Thank you to reviewers 2015

The editors and publisher wish to express their gratitude to the colleagues listed below for their valuable contribution to the peer review process for the Generics and Biosimilars Initiative Journal (GaBI Journal) in 2015.

Professor Saleh Alsuwayeh, Saudi Arabia
Professor Moses Chow, USA
Associate Professor Joshua P Cohen, USA
Professor Theodor Dingermann, Germany
Dr Niklas Ekman, Finland
Professor Laszlo Endrenyi, Canada
Professor Livio Garattini, Italy
Dr Brian Godman, UK
Mr Andy Gray, South Africa
Professor Lars L Gustafsson, Sweden
Assistant Professor Anupam B Jena, USA
Professor Pekka Kurki, Finland
Dr Gerard Lee, UK
Dr Frits Lekkerkerker, The Netherlands
Professor Alan Lyles, USA
Professor Håkan Mellstedt, Sweden
Dr Lembit Rago, Switzerland
Professor Jacques Rottembourg, France
Professor Joan Rovira, Spain
Professor Fatima Suleman, South Africa
Dr Robin Thorpe, UK
Dr Sabine Vogler, Austria
Professor Philip D Walson, USA/Germany
Dr Jeorg Windisch, Austria


Last update: 26/02/2019

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Editor’s introduction to the initial issue of the fifth volume of GaBI Journal

This issue begins with a Letter to the Editor by Professor Fabio V Teixeira from the Brazilian Inflammatory Bowel Disease (IBD) Society that deals basically with the issue of extrapolation of indications. The letter states that ‘vigilance remains essential’ for the use of this agent in IBD patients.

Professor Teixeira’s letter is in response to the approval in April 2015 of the biosimilar infliximab (Remsima or CT-P13) monoclonal antibody product in Brazil for use in all indications granted to the innovator biological, Remicade. This biosimilar was approved for similar use by the European Medicines Agency (EMA) in 2013 and has been recommended for similar approval by the US Food and Drug Administration (FDA) in February 2016.

The basic question raised by the IBD Society and by Professor Teixeira concerns the appropriateness of extrapolating all indications for a biosimilar based on a consideration of mechanism of action rather than on separate clinical trials done in all patient populations.

The two Brazilian Remsima clinical trials conducted to gain approval were in rheumatology rather than IBD patient populations. Professor Teixiera points out the concerns raised by clinicians, investigators and Brazilian disease specific societies about this approach. He also points out that Canadian regulators had also voiced concerns and that a (possibly controversial) study done in Ireland appeared to show differences in clinical performance between the biosimilar and originator versions of this monoclonal antibody.

He makes a non-controversial call for post-marketing (pharmaco)vigilance so that clinicians and patients will be able to judge whether this decision was or was not in the best interest of patients. The question is whether, who and how such ‘vigilance’ can be done in an unbiased, scientifically valid, economically feasible way.

The first Commentary by Dr Joshua D Brown raises an issue that is important for the validity of post-marketing generic pharmacovigilance data coming from the US. Dr Brown explains how US low-cost generic drug programs (LCGPs) interfere with the collection of valid data for generic drugs. When these programmes provide generic drugs to patients without involvement of the patients’ insurance companies, i.e. payers, their insurance claims data do not include these drugs. Yet, claims data are often used to generate pharmaco-epidemiologic information. Dr Brown points out that this ‘loss of information’ can lead to ‘underestimation of overall quality’ and discusses the implications of this underestimation as well as the effects on both cost estimations and ‘signal detection of harmful medications’.

I wrote the second Commentary about the need to obtain a prior consent for chart review studies. Chart reviews can also produce important pharmaco-epidemiologic data. They are also very useful as hypothesis generating tools. However, such studies have to obtain prior approval by the local institutional review boards/ethics committees (IRBs/ECs) in order to be published by medical journals that conform to ethical, medical publishing standards. Investigators should not, and cannot, be responsible for deciding whether a given study, including chart reviews, adequately protects patients’ welfare or privacy. Only properly constituted and run IRBs/ECs can do this. As explained in the Commentary, investigators are responsible for submitting their studies, including chart reviews, to their local IRB/EC for approval in order for their work to be accepted for publication.

The Original Research manuscript by Karampli et al. presents information gathered during interviews with a small number of Greek physicians and patients about their ‘views’ on generic medicines after the introduction by the Greek Government of a number of methods to promote the use of generics. While ‘qualitative’ in nature and based on small numbers, the interviews generated a number of concerns that, if generalizable to a sufficient number of Greek physicians or patients, will need to be dealt with if the use of generics are to increase.

The Review Article by Mr Tim Steele is a review of hybridoma technology. The author explains why he feels that this technology still holds promise as an ‘ideal for commercial applications in the drug discovery, drug development and drug manufacturing paths’.

In a Regulatory paper, Alhomaidan et al. explain how biosimilars are priced in Saudi Arabia, one of a number of countries where price is a consideration in the approval of generics and biosimilars. The authors also discuss factors that influence pricing as well as various approaches to price control of these products both in Saudi Arabia and worldwide.

The two following Regulatory and Special Report manuscripts discuss non-biological complex drugs (NBCDs). First, Dr Falk Ehmann and Dr Ruben Pita describe in some detail the current EU legislation concerning all aspects of NBCDs. Then, Professor Gerrit Borchard discusses the pharmacopeial issues involving monographs for this important class of agents.

The issue ends with two Abstracted Scientific Articles and Pharma News written by the GaBI editorial staff covering ‘Promoting a competitive generics market in the US’ and ‘The case for reforming drug naming’; as well as ‘Top developments in biosimilars during 2015’.

I close this letter with a repeat plea for readers to submit their research as well as comments or concerns for publication in the journal.

Professor Philip D Walson, MD
Editor-in-Chief, GaBI Journal

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

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.


Last update: 31/01/2019

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Waiver of consent for retrospective chart review studies

Abstract:
The importance of obtaining IRB/EC consent for waiver of consent before embarking on retrospective chart review studies was highlighted using the recent case of a manuscript submitted to GaBI Journal.

Submitted: 12 March 2016; Revised: 14 March 2016; Accepted: 14 March 2016; Published online first: 28 March 2016

This commentary was prompted by a recent experience with a manuscript submitted to GaBI Journal but then withdrawn.

The authors of this manuscript conducted a retrospective chart review of patients who had undergone cardiac stent placements at two hospitals in Greece to investigate whether there were any statistically significant differences in outcomes when patients were treated with either brand-name or generic versions of aspirin and clopidogrel. Peer review of the manuscript revealed that there was no statement as to whether the study had been approved by the local institutional review board/ethics committee (IRB/EC) or any mention of whether either informed consent had been obtained or if waiver of consent was approved by the IRBs/ECs at the two involved hospitals. When questioned about this, the authors responded by stating that in their opinion there was no requirement for consent since the study involved only a retrospective chart review of anonymous patient data. On further questioning they admitted that the study had never been submitted to either hospital’s IRB/EC for review or for permission to waive consent. In an attempt to publish the study, the authors were then asked to request a letter from their IRBs/ECs stating that, based on the local guidelines, that they agreed with the authors that no consent was required. The authors replied by claiming that since the study had been done more than two years prior to submission that it was not possible to get such a statement from the IRB and as a result they unfortunately simply withdrew the manuscript.

This commentary was written in an attempt to avoid any repeat of this unfortunate incident that wasted so much of the time and energy of both the journal staff, our reviewers, as well as the authors and their patients.

There is a large volume of material available on what types of research is eligible for waiver of consent. However, the most important point is that the decision to waive consent, written or otherwise, is the sole responsibility of the local IRB/EC. One particularly clear statement about such research comes from the Kansas University School of Medicine Wichita’s (KUSM-W) IRB website (wichita.kumc.edu/research/research-compliance.html) which states, ‘Guidelines for Retrospective Chart Reviews’ are considered to be human subjects research and must be approved by the KUSM-W Human Subjects Committee. Beginning 14 April 2003, retrospective chart reviews must meet both human subjects and HIPAA (Health Insurance Portability and Accountability Act) privacy requirements’.

Readers who are interested in reviewing requirements for waiver of consent are encouraged to review both local and national consent requirements such as those listed on the US Health and Human Services (HHS) website (http://www.hhs.gov/ohrp/policy/faq/informed-consent/what-is-a-waiver-or-alteration-of-informed-consent.html). An important quote from the HHS guidelines states, ‘Waiving the requirement for obtaining informed consent or parental permission means that the IRB has determined that investigators need not obtain the subjects’ informed consent to participate in research’ that makes clear that it is the IRB and not the investigator(s) who determines when waiver of consent is allowed. This is also clear in materials from numerous US university IRBs, including the Northwestern University IRB that states in a section on retrospective chart reviews, ‘Research involving the collection or study of existing* data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.

In addition to national or university guidelines/rules, there are a number of local guidelines and these ‘hospital-internal guidelines may impose stricter conditions than required by federal or cantonal law’. Differences and their implications are illustrated by a publication that ‘provides an overview of the issues for physicians, scientists, ethics committee members and policymakers involved in retrospective research in Switzerland’ [1].

In the case of the manuscript submitted to GaBI Journal but then withdrawn, it is highly likely that the two hospital IRBs/EC’s would have approved the study for waiver of consent; provided that the methods used to protect patient confidentiality were judged to be adequate. However, it is the responsibility of these two IRB/ECs and NOT of the authors to decide whether or not this was true.

It is unfortunate that the authors did not seek this approval prior to initiating the study. The study fits with the scope and interests of our journal and we very much wanted to publish it.

We do not know whether the local IRBs/ECs were asked to approve the study retroactively but refused. Some IRBs (including one that I chaired many years ago) can and do approve such waivers retroactively, but since some do not even consider retroactive approvals investigators are encouraged to always request waiver of consent prior to initiating any such research. This is especially important for authors who wish to publish their research in any journal, including GaBI Journal that requires IRB/EC review of all human subject research submitted for publication.

*‘Existing’ means existing before the research is proposed to the institutional review board to determine whether the research is exempt (https://irb.northwestern.edu/process/new-study/reviews/exempt-categories-examples).

Competing interests: None

Provenance and peer review: Commissioned; internally peer reviewed.

Author: Professor Philip D Walson, MD, Editor-in-Chief, GaBI Journal

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

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.


Last update: 31/01/2019

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The case for reforming drug naming

Submitted: 29 February 2016; Revised: 15 March 2016; Accepted: 16 March 2016; Published online first: 29 March 2016

Use of brand name drugs over generic equivalents after expiration of exclusivity still prevails. Ameet Sarpatwari and Aaron Kesselheim argue the case for reforming drug naming by allowing generic products to share the brand names of their corresponding innovator.

In a recently published article [1], Sarpatwari and Kesselheim argue the case for reforming drug naming. In the US, pharmaceutical manufacturers spend at least US$30 billion annually on marketing brand awareness to physicians and patients [2]. The effects of this, they suggest are two-fold: product recognition of an innovator drug increases, enabling patients to differentiate between drugs, but confusion can also be created between the branded drug name, which can differ from one country to another, and its generic name. This, in their opinion, diminishes the safe and effective use of more affordable generic products.

The authors explain that the convention of assigning innovator drugs a brand and generic name dates back to the late 1950s. Political deliberations on the best way to incentivize innovation and curb monopolies at one point led to the idea of banning brand names altogether [3] but this was promptly met with a backlash from the pharmaceutical industry. The compromise was to continue using brand names but that the US Food and Drug Administration (FDA) would simultaneously issue generic names to all products sharing the same active ingredients. This remit has now fallen to the US Adopted Names Council, which can recommend generic names to the World Health Organization International Nonproprietary Names Programme.

In the 1980s, new legislation allowed drug regulators to approve generic drugs on the basis of bioequivalence: it had to possess an equal amount of the same active ingredient but also be proven to deliver these active ingredients to a target site at an equivalent rate. These products would receive the same generic name as their innovator counterparts. Generic drugs led the way in stimulating market competition and reducing costs.

The authors show that, despite great strides being made in the generic drug industry, branded prescription drugs are still widely used in the US today. They argue that articles on industry-sponsored studies still refer to drugs solely by their brand name; and that doctors continue to prescribe branded drugs even when a drug’s market exclusivity period ends [4]. In the UK, they refer to the 80% generic prescribing rate achieved by doctors, largely the result of a capitated payment model, suggesting to them that reform is possible [5]. Yet, in the US, they argue that pharmacist-driven generic substitution is mandatory in only 20 states, and in the EU in 2010, only seven countries had pharmacist-driven generic substitution legislation in place [6].

Sarpatwari and Kesselheim [1] believe it is now time for reform. They propose a number of steps that can be taken to reduce the effect of brand name use for prescription drugs. Their main recommendation is to allow generic products to adopt the brand names of their corresponding innovator products. Legislating this, they believe, would boost public confidence in the equivalence of generic and innovator drugs. Policies to this effect might help patients and physicians overcome ‘psychological and practical hurdles’ to generic substitution, resulting in substantial savings. It might be less confusing for physicians, they argue, who may default to brand-name prescribing because of the complexity of some generic names. In their opinion, what is important for the physician is a focus on memorable names and ease of use. They believe that their proposal to allow generic products to adopt brand names of corresponding innovator drugs would limit the innovator’s ability to profit extensively though product differentiation and brand recognition as is the case now. The authors maintain, however, that pharmaceutical manufacturers can still differentiate their products through reliance on their corporate name to establish a separate identity from generic drugs.

Another benefit of brand-name sharing, they believe, would be to allow generic manufacturers to enter joint marketing deals with the innovator manufacturer rather than spending money to establish a separate identity. This way, savings could be passed directly to patients.

Finally, they argue that brand-name sharing might reduce the effect of ‘cost-shifting tactics’ undertaken by pharmaceutical manufacturers to the detriment of healthcare insurers and ultimately patients. The authors draw on a previous article [7] explaining how coupon programmes used by pharmaceutical manufacturers in the US are designed to hook patients into opting for brand-name drugs by reimbursing them for the difference in co-payment; yet on expiry of the coupon programme, patients with chronic diseases face co-payment for the brand-name drug that is higher than the generic alternative. Consequently, insurers must still pay the manufacturer the higher cost of the medicine, even though lower cost alternatives are available. These costs are ultimately passed on to the patient through increases in insurance premiums.

Given the increased pressure to reduce drug costs, Sarpatwari and Kesselheim [1] argue that, changing the law to enable generic products to adopt the brand names of their innovator counterparts would help reduce this inefficiency while still permitting product promotion and manufacturer-specific dispensing.

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.

Maysoon Delahunty, GaBI Journal Editor

References
1. Sarpatwari A, Kesselheim AS. The case for reforming drug naming: should brand name trademark protections expire upon generic entry? PLoS Med. 2016;13(2):e1001955.
2. The Pew Charitable Trusts. Persuading the prescribers: pharmaceutical industry marketing and its influence on physicians and patients [homepage on the Internet]. 2013 Nov 11 [cited 2016 Mar 15]. Available from: http://www.pewtrusts.org/en/research-and-analysis/fact-sheets/2013/11/11/persuading-the-prescribers-pharmaceutical-industry-marketing-and-its-influence-on-physicians-and-patients.
3. Greene JA. Generic: the unbranding of modern medicine. Baltimore: Johns Hopkins University Press; 2014.
4. Hochman M, Hochman S, Bor D, McCormick D. News media coverage of medication research: reporting pharmaceutical company funding and use of generic medication names. JAMA. 2008;300(13):1544-50.
5. OECD. Pharmaceutical generic market share. In: Health at a Glance 2013: OECD Indicators. OECD Publishing; 2013.
6. IMS Health Sheppard A. Generic medicines: essential contributors to the long-term
health of society. 2010.
7. Ross JS, Kesselheim AS. Prescription-drug coupons–no such thing as a free lunch.
New Eng J Med. 2013;369(13):1188-9.

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

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.


Last update: 31/01/2019

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The EU is ready for non-biological complex medicinal products

Abstract:
This paper describes the existing European Union legislation and scientific guidance to adequately assess the quality, safety and efficacy, as well as the lifecycle management, of the group of non-biological complex drug (NBCD) products, including nanomedicines such as liposomes, polymeric micelles, glatiramoids and iron-carbohydrate complexes.

Submitted: 15 March 2016; Revised: 1 April 2016; Accepted: 4 April 2016; Published online first: 15 April 2016

Non-biological complex drugs (NBCDs) are defined scientifically as not being a biological medicinal product where the active substance is not a homo-molecular structure, but consists of different closely related and often nanoparticulate structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means, where the structural elements that might impact the therapeutical performance are unknown [1]. Nanomedicines, such as liposomes, polymeric micelles, glatiramoids, iron-carbohydrate complexes and nanocrystals, as well as dry powder inhalers are examples of NBCDs. Although the definition of NBCD is not officially recognized and there is no corresponding term in European Union (EU) pharmaceutical legislation or scientific guidance, it will be argued in this paper that the existing EU legislation and guidance is equipped to adequately assess the quality, safety and efficacy, as well as the lifecycle management, of such a group of medicinal products. We will describe the different mechanisms through which the European Medicines Agency (EMA) promotes the development and entry into the market of innovative medicinal products. This paper aims at addressing important issues, such as the need to follow the biosimilar approach for comparability, harmonization of technical requirements across regions or preparedness of EU legislation for NBCDs, raised in GaBI on the regulation of NBCDs, particularly those mentioned in the paper entitled ‘Non-Biological Complex Drugs and their follow-on versions: time for an editorial section’ published online first on 2 November 2015 [2]. We will start by detailing the role of EMA, the scope of the centralized procedure and the legal basis of submission of marketing authorization procedures. We will continue by providing some examples of products that would fall under the author’s definition of NBCD and describing how these can be submitted for a marketing authorization application in the EU under the existing legislation and scientifically assessed under the framework provided by the existing scientific guidance. We will conclude by substantiating how the EU is adequately prepared for NBCD.

Marketing authorization procedures and legal basis of submission

EMA is an EU body established in 1995 in accordance with Council Regulation (EEC) No 2309/93, now superseded by Council Regulation (EEC) No 726/20014. EMA is responsible for the coordination of the existing scientific resources from a network of national experts for the evaluation, supervision and pharmacovigilance of medicinal products. As part of the mission of EMA, the agency also supports research and innovation to stimulate the development of new medicines to address public health needs. One of the main responsibilities of the agency is the scientific evaluation of applications for EU marketing authorizations for human and veterinary medicines in the centralized procedure. The centralized procedure is compulsory for a discrete class of products:

  • Medicinal products developed by recombinant DNA, controlled expression of genes coding for biotechnologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells, hybridoma and monoclonal antibody methods
  • Medicinal products for human use containing a new active substance for the treatment of acquired immune deficiency syndrome, cancer, neurodegenerative disorder, diabetes, autoimmune diseases and other immune dysfunctions, viral diseases
  • Designated orphan medicinal products

Applicants still have the opportunity to apply for a marketing authorization through the centralized procedure if the medicinal product contains a new active substance not authorized in the EU; or if it constitutes a significant therapeutic, scientific or technical innovation or that the granting of the authorization is in the interest of patient health at Union level. A medicinal product that would not fall under the mandatory scope may be authorized through the EU via the centralized procedure or the national procedures managed by the National Competent Authorities of each Member State of the EU. The Directive 2001/83/EC [3] sets the requirements to support a marketing authorization application for medicinal products relating to medicinal products for human use and is equally applicable regardless of the procedure through which the application is made. Similarly the scientific guidance is drafted and adhered to by the same group of national experts responsible for assessing the quality, safety and efficacy of medicines submitted to the centralized, decentralized, mutual recognition or purely national procedures. The Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for human medicinal products [4] also consults the Committee for Medicinal Products for Human Use (CHMP) and its working parties for scientific opinions when necessary. As a result, all medicines approved in the EU comply with the same legal requirements and are reviewed considering equal scientific standards.

The extent (e.g. full versus bridging studies) and nature (e.g. new active substance versus comparative versus well-established use) will determine the options under which a marketing authorization application may be made.

The legal basis for submission, as detailed in Directive 2001/83/EC, are:

  • Stand-alone application comprised of a full set of pharmaceutical, preclinical and clinical data, or mixed applications comprised of a full set of pharmaceutical data with the option of a combination of reports of limited non-clinical and/or clinical data – Article 8(3)
  • Generic medicinal product – Article 10(1)
  • Hybrid medicinal product – Article 10(3)
  • Similar biological medicinal product or biosimilar – Article 10(4)
  • Well-established use application, where preclinical and clinical data is replaced by detailed references to published scientific literature if it can be demonstrated that the active substance(s) has been in well-established medical use within the EU for at least 10 years, with recognized efficacy and acceptable safety – Article 10(a)
  • Fixed-combination application, where more than one active substance is used in combination in the same medicinal product for therapeutical purposes – Article 10(b)
  • Informed consent applications, where the holder of an authorized medicinal product allows the quality, non-clinical and clinical data submitted for its authorization to be used for future applications – Article 10(c)

NBCDs can potentially be submitted under the seven legal basis above, even as a biosimilar since the determining factor is the biological* nature of the reference medicinal product, regardless of the non-biological nature of the manufacturing process of the NBCD being submitted for a marketing authorization.

It has been debated in this journal [2] that the current EU pharmaceutical legislation does not have a dedicated regulatory scheme that takes into account the special nature of NBCD follow-on products. There exist two options in legislation for a follow-on medicinal product of an NBCD. Depending on the extent of data needed to support bioequivalence, a follow-on of an NBCD will either fall under one of the following legal basis:

  • Generic, if the follow-on medicinal product has the same qualitative and quantitative composition in active substance(s) and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.
  • Hybrid, where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate preclinical tests or clinical trials shall be provided.

In the scientific reflection papers and guidance published, EU regulators are open to the possibility of quality data being sufficient to demonstrate the bioequivalence of two NBCDs [5], it is however recognized that differences observed when performing pharmaceutical comparability studies between reference and test product, or during the different stages of the development of a medicinal product, may require in vivo studies to demonstrate bioequivalence. The extent of in vivo studies that may be necessary to support bioequivalence are considered on a case-by-case basis according to the complexity of the formulation and the data gathered cumulatively by the different quality, non-clinical and clinical comparative studies. Furthermore, it is also recognized that only certain aspects of the conventional bioequivalence approach [6] are applicable and in some cases the need to provide clinical studies to demonstrate the safety and efficacy of follow-on products may be justified. The body of evidence obtained in the quality, non-clinical and clinical purposely-designed studies for NBCDs will be considered as a whole when assessing the benefit risk of the medicinal product undergoing an application for a marketing authorization.

This approach allows for data requirements to be adapted according to the nature of the product, differences observed during the comparability studies and claimed therapeutic indications, hence, guaranteeing the demands from regulators are tailored to a specific product or class of products.

As defended by Schellekens and Borchard [7], NBCDs are made of structures that cannot be isolated and fully quantitated, characterized, and/or described by analytical means, to which it is unknown which therapeutic elements might impact therapeutic performance and with clinical performance highly dependent on the production process. Schellekens and Borchard have argued that an approach common to that applied for biosimilars should also be considered for follow-on NBCDs, it is therefore relevant to identify what are the differences between the two approaches. Although by definition Article 10(4) – biosimilar applications – is not applicable when the reference product would be classed as an NBCD, it is relevant to analyse the legislative provisions for these applications. As it is the case for chemical medicinal products, biosimilar applications are first expected to meet the conditions for the definition for generic medicinal products. It is only failing this definition, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, that results of appropriate preclinical tests or clinical trials relating to these conditions must be provided. Reference is then made to the relevant criteria detailed in Annex I of the Directive. In this annex general requirements and reference to the relevant scientific guidelines are described. As for biosimilars, the Directive also directs the requirements for chemical generic and hybrid applications to the appropriate detailed guidelines (Article 10.2(b)). This is to say that with regards to legal provisions to dossier contents there is no significant difference to how simple or complex chemical products and biosimilars are addressed as for both general requirements and a reference to the applicable guidance is mentioned in the Directive.

Harmonization of requirements across regions

Follow-on products of nanomedicines, a representative group of NBCDs, have been named similar nanomedicines or nano similars [8], highlighting the challenges presented by these products due to a complexity closer to biosimilars than their chemical counterparts. An important aspect of biosimilars is the innovation brought by the ‘Guideline on similar biological medicinal products’ [9] to the origin of batches used in the in vivo comparability studies; the following is stated in that regard:

‘However, with the aim of facilitating the global development of biosimilars and to avoid unnecessary repetition of clinical trials, it may be possible for an Applicant to compare the biosimilar in certain clinical studies and in in vivo non-clinical studies (where needed) with a non-EEA authorised comparator (i.e. a non-EEA authorised version of the reference medicinal product) which will need to be authorised by a regulatory authority with similar scientific and regulatory standards as EMA (e.g. ICH countries). In addition, it will be the Applicant’s responsibility to demonstrate that the comparator authorised outside the EEA is representative of the reference product authorised in the EEA.’

As is the case for biosimilars, follow-on NBCDs may also require extensive in vivo comparability data. The flexibility accorded to biosimilars could be extended for NBCDs allowing for non-EEA reference medicinal products to be used, thus decreasing the need for duplicate studies of applicant wishing to apply for an abridged application in the EU and in another ICH country. Efforts in that direction are currently being made in the Transatlantic Trade and Investment Partnership [10] (TTIP) with the negotiations between the EU and US moving forward towards recognizing each other’s reference medicinal products. This is also an example of the narrowing of any existing differences of approach and flexibility between biosimilars and nanosimilars. The scope of TTIP also extends to the convergence of technical requirements between the EU and US – providing an additional drive to the harmonization to technical requirements to follow-on medicinal products.

Efforts to facilitate the worldwide harmonization of nanotechnology regulation are also demonstrated by the work of the International Pharmaceutical Regulators Forum (IPRF) with respect to a particular type of NBCDs, such as the nanomedicines. The purpose of the IPRF is for pharmaceutical regulators to exchange information on issues of mutual concern and regulatory cooperation. This exchange amongst global regulators will maximize potential efficiencies in addressing the increasingly complex global context of medicines regulation. IPRF intends to promote the implementation of ICH and other internationally harmonized pharmaceutical guidelines. It further contributes to the coordination of a range of international efforts related to regulation of medicines. The IPRF offers the opportunity to leverage expert scientific knowledge, regulatory and operational experience, ongoing technical harmonization work, and information access of other participating regulators. Goals include:

  • Identifying new approaches and specific best practices, and developing smart strategies for dealing with the challenges of a rapidly evolving globalized pharmaceutical industry in the field of nanotechnology
  • Providing a global overview of the different regulatory developments at national and international level and enable open sharing of information and ideas among regulatory leaders with hands-on operational responsibilities. This information sharing will allow the forum participants to discuss issues at an actionable level of detail
  • Supporting international regulatory cooperation in areas that are not covered by existing initiatives

A special IPRF Working Group on Nanotechnology has been created in 2014 and its mandate and 2015/2016 work plan have been adopted and published in 2015 [11].

Deliverables for the IPRF 2015/2016 work plan include:

  • Information sharing and mapping (annual regulatory updates)
  • Compilation, mapping and discussion on terminology and definitions with focus on the classification of nanomedicines/nanotechnology in drug products
  • Compilation of information for understanding synergies between the nano(medicine) safety and nano (medicine) toxicology fields
  • Compilation of investigations required for ‘generic’ nanomedicines/nanotechnology in drug products used in regulatory procedures
  • Mapping and exchange of requirements for nanomedicine/nanotechnology in drug product class specific guidance, e.g. liposomal formulations
  • Exchange and mapping of general Critical Quality Attributes principles for nanomedicines/nanotechnology in drug products

In January 2016, the IPRF Nanotechnology Working Group published a document on ‘Information sharing and mapping’ highlighting the participating regulators’ current available guidance and status on related definitions, technical guidance in the respective region, planned workshops and trainings, legislation and classification system for related pharmaceuticals [12].

EMA scientific guidance

EMA has published a wide range of technical requirements to demonstrate the quality, safety and efficacy of medicinal products. These technical requirements documents are available as reflection papers and scientific guidance. The examples in Table 1 include the published reflection papers on nanomedicines and other guidance that may be applicable to NBCDs; for a full list of scientific guidance published please go to the EMA’s guidance webpage [13].

Fig 1

The provision of scientific advice by National Competent Authorities or EMA [14] is available to applicants. Scientific advice on the appropriate tests and studies in the development of a medicine is designed to facilitate the development and availability of high quality, effective and acceptably safe medicines, for the benefit of patients. During the development of most nanomedicines scientific advice was requested from EMA to enhance the chances for a positive development outcome.

Developers of novel medical products are also encouraged at an early stage of development to seek advice of the EMA’s Innovation Task Force (ITF) [15].

The initiatives described above for harmonization across regions and published guidance, together with the provision of Scientific Advice and ITF meetings, are examples of how EMA aims at facilitating the development of innovative medicines.

Table 2 provides examples of products approved in the EU, through centralized and national authorization procedures, that could be categorized as NBCDs [16].

Fig 2

It is noteworthy that first-generation nanomedicines, including liposomal formulations, iron-based preparations and drug nanocrystal technologies in oral dosage forms, have been established as safe and effective for many years. EMA has evaluated marketing authorization applications for nanomedicines thus demonstrating the suitability of the current legislation and scientific guidance to accept complex medicinal products; the basis on which the scientific opinions were made on the marketing authorization submitted for NBCDs are publicly available [18]. Orphan status has been granted for ten nanomedicines on recognition by EU regulators of the potential benefits stemming from the use of nanotechnology.

Recent publications confirm that approximately 48 nanomedicines and nanoimaging agents are currently under clinical development (phase I–III) in Europe, with others progressing through earlier stages of drug discovery and non-clinical development [19]. In addition, approximately 70 cancer clinical trials are ongoing in the US involving nanomedicines and, therefore, the number of marketed pharmaceuticals using nanotechnology is expected to continuously grow and, thus, benefit patients and public health.

In conclusion, the current EU regulatory framework for medicinal products has been proven to be robust and efficient for the evaluation of NBCDs, including nanomedicines, facilitating the deliverable of safe and efficacious medicines to patients. The EU network recognizes the potential benefits deriving from innovative technologies. Efforts are being undertaken to continuously develop and harmonize across regions the regulatory requirements for complex medicinal products in view of promoting timely access of safe and effective medicines to patients. The EU network is ready for NBCDs.

Competing interests: The views expressed are those of the authors and should not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency.

Provenance and peer review: Commissioned, externally peer reviewed.

Authors

Falk Ehmann, MD, PhD, MSc
Clinical Pharmacology – Science and Innovation
European Medicines Agency
30 Churchill Place, Canary Wharf
London E14 5EU, UK

Ruben Pita, PharmD, LLM
Procedure Management Department
European Medicines Agency
30 Churchill Place, Canary Wharf
London E14 5EU, UK

References
1. Schellekens H, Stegemann S, Weinstein V, de Vlieger JS, Flühmann B, Mühlebach S, et al. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J. 2014;16(1):15-21.
2. Flühmann B, Crommelin DJA, de Vlieger JSB, Borchard G, Scott E McNeil, Mühlebach S, et al. Non-Biological Complex Drugs (NBCDs) and their follow-on versions: time for an editorial section. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(4):167-70. doi:10.5639/gabij.2015.0404.037
3. European Commission. EU Pharmaceutical Informations. EudralLex Volume 1 – Pharmaceutical legislation medicinal products for human use [homepage on the Internet]. [cited 2016 Apr 1]. Available from: http://ec.europa.eu/health/documents/eudralex/vol-1/index_en.htm
4. Heads of Medicines Agencies. CMDH What’s new [homepage on the Internet]. [cited 2016 Apr 1]. Available from: http://www.hma.eu/cmdh.html
5. European Medicines Agency. Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal. EMA/CHMP/806058/2009/Rev. 02. 21 February 2013 [homepage of Internet]. [cited 2016 Apr 1]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500140351.pdf
6. European Medicines Agency. Guideline on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 1/Corr**. 20 January 2010 [homepage of Internet]. [cited 2016 Apr 1]. Available from: http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500070039
7. Borchard G, Flühmann B, Mühlebach S. Nanoparticle iron medicinal products – requirements for approval of intended copies of non-biological complex drugs (NBCD) and the importance of clinical comparative studies. Regul Toxicol Pharmacol. 2012;64(2):324-8.
8. Ehmann F, Sakai-Kato K, Duncan R, Pérez de la Ossa DH, Pita R, et al. Next-generation nanomedicines and nanosimilars: EU regulators’ initiatives relating to the development and evaluation of nanomedicines. Nanomedicine (Lond). 2013;8(5):849-56.
9. European Medicines Agency. Guideline on similar biological medicinal products. CHMP/437/04 Rev 1. 23 October 2014 [homepage on the Internet]. [cited 2016 Apr 1]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf
10. European Commission. Technical paper for regulatory cooperation on generic medicines. Proposal of the European Union. 26 January 2016 [homepage on the Internet]. [cited 2016 Apr 1]. Available from: http://trade.ec.europa.eu/doclib/docs/2016/january/tradoc_154172.pdf
11. International Pharmaceutical Regulators Forum. IPRF Nanomedicines Working Group [homepage on the Internet]. [cited 2016 Apr 1]. Available from: https://www.i-p-r-f.org/en/working-groups/nanomedicines-working-group/
12. International Pharmaceutical Regulators Forum. IPRF Nanomedicines Working group – Information sharing and mapping (as of January 2016) [homepage on the Internet]. [cited 2016 Apr 1]. Available from: https://www.i-p-r-f.org/files/7414/5387/7778/IPRF_Nanomedicines_WG_-_info_mapping_Jan2016.pdf
13. European Medicines Agency. Scientific guidelines [homepage on the Internet]. [cited 2016 Apr 1]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000043.jsp&mid=WC0b01ac05800240cb
14. European Medicines Agency. Scientific advice and protocol assistance [homepage on the Internet]. [cited 2016 Apr 1]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000049.jsp&mid=WC0b01ac05800229b9
15. European Medicines Agency. Innovation Task Force [homepage on the Internet]. [cited 2016 Apr 1]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000334.jsp&mid=WC0b01ac05800ba1d9
16. Adapted from Crommelin, Daan JA, and Jon SB de Vlieger, eds. Non-Biological Complex Drugs: The Science and the Regulatory Landscape. Vol. 20. Springer, 2015.
17. Flynn Pharma Ltd. Depodur marketing ceased [homepage on the Internet]. [cited 2016 Apr 1]. Available from: http://www.flynnpharma.com/about-us/news/depodur-marketing-ceased
18. European Medicines Agency. European public assessment reports [homepage on the Internet]. [cited 2016 Apr 1]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&;mid=WC0b01ac058001d124
19. Noorlander CW, Kooi MW, Oomen AG, Park MV, Vandebriel RJ, Geertsma RE. Horizon scan of nanomedicinal products. Nanomedicine (Lond). 2015;10(10):1599-1608.

*A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterization and the determination of its quality a combination of physicochemical-biological testing, together with the production process and its control – definition from Directive 2001/83/EC.

Author for correspondence: Falk Ehmann, MD, PhD, MSc, Clinical Pharmacology – Science and Innovation, European Medicines Agency, 30 Churchill Place, Canary Wharf, London E14 5EU, UK

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

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Complexity in the making: non-biological complex drugs (NBCDs) and the pharmacopoeias

Abstract:
Pharmacopoeias, as standard references for pharmaceutical drug specifi cations and reference standards in the form of monographs, play a pivotal role to assure drug quality and safety. With emphasis on the activities concerning non-biological complex drugs (NBCDs), the mechanisms by which new monographs are introduced into the European and the US pharmacopoeias are presented.

Submitted: 15 March 2016; Revised: 22 March 2016; Accepted: 24 March 2016; Published online first: 4 April 2016

Introduction

Over the last decades we came to realize that high molecular weight drugs of biological origin, such as therapeutic antibodies, are of a highly complex structure, which determines their activity as well as safety in terms of immunogenicity. The manufacturing of such therapeutics requires highly complex and meticulously controlled up- and downstream processes. Still, the final drug product whose properties are determined by the process is characterized by a certain degree of ‘microheterogeneity’, i.e. the presence of several isomers of the active pharmaceutical ingredient (API).

‘Follow-on’ protein therapeutics will not be manufactured by the same process proprietary to the originator. As the process itself determines the properties, e.g. microheterogeneity, of the final drug product, an originator protein therapeutic and its follow-on product may not be considered to be identical. Hence, the generic principle applied for drugs of low molecular weight, whose properties and composition are well defined and can be reproduced by generic drug producers, cannot be applied to complex drugs such as therapeutic proteins. A regulatory strategy leading to marketing authorization of follow-on biologicals in Europe and by the US Food and Drug Administration (FDA) – the ‘biosimilar’ pathway – has thus been established and refined. This approach includes elements such as clinical testing of the follow-on against the originator product in clinical trials, as well as post-marketing surveillance [1].

Another group of complex drugs of non-biological origin (NBCDs – non-biological complex drugs) share aspects of complex structure, potential immunogenicity and impossibility of full characterization by physicochemical methods alone with biological complex drugs. Examples for these complex drugs include glatiramoids (Copaxone®), liposomal formulations (Doxil®) and nanoparticles such as iron-carbohydrate particles (Venofer®). These drugs are considered to belong to a new class of ‘nanomedicines’ [2]. Their size and attributes at the molecular scale confer these systems certain properties to interact with their biological environment.

Nanoscale drug delivery systems have been under investigation for several decades, yet only very few have actually matured to clinical application. While analytical techniques describing the physicochemical properties of these systems are being constantly refined, we had to understand that these systems need a multi-pronged analytical approach to describe their physicochemical properties. However, little is known on the relation between these properties and the clinical outcome, such that these systems always need clinical assessment to ensure efficacy and safety. The situation is rendered even more complex by the appearance of intended copies of NBCDs. Some of those, e.g. iron sucrose products (‘iron sucrose similars, ISSs’), and ‘generic’ Doxil (approved by FDA in 2013 in view of drug shortages in the US) have entered the market under the generics paradigm, partially due to the absence of a more suitable regulatory evaluation process. Therefore, an effort is needed to discover these correlations between nano-properties and biological activity, develop suitable analytical techniques and define specifications, establish clinical protocols and, last but not least, integrate this knowledge in a science-based regulatory approach to nanomedicines [3].

The principle of nanomedicines being complex drugs is well established within the scientific community. Regulatory authorities are also catching up, as shown by recent activities in the field. FDA is currently sponsoring a study comparing two iron carbohydrate products (Nulecit®, Ferrlecit®) for their similarity, involving physicochemical characterization, in vitro and clinical studies [4]. The European Medicines Agency (EMA) has published a reflection paper on the subject of ‘data requirements for iron-based nano-colloidal products’ in February 2015, which lists a range of characterization methods for these products.

In the context of ensuring the quality and safety of medicines, pharmacopoeias, as standard references for pharmaceutical drug specifications in the form of monographs, play a pivotal role. Derived from the Greek expressions φ ά ρ μ α κ ο ν (pharmakon) and π ο ι ΐ α (making), pharmacopoeias appeared as early as 50 AD (De Materia Media). In Great Britain, the national British Pharmacopoeia (BP) was published for the first time in 1864, the United States Pharmacopeia (USP) already in 1820. In addition to such national pharmacopoeias, international forms do exist as well and may replace national ones. The foundation for the European Pharmacopoeia (Ph. Eur.) was laid in 1964 by a convention of the Council of Europe, and the first volume of the International Pharmacopoeia (Ph. Int.) was published by the World Health Organization (WHO) in 1951.

Having the common goal to ensure access to good quality medicines, the organizational forms of these pharmacopoeias and the procedures followed to introduce new monographs differ largely. This manuscript gives an overview on such issues, and analyses the level of awareness for NBCDs at the European and US pharmacopoeias.

European and US pharmacopoeias and non-biological complex drugs (NBCDs)

1. The European Pharmacopoeia (Ph. Eur.)
The European Directorate for the Quality of Medicines and Healthcare (EDQM) is a directorate of the Council of Europe (CoE), whose function was first defined by the ‘Convention on the elaboration of a European Pharmacopoeia’ [5] signed in 1964. These activities had the goal to define common specifications for medicinal substances and their pharmaceutical preparations, as well as to promote free movement of medicines in the European Union (EU) and the countries of the European Economic Area (EEA). In 1975, a directive by the EC makes compliance with the European Pharmacopoeia Monographs mandatory when requesting marketing authorization for medicines for human use. In 1994, the CoE signed the Ph. Eur. Convention, and the European Network for Official Medicines Control Laboratories (OMCL) was created [6], and its activities organized by EDQM from 1996 onwards. In 2001, EC Directive 2001/83/EC [7] maintains the mandatory character of Ph. Eur. monographs when requesting marketing authorization, superseding all previous directives.

With the task of protecting public health by applying one common compulsory standard in its Member States, the Ph. Eur. is the official pharmacopoeia and legally binding in 37 Member States and the EU. It is complemented by national pharmacopoeias for specific monographs of interest to only one Member State. Ph. Eur. today contains legally binding quality standards for active substances (organic, inorganic), excipients, substances of biological origin and biotechnology, herbal drugs, essential oils and fats, preparations, radiopharmaceuticals, vaccines, sera (human, veterinary), blood derivatives, and homeopathic preparations. These monographs are supplemented by general monographs on dosage forms as well as general texts on quality issues and standard analytical methods. In total, nearly 2,200 monographs currently exist. The first finished product monograph containing a chemically defined active substance (sitagliptin tablets used in type 2 diabetes) was adopted by the Ph. Eur. commission only as recent as March 2015. A second finished product, rosuvastatin tablets, was also added for monograph elaboration to the work programme, taking into account products from multiple manufacturers. In 2016, the EDQM will publish the ninth Edition of the European Pharmacopoeia, which will contain nearly 3,000 monographs and general texts and will become legally binding by 1 January 2017 [8].

The Ph. Eur. Commission (COM) consists of one delegation per each of the 37 members, a delegation from the EU consisting of a representative from Directorate General Health & Consumer Affairs and the EMA, and observers from 22 countries and WHO. Delegates come from health ministries, health authorities, pharmacopoeias, universities, or industry and are appointed by the national authorities on the basis of their expertise. There are currently 20 permanent Groups of Experts and 52 ad-hoc Working Parties dedicated to revising texts that are to be adopted by the COM which also decides on the composition of these groups.

The procedure by which new texts are introduced into Ph. Eur. is depicted in Figure 1.

Fig 1

On submission of a proposal, typically by a national authority of a Member State, the COM decides to have the new monograph elaborated by a group of experts or working party. A draft elaborated by this group is submitted to Pharmeuropa [9], the free online publication of the EDQM for review and comments by interested parties for the duration of three months. The National Pharmacopoeia Authorities (NPA) of the Member States process the received comments on the draft monograph, which are then compiled and resubmitted to the group of experts or working party. On adaptation of the draft according to the comments received, the monograph is proposed to COM, which adopts it and sets the date of implementation into Ph. Eur., where the monograph is published about six months later.

At EDQM, the Non-Biological Complexes (NBC) Working Party was created in 2011 following an initiative of SwissMedic, the Swiss agency responsible for the authorization and supervision of therapeutic products (medicinal products and medical devices). The COM decided to add to its work programme the elaboration of a monograph on Iron Sucrose Concentrated Solution as a first example for NBCDs. Iron sucrose (IS) and its follow-on products, so-called iron sucrose similars (ISSs) products consist of a polynuclear iron core of iron(III)-oxyhydroxide, which is stabilized by a complex coating of sucrose. IS products have been used in parenteral replacement therapy of anaemia, e.g. in chronic kidney disease (CKD) patients on dialysis to stimulate the generation of erythrocytes. ISSs in Europe received marketing authorization through the generic drug pathway, suggesting interchangeability. Clinical reports such as reported in [10], however, have recently shown that IS and ISSs may not have the same or similar efficacy and safety profile, and thus appear not to be interchangeable. A regulatory pathway, comparable to the one applied for biosimilars, is therefore currently discussed as mentioned above.

The working party, consisting of experts from academia, manufacturers and regulatory authorities, is currently in the process of defining, establishing and validating assays for the characterization of iron sucrose concentrated solution to be included in the monograph. The methods considered to be included comprise assays to assess particle size by size exclusion chromatography and differential laser light scattering. The latter will also contribute to the development of a general method on size measurement of nanoparticles currently under discussion. In addition, assays for the measurement of labile iron released from the particles are being developed, as this is recognized as an important parameter for the safety of IS products.

In drafting the monograph, the working party takes into account methods described in existing monographs on Iron Sucrose Injection in the BP and USP. The working party has also participated in commenting on the draft of the EMA reflection paper on the subject of ‘data requirements for iron-based nano-colloidal products’.

2. The United States Pharmacopeial Convention (USP)
The USP was founded in 1820 in attendance of delegates of medical societies from several states, creating a list of standards and a national formulary. In 1850, colleges were invited to contribute to the revision of the USP, and in 1888, the first National Formulary (NF) was introduced by the American Pharmacists Association (APhA). USP was incorporated in 1900 in its present form as a not-for-profit organization; it is thus not a governmental organization like the Ph. Eur. The USP and NF standards for strength, quality, purity, packaging and labelling are recognized as official and enforced by FDA from 1938 onwards. In 1977, the scopes of USP and NF are redefined such that standards for drug substances and dosage forms are specified in USP, whereas excipient standards are included in NF. From 1980 onwards, both USP and NF are published under one cover. The USP-NF is also translated into Chinese and Russian. While being a national organization, USP has developed an international presence with offices and laboratory facilities in Hyderabad (India), Shanghai (China) and São Paulo (Brazil). Along with these facilities, USP also runs an office in Basel (Switzerland).

The procedure by which a USP monograph is developed is shown in Figure 2. In contrast to Ph. Eur., where the process is initiated by the submission of a proposal by a national authority, the USP process is driven by a manufacturer of an originator or generic drug sponsoring the proposal. Together with the proposal, the sponsor supplies USP with information on the drug’s specifications, relevant assays and test methods. The proposal and data submitted is reviewed by scientific staff of USP, who will also perform laboratory testing. A draft monograph is then submitted to the Council of Experts and one of its Expert Committees for scientific opinion and merits of the proposed monograph. The Council of Experts then decides to publish the draft monograph for a three-month public review at Pharmaceutical Forum (PF), the online peer-reviewed journal of USP [11].

Fig 2

Successively, the comments received are reviewed by the Expert Committee and integrated into the monograph draft. A USP liaison (scientific officer) compiles and analyses these comments and the draft, and submits either for further revision or for publication in USP-NF. The draft thereby becomes an official monograph, the specifications stated in the standard must be abided to when marketing the product within the US.

Besides the development and publication of monographs for prescription and over-the-counter (OTC) drugs (a relatively new activity at USP), the preparation of Reference Standards is a major activity and source of income for USP. The more than 3,500 USP Reference Standards are used in the examination of the identity, strength, quality and purity of drugs, biologicals and excipients, thus contributing to the quality of drug manufacturing. The USP Council of Experts is closely interacting with experts from industry and regulatory agencies. Until 2015, USP has made available a compendium of public standards (Medicines Compendium, MC) for approved medicines on a global basis. The MC monographs were freely available online, providing performance tests for critical quality attributes and acceptance criteria, a source-independent Reference Procedure and one or more Acceptable Procedures. The website was discontinued and shall be replaced in the future by a ‘collaborative programme’ [12].

Concerning activities in the area of NBCDs, and in addition to a published monograph on Iron Sucrose Injection as mentioned above, USP has engaged in installing an Expert Panel on glatiramers with a call for candidates published on 15 December 2015. Glatiramers (or glatiramoids) are complex drugs consisting of a large number of synthetic polypeptides of four amino acids (glutamic acid, alanine, lysine and tyrosine). Based on studies at the Weizmann Institute in the 1960s and early 1970s, which were aimed at developing experimental autoimmune encephalitis (EAE) in guinea pigs as a model for multiple sclerosis (MS), glatiramoids were shown to protect against EAE. Successively, the first glatiramoid drug for relapsing forms of MS (Copaxone®) was developed and marketed by Teva Pharmaceuticals (Teva).

As is the case for biological complex drugs, the inherent complexity of glatiramoids requires a very well controlled manufacturing process (‘the process is the product’). In fact, by slight alteration of the manufacturing process, Teva had produced a glatiramoid (TV-5010) that was similar in terms of amino acid ratio and physical properties [13] to Copaxone®. While good safety and tolerability in patients treated with TV-5010 was shown, long-term toxicity studies in rats and monkeys revealed the occurrence of fibrosis in rats and eosinophilia in monkeys. Studies comparing gene expression profiles of Copaxone® to purported ‘generic’ glatiramoids, e.g. Glatimer® (India), Probioglat® (Mexico) and Escadra® (Argentina) revealed essential differences between the originator and the follow-on drugs [14,15]. It was therefore suggested by Teva that follow-on glatiramoids should not receive marketing authorization by the generic drug pathway. However, as stated in a Denial Letter [16] to a Citizen’s Petition Letter by Teva, FDA insisted that sameness between Copaxone® and a generic glatiramoid, Momenta/Sandoz’s Glatopa®, can be demonstrated by showing equivalence in the fundamental reaction scheme, the drug’s physicochemical properties including composition, structural signatures for polymerization and depolymerization and results in a relevant biological assay. On 16 April 2015, FDA approved Glatopa® [17] as a first generic glatiramoid for the treatment of relapsing MS. Based on these discussions, FDA may issue the draft of a guidance document on glatiramoids in the future.

USP is now in the process of establishing an expert panel to discuss the draft of a monograph on glatiramer acetate. The panel will most likely include experts from academia, regulatory authorities and manufacturers. Major issues to be addressed may include the definition of critical quality attributes for glatiramoids, as well as whether bioassays should be included in the monograph to show activity and safety.

International harmonization: ICH and PDG

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) was launched in 1990 at Brussels headquarters of EFPIA (European Federation of Pharmaceutical Industries and Associations) in the presence of representatives from regulatory agencies of Europe, Japan and the US, and from industry. The mission of ICH is to achieve greater harmonization in regulatory requirements for pharmaceutical product registration [18]. Such harmonization would result in the avoidance of the repetition of studies in the research and development of new human medicines. During the last 25 years, ICH has established harmonized technical requirements for the quality, safety and efficacy of new medicines in EU, Japan and the US.

ICH is governed by its Steering Committee (SC), which is composed of representatives from the European Commission, EFPIA, the Japanese Ministry of Health, Labour and Welfare (MHLW), the Japan Pharmaceutical Manufacturers Association (JPMA), FDA, Pharmaceutical Research and Manufacturers of America (PhRMA), Swissmedic, and Health Canada. WHO is an Observer to the SC, and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) participates as a non-voting member of the SC. The involvement of EDQM in ICH activities is given through the SC membership of the EC.

The ICH SC has several activities. It has established a structure to develop the Medical Dictionary for Regulatory Activities (MedDRA) to facilitate sharing of regulatory information internationally for human medicines (pharmaceuticals, biologicals, vaccines and drug-device combination products). MedDRA is available for use in registration, documentation and safety monitoring of medical products both before and after marketing authorization.

SC has appointed Working Groups to review the differences in requirements between EU, Japan and the US and develop the scientific consensus required to reconcile those differences. The four types of ICH working groups include Expert Working Groups (EWG) charged with developing a harmonized guideline, Implementation Working Group that develops Q & As to facilitate implementation of existing guidelines, Informal Working Groups having the objective of developing/finalizing a Concept Paper, as well as developing a business plan for harmonization activities, and Discussion Groups dedicated to discuss specific scientific considerations or views. ICH convenes twice a year with the location of meetings rotating among Europe, Japan and the US. The five-step harmonization process is initiated by endorsement of a concept paper and business plan by the SC [19].

Several ICH guidelines are suggested for stability testing of nanomedicines [20], e.g. guideline for stability testing of non-targeted nanomedicines (Q1A (R2)) [21], new dosage forms (Q1C) [22] and biotechnology-based drug products (Q5C) [23] for targeted nanomedicines including a biological targeting moiety such as an antibody. Stability studies of liposomal formulations following ICH guidelines have been reported in literature [24]. A range of methods for testing nanotoxicology has recently been reviewed [25]. It has been suggested that the ICH-S6 guideline [26] may be applied for non-targeted nanoparticles, whereas the ICH-S8 guideline [27] may be applied for the assessment of toxicity of targeted nanoparticles conjugated to biological targeting moieties.

The Pharmacopoeial Discussion Group (PDG) [28] was formed in 1989 with representatives of EDQM, MHLW representing the Japanese Pharmacopoeia (JP), and the USP. WHO has PDG observer status since May 2001. PDG generally meets twice a year. Main activities of PDG are retrospective harmonization of general chapters and excipients monographs of the major pharmacopoeias in the three regions, serving also the mission of ICH. In some cases full harmonization of an entire monograph may not be possible. In such case, only harmonizable elements of the monograph are harmonized (harmonization by attribute). Such monograph for a drug harmonized by attribute, interchangeability is compiled only with respect to the harmonized elements, whereas for non-harmonized attributes, compliance with the individual pharmacopoeial requirements in each region is necessary. From 2003 to 2010, the ICH SC nominated an EWG with members from the three pharmacopoeias to discuss several general test chapters in the respective pharmacopoeias in connection with the ICH Q6 A [29] guideline.

The Q6A guideline has the purpose to help select common test procedures and acceptance criteria for new drug substances of chemical origin and new drug products not previously registered in the EU, Japan and the US. The guideline does not apply to the clinical test phase, but only to the marketing approval process of new drug products and combinations thereof. The guideline specifically mentions drugs such as low molecular weight peptides and (semi)synthetic antibiotics. Not covered, however, are radiopharmaceuticals and oligonucleotide-based drugs.

Summary

Increasing awareness of the intricacies of NBCDs in the science and regulatory communities was bound to have an effect on drafting of pharmacopoeial content in the form of monographs and general guidelines. Already existing content should be reviewed and revised according to the changing understanding of these complex drugs. International harmonization of pharmacopoeial contents to maintain drug quality, efficacy and safety in the three major areas will be possible through the networks (ICH, PDG) in place today.

Competing interests: The author declares that he is a member of the steering committee of the NBCD Working Group, hosted at the non-profit organization Lygature – formerly known as Top Institute Pharma, Leiden, The Netherlands (www.lygature.org/nbcd).

Provenance and peer review: Commissioned; externally peer reviewed.

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13. Ramot Y, Rosenstock M, Klinger E, Bursztyn D, Nyska A, Shinar DM. Comparative long-term preclinical safety evaluation of two glatiramoid compounds (glatiramer Acetate, Copaxone(R), and TV-5010, protiramer) in rats and monkeys. Toxicol Pathol. 2012;40(1):40-54.
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15. Towfic F, Funt JM, Fowler KD, Bakshi S, Blaugrund E, Artyomov MN, et al. Comparing the biological impact of glatiramer acetate with the biological impact of a generic. PLOS One. 2014;9(1):e83757.
16. U.S. Food and Drug administration Docket No. FDA-2015-P-1050 [homepage on the Internet]. [cited 2016 Mar 22]. Available from: http://www.fda.gov/RegulatoryInformation/Dockets/default.htm
17. U.S. Food and Drug administration. FDA approves first generic Copaxone to treat multiple sclerosis. 16 April 2015 [homepage on the Internet]. [cited 2016 Mar 22]. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm443143.htm
18. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [homepage on the Internet]. [cited 2016 Mar 22]. Available from: www.ich.org
19. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Formal ICH procedure [homepage on the Internet]. [cited 2016 Mar 22]. Available from: http://www.ich.org/about/process-of-harmonisation/formalproc.html#step-1
20. Muthu MS, Feng SS. Pharmaceutical stability aspects of nanomedicines. Nanomedicine (Lond). 2009;4(8):857-60.
21. European Medicines Agency. ICH Topic Q 1 A (R2). Stability testing of new drug substances and products. CPMP/ICH/2736/99. August 2003 [homepage on the Internet]. [cited 2016 Mar 22]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002651.pdf
22. European Medicines Agency. ICH Topic Q 1 C. Stability testing for new dosage forms. CPMP/ICH/280/95. January 1998 [homepage on the Internet]. [cited 2016 Mar 22]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC50
23. European Medicines Agency. ICH Q 5 C. Quality of biotechnological products: stability testing of biotechnological/biological products. CPMP/ICH/138/95. July 1996 [homepage on the Internet]. [cited 2016 Mar 22]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002803.pdf
24. Vorauer-Uhl K, Wagner A, Katinger H. Long term stability of rh-Cu/Zn-superoxide dismutase (SOD)-liposomes prepared by the cross-flow injection technique following International Conference on Harmonisation (ICH) guidelines. Eur J Pharm Biopharm. 2002;54:83-7.
25. Dobrovolskaia MA, Germolec DR, Weaver JI. Evaluation of nanoparticle immunotoxicity. Nature Nanotechnol. 2009;4:411-4.
26. ICH guideline S6 (R1) – preclinical safety evaluation of biotechnology-derived pharmaceuticals. EMA/CHMP/ICH/731268/1998 [homepage on the Internet]. [cited 2016 Mar 22]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002828.pdf
27. European Medicines Agency. ICH Topic S 8. Immunotoxicity studies for human pharmaceuticals. EMEA/CHMP/167235/2004. May 2006 [homepage on the Internet]. [cited 2016 Mar 22]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002851.pdf
28. European Directorate for the Quality of Medicines & Healthcare. Working procedures of the Pharmacopoeial Discussion Group (PDG) [homepage on the Internet]. [cited 2016 Mar 22]. Available from: https://www.edqm.eu/medias/fichiers/Working_Procedures_of_the_PDG.pdf
29. European Medicines Agency. ICH Topic Q 6 A. Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. CPMP/ICH/367/96. May 2000 [homepage on the Internet]. [cited 2016 Mar 22]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002823.pdf

Author: Professor Gerrit Borchard, PharmD, PhD, Professor, Biopharmaceutical Sciences, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30, quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

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.


Last update: 29/01/2019

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Low-cost generic drug programs in the US: implications for payers and researchers

Abstract:
Low-cost generic drug programs (LCGPs) provide affordable generics in the US. However, LCGPs have implications for managed care organizations and researchers relying on claims data.

Submitted: 7 March 2016; Revised: 5 April 2016; Accepted: 5 April 2016; Published online first: 18 April 2016

Low-cost generic drug programs (LCGPs) in the US increase the affordability and accessibility of prescription medication [1]. LCGPs are unique to the US market as a loss-leader pricing strategy, i.e. retailers accept a loss on these cheap medications to bring in customers, used by eight of the top 10 pharmacy chains, e.g. Wal-Mart, Walgreens, Rite Aid; providing many of the most commonly used generic medications at copayments of US$4−5 for 30-day supplies or US$10−12 for 90-day supplies [13]. These prices are much lower than the copayment for the medications; thus, patients using these programmes acquire the medications without the insurance company’s knowledge.

Our group recently assessed the prevalence and patient characteristics associated with LCGP use in the US among those who are privately [4] and publicly (Medicare) [5] insured as well as in uninsured [6] and paediatric [7] populations. Within each group, we analysed which medications are most commonly purchased through LCGPs, the prevalence of LCGP use at the individual level, and the predictors of LCGP use in a nationally representative sample. Most clear from these studies is that there is a high prevalence of use beyond what was previously known with 36.4% of privately insured adults, 37.9% of older Medicare beneficiaries, 39.9% of those who are uninsured, and 23.7% of children and adolescents using LCGP medications.

The high utilization of these programmes has sweeping implications, especially in the insured adult and insured elderly populations. By using these programmes, no information is submitted through an individual’s insurance benefit; thus, medication use data can be missing from administrative claims data. In the US, claims data are widely used as a primary source for health plans to assess their quality of care and for quality measurement, for pharmacovigilance and safety surveillance, as well as for research purposes for pharmaco-epidemiologic [8].

Quality measurement is mandated by the government for publicly funded insurance programmes offered through managed care organizations (MCOs) and is based on a set standard of measures – including some measures of pharmaceutical utilization [9, 10]. Given the multiple levels of care in the healthcare system, these measures have also trickled down to affect provider prescribing quality, as well [11]. LCGPs can be implicated when these plans and providers attempt to measure their quality of care for, as an example, diabetic or post-myocardial infarction patients. The rates at which metformin (16−30%), angiotensin converting enzyme inhibitors (ACE inhibitors; 17−30%); sulfonylureas (14−25%), and beta-blockers (11−23%) are filled through these programmes are tremendous. Thus, each medication filled through LCGP programs goes unobserved in claims data. This will lead to an underestimation of overall quality and a lower quality score, which becomes important given that these scores have been linked to plan enrolment and can impact quality-based reimbursement packages in a ‘pay-for-performance’ healthcare environment [12, 13].

MCOs are beginning to investigate LCGPs as a source of prescription drugs and are desperately searching for ways to curb their use so they can limit the loss of information for quality measurement. However, limiting access to prescription medications through LCGPs cannot be an effective solution given that increasing medication costs could be a barrier to treatment or patient adherence to treatment. Rather, MCOs should work with pharmacy providers to ensure that claims are submitted for these medications, which could be incentivized by including these cheaper generic drug prices as covered costs under the prescription benefit. Otherwise, a system wide change is likely needed to account for the use of LCGP medications, which would need to be part of a Centers for Medicare and Medicaid Services (CMS) mandate to enact a solution to this important issue.

Beyond affecting the bottom-line of MCOs, the implications of LCGP use also extend to those using claims data for signal detection of harmful medications and research. The well known US Food and Drug Administration’s (FDA) Sentinel Initiative is a conglomeration of several claims databases used as a means of medication safety surveillance [14]. Similarly, researchers use claims data for pharmaco-epidemiologic research investigating the harms or benefits of medications. For these types of applications, exclusion of medication exposures introduces exposure misclassification bias when use of the medication of interest is incorrectly assigned [15]. This type of bias nearly always biases an effect measure to the null hypothesis, i.e. it underestimates the true association between the outcome and the medication. The impact of this bias for a harmful effect would then be to increase the chances of accepting a false null hypothesis that the medication is not harmful when it truly is, or for a protective effect it would find that the medication was not protective when it in fact may be. The size of this bias is a function of the proportion of the sample misclassified and the true effect size. The implications of this bias can be tremendous for medication classes used for prevention of negative health outcomes or medications that are associated with serious adverse events. For researchers, awareness of the issue is paramount to conducting a robust study and the astute researcher should use multiple sensitivity analyses or proxy measures to validate and strengthen their findings.

Much more research is needed to assess LCGPs including the overall impact on the quality measurement system, cost savings to patient and MCOs, and examples where reassessment of research findings may be necessary. One thing can be certain, LCGPs are likely to remain given the high consumer demand for cheaper access to medications.

Competing interests: None.

Provenance and peer review: Not commissioned; externally peer reviewed.

References
1. Choudhry NK, Shrank WH. Four-dollar generics–increased accessibility, impaired quality assurance. N Engl J Med. 2010;363(20):1885-7.
2. Czechowski JL, Tjia J, Triller DM. Deeply discounted medications: implications of generic prescription drug wars. J Am Pharm Assoc (2003). 2010;50(6):752-7.
3. Rucker NL. $4 generics: how low, how broad, and why patient engagement is priceless. J Am Pharm Assoc (2003). 2010;50(6):761-3.
4. Pauly NJ, Brown JD. Prevalence of low-cost generic program use in a nationally representative cohort of privately insured adults. J Manag Care Spec Pharm. 2015;21(12):1162.
5. Low-Cost Generic Program use by medicare beneficiaries: implications for medication exposure misclassification in administrative claims data. J Manag Care Spec Pharm. Forthcoming 2016;22(6).
6. Brown JD, Pauly NJ, Talbert JC. The prevalence and predictors of low-cost generic program use in a nationally representative uninsured population. Pharmacy. 2016;4(1):14.
7. Pauly NJ, Talbert JC, Brown JD. The prevalence and predictors of low-cost generic program use in the pediatric population. Drugs Real World Outcomes. 2015;2(4):411-9.
8. Schneeweiss S, Avorn J. A review of uses of health care utilization databases for epidemiologic research on therapeutics. J Clin Epidemiol. 2005;58(4):323-7.
9. Academy of Managed Care Pharmacy, American Pharmacists A. Medicare star ratings: stakeholder proceedings on community pharmacy and managed care partnerships in quality. J Am Pharm Assoc (2003). 2014;54(3):228-40.
10. Pharmacy Quality Alliance. PQA Performance Measures [homepage on the Internet]. [cited 2016 Apr 5]. Available from: pqaalliance.org/measures/default.asp.
11. Centers for Medicare & Medicaid Services. Physician Quality Reporting System [homepage on the Internet]. [cited 2016 Apr 5]. Available from: www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/PQRS/index.html?redirect=/pqri/
12. Reid RO, Deb P, Howell BL, Shrank WH. Association between Medicare Advantage plan star ratings and enrollment. Jama. 2013;309(3):267-74.
13. Erickson SC, Leslie RS, Patel BV. Is there an association between the high-risk medication star ratings and member experience CMS star ratings measures? J Manag Care Spec Pharm. 2014;20(11):1129-36.
14. Robb MA, Racoosin JA, Sherman RE, et al. The US Food and Drug Administration’s Sentinel Initiative: expanding the horizons of medical product safety. Pharmacoepidemiol Drug Saf. 2012;21 Suppl 1:9-11.
15. Blair A, Stewart P, Lubin JH, Forastiere F. Methodological issues regarding confounding and exposure misclassification in epidemiological studies of occupational exposures. Am J Ind Med. 2007;50(3):199-207.

Author: Joshua D Brown, PharmD, MS, Institute for Pharmaceutical Outcomes & Policy, University of Kentucky College of Pharmacy, Lexington, KY 40535, USA

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

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.


Last update: 16/04/2025

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Top developments in biosimilars during 2015

Submitted: 14 January 2016; Revised: 26 January 2016; Accepted: 27 January 2016; Published online first: 9 February 2016

Once again the biosimilars industry has had a busy year [1]. Perhaps the most important milestone achieved during 2015 was the landmark decision made by the US Food and Drug Administration (FDA) on 6 March 2015 to approve Sandoz’s filgrastim biosimilar, Zarxio (filgrastim-sndz), for all five indications of the originator product (Neupogen).

FDA is also reviewing applications for Hospira’s epoetin alfa biosimilar (Retacrit), Celltrion’s infliximab biosimilar candidate (CT-P13), Sandoz’s etanercept biosimilar (GP2015), and Apotex’s filgrastim (Grastofil) and pegfilgrastim biosimilars.

The Centers for Medicare & Medicaid Services (CMS), which provides health insurance for the elderly and children in the US, issued three biosimilar reimbursement documents in April 2015. The documents cover Medicare Part B, Part D and Medicaid and aim to remove incentives from physicians to prescribe more costly brand-name originator biologicals rather than biosimilars.

In Europe, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended approval of Benepali (SB4) in November 2015. The drug is an etanercept biosimilar produced by Samsung Bioepis, which is a joint venture between South Korean electronics giant Samsung and biotechnology company Biogen. The agency is also currently reviewing biosimilar applications for enoxaparin sodium, etanercept, infliximab, pegfilgrastim and rituximab.

In February 2015, injectable generics specialist and biosimilars maker Hospira launched its infliximab biosimilar, Inflectra, in several major European markets. This increased the number of European countries Inflectra is marketed in to 24 and nearly doubled its presence across Europe. This was followed by the launch of Accofil (filgrastim), which is generics company Accord Healthcare’s first biosimilar approved in Europe. In March 2015, Mundipharma launched Remsima (infliximab biosimilar) in several major markets, including Germany and The Netherlands.

In May 2015, Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) recommended the listing of Eli Lilly’s biosimilar insulin glargine, Basaglar, in the country’s Pharmaceutical Benefits Scheme (PBS). Basaglar is the first biosimilar insulin to be approved in Australia. Australia’s PBAC has also recommended that biosimilars are suitable for substitution at the pharmacy level. Meanwhile, Australia’s drug regulator, the Therapeutic Goods Administration (TGA), approved Hospira’s infliximab biosimilar Inflectra in August 2015.

In March 2015, Hospira launched its infliximab subsequent entry biological (SEB) Inflectra in Canada, the country’s first SEB monoclonal antibody therapy.

Elsewhere, the Korean Ministry of Food and Drug Safety (MFDS, formerly the Korea Food and Drug Administration) approved the infliximab biosimilar Renflexis on 4 December 2015 and the etanercept biosimilar Brenzys in September 2015, both from Samsung Bioepis.

Partners Eli Lilly and Boehringer Ingelheim received Japanese regulatory approval for their biosimilar insulin glargine product (LY2963016) in January 2015.

In May 2015, Iran’s National Regulatory Authority, the Food and Drug Organization (FDO), approved its first rituximab biogeneric (Zytux). The medicine received its marketing authorization based on the previously published national guideline for marketing of biogenerics in Iran.

Russia’s Ministry of Health Fig 1 approved Celltrion’s non-originator biological infliximab, Remsima, in July 2015.

Brazil’s medicines agency, the Brazilian Health Surveillance Agency (Agência Nacional de Vigilância Sanitária, ANVISA), announced in April 2015 that it had approved its first follow-on biological medicine Remsima (infliximab) through its ‘development by comparability’ pathway. The Venezuelan medicines agency, the Instituto Nacional de Higiene ‘Rafael Rangel’ (INHRR National ‘Rafael Rangel’ Institute of Hygiene) also approved Celltrion’s infliximab bioterapéuticos similares in April 2015.

Meanwhile, India’s drug regulator, the Drugs Controller General of India (DCGI), granted marketing approval for a rituximab ‘similar biologic’ from Reliance Life Sciences in February 2015. Indian drugmaker Intas Pharmaceuticals (Intas) launched its ‘similar biologic’ of etanercept (Intacept) in India in March 2015. Intas then launched its ranibizumab similar biologic, Razumab, in June 2015. India-based generics maker Hetero Group launched a similar biologic of rituximab, Maball, in August 2015.

Biosimilars naming

The contentious issue of how to name biosimilars was once again a hot topic for discussion during 2015 [2]. According to the World Health Organization, almost half of the comments on its proposed biological qualifier (BQ) for naming biologicals were positive. WHO published a draft policy ‘Biological Qualifier – an INN proposal’ proposing a possible four-letter alphabetic code for all biologicals in July 2014. The Generic Pharmaceutical Association (GPhA), however, argued that ‘INN [International Nonproprietary Name] naming has been simple and intuitive and this should not be changed’, stating that the brand name is the distinguishing factor. Hospira also argued that ‘it is essential for biosimilar drugs to be given the same non-proprietary names as original biologic[al]s to ensure that patients receive the full benefit of greater access and lower costs that these medicines can bring.’

On the other hand, the American College of Rheumatology (ACR) has stated that ‘biosimilars must have distinct names allowing them to be distinguished from each other and their reference products’. This, the ACR states, ‘is essential for ongoing pharmacovigilance’. The ACR also believes that ‘the decision to substitute a biosimilar should only be made by the prescriber’ and ‘objects to compulsory switching of stable patients to a different medication (including a biosimilar)’.

FDA has also proposed that all biologicals and biosimilars have non-proprietary names and that a four-letter suffix be added to the names to distinguish them from each other. Biosimilars makers, however, would prefer to use the same non-proprietary names as the brand-name biologicals without any suffix, while originator manufacturers would prefer completely different names. Others, however, are concerned that using a ‘suffix deliberately designed to be “devoid of meaning” creates an unnecessary barrier to the use of distinguishable suffixes’.

Results of a survey carried out by the Alliance for Safe Biologic Medicines (ASBM) showed that 90% of physicians thought that it was important that a product label for a biosimilar clearly indicates that it is a biosimilar.

Australia’s drug regulatory agency, TGA is also reviewing its plans for naming biosimilars, ‘following recent international developments in the area of biosimilar naming’. The agency had previously proposed that all biosimilars in Australia have distinguishable names.

Substitution of biosimilars for originator biologicals can also be a contentious issue. However, according to a survey carried out in US pharmacists, most (75%) would be confident in substituting an interchangeable biosimilar with the reference product if both shared the same active ingredient or non-proprietary name of the reference biological.

The Sociedade Portuguesa de Reumatologia (Portuguese Society of Rheumatology) advised in its position statement that biosimilars should have a different INN or be prescribed by brand name. The society also recommended that automatic substitution of originators by biosimilars should not be allowed.

State legislation in the US

In January 2015, biologicals companies including Amgen, Actavis, Sandoz, Hospira and Genentech; and the GPhA agreed to support compromise automatic substitution legislation that would allow interchangeable biologicals to be automatically substituted at the pharmacy. Critical points are that the wording does not specify the notification period, and that the communication is to be done via the use of an electronic system where possible – thus reducing any delays for patients and reducing the burden on pharmacists.

During 2015 additional state legislation has been considered that would allow the substitution of biosimilars [3]. Many of these proposed bills use the compromise wording proposed by the GPhA. The latest states to consider or pass legislation allowing substitution of a biosimilar for an originator biological include California, Colorado, Georgia, Idaho, Illinois, Maryland, Massachusetts, New Jersey, North Carolina, Tennessee, Texas, Utah and Washington.

On 18 June 2015, US lawmakers Steve Stivers and Peter Welch reintroduced the Fair Access for Safe and Timely (FAST) Generics Act to increase consumer access to generics, boost market competition and ultimately save consumers money.

Guidance and recommendations

FDA issued four final biosimilars guidance documents in 2015. These included one on questions and answers about the biosimilars pathway, one on formal meetings between FDA and biosimilars sponsors, one on quality considerations in demonstrating biosimilarity, and one on scientific considerations in demonstrating biosimilarity. The agency also published a draft guidance document addressing additional questions and answers, which includes a question on the issue of interchangeability with reference biologicals.

In January 2015, FDA also asked drugmakers to comment on the information requirements for biosimilars interchangeability.

EMA released its finalized guideline on the non-clinical and clinical development of insulin biosimilars in March 2015. The new guideline lays down the non-clinical and clinical requirements for recombinant insulin-containing biosimilars, including human insulin and insulin analogues (both referred to as insulin). The final guideline, however, rejected requests to accept batches of reference (approved) biological products sourced from outside the European Economic Area (EEA), as is now possible for other biosimilars.

The TGA announced on 10 April 2015 that it was carrying out public consultations on the adoption of two European Union (EU) guidelines (the overarching biosimilars guideline and the guideline on non-clinical and clinical issues) in Australia. The TGA has already adopted many of EMA’s guidelines for biosimilars, as well as publishing its own guidance on the evaluation of biosimilars.

The Dutch Medicines Evaluation Board (MEB) updated its position on biosimilars, stating that ‘biosimilars have been proven to have no relevant differences compared to an innovator biological medicinal product as far as quality, safety and efficacy are concerned’.

In May 2015, the Finnish Medicines Agency, Fimea, announced that it was recommending the interchangeability of biosimilars for their reference biologicals. The Fimea recommendation does not, however, recommend automatic substitution at the pharmacy level. The agency specifically recommends that biosimilars are interchangeable with their reference products only under the supervision of a healthcare professional.

Following increasing interest in biosimilars in Canada, the Canadian Generic Pharmaceutical Association (CGPA), which represents Canada’s generics industry, set up a new CGPA Biosimilars Board in April 2015. Canada’s federal department responsible for health, Health Canada, has thus far approved three SEBs for use in Canada. Similarly, in the US, the US Generic Pharmaceutical Association (GPhA) launched its Biosimilars Council, which aims to be an educational resource for the general public and patient groups seeking information about the safety and effectiveness of biosimilars.

In March 2015, the Mexican regulatory body for approval of medicines, the Federal Commission for the Protection against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios, COFEPRIS), issued rules for older non-originator biologicals registered prior to 19 October 2011, when the country’s guidelines for ‘biocomparables’ were first published, mandating that companies conduct clinical trials to prove biosimilarity.

Clinical trials for biosimilars

In October 2015, Baxalta – a spinoff company from Baxter International – and US-based biotechnology firm Momenta Pharmaceuticals (Momenta) started a phase III clinical trial for their adalimumab biosimilar (M923) in patients with chronic plaque psoriasis. Meanwhile, in The Netherlands another study into the effects of switching patients from originator infliximab to biosimilar infliximab was initiated.

In February 2015, US biopharmaceutical giant Amgen announced positive results from its phase III clinical trial for its adalimumab biosimilar (ABP 501) in patients suffering from rheumatoid arthritis. The company is also carrying out a phase III clinical trial of its biosimilar adalimumab in patients suffering from plaque psoriasis.

Phase III trials of etanercept biosimilar SB4 and infliximab biosimilar SB2 from Merck and Samsung Bioepis reportedly ‘met their primary endpoints, demonstrating equivalence’ to the originator biological in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy.

A study of adverse drug reactions reported in Italy showed no relevant difference between the number and type of side effects reported for biosimilars and their corresponding originators, according to researchers from the Clinical Pharmacology Unit at the University of Messina, Italy.

Results of clinical experience with Celltrion’s infliximab biosimilar Remsima (CT-P13) reportedly show comparable safety and efficacy in inflammatory bowel disease patients.

Results of a post-marketing clinical study of infliximab biosimilar Inflectra claim that the biosimilar has equivalent effectiveness compared to the originator biological (Remicade) in patients with rheumatoid arthritis and ankylosing spondylitis when switched from Remicade.

A study of the treatment of patients with chronic kidney disease undergoing haemodialysis with ‘biocomparable’ and originator erythropoietin in Mexico reportedly showed comparable efficacy and safety in terms of changes in haemoglobin levels.

A retrospective analysis of cancer patients who received either originator or ‘similar biologic’ rituximab chemotherapy showed comparable efficacy and safety, according to a study by researchers from the Tata Memorial Centre, Mumbai, India.

Extrapolation

Extrapolation of indications was also a topic discussed during 2015 [46]. EMA has stated that ‘if clinical similarity can be shown in a key indication, extrapolation of efficacy and safety data to other indication(s) of the reference product may be possible’ under certain conditions.

The Spanish Society of Rheumatology (Sociedad Española de Reumatología, SER) in its position statement on biosimilars agrees that ‘extrapolation of indications must be justified by the standards of the EMA’, but adds that ‘if necessary’ this should be ‘individually proven via double-blind randomized clinical trials that directly compare the biosimilar with the reference drug’. Paediatricians from Europe are also concerned about extrapolation of the limited amount of available clinical data from adults with rheumatologic diseases to children with inflammatory bowel disease.

Biosimilars collaborations

Biosimilar deals were also popular during 2015. US-based injectables specialist Hospira and US biotechnology firm Pfenex announced in February 2015 that they had entered into an agreement to exclusively develop and commercialize PF582 (ranibizumab), Pfenex’s leading biosimilar candidate. US-based Epirus Biopharmaceuticals (Epirus) announced in May 2015 that it had made a deal with biosimilars specialist mAbxience for distribution of BOW015 (infliximab) in Latin America.

Other biosimilar collaborations made during 2015 included deals between Cipla and Mabpharm, Strides Arcolab and Oncobiologics, and NeuClone and the Serum Institute.

The future

The increasing number of clinical trials being carried out for biosimilars in 2015, the number of global biosimilar approvals, the first FDA approval and the growing number of biosimilar applications in the US, all suggest that the future for biosimilars is a bright one.

An analysis carried out by the RAND Corporation highlights the cost-savings to be made and therefore the need for biosimilars. The report finds that introducing biosimilars of complex biologicals used to treat illnesses, such as cancer and rheumatoid arthritis, could cut spending on biologicals in the US by US$44 billion over the next decade. Furthermore, if countries can negotiate discounts, such as those seen in Norway (75%) [7] and France (45%), the savings could be even larger.

Biosimilars penetration in Europe still varies widely between different countries. Penetration of biosimilars varies from a low of 0% for human growth hormone (HGH) in countries such as Belgium and Ireland to an incredible high of 100% for granulocyte colony-stimulating factor (G-CSF) in Croatia. In fact, Eastern Europe is leading the way in biosimilars penetration, perhaps driven by economic factors.

Editor’s comment

It should be noted that ‘similar biologics’ approved in India, ‘follow-on biologicals’ approved in Brazil, ‘biocomparables’, approved in Mexico and ‘bioterapéuticos similares’ approved in Venezuela 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’s 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.

Source: GaBI Online

Competing interests: None.

Provenance and peer review: Article prepared based on extensive research; internally peer reviewed.

Michelle Derbyshire, PhD, GaBI Online Editor

References
1. Derbyshire M. Top developments in biosimilars during 2014. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(1):42-7. doi:10.5639/gabij.2015.0401.010
2. Robertson JS. The challenges of nomenclature – INN, biosimilars and biological qualifiers. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):110-2. doi:10.5639/gabij.2015.0403.025
3. Derbyshire M. Update on US state legislation on biosimilars substitution.
Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(2):95-7. doi:10.5639/gabij.2015.0402.020
4. Perks B. Supporting biosimilarity and extrapolation. Generics and Biosimilars
Initiative Journal (GaBI Journal). 2015;4(4):180-4. doi:10.5639/gabij.2015.0404.041
5. Derbyshire M. European biosimilars conference highlights extrapolation as key
issue. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):149-50. doi:10.5639/gabij.2015.0403.032
6. Gerrard TL, Johnston G, Gaugh DR. Biosimilars: extrapolation of clinical use to
other indications. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):118-24. doi:10.5639/gabij.2015.0403.027
7. Mack A. Norway, biosimilars in different funding systems. What works?. Generics
and Biosimilars Initiative Journal (GaBI Journal). 2015;4(2):90-2. doi:10.5639/gabij.2015.0403.027

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

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.


Last update: 31/01/2019

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Pricing of biosimilars in Saudi Arabia

Author byline as per print journal: Ali M Alhomaidan, PhD; Ibrahim A Aljuffali, MSc, PhD; Fahad S Alnutaifi, MHEcon, MPH; Nasseruddeen A AL-Howaimel, MSc

Abstract:
Innovation in the pharmaceutical industry is expensive and risk must be rewarded. Some novel pharmaceuticals may be worth their high prices. Yet, high prices may hinder accessibility to novel products. It is paramount for pharmaceutical companies to demonstrate the value of their products in the face of increasingly budget-conscious stakeholders. This paper will provide background on the pricing of biosimilars in Saudi Arabia and explain the system used for pricing these products. Factors influencing pricing of pharmaceuticals in general as well as approaches to pharmaceuticals price control worldwide will be discussed.

Submitted: 7 January 2016; Revised: 17 March 2016; Accepted: 19 March 2016; Published online first: 31 March 2016

Introduction: pricing of pharmaceuticals

Pharmaceuticals are one of the vital products that are subject to regulatory control in Saudi Arabia. The reason for regulation is due to the fact that pharmaceuticals are one of the most important elements of many countries’ healthcare programme spending and one of the central factors contained in the citizen spending basket, especially for low-income families, which is reflected on the health of the population [1]. A system that installs pharmaceutical prices could be considered as an interference with the economic concept that says that the price of the commodity is determined by supply and demand [2]. It can also be seen as a hindrance to innovation [3]. However, it is not patients who decide what pharmaceutical they will use based on information available to them, whether it is for its properties, advantages, or price. Rather, patients depend on the physician or pharmacist to select the prescribed pharmaceutical based on several factors that direct their choice and affects their decision. Therefore, patients are at the mercy of their doctor or pharmacist [1]. Generally, prices are negotiated by governments to meet policy objectives and by pharmaceuticals manufacturers to attain profitability.

Factors influencing pricing of pharmaceuticals

Although it is easy to calculate the cost of manufacturing and marketing of a drug, it is difficult to calculate the total cost of getting a pharmaceutical product to the market. Therefore, the pharmaceutical companies price their products by allocating the cost distribution of all the elements involved in getting products to the market including research and development, production and quality control, administrative expenses, marketing, and distribution and retailing. However, by looking at pharmaceuticals prices and seeing differences in price between countries, one can argue that there are other factors influencing price than the total cost of manufacturing and selling these products. Examples of these factors include:

  1. Income per capita [4]
  2. Degree of state influence on drug pricing [4]
  3. Market size [5]
  4. Fluctuations in currency rates [5]
  5. The cost of marketing and the possibility of it reaching consumers in the country. For instance, pharmaceutical companies cannot advertise directly to patients in Saudi Arabia, which affects demand
  6. The existence of intellectual property protection system in the country [1].

Approaches to pharmaceuticals price control worldwide

Due to high prices of pharmaceuticals worldwide, which have led to increased economic pressure on countries, countries are trying to control prices through regulation and by encouraging commercial competition among pharmaceutical companies by making way for the marketing of generics and biosimilars. In the face of these developments, countries found themselves obliged to intervene to determine the prices of pharmaceuticals in order to adjust public spending on pharmaceuticals and encourage local pharmaceutical industry growth in a way that ensures the availability of effective and safe pharmaceuticals in their markets. Countries have historically controlled prices of pharmaceuticals through one of the following options:

  1. Full Control in the price system. This is used in Saudi Arabia and several countries in the Middle East and North Africa (MENA) region. In Saudi Arabia, it is mostly applied in the pricing of new chemical entities or innovator products. In Saudi Arabia, the company submits pricing certificates showing the price of its product in the country of origin and its price in the countries where it is marketed (Form 30). A price is set based on ex-factory price. A maximum of 2% is then added for the cost, insurance and freight (CIF price) and 10–15% is added for wholesaler profit, with another 10–20% added for retail profit when it is sold to the public [6]. The percentage depends on ex-factory or CIF price; see Table 1. Despite the difficulties in the application of the system in terms of auditing of certificates and authentication, including outages, it has helped greatly in stabilizing prices in the country and preventing fluctuations. The pricing committee can review prices when there is a change in exchange rates that might affect the availability of products in the Saudi market. In the case of change of price in the country of origin, or in the case that the company asks for a change in price, an appeal against set price is allowed within 60 days of the decision with proper justification [6].
  2. Ceiling price system. The regulator sets an upper limit on the price of the pharmaceutical to be marketed without committing the company to this price. The company is free to sell its products at any price based on market conditions and marketing policy as long as it is less than ceiling price. One of the main benefits of this system is that it opens the field to competition between companies and pharmacies and increases the sales of generic drug products [8]. The success of this system, however, requires an effective regulatory system and the presence of generic drugs industry with an accompanying advanced system and strict sanctions on companies, pharmacies and health practitioners who engage in the unethical marketing of products [8].
  3. Open pricing system. Pricing is left to pharmaceutical companies and retail pharmacies to sell pharmaceuticals at a price that will bring them a reasonable profit without interference from a regulator, allowing market forces to determine the price. This system is applied in the US, and it is noted that the prices of pharmaceuticals in the US are one of the highest in the world [9].
  4. Reference pricing. This is applied mostly to generic drug products in Saudi Arabia. Generics are priced based on the price given to innovator products or new chemical entities. The reference product’s price is reduced by 20% at the license of the first generic drug, which is priced 35% cheaper than the reference product before a reduction in the reference product price; every subsequent generic drug is 10% cheaper, until the fourth generic drug. The reduction in price then stops. For example, if a reference product is priced at Saudi Riyals 100, when the first generic is registered, the price will be reduced to Saudi Riyals 80, the first generic will be Saudi Riyals 65, and subsequent generics 10% cheaper, till the fourth generic. An appeal against set price in Saudi Arabia can be lodged within 60 days of the decision with proper justification.

Fig 1

Evolution of pharmaceuticals pricing in Saudi Arabia

In 1935, the law of pharmaceuticals use was issued by the Royal Decree No. 157/1/18 [10]. The law regulated the practice of pharmacy and the opening of retail pharmacies in Saudi Arabia. The system for pricing of pharmaceuticalswas first issued by Royal Decree No. 12 on 1953, which required the determination of pharmaceuticals prices and set a 15% profit for each of the wholesaler and retail pharmacies. Royal Decree No. M/37 on 1961 was then issued which raised the proportion of profits allowed for the sale of pharmaceuticals by retail pharmacies to 17% of the value of their purchase from the wholesaler. Profits specified for wholesalers remained the same without any increase or decrease of 15% of the value of the imported pharmaceuticals. Royal Decree No. M/37 also required wholesalers to put pricing stickers on every imported pharmaceutical [11].

This continued until 1977 when the Ministerial Decree No. 7 issued the regulations for the registration and pricing of pharmaceuticals [12]. Registration and pricing of pharmaceuticals were entrusted for the first time to the Registration Committee at the Ministry of Health. The committee was to use the following when estimating the price:

  1. The price of pharmaceuticals to the public in the country of origin
  2. The price of pharmaceuticals in other countries
  3. The price is not to exceed export prices to Saudi Arabia for wholesale selling prices in the exporting country.

Regulations also required to provide a number of reference pricing certificates when filing for registration such as certificates describing the selling price to the public in the country certified by the source of the concerned governmental authorities and from the Saudi embassy there or its substitute [12].

In 2004, the law of pharmaceutical products and establishments was issued. It determined in article XIII the proportion of profit is calculated for retail and wholesalers according to Table 1. One of the objectives of this law was to encourage the marketing of cheaper pharmaceuticals with smaller packages by giving higher margins for products at Saudi Riyals 50 or cheaper [13]. In 2008, the responsibility for licensing and pricing of pharmaceuticals was transferred from the Ministry of Health to the Saudi Food and Drug Authority (SFDA). The pricing system was then reviewed by the Registration Committee. A draft executive regulation for the law for pharmaceutical establishments and products was issued and approved by SFDA’s Board of Directors in 2011 and is still in effect [14]. The new system included rules for the first time that allow for lowering innovative pharmaceuticals price by 20% when SFDA license its first generic pharmaceutical. The new system also encouraged the marketing of generic pharmaceuticals and the transfer of manufacturing to the Kingdom. It also gives permissions to the Registration Committee to take required measures to ensure the availability of pharmaceuticals in the Saudi market.

Pricing of biosimilars

A Full Control in the price system is applied to biosimilars in Saudi Arabia. Based on regulatory pricing requirements, the manufacturer is to provide a prices certificate certified by the competent authority in the country of origin and authenticated by the Saudi Embassy that contains information on the following:>

  1. Ex-factory Price
  2. Wholesaler Price, in the country of origin
  3. Retail Price, a wholesale price plus expenses, and retail pharmacy profit, which is the final price paid by the patient
  4. The proposed export price of the company’s product to the Kingdom
  5. Form 30, which shows the price in 30 different countries, in case it is registered in these countries. Table 2 shows a list of these countries.

Fig 2

We will use Remsima, a biosimilar for Remicade (Infliximab), as an example. The company submitted pricing certificates showing the ex-factory price at Saudi Riyals 1,126.029. The cost of insurance and freight was added. Since the ex-factory price is more than Saudi Riyals 200, only 10% is added for the wholesaler profit, and another 10% is added for the retail profit when it is sold to the public. The final price is Saudi Riyals 1,362.50.

Conclusion

Factors influencing pricing of pharmaceuticals in general as well as approaches to pharmaceuticals price control worldwide were discussed in this paper. Pricing of biosimilars in Saudi Arabia and the system used for pricing these products was presented. Remsima was used as an example to illustrate the pricing system. Biosimilars are priced using the Full Control in the price system. Remsima was the first biosimilar registered in Saudi Arabia for Infliximab. The reference product, Remicade, is priced at Saudi Riyals 2,127.95 whilst Remsima is priced at Saudi Riyals 1,362.50, which is about 36% cheaper than Remicade. Applying this pricing system should reduce the price of biosimilars in Saudi Arabia when compared to innovator reference products, allowing for more patient accessibility and affordability. However, it may put pressure on biosimilars manufacturers due to the high costs associated with their development. Hopefully in the long term, this can be negated with more manufacturers entering this niche market. In addition, there is clarity now compared to a few years ago when the regulatory pathways worldwide were not clear regarding data requirements for biosimilars. Now the requirements are clear and some of these products are well characterized. Still, I think we will yet have a Hatch-Waxman moment for biosimilars where the regulatory requirements are streamlined allowing for more competition between manufacturers and for more investments. As it stands, biosimilars are still a high-risk investment.

Competing interests: The authors have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter discussed in this paper.

Provenance and peer review: Commissioned; externally peer reviewed.

Co-authors

Ibrahim A Aljuffali1, MSc, PhD
Executive Vice President for Drug Affairs
Fahad S Alnutaifi1, MSc
Nasseruddeen A AL-Howaimel1, MSc

1Saudi Food and Drug Authority

References
1. World Health Organization. Zerda Sarmiento A. Alternative drug pricing policies in the Americas. Health Economics and Drugs DAP Series No. 1. 1995 [homepage on the Internet]. [cited 2016 Mar 17]. Available from: http://apps.who.int/iris/handle/10665/59412
2. John Lu Z, Comanor WS. Strategic pricing of new pharmaceuticals. Rev Econ Stat. 1998;80(1):108-18.
3. Frank RG, Salkever DS. Generic entry and the pricing of pharmaceuticals. J Econ Manag Strategy. 2004;6(1).
4. Danzo PM, Ketcham JD. Reference pricing of pharmaceuticals for Medicare: evidence from Germany, The Netherlands, and New Zealand. Front Health Policy Res. 2004;7:1-54.
5. Dickson M. The pricing of pharmaceuticals: an international comparison. Clin Ther. 1992;14(4):604-10.
6. Saudi Food and Drug Authority: Pharmaceuticals pricing system 2011:Annex 2 page 14.
7. Saudi Food and Drug Authority: Executive regulation for the law for pharmaceutical establishments and products 2011:Page 13.
8. Kraus L, Transnat’l V. The interaction of international reference pricing and parallel trade in the pharmaceutical industry. Medication misadventures. 2004.
9. International Federation of Health Plans. 2013 Comparative price report: variation in medical and hospital prices by country [homepage on the Internet]. [cited 2016 Mar 17]. Available from: http://www.ifhp.com/
10. Royal Decree number 157/1/18: The law of pharmaceuticals use 1935.
11. Royal Decree number 37/M. 1961.
12. Ministerial Decree No. 7: The regulations for the registration and pricing of pharmaceuticals. 1971.
13. Royal Decree number 31/M: The law for pharmaceutical establishments and products. 2004.
14. The Saudi Food and Drug Authority: Executive regulation for the law for pharmaceutical establishments and products 2011.

Author for correspondence: Ali M Alhomaidan, PhD, Executive Director for Products Evaluation, Saudi Food and Drug Authority, 3292 North Ring Road – Al Nafal Unit (1), Riyadh, Saudi Arabia

Disclosure of Conflict of Interest Statement is available upon request.

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Views of physicians and patients with chronic conditions on generic medicines in Greece after the introduction of measures to promote their consumption: findings from a qualitative study

Author byline as per print journal: Eleftheria Karampli, MSc; Estathia Triga, MSc; Vasiliki Tsiantou, MSc; Kostas Athanasakis, PhD; John Kyriopoulos, PhD

Introduction/Study objectives: Generic medicines uptake is widely acknowledged as a key pharmaceutical policy measure towards cost containment and rational resource allocation. In Greece, due to the persistently low penetration of generics in the pharmaceutical market, a series of policy measures aiming to reverse this trend were implemented during the last years. The aim of the present study was to explore the perceptions and experiences of physicians and patients towards generic medicines as well as the acceptability of the policies implemented.
Methods: A qualitative approach, based on semi-structured interviews to physicians and chronically ill patients residing in the region of Attica formed the basis of the analysis. Recruitment of physicians and patients was performed using a combination of convenience and snowball sampling techniques. Interviews were audio-recorded, transcribed and content analysed, according to international guidelines for qualitative research.
Results/Discussion: Nine physicians (general internists and cardiologists), and nine patients suffering from hypertension, diabetes mellitus and hyperlipidemia participated in the survey. Physicians’ views on generics were positive, although concerns were raised regarding the monitoring mechanisms and the reliability of companies producing generics. Patients were more hesitant to express their opinion on generics because they felt that they were not adequately informed. Prescribing is a multi-criteria decision, whereas for patients the choice of medicine is made by their physician. Cost was not an important factor for both groups. Policy measures on generics were generally acceptable in the case of physicians and there were mixed opinions in the group of patients. Both groups stressed the need for more and reliable information regarding generics.
Conclusion: Patient and physician attitudes can ‘make or break’ even a perfectly planned healthcare policy. Taking into consideration the information available in studies such as the present one, can aid decision-makers towards the design and implementation of viable policies in the sensitive field of generics uptake.

Submitted: 19 January 2016; Revised: 8 April 2016; Accepted: 8 April 2016; Published online first: 22 April 2016

Introduction

Medicines have undoubtedly made important contributions to the improvement of the population health status in developed/developing countries over the last decades. However, the growth rates of pharmaceutical expenditure over the same period has by far exceeded the growth rate of the economy in general [1, 2], raising concerns about the sustainability of social security systems. The latter has led European governments towards the implementation of a series of reforms in order to contain pharmaceutical expenditure and increase the efficiency of healthcare spending [3]. Pharmaceutical policies targeted to the increased uptake and use of generic medicines is considered a key solution for expenditure control and rational allocation of resources [4]. In this sense and, partially, in response to the economic crisis of 2008, the majority of European countries implemented pharmaceutical sector reforms in order to contain public expenditure on pharmaceuticals [5]. Policies to further increase the market share of generics were among the most frequent measures introduced [6, 7].

In Greece, the First Economic Adjustment Programme (EAP) that was agreed under a memorandum of understanding (MoU) with the European Union (EU), the International Monetary Fund (IMF) and the European Central Bank (ECB) set specific expenditure targets for public expenditure on health and pharmaceuticals [8]. Specifically, public health expenditure and public pharmaceutical expenditure were to be reduced to 6% and 1% of the country’s gross domestic product (GDP) (as per the EU average), respectively. In this direction, emphasis was given -among others- to the increase of the use of generic medicines (the so-called ‘generics penetration’), as Greece historically had persistently lower market shares for generics both in terms of value and volume [9] compared to its European peers. Following the positive experience of International Nonproprietary Name (INN) prescribing in Europe [10], in terms of implementation [11], efficacy [12] and potential cost savings [13] a ministerial decision regarding the universal and mandatory implementation of INN prescribing in both the hospital and outpatient setting was implemented in 2012. However, this was not accompanied by measures that could positively influence a workable implementation of this policy such as physician training [11] – thus it faced resistance from the physicians. Further measures towards generics penetration included reductions in prices of generics; compulsory e-prescription by physicians and introduction of prescription guidelines; reintroduction of a positive list in combination with a reference price system. Certain exceptions to INN prescribing were foreseen. Physicians were also allowed to prescribe by brand name up to a maximum of 15% of prescriptions written. Minimum prescription targets for generic medicines were also introduced in 2014 [14]. Both INN prescribing and mandatory prescribing quotas were highly debated by the pharmaceutical industry and health professionals, especially physicians and pharmacists [15]. In April 2015, physicians were given the option of suggesting the commercial name in parallel to INN prescribing, however, this provision was recently revoked. According to the goal set in the Third EAP for Greece which was signed in August 2015 [16], the target market share of generics was set to increase by 40% (in volume) by December 2015 and 60% by December 2016 in the outpatient setting.

However, despite the positive attitude of Greek physicians towards generics and their belief that a policy towards the promotion of generics could result in increases in prescribing [17] and despite the introduction of several measures to encourage generics prescribing and consumption [18], their market share in the outpatient setting still remains low at 22% in volume [19]. This indicates that the implemented policies did not significantly affect the physicians’ prescribing behaviour regarding generics and that the measures severely underperformed. Apart from that, there is a paucity of data regarding the attitudes and behaviour of patients in Greece towards generic medicines, a fact that prohibits the planning and workable implementation of pharmaceutical policies aiming at the uptake of generics.

In light of the above, the objective of this study was to explore the perceptions and experiences of physicians and patients with chronic conditions towards generic medicines as well as the acceptability of the measures that were implemented in aim to promote generics’ consumption in Greece, a country deeply affected by the economic crisis. In parallel, the present study aimed at eliciting patients’ attitudes towards generic medicines, and their knowledge regarding the related policy measures.

Method

Study design
A qualitative research design was considered appropriate for the purpose of this study. A qualitative approach enables the researcher to better understand a social phenomenon within its context [20]. Semi-structured interviews were used for data collection. According to this method the interviewer uses a series of general questions but is also able to vary the sequence of questions and ask additional ones, so that the conversation between the interviewer and interviewee is developed in a free atmosphere in order to explore in depth the attitudes of informants [21].

Participants and settings
Two medical specialties were selected for the physicians’ sample: cardiologists and general internists. This selection was based on the findings of a countrywide study [22], which showed that patients’ visits to physicians were most frequently made to these two specialties. A second reason for focusing on cardiologists and internists was the fact that these specialties are the main prescribers of antihypertensive medicines and statins. The latter were among the ten most frequently prescribed therapeutic classes of prescription medicines according to the Ministerial Decision on the implementation of INN prescribing issued in March 2012.

Recruitment of physicians was performed using a combination of convenience and snowball sampling. Convenience sampling refers to the sampling of individuals that are easily accessible and most likely to accept to participate. In the snowballing technique, the initial respondents are asked to suggest other possible interviewees that fulfill the inclusion criteria in the study [23].

Interviews with patients took place following the completion of the physicians’ interviews. From the physicians’ responses it was derived that they mainly prescribed medicines for patients with hypertension, hyperlipidemia and type-2 diabetes. Therefore, patients with these chronic conditions were invited to participate using also convenience and snowballing sampling techniques.

In both cases participants were informed about the study via an invitation letter, which described the aim of the study and the process of interviewing. The invitation letter also assured participants of the protection of their anonymity and explicitly stated that the study results would be used only for scientific purposes. Participants provided written or oral consent. None of the participants received compensation. Ethical approval was obtained from the Bioethics Committee of the National School of Public Health (Athens, Greece).

Interview guide development and analysis
An interview guide was developed for each group of participants based on the study research objectives. Questions on sources of information on medicines in general, perceptions on generics, attitudes towards generics prescribing/consumption and views on INN prescribing and generics substitution were common in both interview guides. The physicians’ interview guide also included questions regarding their prescribing decisions, as well as their views on pharmacovigilance and policy measures for generics, i.e. electronic prescribing, prescribing guidelines, prescribing quotas. The latter were considered difficult for patients to evaluate and thus were not included in their interview guide.

Pilot interviews with two physicians and two patients were conducted and necessary changes were made to the interview guides. All interviews with study participants were performed by the same researcher Efstathia Triga (ET). Participants also completed a short form on demographic characteristics. Each interview was audio-recorded, transcribed verbatim (ET), anonymized and analysed manually using qualitative content analysis [24]. Specifically, after the first two interviews for each group were performed, transcripts to be reviewed in full were assigned to Eleftheria Karampli (EK) and ET who each compiled a proposed list of codes. Only manifest content was considered. Codes were grouped in categories using hierarchical coding. The procedure was mostly deductive and topics included in the interview guide were used as a background for developing categories. The coding scheme was discussed in a team meeting and changes were implemented following consensus from the team. ET subsequently indexed each new interview transcript and performed the initial analysis. Recruitment of participants ended at the point of data saturation, i.e. when the information collected produced little or no change to the coding scheme (as operationalized by Guest et al. [25]). Another member of the research team (EK) reviewed all coded manuscripts and differences were resolved in a team meeting. All interviews, coding and analysis were performed in the Greek language.

Results

In total, (10) physicians (6 through convenience sampling and 4 through snowballing technique), and (11) patients with chronic conditions were invited to participate in the study. Participating physicians introduced (2) of the invited patients and the rest of them were recruited based on the snowballing technique. Eighteen participants agreed to participate (9 from each group) and were interviewed. All participants resided in the region of Attica.

Interviews with physicians took place between 15 February and 1 March 2013 and lasted on average 30 minutes. Six were face-to-face interviews, which took place at the physician’s office and three were telephone interviews. Phone interviews were conducted in the cases where a face-to-face appointment could not be scheduled. Phone interviews were also audio-recorded after participants gave oral consent.

Interviews with patients took place from 29 March 2013, at a location of their choice and had an average duration of 20 minutes. Participants’ demographic characteristics are presented in Supplementary Material, Table 1.

Fig 3

Content analysis revealed three main categories from both patients’ and physicians’ interviews. These categories and their subcategories are presented in Supplementary Material, Table 2.

Fig 4

A. Physicians

Physicians’ quotes are presented in Table 1.

Fig 1

Category 1: Perceptions about generics and the need to strengthen quality assurance mechanisms in the Greek market

1a. Views on the current situation
When commenting on generic medicines in general, physicians expressed varying views. They tended to make more general comments and referred to both positive aspects and issues of concern regarding the situation in the Greek market. The positive comments that were documented on generics regarded their lower cost and the long-term presence of trustworthy companies with whose products physicians in Greece are familiar. However, those that held a positive view on generics stressed that it was conditional on the quality of the product.

The problematic issues regarding generics that were mentioned by physicians were their cost relative to the reference (off-patent) product, the negative image that was created by the mass media, patients’ reservations towards their use and the lack of trust in the regulatory mechanisms and in some of the pharmaceutical companies that distribute generics in Greece.

1b. Safety and effectiveness of generics
Regarding the effectiveness and safety of generics in specific, most participants held the view that generics that were available at the time of the survey in the Greek market were safe (7/9) and effective (7/9). Participants’ positive view was based on the general experience of Greek physicians with generics and/or their personal experience with prescribing (and in one case consuming) generics. In the latter case, participants tended to clarify that their views with regards to the effectiveness and safety of generics compared to the originator products would apply only to the products that they used; they were hesitant to comment on all generic drug products available in the Greek market. They also expressed positive opinions regarding the existing quality controls and marketing authorization requirements in Greece (4/9). Another argument that was mentioned was that it is not in the commercial interests of generics companies to market products that are not effective.

The reservations regarding the effectiveness and safety of generic drug products were mostly on the effectiveness of the monitoring mechanisms in place (3/9), the reliability of companies that produce and/or market generics (5/9), the quality of bioequivalence studies and the suitability of generics in the case of medicines with narrow therapeutic range (3/9). As was previously mentioned, the reliability of generics companies was a matter of concern. Many physicians tended to distinguish between those companies that have been present in the Greek market for many years and whose products they have been prescribed to patients, and, on the contrary, they expressed concerns regarding the new players in the market (6/9). Generics manufactured by Greek companies were often used as an example of established companies (4/9).

According to the physicians, a company would be characterized as reliable if it had a presence in the pharmaceutical market for an ‘adequate’ (according to the physician’s perception) period of time in order to show positive results for its products and if it had provided bioequivalence studies performed in acknowledged centres. The country of origin was also mentioned as a criterion. Although other criteria, such as a sufficient sales network or the quality of the informational material were also mentioned, they were not considered as important as the aforementioned characteristics. In this view, the need for competent authorities that could ensure that companies are reliable and that generic drug products available in the Greek market are of high quality was emphasized by all participants.

1c. Sources of information on generics
Physicians use a variety of information sources on generic medicines including scientific, commercial and mass media sources. The most frequently mentioned source of information was pharmaceutical companies via their representatives and promotional material (8/9). Additional sources of information included the international literature, the products’ monographs, publications by medical associations, articles in online newspapers (6/9), and also feedback from patients and other physicians regarding their experience with the treatment (2/9). The lack of information from official regulatory bodies was also raised as a reason (2/9). The type of information on a generic drug product that physicians take into consideration relates to the product’s bioequivalence report, safety profile, side effects, effectiveness and also results of relative effectiveness studies in real-life settings.

Category 2: Decisions on prescribing and choice of medication

The most frequent health problems and conditions that physicians prescribe medicines for, in the case of cardiologists, were hypertension, dyslipidemia, type 2 diabetes as well as coronary heart disease, valvulopathy, and other types of heart disease. In the case of general internists the most frequent conditions they prescribed medicines for were hypertension, type 2 diabetes, chronic obstructive pulmonary disease, and also gastrointestinal diseases and acute infections.

2a. Criteria relating to the prescribing decision
When asked about the factors that they take into consideration when deciding on which medicine to prescribe to a patient, participants made reference to a multiplicity of factors. The major factors were disease characteristics (8/9), patient characteristics (9/9) and medicinal product characteristics (6/9). Disease characteristics included the need to prescribe a medicine for the specific indication, the acuteness of the specific episode, whether the disease is chronic, the disease duration (time from onset) and the therapeutic goals the physician sets. Patient characteristics referred to their age, sex, weight, coexisting health conditions and comorbidities, laboratory results, family as well as personal health history, allergies, but also to one’s emotional state, expected compliance with the prescribed pharmacotherapy, income and lifestyle. One participant made the distinction that if the patient was regularly followed by another physician, he/she would not consider changing the patient’s medicine.

Finally, when deciding on the medicinal product of choice, physicians claimed that they consider primarily its indications (4/9), effectiveness (4/9) and side effect profile (3/9). Their personal experience with prescribing a medicinal product to patients was mentioned by some participants as an input on the product’s effectiveness.

2b. Criteria they apply when generic versions of the originator drug product are available
In the specific case when both the originator drug product as well as its generic versions are available in the market, physicians also apply the aforementioned criteria of effectiveness and safety. These are the most important ones, but they also consider additional factors. Effectiveness is evaluated on the basis of the product’s bioequivalence studies (4/9) and also on the basis of previous experience (2/9) with specific products either in his/her private practice or in other settings the physician has worked in. Also, physicians state that over time they have established their preferences regarding the type (originator/generic) and number of products that they prefer to prescribe (3/9).
The marketing authorization holder is considered an important parameter in product choice, as it is considered a proxy of the product’s reliability (8/9). Greek companies that have been present for a long time in the market were used by many participants as examples (5/9), although some physicians also distinguished among them (2/9). Doubts were expressed mostly on generics that are imported from other countries, i.e. products for which physicians had no knowledge or experience with (4/9). Preference towards locally produced generics was also seen as a means to support the country’s economy (4/9). Other criteria for selecting among available products with the same active substance are their price (and consequently the cost to the patient) (4/9) and patient’s preferences (5/9).

The choice between originator and generic medicine was seen by some physicians (3/9) as a factor of their image, i.e. their ‘status’ as a doctor. This was because of the negative image that was created during the past years regarding the relations between companies and physicians, and the view that the choice of type of drug is an indicator of the quality of the services that a physician provides. However, opposing views were also expressed (2/9), with participants arguing that a physician’s reputation and professional experience are more important evaluation criteria for patients than the choice of drug.

Category 3: Attitudes on the measures implemented by the government to promote penetration of generics

The measures introduced with the aim of promoting generics’ consumption were in general acceptable by the majority of the participating physicians (6/9). They saw them as means to decrease public pharmaceutical expenditure and prices of pharmaceuticals. However, they expressed criticism on the actual way that these measures were implemented (3/9) which, according to their opinion, created a negative impression among the public and suggested that the effort towards rationalizing expenditure should not be based on imposed decisions through the MoU. Two participants expressed very negative opinions on the respective measures. They were seen as part of a series of measures that constituted a change in health policy in a wrong direction, especially regarding the impact on the Greek industry and subsequently, economy.

3a-3d. Views on specific measures
Electronic prescribing was positively evaluated and was thought to facilitate promotion of generics (6/9). The occasional technical problems of the system were considered as its only drawback. Participants’ opinions regarding the prescribing protocols that were developed by the National Medicines Agency varied. Some physicians were not aware of their existence (4/9) and, among those that were aware, some believed that they were helpful (3/9) whereas others reported that they never used them as they made decisions based on international scientific guidelines or on their experience (2/9).

Participants expressed opposing views on INN prescribing. This measure was seen as a way to cope with financial ties between physicians and pharmaceutical companies (2/9), but there were reservations regarding its purposefulness (3/9). Specifically, participants expressed criticism to the fact that the prescribing physician could not choose the prescribed medicine and suggested that there were alternative means, such as a combination of INN and brand-name prescribing or discussing with a patient about prescribing a generic medicine (3/9). The majority of physicians were negative on generics substitution by pharmacists during dispensing (7/9). They believed that it deprived the physician of control over the dispensed medicinal product, since the physician cannot be familiar with all the available generic drug products, and that it could also lead to frequent changes between generic drug products. An issue that was raised by many participants was the impact of generics substitution on physician and pharmacist roles and the need to clarify which health professional would be held responsible (5/9).

Additional measures that are foreseen in the MoU and are to be implemented in case the pharmaceutical expenditure targets are not met (i.e. the cost/patient plafond – an average ‘target’ for pharmaceutical spending for each patient that the physician monitors and prescribes medication for depending on physician specialty and diagnosis, and the maximum prescribing targets/physician) were rejected by all participants, as they were characterized as horizontal, unjust to the patients and offensive to the physicians. They also considered that they were difficult to implement from a technical point of view.

3e. Suggestions towards a successful generics policy
Physicians again stressed the need for competing organizations to ensure that the products that are available in the market will be effective and reliable. As long as this prerequisite was met, further measures to promote generics consumption could include the promotion of rational prescribing among physicians, reductions in prices of generics through either free pricing or discount agreements with the local industry, and informational campaigns by the National Medicines Agency targeting both physicians and patients.

B. Patients

Patients’ quotes are presented in Table 2.

Fig 2

Category 1: Knowledge and sources of information on pharmaceuticals for their chronic disease

All patients could name the medicinal products they were taking for their chronic health problems. All but one also knew whether these were the originator products or generics and in most cases (8/9) patients stated that their medicines were originator products.

Interviewed patients had different behaviours regarding information seeking on the medicines they take: patients who were not actively seeking such information (3/9) claimed that they do not take many medicines, that they follow their physician’s orders and that they are satisfied with the medicinal products they have been using for years. Among those that were interested in obtaining information on their medicines (6/9), their main source of information was their physician (6/9), whom they saw as the most reliable source. The pharmacist was also an important source (4/9), provided that patients felt they had a trusting relationship similar to the one with their physician. Complementary sources of information were the product’s package insert with information for the user, the Internet and – for some patients – their social environment. The type of information that is the most important to them is possible side effects (5/9), effectiveness (5/9) and interactions with other medicines (2/9). Some patients also mentioned the product’s dosage and composition (3/9).

Category 2: Factors regarding the choice of their medications

2a. Choice of medication
For almost all participants (8/9), the choice of prescribed medication was made by the physician. For some patients (2/9) the physician had informed them of available therapies and the rationale for choosing the specific medicine, whereas for other patients there was no discussion with the physician. Only one patient claimed that because he/she could not afford the cost of a visit to the physician, the pharmacist was the one that gave him/her a medicinal product similar to the one he/she was taking and was not available in the market anymore.

2b. Factors that they consider regarding the choice of medication
Patients claimed that cost (in terms of the patient’s copayment) was not a decisive factor in their choice of medicinal product (7/9). Although the majority of participants was subject to copayment (8/9), some stated that they would not consider cost at all if it was necessary to take a more expensive medicine that was suitable for them (4/9). For other patients cost would be a consideration but not the most important one; effectiveness and side effects would be the main criteria of choice (3/9). Patients with chronic conditions who were subject to a lower (10% instead of 25%) co-insurance rate said they were more likely to consider cost had their co-insurance been higher. Cost was an important parameter of choice for one participant, who reported having a high copayment.

On the matter of switching to a generic medicine, the majority of patients expressed willingness to try switching to a generic drug product (7/9), however, only if their physician or, in some cases, a pharmacist they trusted, suggested a switch to a specific product and they felt that it had the same effectiveness and side effect profile as the originator product. Few participants reported that they had discussed with pharmacists on the available alternatives but the difference in cost was not considerable so as to choose a generic drug (2/9). In one case, the patient precluded switching to generics because he/she considered that there was no way to ensure that generics were the same as the originator product.

Category 3: Generic medicines

3a. Attitudes on generics
Participants’ views on generics varied. The majority was reluctant to express a definitive opinion as they felt they were not adequately informed (4/9) whereas, others expressed both negative (2/9) and positive views (2/9). Among those that were hesitant towards generics, there was a concern regarding the regulatory mechanisms in place to check their safety and regarding the country of origin. The impression that the main purpose for promoting generics consumption was to cut public pharmaceutical expenditure also had casted doubts on their quality.

3b. Sources of information and information needs
All patients replied that they have heard ‘something’ on generics through various sources, such as the mass media (newspapers, TV, radio, the Internet), friends, the pharmacist, companies’ promotional leaflets and medical conferences. Most patients had not been informed or had not initiated a discussion with their physician on generics (6/9). Participants felt that the mass media were a source of more general information on generics and that someone that wanted to inquire about his/her specific treatment would ask their physician, whom they considered the most reliable source of information, followed by the pharmacist. The type of information they would want to be available includes what generics are, why they exist, their country of origin and quality control mechanisms in place by the local authorities, their effectiveness and safety in relation to the originator products and their cost. Patients preferred to be informed by their physician on generic medicines for their health problems; however, they thought that physicians do not have the time or intention to provide such information. Pharmacists, the National Medicines Agency and the Ministry of Health or other independent organizations and leaflets were suggested as complementary sources of information.

3c. Views on the measures implemented by the government to promote consumption of generics
Patients expressed conflicting views on INN prescribing and generics substitution. Those that held a positive view (5/9) argued that the measures ensure access to a safe and effective medicine without preventing the patient to choose a different product, that they contribute to the financial sustainability of social insurance and that they also provide low cost alternatives to patients. On the other hand, arguments against the measures were related to the patients’ lack of knowledge so as to decide over a generic product, the financial motives that might affect the pharmacists’ behaviour and also to the view that the physician should be the only person responsible for choosing a specific medicinal product for the patient.

Discussion

Physicians in our study expressed varying views on generic medicines. Those that had a positive attitude towards generics expressed a preference towards locally produced products with which they were familiar and they felt confident to prescribe. Physicians claimed that the generics company was important in their choice of generic product. Ensuring that available products in the market are safe and effective and meet the foreseen standards was a precondition for their use that was raised as an issue by both physicians and patients.

Quantitative research efforts on generics prescribing and Greek physicians’ attitudes that were conducted before the economic crisis had shown that although physicians in general had a positive attitude towards generics, they chose to prescribe originator medicines [17]. This behavioural inconsistency in Greek physicians was attributed to inadequate provision of information on generics at the university level, lack of trust in the procedures for marketing authorization of generic drug products, and the absence of financial incentives (the very small price differentials between originator and generic drugs) [17, 26]. Another study conducted in Greece showed mixed opinions among general practioners (GPs) regarding the effectiveness of generics and highlighted the bad reputation of generics in Greece as one of the main factors for their low market share [27].

Patients in this study also appeared hesitant towards the use of generics, whereas, they considered that more information on those products was necessary. This is in line with findings of quantitative studies that were conducted after the first EAP-related policy measures were adopted [28, 29] as well as more recent ones [30, 31].

According to our findings, prescribing is a multi-criteria decision based on the characteristics of the disease, the patient and the medicinal product. This finding is confirmed by a number of studies in the literature that suggest that the prescribing decision is a balance between effectiveness, safety, cost and patient preferences [32]. Other factors such as colleagues, patients, pharmaceutical sales representatives may affect prescribing decisions in general [33] as well as for generics in specific [27]. Pharmaceutical sales representatives had been acknowledged as the main information resource of physicians in other studies as well [17, 26]; according to our findings this source of information remains active, despite the implementation of INN prescribing. This may be explained by the fact that at the early steps of INN prescribing implementation in Greece, physicians had the option to (partially) prescribe by brand name – and thus, established generics companies tried to secure their market share.

On the other hand, for the patients, their physician’s opinion was the most important factor for switching to a generic drug product. Cost was a consideration for some patients, however, but not the primary one and also, at the time of study, cost differentials between generics and originators were not strong enough. This is confirmed by a quantitative cross-sectional study conducted in Greece which investigated the response of patients with chronic conditions to the measure of INN prescribing and found that the majority of the participants (82%) were not willing to change their usual drug and switch to a generic drug despite the extra cost they had to bear [34]. In the study of Skaltsas and Vasileiou (2015) patients acknowledge the lower cost of generics as their main advantage – however their physician or pharmacist plays the most influential role in their choice [31].

Finally, physicians in general seem to accept most of the policy measures implemented towards generics’ prescribing and consumption, however they believe that more actions are necessary, such as more competitive prices for generics and informational campaigns for physicians, patients as well as pharmacists. Similar views were expressed by key stakeholders of the Greek pharmaceutical market regarding the generics policy measures [35]. However, INN prescribing and generics substitution were met with skepticism by participating physicians.

Our findings are in line with those of similar studies in the international literature. Physicians’ beliefs regarding the quality and effectiveness of generic medicines and level of trust in their marketing authorization procedures significantly affect their decision to prescribe generic medications [3639]. Furthermore, patients’ consumption of generics is also associated with their perceived quality, although additional factors such as patient’s characteristics, health literacy, sources of information on generics and cost considerations have a significant impact as well [38, 4042].

Strengths and limitations
Qualitative studies present significant advantages but also suffer from some limitations mainly due to their small sample size and the ability to generalize their findings. In order to address these issues, adherence to international guidelines for qualitative research is essential. In the case of the present study, the methodology was based on the COREQ checklist [43], a widely acknowledged set of guidelines. In this study, our findings come from rather homogeneous and small samples and may not be generalizable to the medical community or patients with all types of chronic disease. However, in the present study sampling continued until data saturation was achieved, meaning that no new additional thematic categories and data emerged. Also, although the recruitment was based on convenience and snowballing techniques, specific criteria were applied (as stated in the methods section) and the study focused on specialties and patients that are most likely to prescribe or consume generics, resulting to the fact that participants were more familiar with the research question. Another controversial issue in the qualitative studies is whether to use numbers to present the results [44]. Several arguments have been presented favouring the one or another view, but the most common approach is to semi-quantify the results when possible, using illustrative quotes to support the results [45]. Finally, the study was conducted in a rapidly changing environment. Further reductions of generics prices were adopted shortly after the completion of our study, which may have an effect on participants’ perceptions of generics prices levels. However, in our study, cost was not the most important factor to patients for switching to a generic medicine and, price reductions have not yet led to an increase in generics market share. A study conducted at a national level in 2014 shows that there is still poor acceptance of the introduced measures regarding generics among physicians [46]. Therefore in our opinion, the fact that our results are in line with other published studies proves that the major issues that emerged in our study remain valid. Finally, our study is to our knowledge the only published qualitative study that explores physicians and patients views on generics and INN prescribing giving answers to the rationale behind these views.

Potential policy implications and future research
Greece has significantly reduced public pharmaceutical expenditure in a short time frame; still, the market share for generics is below the target set in the EAP [19]. The results of our study suggest that physicians and patients have established behaviours and attitudes towards generics, which have not significantly changed despite the policy measures to promote generics consumption. Furthermore, their main concerns remain unaddressed. Addressing physicians’ and patients’ concerns and aligning the incentives in place for all actors in the pharmaceutical market have been acknowledged as core enabling factors for the successful implementation of a generics policy [47]. Specifically, the fact that the policies regarding generics were implemented during the financial crisis in order to contain pharmaceutical expenditure, created doubts on their quality. Therefore, official regulatory bodies should perform additional quality assurance in order to tackle safety and quality concerns. Also, there is a need for reliable information from regulatory and other bodies to dispel the myths regarding generics and convince patients (through their physicians) that generics are not only cheap but effective and safe as well. Finally, the results of our study can be used in future research in order to develop more targeted quantitative research questionnaires and to form specific research questions.

Conclusion

The present study, due to its qualitative methodology elicited the major concerns regarding generics among prescribing physicians as well as among patients and, also, identified their main sources of information and information needs. The information available in studies such as the present one, can aid decision-makers towards the design and implementation of viable policies in the sensitive field of generics uptake.

Acknowledgements: The authors would like to thank all interviewed physicians and patients for their participation.

Disclosure of financial and competing interest: No funding was obtained for this study. The authors declare no conflict of interest.

Provenance and peer review: Not commissioned; externally peer reviewed.

Contributing authors

Eleftheria Karampli, Vasiliki Tsiantou, Kostas Athanasakis and John Kyriopoulos were involved in study design. Efstathia Triga interviewed participants, transcribed interviews, conducted content analysis and interpreted the results. Eleftheria Karampli analysed interview transcripts, interpreted the results and drafted the manuscript. Vasiliki Tsiantou assisted in data analyses and drafted the manuscript. Kostas Athanasakis assisted in data analyses and critically revised the manuscript. JK provided scientific guidance, supervised the study design and revised the manuscript for critically important intellectual content.

Authors

Eleftheria Karampli, MSc
Efstathia Triga, MSc
Vasiliki Tsiantou, MSc
Kostas Athanasakis, PhD
John Kyriopoulos, PhD

Department of Health Economics, National School of Public Health, 196 Alexandras Avenue, GR-11521, Athens, Greece

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Author for correspondence: Efstathia Triga, MSc, Research Associate, Department of Health Economics, National School of Public Health, 196 Alexandras Ave, GR-11521 Athens, Greece

Disclosure of Conflict of Interest Statement is available upon request.

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First biosimilar of infliximab approved in Brazil: response from the Brazilian IBD society

Abstract:
CT-P13 was the first infliximab biosimilar approved in Brazil. Approval was granted for all indications of the innovator. Despite similar efficacy and safety, vigilance remains essential.

Submitted: 4 January 2016; Revised: 27 January 2016; Accepted: 1 February 2016; Published online first: 12 February 2016

On 27 April 2015, the Brazilian Health Surveillance Agency (Agência Nacional de Vigilância Sanitária, ANVISA) approved the first biosimilar monoclonal antibody in Brazil. Remsima (CT-P13) is produced by the South Korean biopharmaceutical company Celltrion and will be marketed and distributed in Brazil by Hospira US [1].

This infliximab biosimilar is based on the originator drug Remicade, produced in the US by Janssen Biotech, Inc and distributed in Brazil by the same company [2].

Approval of Remsima was granted for all indications of infliximab based on its full clinical development, including two clinical trials: the phase I clinical trial PLANETAS, and the phase III clinical trial PLANETRA, which compared Remsima to Remicade in patients with active ankylosing spondylitis and rheumatoid arthritis, respectively. Several real life small series have subsequently been reported. So far, Remsima has shown similar efficacy and safety to the infliximab innovator in inflammatory bowel disease (IBD) patients. However, a randomized equivalence trial comparing Remsima with Remicade is still missing.

The approval of Remsima will reduce costs; most of the individuals currently using infliximab can only do so thanks to funding from the Brazilian Government. Approval of the biosimilar is commendable and approved by the medical societies involved. However, scientific, safety and pharmacovigilance issues have arisen and should be carefully addressed and widely discussed for the benefit of patients. Remsima has been approved for use in Brazil based on comparability strictly following the regulations of ANVISA [1]. Remicade, the infliximab originator, was approved in Brazil in 2001 for the treatment of Crohn’s disease. This drug is also approved in our country for other uses: rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, fistulizing Crohn’s disease and adult/paediatric ulcerative colitis. In line with the European Medicines Agency (EMA), ANVISA also follows strict international standards for approval of biosimilar drugs [3, 4]. As mentioned, Remsima has been approved by ANVISA based on comparability. To be approved by the Brazilian medicines regulatory agency, the drug has been successfully tested in humans in two clinical studies in rheumatology patients: a phase I clinical study in ankylosing spondylitis and a phase III study in patients with rheumatoid arthritis [5, 6]. The use of Remsima for other diseases listed in the reference drug Remicade package insert was approved based on the concept of extrapolation of indications [1].

In October 2014, the Commission of Biosimilar Drugs of the Brazilian Study Group of Inflammatory Bowel Diseases (GEDIIB) submitted to ANVISA an opinion contrary to the approval of Remsima for individuals with IBD [78]. Recently, the Brazilian Societies of Rheumatology, Dermatology and Gastroenterology (represented by GEDIIB) issued the same position [9]. Echoing the opinion of Health Canada, the Canadian agency responsible for the control of drugs, the opinion issued by GEDIIB made it clear that although the biosimilar drug is a positive and welcome measure in the IBD setting, it would be essential to carry out clinical studies with biosimilar products in a population with IBD so that these studies could settle any doubts regarding the efficacy and safety of the long-term use of this biosimilar drug [7, 10]. It is well known in the academic community that only a small number of cases of IBD patients treated with Remsima have been published to date [11]. Moreover, it is known that there is still no prospective randomized study comparing Remsima with the reference drug Remicade.

On the other hand, after the product has been used for over a year in Eastern Europe and Korea, post-marketing studies presented at scientific events have reported good results regarding the efficacy and safety of Remsima used both in adult and paediatric patients with IBD [1218]. However, a retrospective study conducted in Ireland using a controversial methodology showed a significant increase in hospitalizations, in the use of corticosteroids and in surgery among patients treated with Remsima compared with those who received the reference drug Remicade [19]. As this is to date the only study showing discrepancies in efficacy and safety between the biosimilar and the reference drug, it is vital that we carefully analyse these results and that we remain alert and vigilant. Our patients will certainly be grateful!

Acknowledgement

The author wishes to thank the English editing support provided by Dr Bea Perks, GaBI Journal Editor, for this manuscript.

Competing interests: The author is a consultant and member of the advisory board of Janssen, Hospira/Pfizer and Ferring.

Provenance and peer review: Not commissioned; internally peer reviewed.

References
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Author for correspondence: Professor Fabio V Teixeira, MSc, MD, PhD, Medical Director of Gastrosaude Clinic, 62 Sao Paulo Avenue, 17509-190 Marilia, Sao Paulo, Brazil

Disclosure of Conflict of Interest Statement is available upon request.

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