The second issue of the 2018 GaBI Journal volume is being published at a time of increasing uncertainty concerning trade, tariffs, regulations as well as international and even inter-ally co-operation. This issue contains manuscripts discussing some changes which are either being asked for, or which are already occurring, with the potential to increase the global development and use of generics and biosimilars.
The first Commentary in this issue entitled ‘Potential changes to the FDA approach to biosimilars have a global impact’ by Professor Pekka Kurki, This discusses the changes proposed in an article by Adjunct Professor Sarfaraz K Niazi, near the end of this issue, see page 84, to how the US Food and Drug Administration (FDA) regulates biosimilar products. Professor Niazi’s proposals are consistent with the anti-regulatory political rhetoric and administrative actions that are both becoming increasingly common in the US. And while certainly worthy of consideration they must be judged, as Professor Kurki points out, on how well they fit with FDA’s need ‘to balance innovation and safety with competition and availability. Professor Kurki provides important information about FDA’s plans to ‘revise its approach to biosimilars’. Readers are encouraged to evaluate and compare Professors Kurki and Niazi’s comments; including which measures are most likely to be successful in encouraging and accelerating biosimilar drug development; including how to deal with the anticompetitive strategies used by reference product manufacturers. Personally I would like to see more evidence-based evaluation of methods used to increase practitioners’ understanding and acknowledgement of the risks and benefits of biosimilar products. As Professor Kurki points out, while regulators must always make scientific judgements of the benefits and risks of new products based on incomplete knowledge of the true risks, the uncertainties at the time of licensing of a biosimilar are much smaller than they are when a new active substance is being considered. Effective methods must be developed to educate practitioners, their professional organizations, patients and patient interest groups about the extensive, and generally very positive experience in real-world use of biosimilars. Ways must be found to minimize if not negate any unscientific, unjustified anti- or pro-biosimilar opinions generated in practitioners or patients by individuals or groups with interests which conflict with what is medically and scientifically best for patients.
One very positive change is the use of patient-reported outcomes (PROs) to assess follow-on products, generics or biosimilars. In an Original Research Perez-Nieves et al. analyse PROs reported in two previously published, randomized studies of a biosimilar and originator insulin products in the treatment of diabetes patients. The authors found no statistically significant differences in a number of PROs in these two (52 and 24 week) studies by these T1DM and T2DM patients. Studies such as this may, as the authors’ claim, ‘help build the confidence of patients and their healthcare providers alike in use of biosimilar insulins and inform their decisions regarding treatment options for basal insulin therapy’. An important unanswered question is whether/how much the results will increase confidence in and prescribing of such products by treating physicians. The authors/study designers should consider asking treating physicians whether their confidence/willingness to prescribe was changed by their participation. It would also be interesting to know whether non-participating physicians’ opinions are changed in any way after reading or being presented with the study results. Such a study should be relatively easy to do and would be of interest to our readers as well as to the studies‘ sponsors.
Relevant analytical techniques are also evolving as illustrated in a Review Article by Professor Roy Jefferis in which he describes how high-resolution analytical techniques can demonstrate structural micro-heterogeneity within endogenous proteins. The importance of this is that not all micro-particles are ‘seen’ as ‘self’ by the immune system. This is needed to establish immunological tolerance. This has potentially important implications for in vitro comparability studies. It also has implications for safety assessments of biologicals since an individual’s immunological response to such micro-particles is genetically influenced. Professor Jefferis notes that the ‘extensive polymorphisms within and between outbred human populations suggests that any given protein biotherapeutic may be allogenic, and potentially immunogenic, when administered across different population groups’. He postulates that all recombinant biologicals, ‘may be immunogenic, at least in a proportion of patients’, especially in patients treated chronically rather than just acutely with these products or those given products which differ structurally from endogenous proteins. He hypothesizes that gene sequencing techniques could allow for the identification of ‘susceptibility genes’ which could be used to stratify and select patients for treatment and points out that such stratification has major economic implications. Stratification has already identified increasingly small cohorts of patients for a number of diseases including cancer. This has already resulted in increasingly costly development and utilization of personalized therapies and unfortunately to date biosimilars have had relatively little impact on the cost of biological treatments. As pointed out by the author, ‘The conflict between our ability to deliver ever expanding therapies for human healthcare, from conception to death, and to provide equity in delivery will continue and become ever more contentious’.
The disconnect between potential and actual savings from the use of biosimilars is highlighted in a Perspective by Simoens et al. entitled ‘How to realize the potential of off-patent biologicals and biosimilars in Europe? Guidance to policymakers’. This manuscript attempts to offer guidance to policymakers on methods likely to successfully foster, ‘a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe’. The manuscript, which, ‘was commissioned by the Belgian National Institute for Health and Disability Insurance’ is the result of a series of roundtable discussions held in 2016–2017 between various stakeholders. It contains a wide variety of demand- and supply-side as well as gainsharing proposals, including suggestions concerning procurement, reimbursement, choice, switches, incentives and evidence. The authors propose that if implemented, the suggestions could do much to establish, ‘a long-term, multi-stakeholder, specific policy framework for off-patent biologicals and biosimilars’ and ‘a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe’.
One obstacle to maximizing the impact of biosimilars is the lack of standardized approaches to their regulation. A Regulatory article entitled ‘Regulation of copy biologicals in China’ describes how the Chinese Drug Registration Regulation (2007) pathway (and its later versions) classifies therapeutic biologicals and the principles and challenges of the copy biologicals guideline’. As noted in an Editor’s comment, the ‘copy biologicals’ approved in China might not have been authorized following as strict a regulatory process as is required for approval of biosimilars in the European Union’. The lack of standardization and its implications have been mentioned in many prior GaBI publications and is the justification for describing, where available, country specific process descriptions, such as the subsequent article, ‘Biosimilar regulation and approval in Jordan’ by Ms Rana Musa Ali Al-ali “Malkawi” (Head of Clinical Studies Department, Jordan Food and Drug Administration) and colleagues.
GaBI has conducted a number of stakeholder meetings designed to improve understanding and standardization of best practice regulation of generics and biosimilars. The Meeting Report, ‘Quality assessment of biosimilars in Colombia – reducing knowledge gaps’ by Drs Elaine Gray, Paul Matejtschuk and Robin Thorpe (Deputy Editor-in-Chief of GaBI Journal) summarizes two such meetings. The first was an educational workshop held in 2016 to discuss evaluation of biosimilars and the second was a scientific meeting on quality assessment held in 2017. Both meetings were held in Bogota, Colombia provided a forum to exchange knowledge on best practices.
The Opinion entitled ‘Rationalizing FDA guidance on biosimilars—expediting approvals and acceptance’ by Professor Niazi which follows was the subject of the Commentary by Professor Kurki discussed above. Professor Niazi lists a number of specific proposals for how FDA could expedite biosimilar approval and use. The suggestions are clearly worthy of serious consideration. However, it should be noted that the author has a number of potential/real conflicts of interest mentioned in the competing interests paragraph of the article. Examples include his association with Karyo Biologics, LLC and Adello Biologics ‘which have several products at various stages of FDA approval’ and his consulting and publication activities. Conflicts of interest are both common and not necessarily problematic. I have my own both as GaBI Journal editor and in some of my other academic and commercial activities. Experts are often ‘conflicted’. It is only problematic when authors omit them from their conflict statements.
The final Abstracted Scientific Content entitled ‘A call for coherence in EU legislation to promote generics’ summarizes a recent proposal for improved biosimilar legislation published in the Journal of Pharmaceutical Policy and Practice. The major action proposed is the use of exclusivity waivers to improve biosimilar access. The authors point out that data exclusivity waivers are already in existence in some non-EU countries including Chile, Colombia, Guatemala and Malaysia and that EU governments have the right to also grant compulsory licences. The authors propose that such waivers should also be considered in the EU and that the lack of legal coherence within the EU prevents generic medicines from being able to more easily enter the market early.
While not all positive, change is clearly ‘in the air’ globally. As Yogi Berra said, ‘it is difficult to make predictions, especially about the future’. Hopefully some of the changes being made will improve the access for more patients to effective, affordable Generic and Biosimilar treatments.
Professor Philip D Walson, MD
Editor-in-Chief, GaBI Journal
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: Rana Musa Ali Al-ali “Malkawi”, MSc; Wesal Salem Al Haqaish, BPharm; Hayel Obeidat, MD
Abstract: The regulatory oversight of medicinal products in Jordan is the responsibility of the Jordan Food and Drug Administration (JFDA). In 2015, JFDA adopted biosimilar guidelines, which are similar to those used by the European Medicines Agency. This paper outlines the current requirements for approval and use of biosimilars laid out by JFDA.
Submitted: 16 May 2018; Revised: 4 July 2018; Accepted: 5 July 2018; Published online first: 18 July 2018
Introduction
In Jordan, the Jordan Food and Drug Administration (JFDA) is the sole national authority that oversees drug safety and efficacy, and food safety and quality. JFDA strives to achieve both regional and international excellence in the control of food, drugs and related products. To ensure the safety and quality of food and its suitability for human consumption, together with the efficacy, quality and safety of medicine and related products, JFDA applies regulatory legislation based on scientific foundations and recognized global standards. It also has strong collaborations and cooperates with international partners and legislative bodies to ensure international standards are upheld. To help ensure a high level of health care and accessibility to it, JFDA is in charge of setting and implementing legislation, monitoring and surveillance, and raising public awareness.
As part of JFDA, the Drug Directorate is responsible for medicines and their registration in Jordan. This is the only official body responsible for medicines throughout their life cycle, starting from active pharmaceutical ingredients and going through all developmental phases and trials until medicines are ready to be used by patients as finished products. The Drug Directorate is keen to provide both innovative and generic medicines within a reasonable period of time, after ensuring their safety, quality and efficacy.
Biopharmaceutical regulation in Jordan: a history
JFDA was founded in 2003. In 2004, JFDA issued criteria for registration and re-registration of all drugs. In 2009, it was decreed by the higher committee of drug and pharmacy at JFDA that all drug applications submitted to JFDA must follow the International Council for Harmonisation’s Common Technical Document (ICH CTD) format [1, 2], the CTD file is organized into five modules. Module 1 is region specific and an administrative module with country specific requirements; and Modules 2, 3, 4 and 5 are intended to be common for all regions and are the CTD internationally required modules.
In 2013, JFDA issued draft guidance on biosimilar registration in Jordan. This was in response to the rising use and concerns over biosimilar drugs following the expiration of some major originator drug patents, and the emergence of biosimilars in European and international markets. Following its release for comments and review by all concerned parties and stakeholders, the guidance was finally published as the official guideline for biosimilar registration in Jordan on 5 May 2015 [3], and JFDA defined biosimilarity according to its own guidelines [3]. Nonetheless, JFDA evaluators relied on the published guidelines from the European Medicines Agency (EMA) [4] to evaluate biosimilars applications submitted during the period of 2009 to 2015.
At the time that JFDA developed its guidelines on biosimilar registration, EMA had the most well-developed regulatory framework for biosimilars [4]. This consists of general guidelines applicable to all biosimilars as well as specific guidelines, which set the basis for defining the registration requirements for biosimilars. As such, JFDA biosimilars registration guidelines are an adapted version of EMA biosimilar approach and any updates to the current EMA biosimilar guidelines are subsequently adopted by JFDA. In addition, JFDA reserves the right to request any additional information or material, or define specific conditions in order to ensure the safety, efficacy and quality of biosimilars.
Biosimilars under the JFDA registration guidelines
JFDA definition of a biosimilar JFDA defines a biosimilar as a biological medicinal product that is similar to the Reference Biological Product (RBP) in terms of quality, safety and efficacy, and contains a version of the active substance that is similar, in molecular and biological terms, to the active substance of the RBP [3]. On the other hand, according to JFDA, the RBP is the innovator biological medicinal product either already approved/registered in the reference countries in the EU (via the centralized procedure), Australia, Canada, Japan, the US, and/or Jordan. This product should be registered on the basis of a complete dossier (full quality, safety and efficacy).
The definition of a biosimilar sets the road map for the requirements to be submitted within the five modules of the application, of which the most important requirement is the comparability exercise. The comparability exercise must demonstrate proof of similarity in terms of quality, safety and efficacy between the RBP and the biosimilar product. Also, it is an additional element to the requirements of the quality dossier and should be dealt with separately when presenting the data. The comparability exercise is a stepwise development process that compares the physicochemical, biological and clinical aspects of the biosimilar and the RBP.
The purposes of the JFDA biosimilar registration guidelines are to:
Provide assistance to applicants (industry) on how to comply with the regulations
Introduce the concept of biosimilars
Provide a baseline of scientific comparison between the biosimilar and the RBP (the comparability requirements) with regards to quality, safety and efficacy
Identify the level of clinical data needed to evaluate and approve the biosimilar
Focus on the quality assessment of the biosimilar, with a head-to-head comparison RBP with full characterization of quality parameters using state-of-the-art techniques and analytical methods or procedures
Focus on marketing safety studies to monitor any potential differences in safety including immunogenicity between the biosimilar and the RBP that become apparent after a biosimilar enters the market
Specify details to ensure traceability with regards to pharmacovigilance for biosimilars
JFDA biosimilars pharmacovigilance plan and risk management plan [3] JFDA guidelines for biosimilars also emphasizes the need for a pharmacovigilance (PV) plan and a risk management plan (RMP) for biosimilar products at the time of submission.
The PV plan should be designed to monitor and detect both known inherent safety concerns and potentially unknown safety problems that may have resulted from the impurity profiles of a biosimilar, or may have been undetected in pre-market testing or otherwise not expected.
Any post-marketing RMP should include detailed information on a systematic testing plan for monitoring immunogenicity of the biosimilar post-marketing, and to take into account identified and potential risks associated with the use of the reference product and, if applicable, additional potential risks identified during the development programme of the biosimilar and should detail how these issues will be addressed in post-marketing follow-up [3]. There is special focus on the post-marketing safety studies in order to monitor any potential differences in the safety and efficacy between the biosimilar and the RBP that becomes apparent once the biosimilar has entered the market, Here, details must be specified to ensure traceability of biosimilars, to facilitate effective PV monitoring and tracing of adverse safety events and to prevent inappropriate substitution, the specific medicinal product (innovator or biosimilar) prescribed by the treating physician and dispensed to the patient should be clearly identified. Therefore, all biosimilars should be distinguishable by name, i.e. assigned a brand name explicitly, so every medicine will either have invented (trade) name, or the name of the active substance (according to the current International Nonproprietary Name (INN) and Word Health Organization system [5]) together with the company name/trademark.
The approved name, together with the batch number, the country of origin and manufacturer name are important for clear identification to facilitate adverse drug reaction reporting and monitoring of the use of the medicine.
For the purpose of gathering additional information about a product’s safety and efficacy, or optimal use, JFDA requires that a post-marketing surveillance study (phase IV) be conducted in Jordan as a post-registration requirement for biosimilars. An interim report based on the first 50 patients should be provided to JFDA so that it is up-to-date on spontaneous adverse events reports.
Biosimilar application evaluation in Jordan
Biosimilar applications in Jordan are reviewed thoroughly and comprehensively by JFDA’s Technical Committee for the registration of new drugs. Members of the committee are chosen according to Jordan’s Drug and Pharmacy Law [6], these members are chosen for the purpose of reviewing the contents of new drugs registration files and finally approving them. This committee is comprised of members from within JFDA and external assessors who are highly qualified technical scientists from both the public and private sectors.
During the evaluation of the biosimilar dossier, samples of the biosimilar drug are sent to the Drug Control Laboratory Directorate of the JFDA for analysis. In addition, the manufacturing sites responsible for any step in the manufacturing of the biosimilar product, starting from the active biological substance storage and use of the Working Cell Bank, and ending with the finished product, as well as the site responsible for the batch release of the finished biosimilar product, are all accredited and approved by JFDA. This is done via the JFDA’s Sites Accreditation Committee, this is mentioned in the Drug and Pharmacy Law in Arabic on the JFDA website [6], information in Arabic is available from the authors upon request. Under certain circumstances, as laid out in the relevant JFDA guidelines, an on-site inspection visit can be carried out by a team of experts from JFDA and external experts, before issuing final approval and accreditation of sites.
An overview of the biosimilar regulation and approval by JFDA
The JFDA pathway for biosimilars registration is a comprehensive, elaborate and scientific pathway that covers all aspects of the technical dossier as well as the rigorous comparability exercise and extends accreditation of analytic and manufacturing sites. This pathway ensures that biosimilars registered in Jordan have been authorized following a strict regulatory process comparable to what is required for approval of biosimilars by EMA.
The JFDA pathway is in line with the most up-to-date international regulations regarding the review and registration of medicines, especially those of EMA and the US Food and Drug Administration. It is also committed to recruiting well-trained employees and experts form all fields. This results in the supply of reliable, safe and effective drugs.
Competing interests: The authors declared that there is no potential conflict of interest.
Provenance and peer review: Commissioned; externally peer reviewed.
Authors
Rana Musa Ali Al-ali “Malkawi”, MSc, Head of Clinical Studies Department
Wesal Salem Al Haqaish, BPharm, Drug Directorate Director
His Excellency Hayel Obeidat, MD, Ophthalmologist, Director General
Jordan Food and Drug Administration 11181/811951 Amman, Jordan
References 1. Jordan Food and Drug Administration. Drugs registration criteria; check list regarding CTD submission for drug registration purposes [homepage on the Internet]. [cited 2018 Jul 4]. Arabic. Available from: http://www.jfda.jo/EchoBusV3.0/SystemAssets//PDF/AR/LawsAndRegulation/Drug/RegisterSection/%D8%A3%D8%B3%D8%B3%20%D8%AA%D8%B3%D8%AC%D9%84%D9%84%20%D8%A7%D9%84%D8%AF%D9%88%D8%A7%D8%A1%20%D9%84%D8%B3%D9%86%D8%A9%202015%20%D9%88%D8%AA%D8%B9%D8%AF%D9%8A%D9%84%D8%A7%D8%AA%D9%87%D8%A7.pdf 2. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. M4: The Common Technical Document [homepage on the Internet]. [cited 2018 Jul 4]. Available from: http://www.ich.org/products/ctd.html 3. Jordan Food and Drug Administration. Guideline for registration of biosimilars in Jordan [homepage on the Internet]. [cited 2018 Jul 4]. Arabic. Available from: http://www.jfda.jo/EchoBusV3.0/SystemAssets/PDF/AR/LawsAndRegulation/Drug/RegisterSection/10_303.pdf 4. European Medicines Agency. The European Medicines Agency’s scientific guidelines on biosimilar medicinal products help medicine developers prepare marketing authorisation applications for human [homepage on the Internet]. [cited 2018 Jul 4]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c=Overarching%20biosimilar%20 guidelines 5. World Health Organization. International Nonproprietary Names [homepage on the Internet]. [cited 2018 Jul 4]. Available from: http://www.who.int/medicines/services/inn/en/ 6. Jordan Food and Drug Administration. Jordan Drug & Pharmacy Law number 12 issued in 2013 [homepage on the Internet]. [cited 2018 Jul 4]. Available from: http://www.jfda.jo/EchoBusV3.0/SystemAssets/PDF/AR/LawsAndRegulation/Drug/DrugDirectorate/%D9%82%D8%A7%D9%86%D9%88%D9%86%20%D8%A7%D9%84%D8%AF%D9%88%D8%A7%D8%A1%20%D9%88%D8%A7%D9%84%D8%B5%D9%8A%D8%AF%D9%84%D8%A9.pdf
Author for correspondence: Rana Musa Ali Al-ali “Malkawi”, MSc, Head of Clinical Studies Department, Jordan Food and Drug Administration, 11181/811951 Amman, Jordan
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.
Submitted: 6 May 2018; Revised: 7 May 2018; Accepted: 8 May 2018; Published online first: 18 May 2018
Data and market exclusivity for originator medicines in the European Union (EU) create a barrier to market entry for generic medicines. Legislation means that generics cannot reach the market for at least 10 years following the originator marketing authorization. There are no exceptions to this rule which is a cause for concern for many EU Member States. Even high-income countries struggle to afford high-cost medicines under patent to the detriment of patients and overall health care. A recent study published in the Journal of Pharmaceutical Policy and Practice, looks at the current state of EU pharmaceuticals legislation and creates a proposal for greater coherence in this legislation [1].
Regulation concerning the marketing authorization of a generic medicine in the EU currently prohibits the use of the originator’s preclinical and clinical test data for an eight-year period. This is data exclusivity. Following this, market exclusivity means that a generic medicine in the EU cannot then reach the market until 10 years after the originator marketing authorization has passed. In some cases, an additional one year of market exclusivity can also be granted. There are no exceptions made to this rule, which is also known as the 8+2+1 rule.
Current EU medicines legislation goes beyond the requirements of the World Trade Organization (WTO) Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement Art. 39.3. The TRIPS Agreement was set up to protect undisclosed test data in registration submissions of new chemical entities against unfair commercial use. However, it does not require countries to grant originator companies exclusive rights over data related to marketing approval. The legislation in place in the EU does grant such exclusive rights, creating an obstacle to the effective use of compulsory licensing.
As part of the WTO TRIPS Agreement, governments can allow third parties or themselves, the right to use a patent without the patent holder’s permission. Such TRIPS flexibilities were clarified in the 2001 WTO Doha Declaration on the TRIPS Agreement and Public Health. This has since resulted in low- and middle-income countries making use of these flexibilities to enable the supply of low-cost generic medicines for the treatment of HIV (human immunodeficiency virus). These flexibilities have a lot of potential which is being taken note of by many WTO countries. Since 2001, the UN High Level Panel on Access to Medicines has recommended their use and that legislation be implemented to enable compulsory licences to be issued that are ‘designed to effectuate quick, fair, predictable and implementable compulsory licenses for legitimate public health needs’.
The EU is yet to make use of TRIPS flexibilities. However, many European health services are currently being restricted by the high price of patented medicines. This results in reduced or denied access to certain medicines in many Member States. There have been requests for governments to address patent barriers made by many higher-income EU Member States.
In the EU, it is possible for individual nations to issue a compulsory licence to overcome patents. However, the regulatory requirements for marketing authorization within the EU, that include data exclusivity, are a matter of European pharmaceutical legislation. These systems together, lack coherence. This has led to cases such as that which occurred in Romania in 2016. Here, the Romanian Government considered issuing a compulsory licence for sofosbuvir, which is used to treat hepatitis C. However, in accordance with EU legislation, it is not possible to register a generic version of this medicine until 2022 due to data exclusivity, meaning that a compulsory licence could not be issued.
Some voluntary licences include a data exclusivity waiver to ensure effective availability of generic medicines. Such waivers are also provided in some middle- and high-income countries that are members of the WTO. These hope to aid generic medicines registration and sales when required to protect public health. They are explicit medicines regulations data exclusivity waivers or relate to the use of compulsory licences in the patent laws of different countries. Data exclusivity waivers are in existence in some non-EU countries including Chile, Colombia, Guatemala and Malaysia and should be considered in the EU.
In the US, data and marketing exclusivity rules are similar to those in the EU. Small molecule generics have a marketing exclusivity period of five years and this is 12 years for biologicals, with a data exclusivity period for the first four. In 2007, the US New Trade Policy authorized a public health exception to data/market exclusivity in the event of a compulsory licence or other requirements of public health. This allows countries that have signed US developing-country free-trade agreements to disregard data/marketing exclusivity as long as they take measures to protect public health. This can occur even in circumstances where a compulsory licence should be issued, however, its implementation does depend on the status of the patent of the medicine being considered.
In the EU, data and market exclusivity waivers do exist in accordance with the ‘EU regulation on compulsory licensing of patents for the manufacture of pharmaceutical products for export to countries with public health problems outside the EU’. Some EU trade agreements include provisions that can enable exceptions to exclusivity for reasons of public interest or under situations of national emergency or extreme urgency. Under these circumstances, third parties can be allowed access to certain data. Such an agreement exists between the EU and Peru.
Overall, despite the right that EU governments have to grant compulsory licences, there is a lack of legal coherence within the EU which prevents generic medicines being able to enter the market early. This is primarily due to data exclusivity and a lack of data exclusivity waivers. EU governments should attach conditions to licensing that enable the use of waivers within the EU and EU legislation needs to be amended to facilitate this. Such waivers do exist for pharmaceutical products exported from the EU. The burden on health budgets across the EU is considerable and EU law needs to act to ensure that there is easy access to new essential medicines to protect and promote public health.
Competing interests: None.
Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.
Alice Rolandini Jensen, MSci, GaBI Journal Editor
References 1. ‘t Hoen EFM, Boulet P, Baker BK. Data exclusivity exceptions and compulsory licensing to promote generic medicines in the European Union: A proposal for greater coherence in European pharmaceutical legislation. J Pharm Policy Pract. 2017;10:19.
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 drugs have suffered slow entrance and acceptance rates in the US market, due not only to common misperceptions among the public but also US Food and Drug Administration (FDA) licensing laws. This review offers nine major recommendations for the FDA to simplify how biosimilars are licensed and thus make biosimilars more accessible to American citizens.
Submitted: 21 May 2018; Revised: 13 July 2018; Accepted: 17 July 2018; Published online first: 23 July 2018
Background
H.R. 3590 Sec. 7002 [1], commonly known as the Biologics Price Competition and Innovation Act (BPCI Act), a part of the Affordable Healthcare Act, was enacted in 2009 to introduce biosimilars (copies of biological products coming off patent) to the market. Since then, the US Food and Drug Administration (FDA) has licensed 11 products (as of June 2018) [2], comprised of eight molecules: adalimumab, bevacizumab, epoetin, etanercept, filgrastim, infliximab, pegfilgrastim and rituximab. Under the New Drug Application (NDA) filing, insulin glargine products (Lusduna [3] and Basaglar [4]) have also been approved by FDA and from March 2020 all insulin products can be approved as biosimilars [5]. FDA has issued several draft and final guidelines to industry on demonstrating biosimilarity [6], which is the primary determinant for licensing a product, either as a biosimilar or an interchangeable biosimilar. Interchangeable biosimilars are… a separate category of biosimilar products that are additionally tested to demonstrate that automatic substitution of an originator product with the ‘interchangeable biosimilar product’ will not result in reduced efficacy or increased side effects.
The slow entrance and acceptance of biosimilars in the US is the result of high costs and long development times – nearly US$250 million and almost eight years [7] – as well as a gross misunderstanding of the safety of biosimilars among prescribers and the public, principally due to ideas put forward by the products’ originator companies. While FDA has recently launched a campaign to educate stakeholders regarding the safety of biosimilars [8], much work remains to be done in order to simplify and expedite licensing of biosimilars, as emphasized by the author in several publications and a recent citizen petition to FDA [9–11].
The suggestions made in this paper come from decades of experience in developing biosimilar products globally, including through the biosimilars (351(k)) and NDA pathways (505(b)(2)).
The BPCI Act
This review focuses on actions FDA, biosimilar developers and other stakeholders can take, within the boundaries of the statute, to make biosimilars more accessible. In order to first understand what is feasible for FDA and how the relevant guidelines are constructed, a review of the BPCI Act is necessary. Given below are excerpts from the BPCI Act that are relevant to guidelines for the approval of biosimilars by FDA:
(k) Licensure of biological products as biosimilar or interchangeable
(1) In general
Any person may submit an application for licensure of a biological product under this subsection.
(2) Content
(A) In General
(i) Required Information
An application submitted under this subsection shall include information demonstrating that
(I) the biological product is biosimilar to a reference product based upon data derived from
‘(aa) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components;
‘(bb) animal studies (including the assessment of toxicity); and
‘(cc) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product;
(II) the biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product;
(III) the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product;
(IV) the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; and
(V) the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.
(ii) Determination by Secretary. —The Secretary may determine, in the Secretary’s discretion, that an element described in clause (i)(I) is unnecessary in an application submitted under this subsection.
(4) Safety standards for determining interchangeability
Upon review of an application submitted under this subsection or any supplement to such application, the Secretary shall determine the biological product to be interchangeable with the reference product if the Secretary determines that the information submitted in the application (or a supplement to such application) is sufficient to show that—
(A) the biological product—
(i) is biosimilar to the reference product; and
(ii) can be expected to produce the same clinical result as the reference product in any given patient; and
(B) For a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.
The statutory requirements provided in section k.2.A.i.I form the basis of biosimilar development. Remarkably, these requirements are left to the discretion of FDA, as shown in k.2.A.ii, leaving only section k.2.A.i.I–V as unchangeable by FDA [1]. Interchangeable licensing has additional legislation, as shown in k.4.A–B. A biosimilar product must demonstrate the same clinical results as the reference product, which can only be shown by patient testing. Studies using a switching-and-alternating protocol, where an originator biological product is switched with a biosimilar product and then back to the originator product, must show no diminished efficacy and no greater risk when compared to the reference product without alteration or switching. This legislation prevents FDA from making any changes to the requirements for interchangeable biosimilars; thus this paper will address issues related to the approval of biosimilars only.
Actions recommended for US FDA
To allow the faster development and adoption of biosimilar products, the following changes in the regulatory approval process are recommended:
Modify the current requirement for bridging studies between a US-licensed product and a non-US approved comparator, provided the non-US product meets certain specifications, such as same indications, same dosage form and approved using essentially the same dossier as the US-reference product, to establish biosimilarity.
Present clear scientific evidence to the public and, more particularly, prescribers that a biosimilar product has no ‘clinically meaningful difference’ from the originator product and thus should be acceptable for naïve patients, without involving the legality of substitution issue.
Encourage the development of in vitro immunogenicity testing methods to reduce exposure to test subjects, which would have ethical advantages and allow comparison of multiple batches of the biosimilar candidate product, improving safety evaluation.
Replace the current arbitrary comparisons of critical quality attributes, such as protein content or variations in known impurity profiles with clinically-relevant limits and ranges in testing analytical similarity, animal toxicology, pharmacokinetic/pharmacodynamic (PK/PD) immunogenicity, and other safety and efficacy attributes.
Minimize clinical studies by combining studies intended to establish immunogenicity, efficacy and PK/PD profiles to avoid unnecessary testing on patients.
Clarify policy on analytical method validation.
Change the requirement for the use of commercial-scale batches for determination of biosimilarity.
These recommendations are also, in part, the subject of a citizen petition filed by the author to FDA [11].
1. Waiver bridging studies
Developing biosimilars is costly and requires developers to formulate a global strategy where one regulatory dossier can be used to secure regulatory approvals in multiple jurisdictions. Since the BPCI Act requires that a biosimilar be similar to its locally licensed originator (that is, a product approved under Sect. 351(a) of the Public Health Service Act of 1942, as amended) [1], developers are not permitted to use a non-US product as a reference product. As a result, creating a global dossier requires three-way studies, i.e. a US-licensed product, a non-US product, and the biosimilar candidate. To reduce the burden of additional studies, and to reduce unnecessary exposure to humans, several regulatory authorities have established clear policies on bridging studies [12], as shown in Table 1.
The most stringent requirements are imposed by FDA, whose requirements include analytical similarity and PK/PD studies. It should be noted that FDA requirements for bridging studies are not clearly defined but accepted as the default position of FDA. As such, there is no legal obstacle to FDA changing its position and allowing developers to request a waiver to use a non-US-licensed product as the reference product, provided the conditions, enumerated below, are met:
The non-US reference product meets all statutory requirements as shown in section k.2.A.i.II–V; and
The non-US product received approval in its respective jurisdictions by presenting very similar original data, including clinical safety and effectiveness, as the US-licensed reference product; and
The regulatory filing is not intended to claim interchangeable status for the biosimilar product; or
The non-US reference product was judged to be equivalent to the US-licensed product in any regulatory filing that presented a bridging study, such as the recent approvals of infliximab [19] and bevacizumab [20].
FDA Commissioner Dr Scott Gottlieb agrees with the suggestions made above, however, there is wider FDA concern that legislative action would be required to make changes to current practice [21]. The author finds no legal reason why this change cannot be made by FDA.
2. Encourage substitution for naïve patients
The BPCI Act creates two categories of biosimilar products: biosimilar and interchangeable biosimilar. The latter classification was intended to allow the automatic substitution of an originator product with a biosimilar product. The labelling of an interchangeable biosimilar requires in patient studies to demonstrate similar efficacy. When a biosimilar product is repeatedly administered, the two products (biosimilar and reference) are alternated to establish that there is no reduction in efficacy or increase in side effects caused by the biosimilar. As a result of the complexity of these studies making them extremely expensive to conduct, developers have been reluctant to file for interchangeable status; and FDA is yet to approve a product as an interchangeable biosimilar. However, there is a need for a strategic approach to allow the substitution of biosimilars based on how FDA characterizes a biosimilar.
‘A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing the FDA-approved reference product [22]’.
From a scientific and clinical viewpoint, if a product is clinically equivalent, there is no reason why it should not be prescribed to naïve patients. This view is shared by FDA Commissioner Dr Scott Gottlieb who stated that ‘payors can also lead the way in formulary design by making biosimilars the default option for newly diagnosed patients. They can share the savings with patients, maybe by waiving co-insurance [23]’.
The author therefore requests that FDA:
Declare the official position that a licensed biosimilar product has no clinically meaningful difference and that it can be substituted for the originator product when the originator product is prescribed for a naïve patient.
Educate prescribers that biosimilars are safe and equally effective, with no risk of additional immunogenicity when used in naïve patients—the most significant barrier to the entry of biosimilars into the US market.
Motivate and enforce the adoption of biosimilars by payers and make the pricing structure more transparent in order to demonstrate cost savings to patients and prescribers.
3. Allow in vivo immunogenicity study waivers
Immunogenicity is defined as the propensity of biological drugs to generate an immune response to self and related proteins, which may include non-clinical effects and adverse clinical events. Immune responses to biological drugs may hamper their biological activities and result in adverse events, not only by inhibiting the efficacy of the therapeutic element but also by cross-reactions with endogenous protein, leading to loss of its physiological function. For example, neutralizing antibodies to erythropoietin can cause pure red cell aplasia by also neutralizing the endogenous protein. The effects of immunogenicity in biological drug development can be summarized as follows:
Effects on bio-availability, safety, efficacy and PK, including potential cross-reactivity with endogenous proteins
Inhibition of the function of endogenous proteins
Injection site reactions and other systemic reactions, mild or life-threatening
Formation of anti-drug antibodies, neutralizing antibodies, immune complexes and anti-idiotypic antibodies
Immunogenicity, as stated in FDA guidelines on biological drugs, must be assessed in the target population since animal testing and in vitro models cannot predict immune response in humans [24]. Immunogenicity also has a role in demonstrating product comparability following manufacturing changes. Even minor changes can potentially affect the bioactivity, efficacy or safety of a biological drug. As a result, FDA is making important advances in predicting immunogenicity [25], in particular promoting the use of in vitro immunogenicity assays.
The European Medicines Agency (EMA) provides the following statement regarding use of alternate methods of testing immunogenicity:
‘… ongoing consideration should be given to the use of emerging technologies (novel in silico, in vitro and in vivo models), which might be used as tools during development or for the first estimation of risk for clinical immunogenicity. In vitro assays based on innate and adaptive immune cells could be helpful in revealing cell-mediated responses [26]’.
The characterization and screening of biosimilars for physicochemical determinants or formulation-based factors aid both in the prediction of immunogenicity and in the development of less immunogenic therapeutic agents, considering impurities, heterogeneity, aggregate formation, oxidation and deamidation of the molecule. Moreover, predicting potential immunogenic epitopes in therapeutic biologicals is an important and useful strategy to improve their safety.
Immunogenicity testing however substantially increases the cost and time requirements for drug development and the goal of regulatory guidance should be to minimize human testing where possible. A variety of preclinical immunogenicity assessment strategies are currently used during biological development, as listed in Table 2.
A major advantage of in vitro methods is the ability to test multiple batches for immunogenicity, which is not possible in human subjects. In vitro tests can also be more useful in predicting the difference between a biosimilar product and its reference product.
There are clear ethical complications in testing for immunogenicity in healthy subjects when comparing a reference drug to a biosimilar candidate. To advance the science of in vitro immunogenicity further, FDA should:
Allow developers to present in vitro, in silico, or novel in vivo test methods and thus request a waiver from clinical immunogenicity testing.
Continue internal development efforts to find and prescribe testing modalities that reduce the need for clinical testing of immunogenicity.
4. Make pharmacokinetic profiling clinically relevant
Bioequivalence is defined in 21 CFR 320.1 (Hatch-Waxman Act) [27] as ‘the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study’. Since the site of action is not known in most cases and rarely available for sampling, level in blood was selected as a surrogate to the site of action. The PK profile characterizes two stages, absorption and disposition (distribution and elimination), making it most relevant to generic chemical (small molecule) drugs where disposition is less likely to vary. This makes the PK profile relevant to absorption, and therefore bioavailability, thus providing validation of bioequivalence.
The PK profiling of biosimilars follows the same testing protocols as used for generic drugs. However, extrapolation of testing protocols involves a significant misconception – biosimilar drugs are administered parentally, which means that while differences in absorption are unlikely, differences in disposition are likely (distribution may change due to binding effects for example, and elimination may change due to subtle structural differences). This difference between generics and biosimilars should be addressed in the selection of PK parameters and statistical models applied to demonstrate similarity.
When FDA developed guidance on biosimilars, the term ‘clinical relevance’ was introduced, which is the most crucial aspect of determining biosimilarity and addresses the step-by-step approach [1] of demonstrating: analytical similarity, non-clinical toxicology, PK/PD profile, immunogenicity profile and, if there remains any ‘residual uncertainty’, performing additional clinical studies in healthy subjects. Consideration of ‘clinical relevance’ should therefore also be part of PK/PD analysis.
The author suggests the following changes to the criteria of PK/PD profiling of biosimilars compared to a reference product:
Waive PK studies where the product is administered by a route (ocular, otic, and possibly others) that does not provide sufficient concentration of the active moiety in blood, such as the intraocular administration of ranibizumab [28]. However, to allow evaluation of disposition kinetics, PK studies involving intravenous administration in an appropriate animal, such as monkeys, should be required for monoclonal antibodies. This could be integrated into the non-clinical toxicology assessment. In most instances, a study population of 10–12 animals should suffice.
When administered parentally, as most biosimilars are, PK parameters relating to distribution such as distribution volume and parameters relating to elimination such as terminal half-life are more clinically relevant than the area under the curve (AUC) or peak plasma concentration (Cmax). Statistical modelling should include these additional parameters. Distribution volume was introduced as a determinant of clinical efficacy by the author decades ago and finds a new application in the evaluation of biosimilars [29].
While a confidence interval within 80–125% for the log ratio of Cmax and AUC (and for any other parameters added, as suggested above) has performed well as an acceptance criterion for generic drugs, there is no assurance that these intervals are clinically meaningful for biological drugs. Whether FDA should broaden or narrow the interval of acceptance remains to be determined once the additional parameters suggested above are taken into consideration.
Encourage the use of scaled average bioequivalence (SABE) testing protocols that allow collection of immunogenicity profiles in a single study. In those instances where the immunogenicity data are required from a patient population, allow PK/PD profiling in patients, reducing the number of clinical studies required.
Allow PK/PD studies to select a population that is likely to have minimal variation to reduce study sizes. Choosing such populations would help to demonstrate differences between the biosimilar candidate and the reference product.
5. Modify tier testing criteria for analytical similarity
FDA has recently released draft guidance on ‘Statistical Approxaches to Evaluate Analytical Similarity’ for biosimilars [30], one of the most critical components for establishing biosimilarity and a component that determines which additional studies, both clinical and CMC-related, are required. A developer identifies critical quality attributes (CQAs) and tests them using Tier 1, Tier 2, or Tier 3 statistical methods, depending on the nature of data output and the importance of the attribute to the safety and efficacy of a biosimilar product.
For CQAs in Tier 1, equivalence is established by rejecting the interval (null) hypothesis: −1.5 σR ≤ 90% CI of [μT–μR] ≤ 1.5 σ, where μT and μR are the mean responses of the test (the proposed biosimilar product and the reference product lots, respectively). This statistical testing suggests the equivalence acceptance criterion (EAC) = 1.5 × σ, where σ is the variability of the reference product (standard deviation). Statistical justification for the factor of 1.5 [31] follows the idea of the SABE criterion for highly variable generic drug products proposed by FDA. To achieve the desired power for the similarity test, FDA further recommends that an appropriate sample size is selected by evaluating the power using the alternative hypothesis μT − μR = ⅛.
There is no relevance of the factor of 1.5 used in equivalence testing of the most critical CQAs. For example, in the briefing on approval of Sandoz’s filgrastim product [32], FDA stated that one of the CQAs (protein content) initially failed, requiring additional batches to be added to the analyses. While there is a correlation between dose and effect for biological products, a small variation – as observed in the Sandoz data – should not have any clinically meaningful effect, since the release specification provides considerable variability. In essence, a test for analytical similarity may fail, yet such variation is allowed in the commercial product.
The criterion for Tier 1 testing for CQAs can produce misleading results. As an example, 10 batches (a number recommended by FDA) of a biosimilar candidate could be tested against an equal number of reference product batches for a percentage of the labelled quantity of protein. If the variation in the reference product is minimal, approaching a value of zero for σ, then all comparisons will fail, even if there is no clinically meaningful difference. The author has encountered such situations, where an attribute is tightly controlled in the originator product based on decades of manufacturing experience. The question arises if this is a clinically meaningful difference or merely a routine observation. For example, a biosimilar product may be allowed a range of 97–103% or even 95–105% in the Certificate of Analysis (COA) based on the history of manufacturing, yet all samples will fail if the σ of the reference product is minimal. On the other hand, where an attribute has high variability (σ) for the reference product, the product passes the Tier 1 test while failing a Tier 2 test, where 90% of all values fall within 3 × σ. It is for this reason that FDA requires Tier 2 testing for all Tier 1 attributes. To resolve these inconsistencies, the author suggests the following changes to the statistical modelling of CQAs in analytical similarity testing:
Exclude any quality attributes for testing of analytical similarity that are part of the COA. If FDA accepts the variability as shown in the ranges of acceptance provided in the COA, it is illogical to accept or reject a product based on statistical limits of analytical similarity. The COA is clinically relevant, while the tiered testing of these attributes is not. Critical quality attributes of importance are primary, secondary and tertiary structures, receptor binding and impurity profile of timed samples, in addition to many more that are pertinent to differences in the molecules, albeit subtle.
Allow developers to identify the CQAs and their range of variability based on clinical meaningfulness rather than using a factor of 1.5 arbitrarily to establish equivalence in a Tier 2 testing.
If a product fails a Tier 1 test but passes Tier 2 testing, allow this as acceptance of similarity.
6. Clarify analytical testing validation
It is clearly understood that all analytical methods, including bioanalytical methods, must be validated, as provided in a May 2018 final guidance on bioanalytical methods [33]. However, analytical similarity testing requires methods that are often difficult or impossible to validate based on the guidance provided without incurring high cost and time commitments, such as nuclear magnetic resonance techniques or mass spectrometry. While all analytical methods used in the authorization of a biosimilar should be validated, methods used to demonstrate other analytical attributes may be accepted by FDA if they are ‘suitable’, a term often used in FDA guidance but not clearly defined. There is a need for FDA to clearly differentiate between the methods that must be validated and the ones that can be used if found suitable.
7. Encourage development of novel testing methods
Current approaches to evaluating the differences between a biosimilar candidate and a reference product are based on methods for characterizing new molecules; there is a need to develop more sensitive techniques to determine differences in the structure of large molecules, both at steady state and while active within the body. Several new techniques have recently come into practice, including modified capillary electrophoresis, Chip-based (Bioanalyzer) Protein Electrophoresis Assays (CPEA), and many variations of mass spectrometry [34].
FDA defines fingerprint-like similarity as:
‘the results of integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences (i.e. fingerprint-like analyses) permit a very high level of confidence in the analytical similarity of the proposed biosimilar product and the reference product, and it would be appropriate for the sponsor to use a more targeted and selective approach to conducting animal and/or clinical studies to resolve residual uncertainty and to support a demonstration of biosimilarity [35]’.
The introduction of new methodologies could help to demonstrate clinically meaningful similarity between products that will reduce the number of additional studies required [36, 37].
8. Accept smaller batch sizes
Unlike the development of entirely novel drugs, the development of biosimilars requires commercial-scale batches in order to begin testing for similarity. The rationale for this requirement derives from the assumption that there may not be any in patient or ‘phase III’ studies required that are historically conducted using commercial-scale batches. This requirement generates a huge cost and time burden, preventing smaller developers from entering the market. While FDA has not identified what it considers to be ‘commercial scale’, these issues were highlighted in a Type 2 formal meeting between FDA and sponsors of Biosimilar User Fee Act (BsUFA) products [38]. The author suggests that FDA requires a batch size that is adequate to provide samples for stability, clinical or other required testing, instead of making market projections to justify the size of a commercial batch. Should the developer decide to change the batch size after the product has been approved, the developer may use the Comparability Protocol for Biological Drugs [39] to make this post-approval change. This clarification by FDA would have a significant impact on industry, allowing smaller developers to offer market-ready products using smaller batches and at much lower cost.
9. Minimize clinical studies
The largest contributor to the cost and time requirements of marketing a drug are the clinical studies required to establish biosimilarity. When in patient studies are required, the cost and timeline stretch even further. The current mindset of establishing biosimilarity follows phase I to III testing, which is not relevant to establish the non-inferiority status of a biosimilar candidate with the reference product. As a result, the author makes the following recommendations:
If it is determined a priori that studies are required in patients, allow developers to conduct PK/PD profiling in patients as well.
Allow statistical models of PK/PD studies to determine immunogenicity within the same study.
Allow the use of in vitro models for immunogenicity testing to reduce human exposure.
Allow the use of animal models to establish differences in the PK (and, where possible, the PD) profile where blood concentrations are not measurable.
Summary
In developing methods for the evaluation of biosimilars, FDA has created highly specific vocabulary, such as ‘no clinically meaningful difference’ and ‘residual uncertainty’. These terms are scientifically important and represent a creative approach to assuring the safety of biosimilars. However, not all FDA guidance adequately takes these two terms into account. To improve this situation, this review makes a number of recommendations:
Remove the default requirement of conducting bridging studies for non-US reference products, where the reference product meets specific criteria.
Declare that biosimilars have no clinically meaningful difference from the originator product and, therefore, substitutions for naïve patients should be allowed.
Remove the default requirement of conducting in vivo immunogenicity testing and allow developers to offer alternative in vitro and in silico testing methods.
Modify PK/PD protocols and statistical analysis methods to make the outcomes clinically meaningful.
Modify testing of critical quality attributes by separating them from release specifications to demonstrate analytical similarity.
Minimize clinical testing by combining studies.
Clarify the type of validation required for analytical similarity testing.
Allow the approval of products based on smaller scale studies.
FDA recognizes the need for changes to its guidance. Commissioner Dr Scott Gottlieb [23] has recently expressed a willingness to respond to the urgent need to reinterpret guidelines for the increased approval and adoption of biosimilars.
In June 2018, the FDA withdrew its guidance for Analytical Similarity Testing [40] and a few days later FDA announced a new initiative, Biosimilars Action Plan that includes most of the recommendations made by the author in its citizen petition [41].
Disclaimer
This paper represents solely the views of the author and should not be understood or quoted as being made on behalf of or reflecting the position of any regulatory authority or company.
Competing interests: The author of the paper declared that he is a developer of biosimilar products. The author is founder of Karyo Biologics, LLC and Adello Biologics, which have several biosimilar products at various stages of FDA approval.
Provenance and peer review: Not commissioned; externally peer reviewed.
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Author: Adjunct Professor Sarfaraz K Niazi, PhD, SI, FRSB, FPAMS, FACB, Adjunct Professor of Biopharmaceutical Sciences, University of Illinois and University of Houston; 20 Riverside Drive, Deerfield, IL 60015, 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 first draft guidelines for copy biologicals were introduced in China back in 2014. The Technical Guideline was then updated and finalized in 2015. In this paper, how the Drug Registration Regulation (2007) pathway classifies therapeutic biologicals and the principles and challenges of the copy biologicals guideline are described.
Submitted: 3 May 2018; Revised: 8 May 2018; Accepted: 15 May 2018; Published online first: 25 May 2018
Introduction
China has a huge market for copy biologicals, with 40% of China’s US$1.5 billion recombinant biologicals sales coming from copy biologicals, which have enjoyed compound annual growth rate (CAGR) of approximately 25–30% over the past decade. With predicted market growth of 25% per year, the Chinese copy biologicals market is expected to grow to US$2 billion. This makes it an attractive market to move into for more and more multinational biosimilars makers.
China first introduced draft guidelines for copy biologicals back in 2014 [1]. The Technical Guideline was then updated and finalized in 2015 [2]. The legal structure of the current Chinese copy biologicals guideline is based on the Drug Administration Law (Revised 2015) issued by the Chinese Government and on the Drug Registration Regulation (Revised 2007) issued by the China Food and Drug Administration (CFDA).
CFDA (simplified Chinese: 国家食品药品监督管理局) has been the Chinese authority that oversees all drug manufacturing, trade and registration in the country since 2003 [2].
The Drug Registration Regulation (Revised 2007) pathway classifies therapeutic biologicals into 15 categories [3]:
Products that have not been marketed in China and other countries
Monoclonal antibodies
Gene therapy, somatic cell therapy and related products
Allergen products
Multicomponent bioactive products extracted from human/animal tissue/body fluid, or produced by fermentation
New combination products made from marketed biological
Products which have been marketed in other countries but not China
Microbiological products containing components made from strains that have not been approved for use in China
Products that do not have the exact same structure as marketed products and have not been marketed in China or overseas (including locus mutation or absence of amino acid, changes in post-translational mutation or absence of amino acid, changes in post-translational modification caused by using different expression systems, and chemical modification of the product)
Biologicals produced by different methods compared with the marketed products, such as different expression systems, or host cells
The first product produced by recombinant DNA method (for example, replacement of synthesis, tissue extraction or fermentation technologies by recombinant DNA technology)
Products changed from non-injection route to injection route or from topical use to systemic use, which have not been marketed in China or other countries
Marketed products with a new formulation but same route of administration
Marketed products with a new route of administration (excluding Category 12)
Products with national standards
The Chinese copy biologicals guideline is based on four principles:
Comparison
Step-wise
Consistency
Similarity
These core principles should be used across the entire R & D and evaluation process, see Figure 1.
The updated and finalized Technical Guideline for copy biologicals [2] provides a relatively clear regulatory pathway for development of copy biologicals in China. It clarifies some confusion and provides the principles of R & D and evaluation for copy biologicals. It also helps to regulate activities and speed up the entire process. The guideline is also intended to raise the bar for entry into the copy biologicals field, avoiding low quality competition.
The Technical Guideline follows similar standards and principles as guidelines from other major markets. This, it is hoped, will increase the quality of products produced in the country and make them more competitive, as well as increase the possibility of marketing Chinese copy biologicals in other countries.
The main challenges with respect to the guideline include:
Significantly increased R & D costs
Availability of reference product for clinical trials
– ‘reference product for clinical trials should be approved in China’
Basically impossible to waive phase III comparative trials
Extrapolation of indications limited to indications approved in China
Too general and impractical
Some requirements are too stringent
Editor’s comment
It should be noted that ‘copy biologicals’ approved in China might not have been authorized following as strict a regulatory process as is required for approval of biosimilars in the European Union. The European Medicines Agency regulatory requirements ensure the same high standards of quality, safety and efficacy for biosimilars as for originator biologicals, and also include a rigorous comparability exercise with the reference product.
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
Michelle Derbyshire, PhD, GaBI Online Editor
References 1. GaBI Online – Generics and Biosimilars Initiative. China to release biosimilars guidelines [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 8]. Available from: www.gabionline.net/Guidelines/China-to-release-biosimilars-guidelines 2. GaBI Online – Generics and Biosimilars Initiative. Chinese guidelines for copy biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 8]. Available from: www.gabionline.net/guidelines/Chinese-guidelines-for-copy-biologicals 3. Hu H. Challenges & strategies to enter the emerging markets for biosimilars. Biosimilars Europe Congress; 22–23 November 2016; London, UK.
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:
High resolution analytical techniques reveal structural micro-heterogeneity within endogenous proteins, however, they are ‘seen’ as ‘self’ molecules by the immune system and immunological tolerance is established. In contrast the protein biotherapeutics are produced in non-human cells and multiple downstream protocols are employed in the isolation and purification of drug product; consequent micro-heterogeneities may be ‘seen’ as ‘non-self’ and potentially immunogenic. In addition, extensive polymorphisms within and between outbred human populations suggests that any given protein biotherapeutic may be allogenic, and potentially immunogenic, when administered across different population groups. Further heterogeneity may result from differential intra-cellular processing and the addition of co-, trans-, and post-translational modifications. These processes are explored against reported incidences of immunogenicity for recombinant forms of human erythropoietin (EPO) and Immunoglobulin G (IgG).
Submitted: 7 February 2018; Revised: 28 March 2018; Accepted: 2 April 2018; Published online first: 16 April 2018
Introduction
The human genome (HG) is comprised of ~23,000 open reading frame (ORF) genes, however, the human proteome is orders of magnitude greater; due to alternate splicing (AS) of ORF genes, errors in transcription or translation, the addition of co- and post-translational modifications (CTM; PTM). A recent guestimate suggested that each ORF within the outbred human population might be translated to generate 100 structurally distinct proteins [1]. Protein and glycoprotein (P/GP) molecules exist in vivo as discreet entities within complex multi-component media, e.g. plasma, cell sap, and exert their function(s) through specific interactions with target/receptor molecules. In health each individual expresses a unique proteome and personal integrity demands immunological tolerance to all self-molecules. Ordered aggregation of monomer molecules may be essential for normal function; however, inappropriate (non-native) aggregation is implicated in the pathogenesis of numerous autoimmune diseases and the generation of autoantibodies [2, 3]. Similarly, denaturation and/or aggregation of P/GP biotherapeutics may render them immunogenic and result in the development of anti-drug/anti-therapeutic antibodies (ADA/ATA).
The thriving biopharmaceutical industry depends on the production of recombinant P/GPs exhibiting an essential structural fidelity with a selected endogenous molecule; therefore, structural variants generated during production, purification, formulation and/or delivery is a major concern as it may equate to potential immunogenicity [2, 3]. Pharmacovigilance must be exercised over the lifetime of an approved drug since incidences of adverse events are reported for drugs that have been long established in the clinic, e.g. insulin [4] and erythropoietin (EPO) [5]. The presence of ADA/ATA is frequently associated with onset of adverse events and/or loss of efficacy [6, 7] and suggests the presence of structurally altered/denatured molecules that are recognized as ‘foreign’ (non-self) by the patient’s immune system, i.e. immunogenic. This mini review enumerates structural parameters that have to be defined and maintained throughout the production, administration and clinical lifetime of recombinant P/GP therapeutics; illustrated for EPO and antibody therapeutics.
Structural heterogeneity: in vivo and ex vivo Biosynthesis of P/GPs in mammalian cells employs error prone multistep processes and the end product(s) exhibits an inevitable structural heterogeneity. Lack of fidelity with the amino acid sequence encoded by a given ORF may be introduced at multiple stages, e.g. transcription, mRNA translation, miss-incorporation. Additionally, de nova secondary structures may be essential to allow co-translational modifications (CTMs) of the polypeptide as it is extruded from the ribosome tunnel, e.g. the addition of oligosaccharide, N-myristoylation. When released from the ribosome the P/GP transits to the endoplasmic reticulum where it is edited for correct tertiary/quaternary folding and initial oligosaccharide processing; further post-translational modifications (PTMs) are effected during passage through the Golgi apparatus [8–11]; P/GPs may be subject to further modifications throughout their life cycle in vivo, e.g. enzyme cleavage to release secondary bioactive products. It is presumed that all such molecular entities are recognized as ‘self’ by the immune system; therefore the first step in the quest to produce a recombinant P/GP therapeutic is determination of the structure of the natural (endogenous) molecule. However, the techniques employed to isolate and purify P/GPs from body fluids or tissues may result in denaturation and the introduction of non-native chemical modifications (CMs) e.g. deamination; proline isomerisation.
In practice a candidate recombinant P/GP therapeutic is evaluated, structurally and functionally in comparison with the fully characterized endogenous molecule. This approach cannot be realized for a potential recombinant monoclonal antibody (mAb) therapeutic since an endogenous anti-self antibody is not available for comparison. Candidate mAbs are sourced from inbred mice and engineered to generate chimeric or humanized mAbs; from transgenic mice expressing human immunoglobulin genes or random reassociation of human Immuoglobulin (Ig) heavy and light chain expressed within phage display libraries [12, 13]. The choice of production platform is a critical strategic decision since the processes involved in the addition of CTMs, PTMs and CMs are species and cell specific and production of a human P/GP in an alien cell line, e.g. CHO (Chinese hamster ovary) cell line, may result in the introduction of non-self structures and consequent immunogenicity with the generation of ADA/ATA responses [6–8]. Prior to clinical trials a candidate recombinant P/GP therapeutic has to be extensively characterized in comparison with the endogenous molecule, employing multiple orthogonal physicochemical techniques [14, 15]. Patent protection for numerous recombinant P/GP drugs has now expired and many more are approaching expiry, providing opportunities for the production of biosimilar drugs. Candidate biosimilars must be characterized in comparison with the approved innovator drug product [16, 17].
Protein folding: in vivo Proteins are synthesized, within ribosomes, as a linear sequence (string) of amino acid residues covalently linked through the peptide bond; elements of secondary structure may form, de nova, and can include generation of an acceptor site for the addition of high mannose oligosaccharides N-linked to an asparagine residue present within a glycosylation sequon, i.e. the sequence asparagine-x-serine or threonine (asp-x-ser/thr; N-X-S/T), where x is any amino acid residue other than proline. Following release from the ribosome the protein transits to the endoplasmic reticulum where the high mannose oligosaccharide is truncated and exerts a quality control function for correct folding; miss-folded proteins being marked for proteasomal degradation [8–11]. Multiple PTMs may be effected during passage through the Golgi apparatus including further oligosaccharide processing, phosphorylation, sulphation. In this way a P/GP achieves its native, evolutionary determined, structure that ensures it traffics to the appropriate cellular compartment or is secreted [18–21].
It has been estimated that a protein of 100 amino acid residues undergoing random motion in search of the lowest energy form could pass through 1089 conformations, taking 1066 years, to sample all possible structures; however, within the cell the P/GP passes through intrinsic protein folding pathways to achieve the functional tertiary/quaternary conformation within seconds [22]. Our knowledge and understanding of P/GP structure/function relationships is mostly based on the results of X-ray crystallographic studies and tend to represent proteins as having a fixed (solid) structure [15]. Newer techniques show that proteins are ‘living, breathing’ entities that may exist in conformational equilibria, including intrinsically unstructured regions [23, 24]; ex vivo such regions, may act as focal points for aggregation [2, 3, 9, 23, 24]. Algorisms that attempt to analyse or predict structural parameters of P/GPs as they exist within in vivo environments are in their infancy [10, 24].
Protein folding: ex vivo Proteins are comprised of amino acid residues that bear non-polar, polar uncharged and charged side chains and may fold to generate molecules having an overall hydrophobic or hydrophilic character. Proteins that are soluble in aqueous media have an overall hydrophilic character whilst hydrophobic amino acid side chains are orientated towards the internal space and form mutual interactions that stabilise structure; however, a scan of the surface exposed side chains may reveal hydrophobic patches that can act as centres for aggregation [2, 9–11]. This potential is underlined by diseases in which P/GP aggregation results in the deposition of insoluble fibrils in tissues, e.g. neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), transmissible spongiform encephalopathies (TSEs), and amyotrophic lateral sclerosis (ALS) [25–31]. Fundamental studies of protein folding and aggregation have focused on the hen egg white lysozyme molecule, the native form of which has high solubility in aqueous media. However, following exposure to denaturing solvents in vitro, followed by restoration to physiologic conditions it can miss-fold to form aggregates and fibrils, similar to pathogenic species seen in disease. Six spontaneous mutations in human lysozyme have been reported and all except one lead to systemic non-neurogenic amyloidosis involving kidney, liver and spleen [27–29]. Prion disease is an extreme example of the propensity for a soluble protein to form fibrils in vivo [30, 31]. In its soluble form the prion protein has a helical structure; however, in the disease state the protein converts to a beta sheet structure that aggregates to form fibrils; the denatured prion protein can act as a ‘catalyst’ to induce normal prion protein to convert to a beta sheet structure.
As previously stated we do not have means of determining the fine structure of P/GPs as they exist in vivo and are limited to extrapolation from structural studies of isolated P/GPs purified from human fluids and tissues employing multiple physicochemical techniques that may introduce further structural heterogeneity, e.g. deamidation of asparagine and glutamine residues, oxidation of methionine and tryptophan residues, glycation of lysine [10, 14, 24]. Additionally, proteins may undergo subtle reversible conformational changes that results in momentary exposure of hydrophobic regions that can be mutually attractive with formation of ‘partly unfolded clusters’, i.e. aggregates [3, 25–27], see Figure 1. Such clusters can act as nuclei for the formation of larger aggregates, possibly extending to precipitation. Structural heterogeneity is compounded by differing susceptibilities of individual amino acid residues to modifications depending on its position within the molecule and the immediate microenvironment.
Prediction of aggregation prone regions (APR)
Aggregation prone regions (APRs) may be classified as structural or critical. Structural APRs contribute to the stability of the native protein core structure but may be exposed following denaturation ex vivo and form aggregates under refolding conditions; critical APRs are exposed in the native state and may contribute to physiological protein/protein interactions in vivo and in vitro. Multiple physiochemical techniques and algorithms have been developed to identify APRs and inform protein engineering to reduce a propensity for aggregation [32–34]; a concomitant increases in recombinant proteins productivity has been reported [35]. Since hydrophobic binding contributes to protein/protein interactions APRs may be anticipated as a feature of functional sites and much attention has been focused on the antigen-binding site, i.e. the paratope, of antibody molecules [35, 36]. However, antibodies are multifunctional molecules and the formation of antigen/antibody complexes is an essential prelude to the activation of downstream effector functions activated by interactions of the Fc region with soluble and/or cell bound and ligands, e.g. cellular Fc receptors (FcγR, FcRn), the C1 component of complement [37, 38]. Interaction sites for these ligands have been identified and include the hydrophobic sequence 231-APELLGGPSVFLFPP-245 [15, 20, 37, 38]. Protein engineering has been employed to reduce the propensity for aggregation whilst retaining activation of effector molecules that determines their mechanism of action (MoA).
Immunogenicity
In health an individual is tolerant to their proteome, however, multiple autoimmune diseases manifest the potential for loss of tolerance to self-molecules or aberrant (mutant) forms of self-molecules arising in vivo. The potential for immunogenicity of biotherapeutics in humans may vary depending on the character of the disease being treated, three broad categories may be identified [39–41]:
A disease in which a patient fails to express an essential P/GP or expresses a mutant inactive form, e.g. enzyme deficiencies. In each case an active therapeutic is ‘non-self’ and has potential to be immunogenic.
Therapeutics that augment the patients endogenous production, e.g. insulin, erythropoietin. The patient may be expected to be tolerant unless there is a mismatch between P/GP polymorphic variants present in outbred population or the therapeutic has been subject to denaturation/aggregation, with exposure of altered structure during production, storage and/or delivery.
Antibody therapeutics are a special case in that, in addition to polymorphisms within the ‘constant’ regions, the unique specificity is reflected in unique antigen binding site (paratope) structure that will be ‘non-self’ to a majority of patients in an outbred population.
Monoclonal antibodies: commercial evolution
The antibody response in humans is comprised of five immunoglobulin (Ig) classes: IgM, IgG, IgA, IgE and IgD; in addition IgG is comprised of four subclasses (IgG1, IgG2, IgG3, and IgG4) and IgA two (IgA1, IgA2) generating nine Ig isotypes [15, 42, 43]; each antibody isotype expresses a unique profile of effector mechanisms. The IgG1 subclass predominates in serum and has been the focus for structure/function studies and the predominant format adopted for approved mAb therapeutics. Following binding to its target, with the formation of antibody/antigen complexes, antibodies of the IgG1 subclass may trigger a cascade of inflammatory effector mechanisms that constitute its MoA. Activation of IgG1 mAbs provides natural protection in the killing and removal of bacteria and other ‘foreign bodies’; recombinant antibody therapeutics specific to cancer cells may similarly be activated, resulting in their killing and removal. Each IgG subclass may be exploited to offer a MoA profile appropriate to differing disease indications. The antibody landscape is developing rapidly, as new engineered constructs are customized to optimize treatment protocols, e.g. antibody fragments that enhance solid tumour penetration, antibody-drug conjugates that are internalized into target cells where drug release is effected [12, 13]. It should be noted that the binding of a divalent antibody to a multivalent antigen, e.g. a cancer cell, results in the formation of an immune complex (IC) that is itself an aggregated form of the antibody. ICs are removed and degraded by leucocytes that are also antigen-presenting cells and may therefore, present peptides derived from the paratope of a mAb [44].
The first GP approved by the European Medicines Agency and US Food and Drug Administration was the murine mAb Muromonab (1986, anti-human CD3 OKT3), produced in mouse hybridoma cells; it was administered to patients undergoing acute rejection of a liver transplant. Whilst successfully suppressing the rejection episode, vigorous anti-mouse IgG antibody responses developed in a majority of patients; excluding the possibility of exposing patients to the therapeutic on a subsequent occasion. Over succeeding years genetic and protein engineering techniques were employed to limit immunogenicity by successively increasing the human IgG character of mAbs and expression of selected IgG-Fc mediated MoA. The commercial mAb therapeutic era may be identified with the development of chimeric mouse/human mAbs comprised of the variable regions of a mouse antibody linked to the constant regions of human IgG1, generating a molecule that is ~30% mouse and ~70% human in structure [6–8, 15]. A significant reduction in immunogenicity resulted and a majority of patients could be repeatedly dosed with these mAbs. Further developments defined the amino acid residues of the mouse antibody that formed the antigen binding site (paratope) and transplanted them into selected human variable regions; generating a ‘humanized’ mAb [6–8, 15]. This technology is being superseded by protocols allowing the generation of ‘fully human’ antibodies. These mAbs are products of rearranged human variable region genes, however, by virtue of the fact that they are selected to be anti-self their unique paratope structure may provoke ADA/ATA responses [12, 13] in an outbred human population.
Meta-analysis of the incidence of ADA for the first approved ‘fully human’ anti-TNF-alpha (TNF-α), antibody (Adalimumab, Humira), generated by phage display, ranged from 1–54 %; when administered across multiple inflammatory diseases [6, 7]. The ADA responses may be transitory and/or of low titre and, with good patient management, do not necessarily result in significant adverse reactions [45]; a threshold for immunogenicity is evidenced by the fact that ADA responses are reduced when patients are concomitantly receiving a mild immunosuppressant, e.g. methotrexate [46]. Antibodies generated from phage display libraries depend on the pairing of VH and VL sequences that express anti-self specificities and would be forbidden in vivo, consequently they may express foreign (non-self) epitopes. The alternative technology for generating fully human antibodies from mice rendered transgenic for human immunoglobulin genes results in a natural pairing of VH and VL sequences and the incidence of ADA for the anti-TNFα Golimumab is reported as 0–19% [6].
Glycosylation: recombinant erythropoietin and IgG antibodies
A majority of proteins are generated utilizing the standard 20 amino acids linked through the peptide bond between alpha carbon atoms; in contrast oligosaccharides utilize multiple linkages with a potential to generate enormous glycome and glyco-proteome diversity; it is estimated that six sugar residues can be assembled to generate 1012 unique hexasaccharides [47]. The repertoire of sugars utilized varies between species, gender, cell line, etc.; to generate N-linked oligosaccharides, as previously discussed, or oligosaccharides O-linked through serine, threonine or mannose residues. Importantly, CHO and NS0 (murine) cell lines may add immunogenic non-human oligosaccharide structures to intended ‘fully’ human recombinant therapeutics [13, 48, 49]. Protein engineering and gene ‘knock-out’/‘knock-in’ techniques have been employed to modulate the glycoform profile of GPs; as illustrated in this text for EPO and IgG.
Erythropoietin: Recombinant EPO produced in CHO cells was initially shown to exhibit enhanced activity in vitro, in comparison with approved therapeutic isolated from urine. However, trials in vivo revealed a lack of therapeutic efficacy due to its rapid clearance from the circulation. It was later shown the attached oligosaccharides bore terminal galactose sugar residues, rather than the required sialic acid, resulting in clearance in the liver via the asialoglycoprotein receptor. Fractionation of the CHO-derived EPO allowed preparation of an active sialylated glycoform establishing this parameter as a Critical Quality Attribute (CQA); recombinant EPO, Epoetin received regulatory approval in 1989, is comprised of 165 amino acid residues and bears three N-linked and one O-linked oligosaccharide that accounts for ~40% of its mass [50–53].
Successful worldwide use of recombinant EPO followed but in 1999 a cohort of patients in Europe developed pure red cell aplasia (PRCA) (failure of erythrocyte production) due to the generation of ADA that neutralized not only the therapeutic but also endogenous EPO. Investigation showed that ‘minor’ changes had been introduced in the formulation of EPO produced in Europe, in contrast to the US, that were presumed to have resulted in denaturation/aggregation rendering the product immunogenic [51]. This illustrates the structural fragility of P/GPs and the need for pharmacovigilance throughout the lifetime of a drug. Incidences of PRCA continue to be reported around the world and include ‘biosimilar’ EPOs produced by multiple manufacturers and approved by regional or national regulatory authorities [52]. Experiences of Thailand are salutary, as of 1 January 2009, 14 EPO drugs were licensed in Thailand [53]; they originated from various countries and were not biosimilars as defined by the EU/USA/WHO (World Health Organization) requirements. The cost advantage for these versions of EPO resulted in widespread usage but was coincident with an increase in reports of PRCA due to the generation of ADA [53].
Anticipating expiration of patent protection and the advent of biosimilars the innovator company (Amgen) developed an improved (biobetter) product (darbepoeitin alfa), exhibiting increased efficacy and an extended in vivo half-life; it was approved and received patent protection [54, 55]. The improvement was achieved by the introduction of two additional N-linked oligosaccharide attachment sites resulting in the production of glycoforms bearing additional N-linked oligosaccharides expressing terminal sialic acid residues.
Antibodies: An IgG molecule is comprised of ~1,440 amino acid residues and two N-linked oligosaccharides each comprised of 7 to 13 sugar residues. For decades little account was taken of this ‘minor’ structural feature until it was shown that removal of the oligosaccharide resulted in loss of the ability of ICs to trigger MoAs mediated by activation of FcγR and the C1 complement component, i.e. glycosylation of IgG is a CQA [44, 45]. A minimum requirement for MoA activation is the presence of a seven-residue oligosaccharide on each heavy chain. Differential addition of sugar residues generates a multiplicity of IgG glycoforms that may each modulate the affinity of binding of ICs to effector ligands and hence MoAs, see Figure 2 [44, 45, 56–58].
The glycoform heterogeneity of human serum IgG is not mirrored by the glycoform profile of mAbs produced in CHO, NS0 or Sp2/0 cells; in contrast these cells express a restricted glycoform profile that may include immunogenic non-human glycoforms. The glycoform profile cannot be significantly manipulated by changes in culture conditions, therefore, the contribution of individual glycoforms to MoAs has been investigated by in vitro enzymatic modification of mAb or genetic engineering of the producer cell line. A dramatic outcome from these studies has been the demonstration that IgG antibodies that bear oligosaccharides devoid of fucose residues can exhibit a 10–102 folds increase in their ability to mediate killing of cancer cells by NK (natural killer) cells, similar increases can be achieved for mAb expressing a bisecting N-acetylglucosamine residue. New production CHO cell lines have been established following the ‘knock-out’ of the fucosyltransferase gene or ‘knock-in’ of the bisecting N-acetylglucosamine transferase gene [48, 56–58]. These cell lines have been used to generate approved ‘biobetter’ versions of previously approved mAbs.
Mechanism/Mode of action (MoA)
An antibody may be protective and deliver therapeutic benefit due to its binding specificity for target, e.g. neutralizing an exogenous bacterial toxin or endogenous TNFα, however, when the target is a bacterium or a cancer cell MoAs that result in killing and removal of debris are essential. [56–58]. The IC formed in turn become targets for leucocytes that bear cell surface receptors (FcγR) specific to the IgG heavy chain Fc region. The cross-linking of multiple FcγR results in leucocyte activation with the release of toxic agents and/or ingestion (phagocytosis), ICs may also activate the C1 component of the complement system to trigger a cascade of enzymatic reactions resulting in the formation of a membrane attack complex that inserts into the cellular membrane with the formation of pores that allow the ingress of water and egress of cellular constituents. Molecules released from the complement cascade also adhere to the IC and engage complement receptors expressed on leucocytes to further enhance cellular activation.
There are three families of FcγR (FcγRI, FcγRII, FcγRIII) that are differentially expressed on leucocytes and bind the IgG subclasses selectively, see Table 1; similarly, the C1 component of complement exhibits selective IgG subclass binding. An important parameter that contributes to mAb efficacy is the long half-lives of ~21 days, for IgG1, IgG2 and IgG4, this allows for extended intervals between administered doses; IgG3 has a shorter half-life of ~7 days [59]. Clearance of IgG is mediated via binding to the neonatal Fc receptor (FcRn) that is expressed on many cell types and is independent of the IgG glycoform, [56–58]. Antibodies of the IgG1 and IgG3 subclass have very similar functional profiles but the IgG2 and IgG4 subclasses exhibit unique profiles. It is important therefore when developing a mAb therapeutic to anticipate the preferred MoA in vivo and generate mAbs of an appropriate IgG subclass. To date, of the 160 mAbs listed in the international immunoglobulins database (IMGT: ImMunoGeneTics) 136 are IgG1, 8 IgG2, 2 IgG3 and 14 IgG4 [58, 60]
Summary
It is posited that all recombinant P/GP therapeutics may be immunogenic, at least in a proportion of patients, resulting in loss of efficacy and/or the advent of adverse events. The significance of this outcome should be assessed with respect to the disease being treated, thus cancer and transplant patients will be receiving concomitant cytotoxic drugs that induce various levels of immunosuppression. By contrast patients with chronic diseases undergo long-term exposure to recombinant P/GPs and are at greater risk of developing ADA, that may be circumvented by treatment with mild immunosuppressive agents. Currently, an ever expanding armamentarium of biologicals is being developed that includes engineered IgG molecules that differ in structure to endogenous IgG and/or their fragments. Such manipulations increase the propensity for immunogenicity, however, outcomes may differ between acute conditions for which treatment may be within a relatively short time frame and chronic diseases that require long-term exposure.
Advances in gene sequencing techniques are allowing identification of polymorphisms in ‘susceptibility’ genes that allows for stratification of patients. Stratification can contribute to the development of personalized medicine through identification of cohorts of patients responsive to a given therapeutic whilst similarly identifying patients that are not likely to benefit. Stratification of ‘common’ diseases may identify increasingly small cohorts of patients such that their condition may be classified as an orphan disease, indicative of a need for treatment with expensive customized biologicals, i.e. personalized medicine. This may result in a conflict between the high cost of development of specialist biologicals and the diminished market that stratification identifies. Some ‘respite’ may be offered by the development of biosimilars, however, they are currently providing only ~15–30% reduction in cost. The conflict between our ability to deliver ever expanding therapies for human health care, from conception to death, and to provide equity in delivery will continue and become ever more contentious.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
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Author: Professor Roy Jefferis, PhD, DSc, MRCP, FRCPath, Emeritus Professor of Molecular Immunology, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
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Abstract:
Biosimilar medicines are having a global effect, and as such regulatory agencies worldwide are assessing how to respond to them. Here, two events held by GaBI for the Colombian medicines regulatory agency (INVIMA) are reported. The first was an educational workshop held in 2016 to discuss approaches to evaluating biosimilar products and the second was a scientific meeting on the quality assessment for biosimilars held in 2017. Both provided a forum to exchange knowledge on best practice in this new and important area.
Submitted: 7 February 2018; Revised: 8 May 2018; Accepted: 9 May 2018; Published online first: 22 May 2018
Introduction
Similar Biotherapeutic Products (SBPs or biosimilars) have emerged as a new class of biotherapeutic agent. They are being increasingly developed and are becoming more available worldwide. However, approaches to how they are regulated vary across the world. The European Union (EU) has successfully pioneered regulatory procedures and has over 10 years of experience in the regulation and approval of biosimilars. In light of this, other countries across the globe are turning to regulatory experts from Europe and the US for advice on how best to conduct quality assessment of biologicals/biosimilars, to ensure that safety and efficacy of treatment is upheld.
To facilitate discussion concerning quality assessment of biologicals/biosimilars in Colombia, the Generics and Biosimilars Initiative (GaBI) organized an educational workshop [1] and a follow-up meeting [2] in collaboration with the National Food and Drug Surveillance Institute of Colombia (Instituto Nacional de Vigilancia de Medicamentos y Alimentos, INVIMA), in 2016 and 2017 respectively. Presentations were made by both international speakers, as well as regulators from Colombia.
The First INVIMA Educational Workshop on the Assessment of Similar Biotherapeutic Products [1] was an interactive event held on 14 June 2016. The format used was similar to that used in prior educational workshops as reported in GaBI Journal [3, 4]. More details of the methods and case presentations can be found in the published reports of the First Latin American Educational Workshop on Similar Biotherapeutic Products [3] and the First MENA Educational Workshop on Regulation and Approval of Similar Biotherapeutic Products/Biosimilars [4]. Summaries of the presentations that were given on analytical comparability, clinical and non-clinical assessment, and safety assessment, are available in the published reports of the Roundtable on biosimilars with European regulators and medical societies [5].
The Second Colombian Scientific Meeting on Quality Assessment of Biosimilars/Similar Biotherapeutic Products [2] was held on 15 August 2017, and focussed on the key topics of: comparability of production processes, design and execution of analytical comparability studies/forced degradation studies, analytical methods, preparation and production of reference standards, and development and validation of host cell protein assays, with a keynote presentation on the Norwegian NOR-SWITCH study on the replacement from originator product to biosimilar infliximab. The meeting was chaired by Dr Elaine Gray and Dr Paul Matejtschuk, who are both Principal Scientists at the UK’s National Institute for Biological Standards and Control (NIBSC).
Both Colombian meetings were held in Bogotá. The list of speakers and the slides they presented are available on the GaBI Journal website (www.gabi-journal.net/about-gabi/educational-workshops).
2016 Quality Assessment of Biosimilars Educational Workshop
In addition to the expert presentations as delivered in prior meetings [3–5], Dr Elwyn Griffiths, former Director General of the Biologics and Genetic Therapies Directorate, Health Canada, gave a presentation entitled ‘Regulatory assessment of already approved rDNA-derived biotherapeutics’, which was an update to that given at the First Turkish Interactive Workshop on Regulation and Approval of Similar Biotherapeutic Products/Biosimilars [4]. He highlighted the role of the World Health Organization (WHO) to ensure global harmonization and regulation of rDNA-derived biotherapeutics. He also summarized the issues they have encountered in implementation, particularly related to products already approved prior to the development of regulatory processes. He introduced the WHO’s new guideline for stepwise product specific regulatory assessment and highlighted the WHO document on regulatory assessment on rDNA derived biotherapeutics.
Summary of the discussion that followed the regulatory presentations of the 2016 workshop
Initially, a query was raised on whether clinical data is required when a manufacturing process is scaled up; with a simple linear up-scaling of a process it was considered that clinical data is not generally required but if there are procedural changes, then such data may be required and comparability cannot be assumed. Currently, for a biosimilar to be approved, clinical data must be supplied to support biosimilarity.
When asked if small biologicals approved without clinical studies, could be termed biosimilars, it was noted that this had not been done in Europe nor in the US. It was explained that, in biosimilar production, a biosimilar does not need to be manufactured using the same expression system as the reference biological and, in practice, using the exact same system would be impossible. However, the manufacturing process must produce an active substance sufficiently similar to that produced by the originator manufacturer. When developing a biosimilar, companies create a database based on a relatively large number of reference batches in order to have sufficient information on the reference product to produce their own Quality Target Product Profile (QTPP). This is not directly required by regulators, but such data is needed to ensure product comparability.
Regarding compiling comparability data, the biosimilar manufacturer must also produce data on the reference product at the same time as producing data on the biosimilar. This data is not readily available and, although some results relating to originator products are published on occasion, these should always be reproduced and made available by the biosimilar manufacturer in order for them to undertake comparability studies. For clinical comparison, pharmacokinetic (PK) and pharmacodynamic (PD) comparisons are a minimum requirement for authorization of biosimilars and in addition, a clinical assessment of the immunogenicity.
Parallel case study working sessions
Case study working sessions took place following the presentations (downloadable from the GaBI website [1]). These followed the same format as those described in previous workshops [3, 4, 6], where two fictional cases of follow-on biological therapeutics are described, one an erythropoietin product and the other a monoclonal antibody. The participants were divided into discussion groups where they evaluated the fictional data supplied. The group discussions are summarized in Tables 1 and 2.
2017 Quality Assessment of Biosimilars/Similar Biotherapeutic Products Scientific Meeting
The 2017 meeting began with Welcoming Remarks by Mr Javier Humberto Guzmán Cruz, Director General of INVIMA, who gave a short presentation on the current development of INVIMA and the health system in Colombia.
The presentation began with an outline of the progress made in Colombia in the last 25 years in terms of universal health coverage. Mr Guzmán noted that Colombia is now in the process of entering the Organisation for Economic Co-operation and Development (OECD). As part of this, experts visited Colombia and carried out a review of Colombia’s health system in which they stated that, ‘Colombia has a well-designed health system, with broadly effective policies and institutions that other countries could learn from and that deserves to be better known internationally’. However, he added that the health system in Colombia is fragile and needs to remain sustainable. To ensure this, pharmaceutical policy needs to be kept up-to-date and innovations incorporated in a controlled manner to guarantee access to safe and efficacious products. Here, Mr Guzmán noted that INVIMA can have an important role in influencing pharmaceutical policy.
INVIMA was created in 1993, and the institute became officially established in 1995, following the passing of a law that aimed to achieve healthcare reform. It has grown substantially in 25 years and now has a budget of US$48 million and many facilities. However, INVIMA faces challenges in the coming years, particularly those posed by the entry of products from large pharmaceutical manufacturers to the Colombian market. Regulators and the Colombian health system need to do work on deciding what gets included in the market to enable the development of frameworks that encourage competition to create access to generics and biosimilars. Mr Guzmán stated that, in Colombia, improving competition that guarantees quality, safety and efficacy is more important than regulation of the pricing of therapeutics. In the last seven years, no biosimilars have been approved, as the guidelines for regulatory approval were not yet developed. Now that the regulations on biologicals/biosimilars are in place, the next challenge is effective implementation. INVIMA has the role of implementing the new regulation on biologicals/biosimilars, and staff are trained both internally and abroad to implement this new legislation. Nonetheless, they are keen to receive advice from those in Europe and the US, who have useful experience in implementation of similar regulations.
Following the Welcoming Remarks, a series of additional presentations were given by experts from Europe and the US (presentations downloadable from the GaBI website [2]). A full manuscript on the presentation of ‘Biosimilar regulations in Colombia,’ is published in GaBI Journal [7]; and information about the presentation entitled ‘Switching from originator products to biosimilars in rheumatology, dermatology and gastroenterology: clinical evidence,’ which described the NOR-SWITCH study, is also published in GaBI Journal [8].
Summary of the discussion that followed the speaker presentations of the 2017 meeting
Discussion following ‘Biosimilar regulations in Colombia’ Dr Gray asked if Colombia expects that a national pharmaceutical company would attempt to register for the three different pathways for products in the future, either via the complete dossier, comparability, and abbreviated comparability approach. Ms Garcia responded that currently, Colombia does not yet have laboratories that will submit information to comply with the new regulations as they have not yet been implemented, however, there are interests from multinational companies to support this requirement.
Discussion following ‘Switching from originator products to biosimilars in rheumatology, dermatology and gastroenterology: clinical evidence’ Professor Tore Kristian Kvien was asked about the results obtained in the switching clinical trials in Scandinavian populations and to what extent these results can be extrapolated to populations, such as the Colombian population. He stated that, in terms of efficacy, there should be no concern using the data with another population and that the NOR-SWITCH data can be used in Colombia.
With regard to patients whose treatment was switched to the Remsima biosimilar and whose disease then worsened, Professor Kvien noted that all patients were followed for one year, and those whose condition worsened also received additional treatment. If they had progression of their disease that required some change in therapy, then they were switched to another biological agent and no patients received the originator Remicade.
In relation to pharmacovigilance data, Professor Kvien noted that this was not part of the NOR-SWITCH study because it was a randomized clinical trial. However, he added that, in Norway, there is a registry called the NOR-DMARD, the Norwegian Antirheumatic Drug Register, and that the data from NOR-DMARD was also examined regarding patients who started with the biosimilar infliximab and patients who have switched from Remicade to Remsima. There does not seem to be any major concern with regards to differences in pharmacovigilance data. Despite this, he noted that the data from NOR-DMARD are not as robust as the data from DANBIO (the nationwide registry for biological therapies in Denmark), which includes some pharmacovigilance data which also support switching.
When asked if he thinks clinical trials are absolutely necessary to confirm efficacy and safety of a biosimilar agent, Professor Kvien said there is a general agreement that, with the current regulations, preclinical quality data need to be generated which support biosimilarity, but this needs confirmation using clinical studies (as outlined in his presentation for CT-P13 and SB4) [8]. Regarding whether or not a NOR-SWITCH study for every biosimilar is needed, another randomized switch study may be required. He gave the example of adalimumab, which is in need of this as it is also immunogenetic. However, it may not be feasible to perform a blinded controlled study of switching from an originator to a biosimilar self-administered drug.
Given the progress in Norway with the adoption of biosimilars, Professor Kvien noted that they would continue on the current path and introduce more biosimilars as they enter the market. The annual tender system means that the system is very competitive which leads to lower prices for the different biosimilars, and the originator products. Regarding his advice for Colombia, he thinks that in general, transparency and competition is important. It is also important that regulators collaborate with key opinion leaders and experts in the different clinical disciplines, so that there are alliances with the clinical environment, which will help to implement the use of biosimilars in Colombia.
Discussion following ‘Preparation and production of reference standards in support of biotechnology products’ Dr Matejtschuk was asked about secondary standards and what they are used for. He said that a secondary standard might be a pharmacopoeial standard and gave the example of a standard from the United States Pharmacopeia (USP) or European Directorate for the Quality of Medicines & HealthCare (EDQM). This will not usually be a primary standard as the dose is not defined, but will actually be a secondary reference material. He noted that working standards could also be secondary standards. Dr Gray added that the WHO International Standards (IS) are primary standards and as such are produced infrequently with a substantial international collaboration required to assign values, and their usage is carefully controlled to maintain stocks and ensure continuity. Pharmacopoeial, regional, working or in-house standards are secondary standards, calibrated against the IS.
Discussion following ‘Value assignment of International Standards: challenges for potency labelling of biotechnology/biosimilar products’ There was a question about reference units, standards and dosing. Dr Gray said that, for a product such as a monoclonal antibody, which is already dosed in milligrams, there would be no attempt to change the dosing to arbitrary units. So, the activity in terms of the international unit is really for the control of the bioassay, this does not impact on the dosing and potency labelling of these products. The aim of such standards would be to aid manufacturers in monitoring consistency of production. For other biological products that do label potency in international units, such as for the coagulation factors, the continuity of the unit is ensured by calibrating against the existing standard, in order to have traceability of the unit each time a replacement standard is made. However, some slight variability is inevitable because batches of such materials are unique, and there may be some drift in potency depending on the assay and the materials themselves.
Conclusion
Colombia’s health service has improved greatly over the past 25 years and standards of heath care and access to treatments are high. Over the last seven years the country has been developing a regulatory framework to allow biosimilar products to enter the market and Colombia is now at a point where it can start implementing regulatory approval policy for biologicals/biosimilars. The educational workshop and the scientific meeting created a platform for those involved with biological/biosimilar regulation in Colombia to meet with experts from Europe and the US and a number of interactive discussions took place. The attendees shared ideas with the speakers and received clarification on issues of interest and concern.
Speaker Faculty and Moderators
Speakers 2016 Educational Workshop Niklas Ekman, PhD, Finland Thijs J Giezen, PharmD, MSc, PhD, The Netherlands Gustavo Grampp, PhD, USA Elwyn Griffiths, DSc, PhD, UK Professor Andrea Laslop, MD, Austria Robin Thorpe, PhD, FRCPath, UK
2017 Scientific Meeting Johanna Andrea Garcia Cortes, MSc, Colombia Elaine Gray, PhD, UK Professor Tore Kristian Kvien, MD, Norway Jennifer Liu, PhD, USA Paul Matejtschuk, PhD, CChem, UK Sundar Ramanan, PhD, USA
Moderators and Co-moderators 2016 Educational Workshop Jeannette Daza Castillo Andrey Forero Espinosa Angélica Fula Arguello Diego Alejandro Gutierrez Triana Inés Elvira Ordoñez Claudia Yaneth Niño C
Acknowledgement
The Generics and Biosimilars Initiative (GaBI) wishes to thank Dr Robin Thorpe and Professor Andrea Laslop, chair and co-chair of the 2016 workshop; and Dr Elaine Gray and Dr Paul Matejtschuk, chair and co-chair of the 2017 meeting; for their strong support through the offering of advice and information during the preparation of the workshop and meeting, respectively. Further, GaBI wishes to thank Mr Francisco Javier Sierra Esteban of INVIMA for his feedback and comments on this Meeting Report.
The authors would like to acknowledge the help of all the workshop and meeting speaker faculty and participants, each of whom contributed to the success of the workshop and meeting and the content of this report, as well as the support of the moderators and co-moderators for the 2016 workshop: Jeannette Daza Castillo, Andrey Forero Espinosa, Angélica Fula Arguello, Diego Alejandro Gutierrez Triana, Inés Elvira Ordoñez, Claudia Yaneth Niño C, in facilitating meaningful discussion during the parallel group discussions; and presenting the discussion findings at the 2016 workshop.
Lastly, the authors wish to thank Ms Alice Rolandini Jensen, GaBI Journal Editor, in preparing this meeting report manuscript and providing English editing support on the group summaries and for finalizing this manuscript.
Competing interests: The workshop and meeting were sponsored by an unrestricted educational grant to GaBI from Amgen Inc.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Elaine Gray, PhD
Principal Scientist, Haemostasis Section Biotherapeutics Group
Paul Matejtschuk, PhD, CChem
Principal Scientist – Standardisation Science
National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK
Robin Thorpe, PhD, FRCPath
Deputy Editor-in-Chief, GaBI Journal
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Author for correspondence: Robin Thorpe, PhD, FRCPath, Deputy Editor-in-Chief, GaBI Journal
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: Magaly Perez-Nieves1, MPH, PhD; Robyn K Pollom1, ANP; Ran Duan1, PhD; Samaneh Kabul1, PharmD; Amy M DeLozier1, MPH; Puneet Kaushik2, MPharm; Liza L Ilag1, MD
Background: This analysis evaluates the patient-reported outcomes (PROs) in two randomized studies of biosimilar LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), when used in combination with mealtime insulin lispro in patients with type 1 diabetes mellitus (T1DM) or oral anti-hyperglycaemics in patients with type 2 diabetes mellitus (T2DM). Methods: Patients with T1DM on basal-bolus insulin therapy were randomized to receive once-daily LY IGlar or IGlar in combination with mealtime insulin lispro for 52 weeks (ELEMENT 1) or patients with T2DM on oral agents with or without previous basal insulin were randomized to receive once-daily LY IGlar or IGlar for 24 weeks (ELEMENT 2). PROs assessed included Insulin Treatment Satisfaction Questionnaire (ITSQ) and the Adult Low Blood Sugar Survey (ALBSS). Results: In ELEMENT 1 (LY IGlar, n = 268; IGlar, n = 267) and ELEMENT 2 (LY IGlar, n = 376; IGlar, n = 380), there were no statistically significant between-group differences in either trial on the ITSQ or ALBSS. In ELEMENT 1, patients in both treatment groups demonstrated improvements from baseline in all domains and total scores with significant improvements in ITSQ inconvenience of regimen, glycaemic control, insulin device satisfaction domains, and total transformed score; patients using LY IGlar had significant improvements in ALBSS total score. In ELEMENT 2, both treatment arms showed significant improvements in the ITSQ and glycaemic control domains, and LY IGlar also showed significant improvements in the ALBSS behaviour subscale. Conclusion: Findings demonstrated that patients with T1DM and T2DM receiving LY IGlar reported similar levels of insulin treatment satisfaction and fear of hypoglycaemia as patients using IGlar.
Submitted: 24 November 2017; Revised: 4 July 2018; Accepted: 9 July 2018; Published online first: 23 July 2018
Introduction
Diabetes is a public health concern affecting an estimated 29.1 million people in the US [1] and an estimated 382 million people worldwide [2]. Insulin is a lifesaving treatment in patients with type 1 diabetes mellitus (T1DM) and is frequently used to improve glycaemic control in patients with type 2 diabetes mellitus (T2DM). In spite of the fact that 44% of diabetes patients in the US have HbA1c levels over 7%, there is only a 26% reported use of insulin. This indicates the possibility of barriers to broad acceptance of insulin with cost being considered one of the various possible limiting factors to the access of biologicals [3]. This paves the way for follow-on versions of the biological, namely biosimilar insulin with potential cost savings [4, 5].
The current evidence required to establish biosimilarity is limited to clinical measures of efficacy and safety without involving patient-reported information about their experiences [6]. Incorporating the patient perspective in the development, regulatory approval and health technology assessment of new medicines continues to gain importance to decision makers in the healthcare environment today. Patient-reported outcomes (PROs) provide a critical understanding of drug benefits and harm from the patients’ perspective and come directly from them without any evaluation by a clinician, or anyone else. They are not only an important part of a successful drug development, but also an addition to cost savings as key drivers of value proposition [7, 8]. Incorporating the patient perspective aids in gathering patient acceptability information and can serve as important drivers for the clinical decision makers [9].
Once-daily insulin glargine (IGlar, Lantus®; Sanofi US, Bridgewater, NJ, USA) is a widely used basal insulin analogue that has been shown to have a lower tendency toward hypoglycaemia compared to Neutral Protamine Hagedorn (NPH) insulin [10], and has been associated with improvements in treatment, patient satisfaction and well-being [11–13]. LY2963016 insulin glargine (LY IGlar; Eli Lilly and Company, Indianapolis, IN, USA) is an insulin glargine product with similar efficacy and safety to IGlar as evident in two phase III trials (a 52-week, open label trial in adults with T1DM; and a 24-week, double-blind trial in adults with T2DM) [14, 15]. The scope of the phase III studies was to evaluate the clinical efficacy and safety outcomes of LY IGlar compared to IGlar. A secondary objective of these clinical trials was to evaluate the patient-reported outcomes of treatment satisfaction and fear of hypoglycaemia between the two treatments.
LY IGlar is the first insulin product to be approved through an abbreviated approval pathway under the Federal Food, Drug, and Cosmetic Act, requiring submission of 505(b)(2) application, which relied in part, on the US Food and Drug Administration’s (FDA) assessment of effectiveness and safety for Lantus IGlar to support approval. The use of this pathway is for cases where the drug relied upon made its application under section 505 requiring new drug application (NDA) and has been explored by insulin, calcitonin and human growth hormone. For other follow-on biologicals, the 351(k) pathway is used which represents an abbreviated pathway for approving products shown to be biosimilar to an FDA-approved reference product [16, 17]. LY IGlar was demonstrated to be sufficiently similar to Lantus to scientifically justify reliance. LY IGlar-specific data was also furnished to FDA to establish the drug’s safety and efficacy [18].
The objective of the analysis was to evaluate patient-reported outcomes of insulin treatment satisfaction and fear of hypoglycaemia in patients on LY IGlar compared to IGlar.
Methods
Study design Details regarding the primary efficacy and safety outcomes of ELEMENT 1 and ELEMENT 2 have been reported previously [14, 15]. Briefly, ELEMENT 1 was a phase III, randomized, open-label, non-inferiority study in adult patients with T1DM on basal-bolus insulin therapy. Patients were randomized to LY IGlar or IGlar, using a 1:1 unit conversion from pre-study insulin regimen to once daily LY IGlar or IGlar in combination with premeal insulin lispro. Treatment groups used a prefilled insulin injection device to deliver study drug; KwikPen™ for LY IGlar and insulin lispro or SoloSTAR® for the reference product IGlar. The treatment period was 24 weeks (primary endpoint) with a 28-week extension (52 weeks total) [19]. PROs were assessed at Week 2 (baseline), Week 24, and Week 52 or Early Discontiuation visit.
ELEMENT 2 was a phase III, randomized, double-blind 24-week, non-inferiority study in adult patients with T2DM on two or more oral anti-hyperglycaemic medications who were either insulin naïve or on prestudy IGlar. Patients administered insulin using syringes and covered insulin vials provided during the study to maintain the blinding of treatment [20]. PROs were assessed at Week 4 (baseline), Week 12, and Week 24 or Early Discontinuation visit.
Each patient provided informed consent. Protocols for each of the research trials were approved by the governing institutional review boards, and both trials conformed to the provisions of the Declaration of Helsinki.
Patient-reported outcomes Insulin Treatment Satisfaction Questionnaire Treatment satisfaction related to insulin therapy was assessed using the Insulin Treatment Satisfaction Questionnaire (ITSQ) [19], see Table 1. The ITSQ is a 22-item instrument with five domains: 1) inconvenience of regimen; 2) lifestyle flexibility; 3) glycaemic control; 4) hypoglycaemic control; and 5) insulin delivery device satisfaction. All raw data (domain and total) were transformed to a 0–100 scale, with higher scores corresponding to better treatment outcomes.
Adult Low Blood Sugar Survey Fear or worry of hypoglycaemic events associated with insulin therapy and subsequent behaviours associated with avoiding future events was measured using the Adult Low Blood Sugar Survey (ALBSS), see Table 1, [20, 21]. The ALBSS is a 33-item instrument with two domains, behaviour and worry. Scores were calculated by summing patient responses to items (behaviour range 0–60; worry range 0–72). Higher scores on ‘behaviour’ items (related to avoidance of hypoglycaemia) reflect greater awareness and/or effort of the patient to prevent low blood sugar; higher scores on ‘worry’ items (related to worries about low blood sugar and its related consequences) reflect greater patient concern about having low blood sugar and related symptoms.
Statistical analysis Demographic and baseline characteristics were summarized by treatment group for the full analysis set populations, which are based on the intent-to-treat principle and included all patients who were randomized and had taken at least one dose of study medication. The treatment groups were compared with a two-sample t-test for continuous variables and Fisher’s exact test or Pearson’s chi-square test for categorical variables. All analyses were conducted with SAS version 9.2.
All individual patient domain scores were calculated at baseline, 24 weeks, and endpoint using the non-missing items. The transformed scores (domain and total) in ITSQ and the raw scores (domain and total) in ALBSS were analysed using the analysis of covariance model for the full analysis set as specified above, including imputation of domain and total scores by last observation carried forward.
Results
Baseline characteristics ELEMENT 1 (T1DM) The baseline characteristics in the LY IGlar and IGlar treatment arms in ELEMENT 1 were well balanced, see Table 2. There were 535 patients with T1DM (LY IGlar, n = 268; IGlar, n = 267) with a mean age of 41 years and a mean duration of diabetes of 16.4 years. Eighty-five per cent of the patients were using insulin glargine once daily instead of Neutral Protamine Hagedorn insulin or insulin detemir before randomization (88% IGlar, 81% LY IGlar). During the study period, most patients took their basal insulin injections in the evening or at bedtime (81% LY IGlar, 82% IGlar). Some individuals did not have data collected on the ITSQ (LY IGlar, n = 4; IGlar n = 4) and ALBSS (LY IGlar, n = 3; IGlar n = 4) questionnaires at baseline or during a follow-up visit.
ELEMENT 2 (T2DM) In ELEMENT 2, the baseline characteristics in the LY IGlar and IGlar treatment arms were well balanced, see Table 2, and included 756 patients with T2DM (LY IGlar, n = 376; IGlar, n = 380) with a mean age of 59 years and a mean duration of diabetes of 11.5 years; most patients were insulin naïve (LY IGlar 59% and IGlar 62%). In the LY IGlar treatment group, approximately 41% of the patients reported previously taking IGlar at study entry compared to 38% in the IGlar group. At Week 4 (baseline in ELEMENT 2), 7% and 9% of the individuals in the LY IGlar and IGlar treatment arms, respectively, did not take the ITSQ and ALBSS questionnaires.
Patient-reported outcomes
ELEMENT 1 (T1DM) LY IGlar and IGlar treatment comparisons of ITSQ and ALBSS outcomes showed no statistically significant between treatment differences in any domains, see Table 3. In both the LY IGlar and IGlar treatment arms, there were improvements from baseline on all domains and total scores, and significant improvements on the ITSQ inconvenience of regimen, glycaemic control, and insulin delivery device satisfaction subscales, and total transformed score. Patients using the LY IGlar had significant improvements in ALBSS total score indicating reduced patient fear of hypoglycaemic events.
ELEMENT 2 (T2DM) Treatment comparisons between LY IGlar and IGlar showed no statistically significant differences in change from baseline (Week 4) of the ITSQ and ALBSS total and domain scores, see Table 4. In ELEMENT 2, the ITSQ glycaemic control subscale measure for LY IGlar and IGlar demonstrated significant improvements, and inconvenience of regimen, lifestyle flexibility, and hypoglycaemic control showed a numerical worsening of scores in both treatment arms. The LY IGlar treatment arm showed significant improvements on the ALBSS behaviour subscale indicating reduced behaviours to avoid low blood sugar and its consequences.
Discussion
The findings of the studies indicate no differences in terms of PROs for biosimilar and reference insulin, signifying equal patient acceptability to use of either LY IGlar or IGlar for treatment of T1DM and T2DM. Results from clinical trials have already shown similarity in clinical efficacy and safety profiles for the two treatments in the pivotal ELEMENT 1 (NCT01421147) and ELEMENT 2 studies (NCT01421459). The PRO findings together with clinical efficacy and safety profiles demonstrate similarity between the biosimilar and reference product [14, 15].
In previous studies, IGlar was associated with greater treatment satisfaction, less fear of hypoglycaemia, and improvement in PROs when compared to therapy intensification with oral anti-diabetics or other premix insulin regimens [22, 23]. In our study, improvements from baseline on the ITSQ subscales, and total transformed score for both the LY IGlar and IGlar demonstrated patient satisfaction with the treatments. Patient satisfaction not only leads to improvement in patient’s acceptance of therapy, but may positively influence adherence and persistence which are important factors in assessing overall treatment success, in addition to the benchmark HbA1c marker [24].
Fear of hypoglycaemia has been a significant barrier for patients and physicians when deciding to start insulin therapy [25]. This can sometimes lead to delay in initiation or impact adherence/persistence of insulin, which can impact glycaemic control and lead to long-term complications with diabetes. However, in our study, where about 60% of patients were insulin-naïve, improvements in ALBSS total score indicate reduced patient fear of hypoglycaemic events in patients administered LY IGlar or IGlar. This is similar to another study comparing IGlar with targeted glulisine versus premixed insulin, which showed a less marked rise in fear of hypoglycaemia in IGlar-treated patients [26].
Further, mode of administration of drug also plays an important role in patient satisfaction. Insulin pens lead to improved patient satisfaction and adherence, greater ease of use, and improved dosing accuracy [27]. In a direct comparison in two separate clinical trials, the pen delivery devices were preferred over vial and syringe by patients [28, 29]. In ELEMENTS 1 trial, all patients used insulin pen delivery devices and experienced similar overall satisfaction with biosimilar and reference insulin.
Although these insulin therapies had similar efficacy and safety, including incidences and rates of hypoglycaemia in the pivotal ELEMENT 1 and ELEMENT 2 studies [14. 15], it is important to also look closely at the patient perspectives with consideration that these insulin glargine products are manufactured by different companies. Further, the findings should be considered cautiously as ELEMENT 1 was an open label study and there were no observed differences in hypoglycaemia rate or incidence between the two groups.
Conclusion
Patient-reported outcome measures are increasingly used alongside clinical efficacy and safety measures for the evaluation of treatment and management for diabetes. The use of this type of data is particularly important in chronic conditions where treatment can influence a person’s quality of life [30]. As expected, in our study, the patient-reported outcomes indicate similar treatment satisfaction and fear of hypoglycaemia between the two insulin glargine products: LY IGlar and IGlar. These findings along with clinical data will provide reassurance to both patients and healthcare providers that LY IGlar provides similar efficacy, safety, and patient-reported outcomes when compared to IGlar. This study further supports LY IGlar as an option for physicians and patients when choosing a basal insulin therapy that meets individual needs. The findings in this study may also help build the confidence of patients and their healthcare providers alike in use of biosimilar insulins and inform their decisions regarding treatment options for basal insulin therapy.
Acknowledgments
The authors wish to thank Emily Cullinan, PhD, and Teri Tucker, BA, from inVentiv Health Clinical (funded by Eli Lilly and Company) for their writing and editorial support.
Competing interests: This study was supported by Eli Lilly and Company and Boehringer-Ingelheim. The authors are employed by Eli Lilly and Company and/or one of its subsidiaries and minor stockholders in Eli Lilly and Company. The authors have indicated that they have no other conflicts of interest with regard to the content of this manuscript.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Magaly Perez-Nieves1, MPH, PhD
Robyn K Pollom1, ANP
Ran Duan1, PhD
Samaneh Kabul1, PharmD
Amy M DeLozier1, MPH
Puneet Kaushik2, MPharm
Liza L Ilag1, MD
1Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA 2Eli Lilly Services India Private Limited, Group Leader-GPORWE, Global Patient Outcomes and Real World Evidence, 1st Floor, Building Primrose (7B), Wing B, Embassy Tech Village, Devarabisanahalli, 560103 Bengaluru, India
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RAND. 2014. 6. U.S. Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry [homepage on the Internet]. [cited 2018 Jul 4]. Available from: https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf 7. U.S. Food and Drug Administration. FDA Center for Drug Evaluation and Research (CDER). Strategic plan 2013-2017 [homepage on the Internet]. [cited 2018 Jul 4]. Available from: https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM376545.pdf 8. Shivers JP, Brown AS, Yarchoan M, et al. Patient and Educator attitudes toward biosimilar insulin. Cureus. 2012;4(9):e10. [cited 2018 Jul 4]. Available from: https://www.cureus.com/posters/12-patient-and-educator-attitudes-toward-biosimilar-insulin 9. Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0): What are patient-reported outcomes (17.1). 10. Clissold R, Clissold S. Insulin glargine in the management of diabetes mellitus: an evidence-based assessment of its clinical efficacy and economic value. Core Evid. 2007;2(2):89-110. 11. Barnett AH. Insulin glargine in the treatment of type 1 and type 2 diabetes. Vasc Health Risk Manag. 2006;2(1):59-67. 12. Gallen IW, Carter C. Prospective audit of the introduction of insulin glargine (lantus) into clinical practice in type 1 diabetic patients. Diabetes Care. 2003;26(12):3352-3. 13. Witthaus E, Stewart J, Bradley C. Treatment satisfaction and psychological well-being with insulin glargine compared with NPH in patients with Type 1 diabetes. Diabet Med. 2001;18(8):619-25. 14. Blevins TC, Dahl D, Rosenstock J, Ilag LL, Huster WJ, Zielonka JS, et al. Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus®) in patients with type 1 diabetes in a randomized controlled trial: the ELEMENT 1 study. Diabetes Obes Metab. 2015:17(8):726-33. 15. Rosenstock J, Hollander P, Bhargava A, Ilag LL, Pollom RK, Zielonka JS, et al Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study). Diabetes Obes Metab. 2015:17(8):734-41. 16. McShea M, Pollum RD. Biosimilars and follow-on biologics: a pharmacist opportunity. Pharmacy Times. 2016 Nov 16. 17. Johnson JA. FDA regulation of follow-on biologics. Congressional Research Service Report for Congress 2010. 18. U.S. Food and Drug Administration. FDA approves Basaglar, the first “follow-on” insulin glargine product to treat diabetes [homepage on the Internet]. [cited 2018 Jul 4]. Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm 19. Anderson RT, Skovlund SE, Marrero D, Levine DW, Meadows K, Brod M, et al. 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Author for correspondence: Magaly Perez-Nieves, MPH, PhD, Research Scientist, Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Disclosure of Conflict of Interest Statement is available upon request.
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Abstract:
The Opinion article of Niazi urges the US Food and Drug Administration (FDA) to make adjustments to its guidance on biosimilar development. This article comments on some of the proposals from a global perspective, including the global reference product and the biosimilar comparability programme. FDA Commissioner Scott Gottlieb has stated that the biosimilar market suffers from a lack of competition. Therefore, the FDA approach to biosimilars, including many of the issues raised by Niazi will be revisited in the new Biosimilar Action Plan of the FDA.
Submitted: 26 July 2018; Revised: 26 July 2018; Accepted: 27 July 2018; Published online first: 30 July 2018
The Opinion article of Adjunct Professor Niazi in this issue of GaBI Journal argues that the US Food and Drug Administration (FDA) could make several adjustments to its guidance in order to facilitate the development of biosimilars [1]. The author points out that the current requirements have led to high costs and long development times which discourage small- and medium-sized enterprises from entering biosimilar development. Indeed, FDA Commissioner Scott Gottlieb has stated that the biosimilar market suffers from a lack of competition [2, 3]. Some of the proposals of the author deserve comments from a global perspective.
Bridging studies and substitution
Acceptance of a foreign-sourced reference product in clinical studies is highly desirable for global development programmes of biosimilars. Repetition of clinical trials in different regulatory regions is unnecessary, expensive and ethically questionable. Most regulatory agencies require ‘bridging studies’ to demonstrate that the foreign-sourced reference product and the corresponding domestic product are highly similar. FDA has the most stringent requirements, including not only analytical comparability but also additional human pharmacokinetic/pharmacodynamic (PK/PD) studies [4].
The author proposes that bridging studies should not be required if the foreign and domestic products have the same composition and have been licenced on the basis of the same documentation. In this case, products sourced from different but ‘highly regulated’ regions should be very similar and safe since they have been used over 10 years under regulatory surveillance. However, if there are significant differences in the regulatory history, there is a theoretical possibility that the two products have ‘drifted apart’ over the years because of different changes to their manufacturing processes. In addition, the waiver of bridging studies may face legal obstacles in some jurisdictions. Nevertheless, the developers should be able to get waivers for at least some bridging studies if they can demonstrate that, based on the regulatory history of the products, differences between the domestic and foreign reference product are highly unlikely. Collaboration and data sharing between the key regulatory agencies would facilitate the acceptance of a global reference product. Global development of biosimilars is in the interest of all countries, including the US. Therefore, FDA should act in a pragmatic way to promote global development of biosimilars.
The author argues that a waiver of bridging studies would not be possible in a study intended to support interchangeable status of a biosimilar product. This recommendation is based on the current FDA draft guideline on the interchangeable biosimilars [5]. Unfortunately, the requirement may create a bottleneck for global development by promoting the use of a US reference product. Furthermore, it would harm the basic concept of biosimilarity by creating two levels of biosimilarity.
Clinical trials
The author makes several proposals to reduce the requirements of PK evaluation. Most of them will not significantly change the burden of PK studies.
The author regards PK studies in healthy volunteers as ethically questionable and proposes PK studies in monkeys.
Single-dose comparative PK studies are recommended by regulators as a simple model with minimal confounding factors in cases where the product can be safely administered to healthy volunteers [6, 7]. The proposal to study disposition kinetics in monkeys is problematic from scientific, ethical and global development points of view. In addition, studies to convincingly demonstrate comparable PK in monkeys are hardly feasible from a practical point of view.
The author promotes the use of in vitro and in vivo non-clinical testing of immunogenicity to justify waivers of clinical immunogenicity studies. While such testing may be useful in the selection of the lead compound for development, the ability of in vitro tests to fully mimic the human immune system is still inadequately documented for regulatory purposes. The issue is not immunogenicity as such. FDA guidance speaks about clinical immunogenicity studies since the ultimate goal of these studies is to look for harmful immunogenicity. For the time being, this is possible only in the context of clinical safety and efficacy studies [8, 9]. Abandoning clinical safety and efficacy studies in a near future would be a strategic mistake considering the mindset of prescribers.
Interchangeability
The ability and willingness to switch between originator products and their biosimilars are the keys to the economic benefits of biosimilars. The author does not comment on the draft interchangeability guideline [5] as it is assumed to be bound to the legal provisions outside the mandate of FDA.
It is assumed by some experts that the US legislation guiding the development of biosimilars is biased because of lobbying by the originator industry [10, 11]. The industry is also active in promoting a very conservative guidance, recently in case of the draft guideline for interchangeability [5]. In general, the current US legislation and guidance may not ensure satisfactory availability biological therapy for patients because they allow anticompetitive behaviour [3].
In the EU, biosimilars are generally regarded as interchangeable under the supervision of the prescriber and in Australia, biosimilars may even be substituted at the pharmacy level [12]. It is unfortunate that the leading regulatory authorities have adopted different policies with regard to interchangeability as it creates confusion and uncertainty among regulators and their stakeholders worldwide.
It would be beneficial for the global market if FDA would clearly separate interchangeability without (automatic) substitution from interchangeability associated with substitution at the pharmacy level and allow prescribers and local regulatory authorities to develop safe methods for switching between a biosimilar and its reference product. After all, FDA approved biosimilars and their reference products, by definition, are highly similar and have no clinically meaningful differences [13]. Tens of clinical switching studies have not raised any significant efficacy or safety signals [14, 15]. The requirement of specific switching studies using the local reference product is a serious blow to the hopes for significant savings for the US healthcare system and may discourage global development of biosimilars.
Education
The author requests FDA to intensify its information on the safety of biosimilars. FDA and other agencies that have licensed biosimilars are in a very unusual situation since the safety of biosimilars is widely and publicly questioned by some parts of the industry. According to the author, this has led to misunderstandings about the safety of biosimilars, ‘integrated into the minds of prescribers and the public by the products’ originator companies’. This situation is difficult to change because only originator companies (Big Pharma) have the resources and channels to reach each individual prescriber.
The problem is not the availability of information on biosimilars. Regulatory agencies, including FDA, have delivered information on the benefit-risk of biosimilar products and their approval process. However, this information is likely to reach only prescribers that have a genuine interest to seek and review the available data, such as opinion leaders who are drafting position papers for their specialties.
The recent consultation on FDA draft guidance on interchangeability clearly demonstrated that the views of physician societies are closely following the opinions of the innovator sector of the industry [16]. This association may be partially due to the lack of understanding/acceptance of the comparability concept, on one hand, and the public health impact of biosimilars, on the other hand. Therefore, FDA is encouraged to engage in frank discussion with medical societies who issue position papers on biosimilars. In Europe, the physician societies originally discouraged biosimilar use [17] but have recently reversed their positions on controversial issues, such as extrapolation of therapeutic indications and interchangeability [18–20]. Such a change may happen also in the US [21].
How to balance innovation and safety with competition and availability – FDA dilemma
The author criticizes the FDA approach to manufacturing, analytical comparisons and clinical development of biosimilars. This discussion is important since FDA has recently published a plan to revise its approach to biosimilars, the Biosimilar Action Plan (BAP) [22]. The goal is to restore the balance between protection of innovation, on one hand, and competition and access to biologicals, on the other hand. Interestingly, FDA will not only take measures to streamline its own processes but also pay attention to the anticompetitive strategies of the manufacturers of the reference products.
The BAP aims to streamline the biosimilar guidance in order to allow more focused development programmes, including critical quality attributes for different classes of biosimilars, development and validation of PD biomarkers tailored to biosimilar development and in silico modelling and simulation to evaluate PK and PD response versus clinical response relationships. In addition, FDA aims to provide additional guidance for biosimilar development. Most importantly, FDA will enhance collaboration with Canada, Europe and Japan aiming on regulatory harmonization as well as addressing the use of foreign reference products and real-world data. Furthermore, FDA will increase its information on biosimilar regulation for its stakeholders, especially healthcare professionals. Thus, many of the points raised in the article of Niazi will be considered.
In designing the regulatory framework for new areas of pharmacotherapy, regulators will initially have to perform a scientific judgement of the benefits and risks while the true risks are not completely known. A conservative approach is justified initially but it should not lead to obstruction of drug development. The same concept can be applied to biosimilars whilst keeping in mind that the uncertainties at the time of licensing are minute as compared to products with a new active substance. In addition, there is a wide experience in real-world use of biosimilars that is a striking contrast to the concerns entertained by the anti-biosimilar lobby and, to a certain extent, to some elements in the regulatory guidance. FDA now has an opportunity to show leadership to the regulation of biosimilars for the benefit of healthcare systems worldwide.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. Niazi SK. Rationalizing FDA guidance on biosimilars—expediting approvals and acceptance. Generics and Biosimilars Initiative Journal (GaBI Journal). 2018;7(2):84-91. doi: 10.5639/gabij.2018.0702.018 2. Gottlieb S. Capturing the benefits of competition for patients; Speech presented at America’s Health Insurance Plans’ (AHIP) National Health Policy Conference; 2018; Washington, DC. 3. U.S. Food and Drug Administration. Remarks from FDA Commissioner Scott Gottlieb, M.D., as prepared for delivery at the Brookings Institution on the release of the FDA’s Biosimilars Action Plan [homepage on the Internet]. [cited 2018 Jul 26]. Available from:https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613881.htm 4. U.S. Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. April 2015 [home page on the Internet]. [cited 2018 Jul 26]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf 5. U.S. Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product. Guidance for industry. January 2017 [homepage on the Internet]. [cited 2018 Jul 26]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf 6. U.S. Food and Drug Administration. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. Guidance for industry. December 2017 [homepage on the Internet]. [cited 2018 Jul 26]. Available from:https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf 7. European Medicines Agency. Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues [homepage on the Internet]. [cited 2018 Jul 26]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001378.jsp&mid=WC0b01ac058002958c 8. U.S. Food and Drug Administration. Guidance for industry. Immunogenicity assessment for therapeutic protein products. August 2014 [homepage on the Internet]. [cited 2018 Jul 26]. Available from:https://www.fda.gov/downloads/drugs/guidances/ucm338856.pdf 9. European Medicines Agency. Immunogenicity assessment of biotechnology-derived therapeutic proteins [homepage on the Internet]. [cited 2018 Jul 26]. Available from: http://www.ema.europa.eu/ema/index.jsp? curl=pages/regulation/general/general_content_001391.jsp&mid=WC0b01ac058002958c 10. Banthia V. Biosimilar regulation: bringing the United States up to speed with other markets. Minn. J.L. Sci. & Tech. 2015;16(2):879-916. 11. Cornes P. The economic pressures for biosimilar drug use in cancer medicine. Target Oncol. 2012;7(Suppl 1):S57-67. 12. Medicines for Europe. Positioning statements on physician-led switching for biosimilar medicines. Updated April 2018 [homepage on the Internet]. [cited 2018 Jul 26]. Available from: https://www.medicinesforeurope.com/wp-content/uploads/2017/03/M-Biosimilars-Overview-of-positions-on-physician-led-switching.pdf 13. U.S. Food and Drug Administration. Guidance for industry on biosimilars: Q & As regarding implementation of the BPCI Act of 2009: background [homepage on the Internet]. [cited 2018 Jul 26]. Available from: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm259806.htm 14. Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching reference medicines to biosimilars: a systematic literature review of clinical outcomes. Drugs. 2018;78(4):463-78. 15. McKinnon RA, Cook M, Liauw W, Marabani M, Marschner IC, Packer NH, Prins JB. Biosimilarity and interchangeability: principles and evidence: a systematic review. BioDrugs. 2018;32(1):27-52. 16. LeRay D, Royzman I. Part II: Stakeholder comments on FDA’s interchangeability guidance for biosimilars. Biologics Blog; 2017 [cited 2018 Jul 26]. Available from: https://www.biologicsblog.com/part-ii-stakeholder-comments-on-fdas-interchangeability-guidance-for-biosimilars 17. Annese V, Avendano-Sola C, Breedveld F, Ekman N, Giezen TJ, Gomollón F, et al. Roundtable on biosimilars with European regulators and medical societies, Brussels, Belgium, 12 January 2016. Generics and Biosimilars Initiative J (GaBI Journal). 2016;5(2):74-83. doi:10.5639/gabij.2016.0502.019 18. Danese S, Fiorino G, Raine T, Ferrante M, Kemp K, Kierkus J, et al. ECCO Position statement on the use of biosimilars for inflammatory bowel disease – an update. J Crohns Colitis. 2017;11(1):26-34. 19. Tabernero J, Vyas M, Giuliani R, Arnold D, Cardoso F, Casali PG, et al. Biosimilars: a position paper of the European Society for Medical Oncology, with particular reference to oncology prescribers. ESMO Open. 2016;1(6):e000142. 20. Kay J, Schoels MM, Dörner T, Emery P, Kvien TK, Smolen JS, et al. Consensus-based recommendations for the use of biosimilars to treat rheumatological diseases. Ann Rheum Dis. 2018;77(2):165-74. 21. Bridges SL Jr, White DW, Worthing AB, Gravallese EM, O’Dell JR, Nola K, et al; American College of Rheumatology. The science behind biosimilars: entering a new era of biologic therapy. Arthritis Rheumatol. 2018;70(3):334-44. 22. U.S. Food and Drug Administration. Biosimilar Action Plan: balancing innovation and competition [homepage on the Internet]. [cited 2018 Jul 26]. Available from: https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm613761.pdf
Author: Professor Pekka Kurki, MD, PhD, University of Helsinki, 19 Lukupolku, FI-00680 Helsinki, Finland
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: Steven Simoens, PhD; Claude Le Pen, PhD; Niels Boone, PharmD; Ferdinand Breedveld, MD, PhD; Antonella Celano; Antonio Llombart-Cussac, MD, PhD; Frank Jorgensen, MPharm, MM; Andras Süle, PhD; Ad A van Bodegraven, MD, PhD; Rene Westhovens, MD, PhD; Jo De Cock
Introduction/Objectives: This manuscript aims to provide guidance to policymakers with a view to fostering a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe. Methods: Individuals and stakeholder representatives from patient groups, clinicians, healthcare professional organizations, government bodies, and industry participated in a series of roundtable discussions. Results: Policymakers need to involve physicians and other stakeholders in designing smart procurement and reimbursement mechanisms that incite competition in the market for off-patent biologicals and biosimilars, and that guarantee the availability of choice between products. With respect to the demand-side, the clinical profession, academia and patients need to be involved in developing a prescribing and switching framework for off-patent biologicals and biosimilars. The physician prescribes an off-patent biological or biosimilar, or switches between products based on clinical judgement and high quality evidence. In this respect, hospital pharmacists provide a ‘hub of information’ about the uptake, real-world use and evidence based on off-patent biologicals and biosimilars. Other demand-side incentives, such as physician quotas, should not be introduced without examining the impact together with relevant stakeholders including medical professionals, patients and regulators in order to meet different policy goals. Pharmacist substitution should only be considered in well-defined circumstances, motivated by specific needs and informed by high quality evidence. Conclusions: Policymakers need to introduce a long-term, multi-stakeholder, specific policy framework for off-patent biologicals and biosimilars.
Submitted: 6 June 2018; Revised: 13 July 2018; Accepted: 13 July 2018; Published online first: 20 July 2018
Introduction
Reference biologicals are originator medicinal products made by or derived from living organisms using biotechnology. When the patent and exclusivity rights on a reference biological expire, biosimilar medicines can enter the market. A biosimilar is a biological product that contains a version of the active substance of an already authorized reference biological medicinal product [1]. On the one hand, the European Medicines Agency (EMA) and regulatory authorities guarantee the quality, safety and efficacy of registered biosimilars. After a decade of experience with biosimilar products, no unexpected concerns have emerged [2, 3]. Also, health economists of international organizations refer to the important savings potential of a competitive off-patent biologicals and biosimilars market and to the opportunity to improve patient access. On the other hand, the market access, uptake and price evolution of off-patent biologicals and biosimilars stay heterogeneous between countries and between therapeutic classes, e.g. erythropoiesis-stimulating agents, granulocyte colony-stimulating factors, human growth hormones, antitumour necrosis factors, follitropin alfa and insulins [4].
This implies that European countries are not realizing the full potential of the off-patent biologicals and biosimilars market. In this respect, the European Commission and the Organisation for Economic Co-operation and Development (OECD) have argued that competition in the off-patent biologicals and biosimilars market could yield substantial savings to healthcare systems [5, 6]. To capture these savings, the European Commission (Directorate-General for Internal Market, Industry, Entrepreneurship and small and medium-sized enterprises [SMEs]) has supported a multi-stakeholder approach and has hosted multiple workshops with a view to facilitating access to and uptake of biosimilars [7, 8]. The European Commission also issued a consensus information paper in 2013, an information document for patients in 2016, and an information guide for healthcare professionals in 2017 [8].
However, the development of a competitive market for off-patent biologicals and biosimilars is not certain because of numerous factors including the risk of non-recognition of the difference between biosimilars and generics, physician and patient lack of confidence, and unbalanced payer pricing and procurement policies. In particular, after a decade of experience with these products, it seems clear that a simple logic whereby price reductions multiplied by prescribed volumes of reference biologicals will lead to potential savings is misleading and inappropriate. Price reductions alone do not appear to be the key factor guaranteeing greater market penetration of biosimilars [4]. On the contrary, price reductions can lead to a race to the bottom, preventing manufacturers to enter the market.
It is also important that policymakers keep in mind that biosimilars (where the reference product is a biological medicine) are inherently different from generics (where the reference product is a chemically synthesized medicine), due to their more elaborate size and structure of the molecule, higher risks and costs of research and development, more complex manufacturing processes, extended development times, and the need to institute post-marketing pharmacovigilance programmes [9]. Therefore, policy must be adapted to the specific needs of the off-patent biologicals and biosimilars market.
Developing a competitive market for off-patent biologicals and biosimilars in Europe is a necessary condition for stakeholders to reap the benefits that such competition may create. These benefits include more control of drug expenditure for healthcare payers, expanded access to health care for patients, increased treatment choices for physicians, and headroom for innovation for industry. The development of such a market requires the implementation of a long-term, sustainable and specific policy framework based on a multi-stakeholder approach. Thus, the aim of this manuscript is to provide guidance to policymakers with a view to fostering a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe, taking into account the role of all stakeholders.
Methods
This manuscript has been commissioned by the Belgian National Institute for Health and Disability Insurance. Individuals and stakeholder representatives from patient groups, clinicians, healthcare professional organizations, government bodies, and industry have participated in a series of roundtable discussions in 2016–2017 which have contributed to the development of the manuscript. These discussions were held under Chatham House Rules. This manuscript represents the authors’ views on the topic which have been informed by their participation in the roundtable discussions and do not represent the position of their respective organization/institution.
When developing guidance to policymakers, the focus of this manuscript is specifically on those product classes for which patent expiry and loss of exclusivity has recently occurred or is imminent, such as monoclonal antibodies for the treatment of inflammatory diseases (rheumatoid arthritis, inflammatory bowel diseases, psoriasis) and cancers.
Results
Guidance to policymakers
Supply-side incentives A building block of a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe, see Box 1, relates to the need to put in place appropriate supply-side incentives. In particular, policymakers need to design smart procurement and reimbursement mechanisms with a view to allowing physicians to prescribe off-patent biologicals and biosimilars based on scientific evidence and clinical experience. The design of such mechanisms needs to be anchored in good clinical practice, which will evolve with knowledge, and needs to respect the European legislative framework on public procurement [10, 11]. Physician involvement in procurement and reimbursement mechanisms is vital to ensure that physicians maintain the freedom to prescribe. Also, there is a need to build up technical and practical expertise, and exchange experiences between countries with respect to designing smart procurement and reimbursement mechanisms.
Box 1: Recommendations for developing policy on off-patent biologicals and biosimilars in Europe
Supply-side incentives
Policymakers need to involve physicians and other stakeholders in the design of smart procurement and reimbursement mechanisms to ensure that such mechanisms are sufficiently flexible to permit the prescribing physician to act in the best interests of the patient, including the availability of choice between products.
There is a need to build up the technical and practical expertise, and exchange experiences between countries with respect to designing smart procurement and reimbursement mechanisms.
Although procurement and reimbursement mechanisms may generate price competition and produce short-term savings, policymakers also need to consider the possible impact of these mechanisms on the sustainability and the level of competition in the market for off-patent biologicals and biosimilars in the long run.
Tendering mechanisms can be applied to off-patent biologicals and biosimilars, but should avoid a ‘winner takes all’ approach as shortages may occur if that supply fails.
Policymakers need to appreciate that the application of a reference pricing system could imply that off-patent biologicals and biosimilars included in the same reference group could be used interchangeably. In such cases, the relevant policymaker should clarify the status of the medicine.
Demand-side incentives
The clinical profession, academia and patients need to be involved in developing a prescribing and switching framework for off-patent biologicals and biosimilars.
The physician prescribes an off-patent biological or biosimilar, or switches between products based on clinical judgement and high quality evidence, and based on shared decision-making with the patient. The physician’s freedom to prescribe also considers his/her therapeutic and budgetary accountability based on scientific evidence, clinical experience and expert judgement.
In order to make an informed and documented decision, physicians need to be supported by developing the evidence base around switching, including real-world data, pharmacovigilance data, switching data and outcome data.
Position statements issued by scientific and medical societies are a critical factor in supporting the appropriate use of off-patent biologicals and biosimilars.
Additionally, hospital pharmacists play an essential role by providing a ‘hub of information’ in respect of the uptake, good use and evidence base on off-patent biologicals and biosimilars (monitoring of outcomes, real-world use and reporting of adverse events).
Physician quota can be instrumental in developing a competitive and sustainable market for off-patent biologicals and biosimilars as far as the medical profession and other relevant stakeholders are formally involved in this process.
Pharmacist substitution should only be considered in well-defined circumstances, motivated by specific needs and informed by high quality evidence. If considering pharmacist substitution, any such policy needs to be designed in such a way that the prescribing physician is aware of and approves which specific product is dispensed, that pharmacists are trained to provide unbiased information about off-patent biologicals and biosimilars, and that patients are fully informed and agree with substitution.
Gainsharing
Experience needs to be gathered with the design and impact of gainsharing arrangements, which share the savings generated from off-patent biological and biosimilar competition between stakeholders, e.g. healthcare payers, hospitals, physicians and patients.
Box 1: Recommendations for developing policy on off-patent biologicals and biosimilars in Europe In the hospital setting, tendering mechanisms, i.e. public procurement mechanisms for medicines based on competition between pharmaceutical suppliers [12], can be applied to off-patent biologicals and biosimilars nationally or locally, although future studies need to provide guidance to policymakers on how to optimize the features of these mechanisms, such as the frequency of tenders, the criteria to grant the tender, the reward for the winner(s), and the number of winners. For example, tendering may lead to a market where only one medicine is available, i.e. the ‘winner takes all’ principle, and shortages may occur if that supply fails. Thus, tendering mechanisms need to be monitored to ensure that several pharmaceutical suppliers participate and that the market does not fail [13].
In the ambulatory care setting, off-patent biologicals and biosimilars can be included in a reference pricing system, which sets a common reimbursement level for a group of medicines. Policymakers need to appreciate that the application of a reference pricing system could imply that off-patent biologicals and biosimilars included in the same reference group could be used interchangeably (which indicates that a patient can be alternated between products whilst expecting the same clinical outcomes in respect to efficacy and safety as if no alternation were to occur) [14]. In such cases, the relevant policymaker should clarify the status of the medicine.
If implemented, smart tendering mechanisms and/or reference pricing systems need to be sufficiently flexible to permit the prescribing physician to act in the best interests of the patient, including the availability of choice between products. In our opinion, this also implies that physicians are in charge of any switching protocols and that no forced switching occurs. Although procurement and reimbursement mechanisms may generate price competition and produce short-term savings, policymakers also need to consider the possible impact of these mechanisms on the sustainability and the level of competition in the market for off-patent biologicals and biosimilars in the long run.
Demand-side incentives In our opinion, a key challenge relates to how physicians should use off-patent biologicals and biosimilars in real-life, clinical practice. It is clear that biosimilars can be administered to treatment-naïve patients in all approved indications. However, there is debate and concern about whether it is appropriate to introduce incentives that encourage patients to be switched from a reference biological product to a biosimilar; from one biosimilar to another biosimilar; and about switching on multiple occasions. Although such incentives purport to encourage price competition between manufacturers, there remains residual uncertainty and resistance from different stakeholders to these various forms of switching.
Therefore, we believe that the clinical profession, academia and patients need to be involved in the policy framework for off-patent biologicals and biosimilars, see Box 1. Due to the complex nature of off-patent biologicals and biosimilars, it is clear that the appropriate use of these products needs to be a clinical decision made by a treating physician for an individual patient on the basis of shared decision-making with that patient [15]. The decision needs to balance the physician’s freedom to prescribe with his/her therapeutic and budgetary accountability based on scientific evidence, clinical experience and expert judgement. In order to make an informed and documented decision, physicians need to be supported by developing the evidence base around switching, including real-world data, pharmacovigilance data, switching data and outcome data [16]. Scientific and medical societies have a particular responsibility to provide detailed guidance on appropriate use through position statements [17]. Furthermore, the role of hospital pharmacists is important as they provide a ‘hub of information’ in respect of the uptake, good use and evidence base (monitoring of outcomes, real-world use and reporting of adverse events).
A number of European countries have implemented other physician incentives, such as quota [18]. From those experiences applied in countries with social health insurance systems clearly results that sufficient success will only be realized as far as a formal involvement of the medical profession and other relevant stakeholders is put in place.
In Europe, pharmacist substitution, i.e. the practice of a pharmacist dispensing a different, but similar biological medicine other than that which was prescribed, is a Member State responsibility. Today, the majority of European countries do not favour pharmacist substitution of a biosimilar for a reference biological medicine, although several countries are experimenting with various pharmacist substitution policies [18]. Pharmacist substitution should only be considered in well-defined circumstances, motivated by specific needs and informed by high quality evidence. If a country would consider pharmacist substitution, policymakers need to ensure that any substitution policies guarantee that the prescribing physician is aware of and approves which specific product is dispensed, that pharmacists are trained to provide unbiased information about off-patent biologicals and biosimilars, and that patients are fully informed and agree with substitution.
Gainsharing A third building block that can align different supply- and demand-side stakeholders in promoting a competitive and sustainable market for off-patent biologicals and biosimilars relates to the recent trend of ‘gainsharing’, see Box 1. Several European countries are experimenting with gainsharing arrangements, which share the savings generated from off-patent biological and biosimilar competition between stakeholders, e.g. healthcare payers, hospitals, physicians and patients [19]. For instance, savings can be invested in supporting physicians and nurses when switching patients or in providing additional services to patients. Today, the experience with gainsharing arrangements is limited and future studies need to investigate the optimal design and impact of such arrangements.
Conclusions
In our opinion, policymakers need to introduce a long-term, sustainable and specific policy framework based on a multi-stakeholder approach with a view to fostering a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe. Although there exists residual uncertainty regarding the appropriate terms for switching off-patent biologicals and biosimilars, we believe that such issues will be clarified and resolved over the coming years with the development of new studies, data and experience with these products. Additionally, we advocate that a policy framework for the off-patent biological and biosimilar market needs to be founded on multiple building blocks including the implementation of supply- and demand-side incentives, and the prospective evaluation of gainsharing arrangements.
For patients summary
Competition among off-patent biologicals and biosimilars in Europe benefits patients as it may help to control drug expenditure, expand access to health care, increase treatment choices, and encourage pharmaceutical innovation. However, there remains uncertainty about switching patients from a reference biological product to a biosimilar; from one biosimilar to another biosimilar; and about switching on multiple occasions. Therefore, we believe that the clinical profession, academia and patients need to be involved in developing a policy framework for off-patent biologicals and biosimilars. Due to the complex nature of off-patent biologicals and biosimilars, it is clear that the appropriate use of these products needs to be a clinical decision made by a treating physician for an individual patient on the basis of shared decision-making with that patient.
Acknowledgements
The authors would like to thank John Bowis, Laura Batchelor and Johan Van Calster from FIPRA for facilitating and chairing the roundtable discussions.
Funding sources
This work was enabled by Amgen, MSD and Pfizer.
Competing interests: SS is one of the founders of the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity. SS has previously conducted biosimilar research sponsored by Hospira (now Pfizer Inc); and has participated in an advisory board meeting on biosimilars for Pfizer Inc. NB and AvB declare no competing interests. RW is currently principal investigator for Galapagos/Gilead and Celltrion; and has received unrestricted research grants to the KU Leuven from BMS, Janssen and Roche.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Professor Steven Simoens, PhD
KU Leuven, Faculteit Farmaceutische Wetenschappen
Department of Pharmaceutical and Pharmacological Sciences
Onderwijs en Navorsing 2, bus 521 49 Herestraat
BE-3000 Leuven, Belgium
Professor Claude Le Pen, PhD
Paris Dauphine University LEGOS Laboratory of Economics and Management of Health Organizations
Place du Maréchal de Lattre de Tassigny FR-75775 Paris Cedex 16, France
Niels Boone, PharmD
Orbis Medical Center
Department of Clinical Pharmacy and Toxicology
PO Box 5500
NL-6130 MB Sittard-Geleen, The Netherlands
Professor Ferdinand Breedveld, MD, PhD
Professor of Rheumatology
European League Against Rheumatism Leiden University Medical Center EULAR/EMA Liaison
83a Rapenburg
NL-2311 GK Leiden, The Netherlands
Antonella Celano, President
Italian National Association of People with Rheumatological and Rare Diseases 16 Via Molise
IT-73100 Lecce (LE), Italy
Antonio Llombart-Cussac, MD, PhD
Medica Scientia Innovation Research (MedSIR ARO)
Barcelona, Spain
Hospital Arnau de Vilanova de Valencia Valencia, Spain
Frank Jorgensen, MPharm, MM
The Hospital Pharmacy Bergen
NO-5085 Bergen, Norway
Andras Süle, PhD
Chief Pharmacist
Péterfy Hospital and Trauma Center 8-20 Peterfy Sandor u
HU-1076 Budapest, Hungary
Ad A van Bodegraven, MD, PhD Gastroenterologist
Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (COMIK)
Zuyderland Medical Centre
PO Box 5500
NL-6130 MB Sittard-Geleen, The Netherlands
Department Gastroenterology
Amsterdam University Medical Centres (AUMC), location Vrije Universiteit
1117 De Boelelaan
NL-1081 HV Amsterdam, The Netherlands
Professor Rene Westhovens, MD, PhD
Professor of Rheumatology
University Hospital Leuven – Rheumatology
49 Herestraat
BE-3000 Leuven, Belgium
Rijksinstituut voor ziekte- en invaliditeitsverzekering
Jo De Cock, Administrator-General 211 Tervurenlaan
BE-1150 Brussels, Belgium
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Author for correspondence: Professor Steven Simoens, PhD, KU Leuven, Faculteit Farmaceutische Wetenschappen, Department of Pharmaceutical and Pharmacological Sciences, Onderwijs en Navorsing 2, bus 521, 49 Herestraat, BE-3000 Leuven, Belgium
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.
GaBI Journal is an independent and peer reviewed academic journal. GaBI Journal encompasses all aspects of generic and biosimilar medicines development and use, from fundamental research up to clinical application and policies.