by the companies in low- and middle-income countries, and which make these medicines out of reach for the vast majority of patients. The data also show that when alternative drugs are available, for example, in Egypt and India, the innovator companies have lowered the price of their product significantly. It is urgent that Merck and Roche adopt a preferential pricing policy so that HCV treatment can be expanded and scaled up in the public and private sectors in low- and middle-income countries.
Given the crucial role in decreasing prices of biosimilars marketed in developing countries, plus the long lead-times for developing new ones, it is critical that the existing drugs (the additional identified sources of pegylated interferon alpha other than the innovator drugs which have been evaluated by stringent regulatory authorities) are evaluated for safety and efficacy by an independent body such as WHO.
The majority of developing countries have little or no regulatory capacity in the area of biological drugs, nor do non-governmental organizations (NGOs) have the capacity to assess biological drugs (as opposed to small molecule generics) using international standards. Countries and NGOs therefore need to rely on international evaluation frameworks to access safe, quality-assured pegylated interferon, for example, via a WHO pre-qualification system for biological drugs/biosimilars that enables member states to access to safe and effective pegylated interferon alpha and other essential biological medicines. The WHO pre-qualification system for HIV medicines had a huge impact in securing quality-assured generic antiretroviral medicines, to allow for competition in the market space, decrease prices tremendously and therefore to allow scale up of treatment in developing countries [10].
Today, WHO and the regulatory authorities are confronted by the key challenge of comparability exercise at the clinical level, and of how manufacturers can meet this requirement despite a much lower level of investment than in the European biosimilars industry. The compelling but unmet needs for targeted biological drugs in developing markets have fostered local regulatory processes with reduced requirements for comparative clinical trials [53, 56–59, 69]. Biosimilars regulatory guidance should be reviewed in light not only of the scientific and regulatory experience gained over time, but also of the needs and interests of national health systems and pharmaceutical markets in low-resource countries [70]. Stringent regulatory authorities such as EMA have already begun to waive requirements for comparability exercise at clinical level under appropriate circumstances. This approach is supported by academic experts who claim that non-comparative clinical trials are sufficient for regulatory purposes, and who call for pragmatic approaches focused primarily on the patients clinical outcomes and on scientific principles, using the state-of-the-art tools [31, 33, 71].
Conclusion
The current WHO guidelines on similar biotherapeutic products should be reassessed based on accumulated science and experience, and in ways that foster the development and marketing of quality-assured, safe and effective biological drugs. In parallel, a WHO-supported programme for evaluating pegylated interferon alpha products is needed to ensure competition, and consequently affordable prices and sustainable medicines supplies. Without such an evaluation scheme, the addition of pegylated interferon alpha to the essential medicines list will have only limited impact, even in countries where political will and financial resources are present. Preferential pricing policies by the innovator companies are also needed, but they will not be able to satisfy all demands for initiating and scaling up HCV treatment across different countries and organizations. Competition with quality-assured sources of pegylated interferon alpha products is the key to expand access to HCV treatment with pegylated interferons either in combination with ribavirin or with the oral promising antiviral drugs coming onto the market. Therefore, there is a need to support regulatory work in WHO in the biosimilars field both in guidance definition and in product evaluation for essential biological medicines.
Acknowledgements
We gratefully acknowledge Mr Karen Gharagyozyan for the survey of innovator pegylated interferon alpha prices in countries of Eastern Europe and Central Asia, Ms Patricia Kahn for editing of the manuscript, Ms Elena Rosso and Mr Rizwan Ahmed for providing information on the Indian prices of pegylated interferon alpha, Ms Suzette Kox (EGA) for authorization to reproduce Figure 2, Mr Mishra Neelkanth, Mr Aggarwal Anubhan, Mr Walton Jo (Credit Suisse) for authorization to reproduce Figure 3, the pharmaceutical companies that authorized the publication of data beyond the label of their pegylated interferon alpha product and finally the academic and industry experts who provided valuable input into this project.
Disclosure of financial and competing interests: The authors are employed by the Médecins Sans Frontières’ Access Campaign and they declare no conflict of interest. Neither the authors Ms Barbara Milani and Ms Sara Gaspani, nor their organization have received any type of funding, incentives or in-kind payments and donations from pharmaceutical companies or have any vested interest in the use of any particular product belonging to the category of innovator or of off-patent biopharmaceuticals presented in this paper.
Médecins Sans Frontières (MSF) is an international, independent, medical humanitarian organization that delivers emergency aid to people affected by armed conflict, epidemics, natural disasters, and exclusion from healthcare. In 1999, in the wake of MSF being awarded the Nobel Peace Prize, MSF launched the Access Campaign. Its purpose has been to push for access to, and the development of life-saving and life-prolonging medicines, diagnostic tests and vaccines for patients in MSF programmes and beyond.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors are responsible for English language editing of this manuscript.
Co-author
Sara Gaspani, Project Pharmacist, Médecins Sans Frontières, Access Campaign
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Available from: http://fr.slideshare.net/brandsynapse/the-newindiabiosimilarguidelines 61. European Medicines Agency. PEG-Intron authorisation details [homepage on the Internet]. 2013 [cited 2013 Oct 21]. Available from: www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000395/human_med_000974.jsp&mid=WC0b01ac058001d124 62. U.S. Food and Drug Administration. PEG-Intron Label and Approval Information. Drugs@FDA. [homepage on the Internet]. [cited 2013 Oct 21]. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm 63. European Medicines Agency. Pegasys authorisation details [homepage on the Internet]. 2013 [cited 2013 Oct 21]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000395/human_med_000974.jsp&mid=WC0b01ac058001d124 64. U.S. Food and Drug Administration. Pegasys Label and Approval Information. Drugs@FDA. [homepage on the Internet]. [cited 2013 Oct 21]. 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Author for correspondence: Barbara Milani, Pharmaceutical Coordinator, Médecins Sans Frontières, Access Campaign, 78 Rue de Lausanne, PO Box 116, CH-1211 Geneva 21, Switzerland
Disclosure of Conflict of Interest Statement is available upon request.
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Abstract:
As a practicing endocrinologist and Chairman of the Alliance for Safe Biologic Medicines, I am writing to commend the World Health Organization for its attention to and upcoming action on the important issue of non-proprietary names for biotech medicines.
Submitted: 20 September 2013; Revised: 21 September 2013; Accepted: 21 September 2013; Published online first: 27 September 2013
More than 50 years ago, World Health Organization (WHO) established the International Nonproprietary Name (INN) expert group to assign non-proprietary names to medicinal substances so that each could be recognized globally by a unique name. Although initially intended to facilitate prescribing, non-proprietary names have come to play an essential role in tracking and tracing, and attributing adverse events to the right product – an important aspect of ensuring medicine safety once a product is on the market. Distinguishable names are particularly important for biologicals.
WHO has shown thoughtful leadership in facilitating the further development of effective biological identification via a unique and universally available designated name for each pharmaceutical substance. This action is very timely in light of the growing number of biosimilars and non-biocomparables arriving on the market. The urgency of this action is apparent with the first monoclonal antibody biosimilar approved in Europe by the European Commission in September 2013 bearing the identical INN as the innovator product.
The practicality of WHO’s action is evidenced in Australia, where the Therapeutic Goods Administration (TGA) has already acted on WHO’s vision for biological and biosimilar naming conventions. Indeed, TGA’s action demonstrates both the importance and the functionality of distinguishable INNs. Under the new regulation, TGA requires the non-proprietary name to include a biosimilar identifier, consisting of the prefix ‘sim(a)’, and a three-letter code issued by WHO’s INN Programme Committee according to its draft policy. The TGA regulation explains, ‘As small differences between biosimilars can give rise to differences in clinical behaviour, in particular in immunogenic effects, certain additional nomenclature provisions are necessary to ensure that it is possible to distinguish between biosimilars and clearly identify the reference product.’
Since the active substance of biologicals is made by or derived from living organisms and most biologicals are very large molecules, biologicals can be sensitive to very minor changes in the manufacturing process. Unlike chemically based drugs, small differences in the manufacturing process and handling, etc.; can significantly affect the nature of the finished biological and the way it functions in the body. Therefore, no two biologicals made from different cell lines and/or using different manufacturing processes are ever identical to the reference product they aim to replicate and, hence, can have a significant impact in a patient’s body.
Knowing specifically which product, produced by which manufacturer a patient received is essential to keeping medicines and patients safe. If a patient develops an unwanted immune response over time, the doctor and regulators will know exactly which product to evaluate. For that reason, product naming is one of the key elements of biological product safety. In fact, the Alliance for Safe Biologic Medicines (ASBM) conducted a survey of more than 350 specialists who prescribe or treat patients with biologicals. We found that non-proprietary product names are the primary means by which physicians identify products.
The vast majority of physicians (99 per cent) refer to biological medicines by INN and not by the ‘national drug code’ number assigned to each product in the United States – for both recording in charts and for reporting adverse events. If distinct non-proprietary names are not given to products, we cannot appropriately track and trace adverse events nationally and even more so globally and may waste valuable treatment time trying to identify the root cause.
ASBM has worked for nearly three years to support health agencies including the US Food and Drug Administration and WHO, in the mission to safely bring biosimilars to patients. We believe all biological policies must be guided by the recognition that biologicals are scientifically different than traditional chemical drugs and the laws governing their approval and regulation must reflect that scientific reality. ASBM will soon be attending the WHO’s upcoming Consultation on International Nonproprietary Names (INN) for Pharmaceutical Substances meeting in October 2013, to further build on the emerging consensus that distinct names are the only way to keep patients safe.
Funding sources
The Alliance for Safe Biologic Medicines (ASBM) is an organization composed of diverse healthcare groups and individuals – from patients to physicians, innovative medical biotechnology companies and others who are working together to ensure patient safety is at the forefront of the biosimilars policy discussion. The activities of ASBM are funded by its member partners, who contribute to ASBM’s activities, with the primary funding provided by the Steering Committee, funds the ASBM’s efforts. Visit www.SafeBiologics.org for more information.
Disclosure of financial and competing interests: Dr Richard O Dolinar, Chairman of the Alliance for Safe Biologic Medicines (ASBM), is employed by ASBM.
This paper is funded by ASBM and represents the policies of the organization.
Provenance and peer review: Not commissioned; internally peer reviewed.
Author: Richard O Dolinar, MD, Chairman, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Biosimilar monoclonal antibodies (mAbs) are making their way onto the drug market. Because these are complex molecules in terms of structure and function, assessing similarity between originator and biosimilar mAb is challenging. This review discusses the hallmarks of similarity testing between originator products and mAb biosimilars in terms of product quality attributes, non-clinical and clinical studies, with a focus on immunogenicity. Sparse data on immunogenicity of biosimilar mAb products is given.
Submitted: 5 July 2013; Revised: 5 September 2013; Accepted: 6 September 2013; Published online first: 20 September 2013
Introduction
The upsurge of antibody-induced pure red cell aplasia during erythropoetin alpha treatment more than a decade ago triggered the awareness that immunogenicity of therapeutic proteins can be a serious health risk [1]. Since then, multiple reports have shown that antibodies formed against therapeutic proteins such as factor VIII, interferon beta, and monoclonal antibodies (mAbs) can change pharmacokinetics, lower efficacy, and can lead to hypersensitivity reactions [2–5]. In fact, current belief is that all biotech-derived products can be immunogenic [6]. Therefore, appropriate immunogenicity testing is required for authorization of new therapeutic proteins on the US and EU drug market by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) respectively.
Since the development of so-called biosimilar products, the discussion on immunogenicity has intensified. Biosimilars are protein equivalents of generic chemical drugs that come onto the market after patent expiration of an originator therapeutic protein. However, the size and complexity of proteins make it virtually impossible to produce an exact copy of an originator product, hence the name ‘similar’. A major concern with biosimilars is that small (undetectable) differences compared with originator products might lead to unexpected immunogenicity in patients [7].
Up to now 16 biosimilars have been approved by EMA, including erythropoietin, growth hormone and granulocyte colony-stimulating factor products [8]. With the exception of a report on unexpected immunogenicity of the biosimilar erythropoietin alpha HX575 [9], these products seem to be of equal or perhaps better quality compared with the originator products [10].
Unfortunately, there is very limited clinical data on the immunogenicity of mAb biosimilars, since they have not yet entered the EU or US drug market.
Monoclonal antibodies are often considered a separate class of therapeutic proteins because of their increased complexity in structure and function compared to non-mAb proteins. Analysis of mAbs, including their physicochemical characterization, in vitro functioning, in vivo safety and immunogenicity, is therefore challenging. Several researchers have indicated that similarity testing between originator mAbs and biosimilar mAbs is more difficult than similarity testing between non-mAb originator and biosimilar products [11, 12]. EMA and FDA have acknowledged the difficulty in assessing similarity between mAb products, and in 2012 EMA published specific guidelines for similarity and immunogenicity testing of biosimilar mAbs [13, 14]. This difficulty in assessing similarity fuelled the discussion on immunogenicity, but now with a focus on mAb biosimilars. Again a major concern is whether small (undetectable) differences between originator mAb and biosimilar mAb might lead to unexpected immunogenicity in patients.
This review discusses similarity assessment between biosimilar mAbs and their originator products in terms of (i) product quality attributes; (ii) non-clinical, and (iii) clinical studies, with a focus on immunogenicity. It ends with a summary of the sparse clinical data on immunogenicity of mAb biosimilars.
How to assess similarity – quality attributes
Monoclonal antibodies are very big molecules with complex structures and functions that partly rely on their production processes. Detailed information on the production processes of originator products is not publically available, and production technologies are improving. Therefore, companies developing a biosimilar mAb will use distinct production conditions compared with the conditions used to produce the originator mAb. Differences in expression system, culture conditions, purification processes and primary packaging can evoke distinct product quality attributes such as differences in structure, post-translational modifications, biological activity and stability of the protein [15, 16]. As such, biosimilar mAb products should be tested for similarity of product quality attributes compared with the originator product before continuing with in vitro and in vivo comparability exercises.
First, a full physicochemical characterization of the mAb biosimilar is performed [17], and subsequently its characteristics are compared with the originator product. This last comparison is proof of biosimilarity at the quality level. Without going into detail on the exact methodology, it is important to mention that multiple orthogonal methods are used to study and compare the physicochemical characteristics of the mAbs. These characteristics include primary (amino acid) sequence, protein folding, truncations, post-translational modifications (glycosylation), the amount of mAb protein, the presence of degradation products and presence of aggregates [18–20]. The suitability of different excipients and primary packaging (vials, for example) will be tested, and the presence of host-cell impurities will be determined.
Regarding immunogenicity, several product quality attributes have been shown to be of importance [21]. First, the primary sequence can have an effect on immunogenicity. When the human immune system is exposed to a non-human protein, the protein will be recognized as foreign, and will induce an adaptive immune response. Early mAbs were of murine origin and caused an antibody response that greatly decreased their efficacy, most likely due to their foreignness [22]. After the development of recombinant DNA techniques, chimeric, humanized and fully human mAbs have been brought onto the market. Indeed, these mAbs are thought to be less immunogenic [23], however, it has been shown that even fully human mAbs such as adalimumab can be immunogenic [24].
The second quality attribute shown to affect immunogenicity of therapeutic proteins, including mAbs, is aggregation. [25–29]. Interestingly, not all aggregates are immunogenic, but rather a specific subset is. However, there is only limited data on the exact types of aggregates that are triggering immunogenicity, and on the amounts of aggregates needed to induce anti-drug antibodies. So, for now the aim is to lower aggregate content in the finalized product to a minimum. Why aggregates can induce immunogenicity is not exactly known, one hypothesis suggests that uptake of aggregates by antigen presenting cells and subsequent activation of the immune system is more efficient compared with uptake and activation of the immune system by protein monomers [30], while another hypothesis suggests that aggregates might mimic the structure of microorganisms [31].
Another quality attribute associated with immunogenicity of therapeutic proteins is host-cell impurities. Purification processes may be insufficient to completely eliminate impurities such as DNA, host-cell proteins, or endotoxins from the final product. As a result, therapeutic proteins might contain low levels of host-cell impurities. A study performed at FDA has shown that trace levels of lipopolysaccharide from E. coli and DNA impurities containing CpG motifs can activate the immune system and therefore increase immunogenicity of therapeutic proteins in mice [32].
Additionally, post-translational modifications such as glycosylation can have a significant impact on immunogenicity. Glycosylation is a common post-translational modification that can affect physicochemical properties of the protein such as solubility, folding, stability and biological activity. Glycosylation is species dependent, and is influenced by the cell line and culture conditions used during production processes [33]. Glycosylation of cetuximab is a well-known example of how glycan structures can affect immunogenicity. Cetuximab is a chimeric mouse–human IgG1 mAb used to treat colorectal cancer and squamous cell carcinoma of the head and neck, and contains galactose-a-1,3-galactose (a-Gal). This glycan can induce IgE responses within minutes of first exposure to cetuximab, leading to severe hypersensitivity reactions [34, 35]. a-Gal is not endogenously expressed by humans, but the cell line used to produce cetuximab (the murine Sp2/0 cell line) does give rise to this type of glycan. Possibilities to prevent a-Gal glycosylation are genetically modifying the gene encoding for a 1,3-galactosyltransferese, the enzyme involved in the synthesis of a-Gal in the Sp2/0 cell line, or changing to another expression system [21].
Last, the presence of metal and glass particles in the final product can cause immunogenicity. Spiking glass and metal particles into low immunogenic therapeutic proteins such as growth hormone and interferon beta has been shown to increase immunogenicity in mice [36, 37]. Additionally a clinical study showed that low amounts of tungsten present in the syringes of an erythropoietin biosimilar caused denaturation and aggregation of the protein and increased the incidence of immunogenicity [38].
Similarity – non-clinical studies
After determining similarity in product quality attributes between the originator and biosimilar mAb, subsequent preclinical in vitro and in vivo similarity assessment takes place. These tests are designed to optimally investigate and compare the complex biological activity of the multiple domains of the mAb and its biosimilar. These domains are the Fab region, which includes the variable domains, and which is involved in target interaction, and the Fc region, which is involved in antibody dependent cell mediated cytotoxicity and in complement dependent cytotoxicity. The Fc region, but sometimes also the Fab region, is glycosylated, and the type and size of glycan is important in effector function [39].
The EMA guideline on similar biological medicinal products containing monoclonal antibodies includes crucial steps in similarity testing—non-clinical and clinical issues are summarized below [14].
The first step describes in vitro testing. The guideline states that ‘because in vitro assays may be more specific and sensitive than studies in animals, these assays can be considered paramount in the non-clinical comparability exercise’. Comparative in vitro studies are thus considered very important, if not the most important when assessing preclinical similarity in biological functioning. In these tests, the originator and biosimilar mAb should show similar: (i) binding to target antigen(s); (ii) binding to representative isoforms of the three Fc gamma receptors; (iii) Fab-associated functions, e.g. neutralization of a soluble ligand, receptor activation or blockade; and (iv) Fc-associated functions, e.g. antibody dependent cell mediated cytotoxicity, complement dependent cytotoxicity and complement activation.
Importantly, the studies should be designed to detect minute differences between the biosimilar and in the original product in the relationship between protein concentration and biological activity, and should not just assess the response per se. Also, multiple batches should be included in similarity testing.
The second step describes the need for animal studies [14]. Important considerations when deciding if animal studies are necessary for similarity assessment are the presence of: (i) relevant quality attributes in the mAb biosimilar that have not been detected in the originator product, such as differences in post-translational modification; (ii) significantly different numbers of quality attributes than those present in the originator product; and (iii) relevant differences in formulation, e.g. use of excipients that are not commonly used for mAbs. If no concerns are identified, in vivo animal studies could be unnecessary, especially because suitable animal models are often unavailable. However, if concerns are identified, additional animal studies on pharmacokinetics, pharmacodynamics and/or safety might be necessary [14].
Nevertheless, in vivo similarity assessment between mAb originator and biosimilar in terms of pharmacokinetics, pharmacodynamics and safety (including immunogenicity) is often tested first in clinical studies. The following section describes how immunogenicity testing and comparison takes place during these clinical studies.
Similarity – clinical studies
There are multiple patient and treatment-related factors that can affect immunogenicity of therapeutic proteins during clinical studies [40]. These include the disease state of the patients, genetic factors, age, concomitant medication, duration and route of administration, and previous exposure to similar proteins. Additionally, the sampling schedule and the assay used to detect antibodies will influence immunogenicity assessment [40, 41]. Therefore, before starting a clinical study measuring immunogenicity, all these factors need to be taken into account, and an optimal study design should be chosen depending on the product.
Concerning immunogenicity testing of mAb, and their biosimilars, in particular, several critical factors should be considered in the EMA guidelines on (1) immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use, and (2) similar biological medicinal products containing monoclonal antibodies–non-clinical and clinical issues [13, 14].
First, well-validated assays to detect anti-drug antibodies should be in place, and these tests should be the same for the mAb biosimilar and originator product. Assays used to detect antibodies against mAb can be technically challenging. Often, conventional ELISAs and radio-immunoprecipitation assays involve the use of anti-immunoglobulin reagents to detect antibodies bound to the drug. However, in the case of anti-mAb antibody assays, these anti-immunoglobulin reagents will not only bind to the antibodies bound to the drug, but also the drug itself [42]. As a result, different assay approaches should be developed for mAbs. These can include the bridging format ELISA, electrochemiluminescence-based detection of anti-drug antibodies, or surface plasmon resonance-based assays. For these assays, the matrix interference due to serum or plasma components, interference due to the presence of the mAb, sensitivity and specificity should be assessed. If antibodies are detected, it is expected that the neutralizing capacity of the antibodies will be tested. The guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use suggests that competitive ligand binding assays may be the choice of assay [13].
Second, the best population to study immunogenicity should be chosen. That means that immunogenicity might be tested during a population pharmacokinetics study, in which sparse sampling and determination of drug concentration together with anti-drug antibody detection is acceptable. However, for some mAb, immunogenicity can be better detected in healthy volunteers, who develop a strong immune response after a single dose within a few days [14].
Third, the dose of the originator and biosimilar mAb used during clinical studies should be optimal for antibody assessment. The EMA guideline on similar biological medicinal products containing monoclonal antibodies—non-clinical and clinical issues states that ‘some mAbs inhibit antibody formation when administered at high doses, and therefore studies conducted with low doses can be more sensitive to compare immunogenicity of the mAb biosimilar and original product’ [14].
The guidelines also stress that studies on immunogenicity are of particular importance when a different expression system is used to produce the biosimilar mAb compared with the originator product. Differences in post-translational modifications like glycosylation, could affect biological activity and immunogenicity. Therefore, they describe that ‘In some instances, IgE testing prior to clinical administration needs to be considered for patients if the mAb contains non-human carbohydrate structures, e.g. a-Gal, in order to prevent severe anaphylaxis’ [13].
An important consideration in developing biosimilar mAbs is that products with lower immunogenicity than the original products would not be excluded for market approval. However, higher immunogenicity than the originator mAb would question biosimilarity between the two products.
Furthermore, if the incidence of immunogenicity is expected to be rare and thus unlikely to be measured before market approval, an additional post-marketing study designed to detect subtle differences in immunogenicity may be requested.
MAb biosimilar products under development
It is expected that eight mAb products will encounter patent expiration in the EU and US before 2020, see Table 1 [43, 44], opening the drug market for the development of biosimilar mAb products. Until now (August 2013), mAb biosimilars have not yet entered the EU or US markets, however, two products have received recommended approval from EMA’s Committee for Medicinal Products for Human Use (CHMP). Between 2003 and 2011, about 40% of all requests for scientific advice EMA received were for biosimilar mAbs [45], indicating the extensive interest in developing these products. This is not surprising as the monoclonal antibody products on the market are very profitable and can generate huge revenues. For example, global sales of Infliximab (Johnson & Johnson) are estimated at US$6.1 billion, and those of adalimumab (Abbott) are estimated at US$9.3 billion [45]. Because of the high number of biosimilar mAbs under development, only those with ongoing market approval, with ongoing clinical trials (clinicaltrials.gov), or with publically accessible clinical data are discussed.
Infliximab Infliximab is a chimeric human–mouse antitumour necrosis factor alpha monoclonal antibody used for the treatment of autoimmune diseases such as rheumatoid arthritis, Crohn’s disease and ankylosing spondylitis. It is expected that the EU patent of Infliximab will expire in 2014, followed by the US patent in 2018, see Table 1.
In July 2012, the Korean FDA approved an Infliximab biosimilar (Remsima) for the Korean market, and in June 2013 two biosimilar Infliximab products (Remsima and Inflectra) received recommended approval from EMA’s CHMP for the EU market [46].
There are two clinical studies published on Remsima that could give an indication on the immunogenicity risk of this product. A phase III study by Yoo et al. performed in patients with active rheumatoid arthritis showed that besides similar efficacy and general safety, immunogenicity incidences are also similar between the originator and biosimilar product. For both products, an incidence of antibody positive patients of ~25% was found after 14 weeks of treatment and ~50% at 30 weeks of treatment [47]. The authors mention that the effect of antibody formation on treatment efficacy was tested, but they do not clearly show these results. Nevertheless, no significant difference in response was found between Infliximab and the biosimilar mAb. A phase I study by Park et al. in patients with active ankylosing spondylitis showed antibody incidences of 9.1% in patients treated with the Infliximab biosimilar and 11.0% in Infliximab treated patients at week 14. At week 30, patients treated with the Infliximab biosimilar displayed antibody incidences of 27.4%, and 22.5% of the patients treated with Infliximab were antibody positive [48]. In this study the authors do not report on the use of a bioassay (or similar) to check the antibodies for neutralizing activity, however, post hoc analysis revealed that antibody positive patients had a less robust response to the drug. No significant differences were found between the Infliximab biosimilar and Infliximab.
Etanercept Etanercept is a fusion protein consisting of a portion of the human tumour necrosis factor receptor linked to the Fc portion of human IgG1, and is used to treat inflammatory conditions. It is expected that in 2015 the EU patent for etanercept will expire, and the US patents are expected to expire in 2013 and 2023, depending on the formulation, see Table 1.
Gu et al. have performed a study in which they showed comparable tolerability and pharmacokinetics in 19 healthy Korean men between etanercept and its biosimilar [49], however, no immunogenicity data has been published for this study. A similar study by Yi (2012) in 37 healthy volunteers also showed comparable tolerability and pharmacokinetics between etanercept and its biosimilar (HD203) [50]. It is unclear from these reports if the same biosimilar product was used.
Trastuzumab Trastuzumab is a humanized mAb that interferes with the HER2/neu receptor, and is used to treat HER2 positive cancers, including HER2 breast cancer. Celltron, the Korea-based biosimilar company that launched the Infliximab biosimilar Remsima on the Korean market, is also pursuing the market approval of a trastuzumab biosimilar. On 6 June 2013, they applied for approval at the Korean Ministry of Food and Drug Safety (MFDS, formerly the Korea Food and Drug Administration). Clinical comparison trials have been executed for approval, however detailed data on immunogenicity are not yet publically available. In addition, Synthon has a global licensing agreement with Amgen and Watson Pharmaceuticals for the development of a biosimilar trastuzumab. A clinical phase I trial shows bioequivalence between Synthon’s trastuzumab biosimilar and the originator product, and they are now starting a phase III study with this biosimilar.
Rituximab Rituximab is a humanized mAb used to treat CD20-positive non-Hodgkins lymphoma, chronic lymphocytic leukaemia and rheumatoid arthritis, see Table 1. Sandoz, Celltron and Biocad have ongoing clinical trials for similarity testing of their rituximab biosimilars (clinicaltrials.gov; search ‘biosimilar’). Sandoz is starting a phase III trial to compare the efficacy, safety and pharmacokinetics of their rituximab biosimilar (GP2013) to rituximab in patients with advanced stage follicular lymphoma (identifier: NCT01419665). Celltrion has an ongoing phase I study designed to demonstrate comparable pharmacokinetics between their biosimilar (CT-P10) and rituximab in patients with active rheumatoid arthritis (identifier: NCT01534884). In addition, Celltrion is starting a phase I study to provide initial evidence of safety, pharmacokinetics, pharmacodynamics, and efficacy of their rituximab biosimilar in patients with diffuse large B-cell lymphoma (CT-P10; identifier: NCT01534949). Lastly, Biocad is starting a phase III trial to prove that efficacy, safety and immunogenicity of their rituximab biosimilar (BCD-020) is equivalent to rituximab in patients with rheumatoid arthritis (identifier: NCT01759030). Unfortunately, no information on the outcome of these trials is available yet.
Conclusion
Immunogenicity is a major concern when developing biosimilar mAb. Despite the limited clinical data currently available, first reports show similar immunogenicity between infliximab and infliximab biosimilars. Although these data are encouraging, post-marketing surveillance of these products, and additional clinical studies, will be needed to obtain a good overview on immunogenicity of biosimilar mAb.
Disclosure of financial and competing interests: Dr Vera Brinks has received a grant from the Dutch Technology Foundation ‘STW’, grant number 11196, and has worked on projects that involve funding from Biogen Idec, Genzyme, Merck Serono, Sandoz, Shire and Vifor Pharma.
This manuscript received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Provenance and peer review: Commissioned, externally peer reviewed.
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Author: Vera Brinks, MSc, PhD, Utrecht University, Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, 99 Universiteitsweg, NL-3584 CG Utrecht, The Netherlands
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