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This commentary was prompted by a recent experience with a manuscript submitted to GaBI Journal but then withdrawn.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.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
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 [1–3]. 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.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal:Christoph Baumgärtel, MD, MSc; Brian Godman, BSc, PhD
Abstract:
Stricter bioequivalence criteria are in place for generics where there are narrow therapeutic indexes such as generic immunosuppressives, enhancing their acceptance despite limited published studies. No serious issues have been reported to date with generic ciclosporin despite being on the market in Europe for more than 10 years.
Submitted: 29 September 2015; Revised: 19 October 2015; Accepted: 19 October 2015; Published online first: 2 November 2015
Regulatory bioequivalence rules for usual generics are well established and already recognized. However, for narrow therapeutic index drugs and immunosuppressives, there are specific and tighter criteria in place.
Drugs with a narrow therapeutic index are defined by a narrow distance between the dosage that induces a desired effect and that dosage which already has a toxic effect. Typically, this ratio in the field of pharmacology is indicated by the quotient of LD50/ED50 (LD50 = the dose at which 50% of the animals die, ED50 = the dose at which 50% of the animals show the desired effect). Alternatively, the quotient of LD5/ED95 can be used, which can better illustrate a non-linear dose-response curve.
For a perfectly safe drug, the ratio should therefore be very high. If in contrast the ratio is low, i.e. if a drug shows a value of only 3 or 4, this is called a ‘narrow therapeutic index drug’ (NTI), which must always be dosed with particularly high accuracy. Even a minor variation in plasma levels may lead sometimes to treatment failure on the one hand or inevitably to toxic effects on the other. Examples of such agents typically include immunosuppressants, digitalis, theophylline and some anti-epileptic drugs.
The acceptance range of bioequivalence trials which is usually applied for a marketing authorization of a generic drug is 80–125% of the 90% confidence interval of the ratio of the test and reference products’ AUC (area under the curve) and Cmax (maximum plasma concentration). For drugs with a narrow therapeutic index, and especially for immunosuppressives, the European Medicines Agency (EMA) demands even greater accuracy in justified cases and therefore has set more stringent criteria. This is despite in practice ratios for authorized conventional generics usually differ on average by only three to four per cent from their originator [1–4].
EMA’s overhauled bioequivalence guideline [5], in force since 2010, requires that for potential narrow therapeutic index drugs the EMA’s Pharmacokinetic Working Party (PKWP) [6] will evaluate if a generic drug newly submitted for authorization is to be thought of as an NTI and whether for this NTI actually stricter bioequivalence criteria have to be applied. It is important for a pharmaceutical manufacturer or applicant to know that there is no precasted list that names all such agents, but that all agents submitted for generic drug authorization will be evaluated by the authority on a case-by-case basis with regard to their NTI requirements.
Examples where this has already been practised are the regulatory requirements for ciclosporin and tacrolimus generics as described in a PKWP Questions and Answers document published on the EMA website [7]. In the case of these two immunosupressives, restricted bioequivalence criteria were set.
For ciclosporin, narrower acceptance intervals of 90.00–111.11% are required for both the AUC and the Cmax. Whereas, for tacrolimus the narrow acceptance interval is only required for the AUC but is not required for the Cmax. This is because tacrolimus plasma levels show accumulation with repeated dosing, resulting in a lower relevance being given to differences in initial peak plasma concentrations..
The narrower acceptance range limits for the confidence intervals for NTIs, see Figure 1, provide a greater confidence in the true bioequivalence for these drug substances. However, this requirement significantly increases the number of subjects necessary for the bioequivalence studies. Tacrolimus, for example, is a drug which is not merely an NTI, but additionally shows relatively high intra-individual variation in plasma levels. It has a relatively high coefficient of variation, close to 30%, which would classify it as a highly variable drug. Even in bioequivalence trials of tacrolimus, when a conventional acceptance range is applied, this would typically necessitate enrolling substantially higher numbers of trial participants than in the usual, bioequivalence guideline requiring a minimum of 12 to 24 subjects. One would need at least 40 subjects for a tacrolimus product, and in fact to demonstrate compliance with EMA’s mandatorily required narrower acceptance limits, it might require up to 200 to 300 subjects.
To increase the safety of generic immunosuppressives even more, it is also recommended that the summary of product characteristics (SPC) states that patients who are prescribed either a generic immunosuppressant after an originator or are switched in any other way, have their plasma levels monitored during the time of the switch to avoid potential rejection [8]. This is however similar to what is undertaken in normal clinical practice when patients are first placed on an immunosuppressant after receiving a solid organ graft.
Because of the issues concerning generic immunosuppressive medicines, Molnar et al. recently undertook a systematic review and meta-analysis of all available studies since 1980 comparing generic with originator (innovator) immunosuppressive medicines [9]. The authors documented that acute rejection was rare in transplant patients given generic immunosuppressive medicines and the incidence of rejection did not differ between the groups. However, as recently stated, the methodological standard of the published studies included was very variable and follow-up times were short [10].
In the evaluation of the pooled pharmacokinetic data, Molnar et al. showed that the generics met the US Food and Drug Administration (FDA) bioequivalence criteria, but did not all meet the stricter EMA criteria [9]. It appears that the small number of patients in some of the included studies, and as a result the wide confidence intervals, significantly contributed to this finding. For statistical reasons, in order for results to meet the stricter acceptance criteria for immunosuppressives, requiring narrow confidence intervals, a sufficiently higher number of patients must be included in the trials [11].
This effect on subject numbers needed is illustrated by the wide confidence intervals found in immunosuppressive studies with less than 20 subjects. As reviewed in the paper by Molnar et al., only trials with approximately 50 to 70 patients were able to fulfil the EMA acceptance criteria [9]. In detail, their sub-analysis of two randomized kidney trials showed that with a mean of 30 subjects, both failed to fulfil the stricter EMA bioequivalence criteria, whereas the pooled sub-analysis of seven non-randomized interventional kidney studies with a 53% higher mean sample size of 46 patients did fulfil these criteria.
Notably, the mean ratios of the test and reference products’ AUC and Cmax in most of the reported trials were well within the expected range [12]; and were in fact only a few percentage points higher or lower than 100% [9]. These data strongly suggest that there are no clinically important problems with generic immunosuppressive agents, especially with those that meet the EMA criteria, but rather that there are problems with the scientific value, relevance and interpretation of smaller studies.
It should also be noted that EMA’s precautious narrowing of bioequivalence limits was specifically implemented for situations where it is suspected that plasma level monitoring will – against the SPC advice – not be complied with; such as following a switch from an originator to a generic drug [7]. This narrowing can therefore be seen as a ‘safety net’ for the use of immunosuppressive generics. This suggests that generic immunosuppressive drugs, used in the correct manner by practitioners aware of their precautions, especially the requirement for monitoring of plasma levels at the time of switching, may indeed be considered to be bioequivalent and expected to produce outcomes that are similar to those produced by originator products.
This expectation is supported by the fact that generic versions of immunosuppressive medicines, i.e. ciclosporin, have been on the market in Europe for more than 10 years and authorities’ pharmacovigilance systems have not identified any serious issues specific for generic immunosuppressives, even after an estimated hundreds of thousands of prescribed and dispensed doses. This should alleviate major concerns among clinicians and patients when considering or undertaking a switch. However, it is expected that further well-designed studies with a suitable number of patients will help to fully address any remaining concerns with generic immunosuppressives. Further education among physicians about the need to reliably moni tor blood levels in patients when first prescribed generic immunosuppressives will also be needed. Such activities may also help to enhance adherence to immunosuppressive medicines, which is a crucial concern in transplant patients [13].
Competing interest: None.
Provenance and peer review: Not Commissioned; externally peer reviewed.
Co-author
Christoph Baumgärtel, MD, MSc, Senior Scientific Expert, Coordination Point to Head of Agency, AGES Austrian Medicines and Medical Devices Agency and Austrian Federal Office for Safety in Health Care, EMA European Expert, Vice Chair of Austrian Prescription Commission, 5 Traisengasse, AT-1200 Vienna, Austria
References 1. American Medical Association. Featured report: generic drugs (A-02), June 2002 AMA Annual Meeting [homepage on the Internet]. [cited 2015 Oct 19]. Available from: http://www.ama-assn.org/ama/pub/about-ama/our-people/ama-councils/council-science-public-health/reports.page? 2. Henney JE. From the Food and Drug Administration. JAMA. 1999;282(21):1995 3. Nwakama PE. Generic drug products demonstrate small differences in bioavailability relative to brand name counterparts: Review of approved ANDAs, FDA. 2015 4. Davit BM, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother. 2009;43(10):1583-97. 5. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on the investigation on bioequivalence. EMA: CPMP/EWP/QWP/1401/98 Rev. 1. January 2010 [homepage on the Internet]. 2010 Mar 10 [cited 2015 Oct 19]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf 6. European Medicines Agency. Pharmacokinetics Working Party [homepage on the Internet]. [cited 2015 Oct 19]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/contacts/CHMP/people_listing_000070.jsp&mid=WC0b01ac05802327c9 7. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Questions & answers: postitions on specific questions addressed to the Pharmacokinetics Working Party (PKWP). EMA/618604/2008 Rev. 12. 25 June 2015 [homepage on the Internet]. 2015 Jul 20 [cited 2015 Oct 19]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002963.pdf 8. Austrian Federal Office for Safety in Health Care. Austrian Medicines and Medical Devices Agency. Available from [homepage on the Internet]. [cited 2015 Oct 19]. Available from: https://aspregister.basg.gv.at/aspregister/ 9. Molnar AO, et al. Generic immunosuppression and solid organ transplantation: systematic review and meta-analysis. BMJ. 2015;350:h3163. 10. Godman B, Baumgärtel C. Are generic immunosuppressants safe and effective? BMJ. 2015;350:h3248. 11. Baumgärtel C. [Bioequivalence – narrow therapeutic index drugs]. Bioäquivalenz – Arzneimittel mit enger therapeutischer Breite. ÖAZ, Österreichische Apotheker Zeitung. 2012;66(23):60-1. German. 12. Baumgärtel C. Myths, questions, facts about generic drugs in the EU. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):34-8. doi:10.5639/gabij.2012.0101.009 13. Tong A, Howell M, Wong G, Webster AC, Howard K, Craig JC. The perspectives of kidney transplant recipients on medicine taking: a systematic review of qualitative studies. Nephrol Dial Transplant. 2011;26(1):344-54.
Author for correspondence: Brian Godman, BSc, PhD, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
A novel global and company specific biological qualifier, distinct from the International Nonproprietary Name (INN), is proposed by World Health Organization (WHO) for all biological active substances.
Submitted: 14 May 2015; Revised: 2 July 2015; Accepted: 6 July 2015; Published online first: 20 July 2015
Introduction to INN
The concept of one single non-proprietary name to be used worldwide for active pharmaceutical substances was established by the World Health Organization (WHO) in 1950, by World Health Assembly Resolution WHA3.11 and became operational in 1953. Since then, there have been more than 10,000 applications for an international non-proprietary name, or INN, as they are commonly called. INNs are intended for use in drug regulation, prescribing, dispensing, pharmacopoeias, labelling, pharmacovigilance and in scientific literature. They are also used by the World Intellectual Property Organization (WIPO), Trademark offices, and Customs and Excise agencies, including the World Customs Organization (WCO).
An INN itself often is an unusual word; this is because the name has information regarding the active substance it represents built into it. Typically, the name begins with a fantasy prefix of one, two or more syllables, followed by a stem suffix. Stems indicate chemical and/or pharmacological relationships and substems that further refine the relationship may be used. Stems do not necessarily exist for every conceivable pharmacological group and when an INN is requested for a new class of drug, a novel suffix is determined which may or may not become established as a stem at a later date. Take the INN alvelestat as an example. From the end of the name moving forwards, it is constructed as follows: the suffix -stat is indicative of an enzyme inhibitor, the middle part -ele- is a substem indicating a subclass of inhibitors, in this case elastase inhibitors, whilst the prefix alv- is the fantasy part that identifies the unique substance represented by the INN. INN and stems have protection within the trademark arena and a list of current stems and substems is issued by WHO [1]. To avoid confusion, which could jeopardize the safety of patients, trademarks should neither be derived from INNs nor contain common stems used in INNs. In contrast to the INN, which is global, non-proprietary, not owned by anyone (including the INN applicant) and applied to the drug substance, medicines usually will also have a company-specific name – the trade name or brand name – that tends to be region-specific, not global, is owned by the company and is applied to the drug product.
INN for biological medicines
Increasingly, INNs are being requested for complex biological drugs. Biological medicinal products are of increased molecular complexity compared to chemical drugs, including structural micro-heterogeneity. For biological drugs there has been a need, not only for new stems but for new naming schemes and policies. These new schemes are provided in the WHO publication ‘INN for Biological and Biotechnological Substances (A review)’ which is updated regularly and available on the WHO website [2].
Currently, there are 11 general policies for specific classes of biological and biotechnological substances. Three particular policies are relevant for this paper – policies for non-glycosylated compounds, for glycosylated compounds and for monoclonal antibodies. For non-glycosylated compounds and specifically non-glycosylated proteins, the naming format is similar to that mentioned above for INN in general, that is identification of the pharmacological group with a stem/substem whilst the specific amino acid sequence, i.e. structure of the protein, is indicated by the fantasy prefix. Thus, the constituent parts of the INN filgrastim are –stim, the stem for colony stimulating factors, -gra- a substem used specifically for granulocyte colony-stimulating factors, and the prefix fil- is a fantasy syllable indicating the specific amino acid sequence of this substance and in this case also the expression system used (bacterial).
For glycosylated proteins, in addition to the naming policy applied to non-glycosylated proteins, differences in the glycosylation (or glycoform) pattern are represented by a Greek letter second word, spelled out in full; for example, there are now nine distinct epoetin INN with the second word Greek letters alfa, beta, delta, gamma, epsilon, kappa, omega, theta and zeta, all having the same amino acid sequence for the protein but possibly differing in their glycosylation profile.
INN for monoclonal antibodies (mAbs) are typically composed of a fantasy prefix, substem 1 to indicate the biological target of the mAb, for example, -t(u)- for tumour targeting mAbs, and -li- for immuno-modulating mAbs; substem 2 to indicate the type or origin of the mAb, for example, -u- to indicate a human derived mAb, and -xi- to indicate a mAb of chimeric origin; and finally the suffix/stem -mab to indicate that it is a monoclonal antibody. Thus, a monoclonal antibody ending in -tuximab would be tumour targeting and of chimeric origin.
Biosimilars and INN
Whilst identical copies of a particular chemical drug are known as generics, the name has not been applied to copies of biological drugs because of the high level of complexity and heterogeneity in their structure such that one manufacturer’s biological drug will not necessarily be fully identical to the same substance from another manufacturer. Instead of the name ‘generic’ a variety of terms has been used including similar biological product (SBP), biosimilar, follow-on product, subsequent entry biologic, me-too, and non-innovator biologic, with no global consensus. All terms tend to be used interchangeably, with ‘biosimilar’ probably being the most common. However, the term biosimilar was originally coined specifically for biological products that have been licensed via a regulatory pathway in which full quality and specific and usually abbreviated non-clinical and clinical studies have demonstrated the product to have a similar quality, safety and efficacy profile to an already licensed reference product, with the reference product itself having been licensed following a full assessment of quality, safety and efficacy, for example, see WHO and European Union (EU) biosimilar guidelines [3, 4]. The frequent but inconsistent and improper use of the term ‘biosimilar’, and other terms, for products where there has been no comparability regulatory exercise causes confusion, is a potential concern for patient safety and efficacy, and can lead to misconceptions in published reports on apparent problems with ‘biosimilars’ [5, 6].
In recent years, there has been debate and mounting concern as to what INN should be given to biosimilars. This reveals a further issue and miscomprehension with biosimilar nomenclature because WHO has no policy on how to name a biosimilar. The concept of biosimilarity is a regulatory procedure and INN are not assigned on the basis of how a medicinal product achieves licensure. Indeed, at the time of an INN application, it is usually not known to the INN Expert Group* what regulatory pathway will ultimately be followed for licensure of the substance. Furthermore, the INN Expert Group does not receive and is not privy to the vast amount of information submitted in registration dossiers; the amount of data submitted in support of a new INN is quite scant and decisions on INN assignment have to be made before full quality, non-clinical and clinical information on the substance is derived.
INN for non-glycosylated proteins follow the approach for small molecule drugs in that following the first INN assignment for a particular amino acid sequence, no further applications are made. For example, for somatropin, a growth hormone derivative, multiple innovator and biosimilar somatropins all use the same INN.
The glycoform profile of a glycosylated protein is dependent on the expression system used to manufacture the protein, the fermentation conditions and potentially also on downstream processing. For an INN application for a glycoprotein, where glycosylation is stated to be different, or where no statement is made regarding glycosylation, the INN Expert Group assumes it to be different, and so a new Greek letter second word is assigned. Regardless of whether a glycoprotein is (eventually) subject to a biosimilar, subsequent entry, follow-on or a stand-alone registration process, assignment of the INN follows the above rule for glycoproteins. It is important to emphasize that the INN for a glycosylated protein reflects the structure and nature of the substance and is not influenced by the status or the pathway followed for its registration with a regulatory authority. Unfortunately, one issue remains and that is how to determine how different is ‘different’. Interestingly, glycoform differences can occur as a result of manufacturing changes to an already licensed glycoprotein but this has not resulted in a change to a previously assigned Greek letter INN.
The Greek letter system has not been without its complications. Janssen-Cilag’s erythropoietin (EPO) Eprex® had been assigned the INN epoetin alfa; this was subsequently licensed within the EU by an innovator stand-alone registration pathway. Despite a distinct glycosylation profile, the EPO biosimilar HX575 (from Sandoz) adopted the same INN of its reference product, epoetin alfa. In Australia, the Therapeutic Goods Administration (TGA) reacted to the distinct glycosylation profile of HX575 and assigned it the ABN non-proprietary name epoetin lambda. Thus, a single biotherapeutic product has a regional non-proprietary INN-like name distinct from the INN used within the EU. Notwithstanding this particular situation, the Greek letter system in general works well.
Pharmacovigilance and INN
A strong and reliable pharmacovigilance and post-authorization risk management system cannot rely solely on the INN. Reporting of adverse events should rely on other characteristics of a drug, such as the brand name of the product, the manufacturer and the batch or lot number as well as the INN. However, a survey of adverse event reporting by physicians in the EU, conducted by the Alliance for Safe Biologic Medicines in 2013, found that 17%, or one in six physicians, still reported only the INN and only slightly over half reported both the INN and the brand name [7]. Also, slightly over 25% of physicians never reported the batch number whilst only 40% always included the batch number in adverse event reports.
Regional nomenclature schemes
Individual regulatory regions are starting to create their own non-proprietary nomenclature schemes for biosimilars. The TGA in Australia plan to add a second word comprising the prefix sim- followed by a fantasy single syllable to each biosimilar. The Japanese Accepted Name (JAN) for biosimilars uses the INN followed (in parentheses) by the name of the reference substance + BS1, BS2, etc. In the US, FDA has given short prefixes to three stand-alone registered biologicals – tbo-filgrastim, ziv-aflibercept and ado-trastuzumab emtansine. For at least the latter product, this was done for safety reasons to distinguish it from the non-conjugated mAb trastuzumab, which itself is a registered drug with a differing dosage profile.
Biological qualifiers
In the face of regional development of nomenclature schemes for biosimilars, and at the request of some regulatory authorities, WHO has proposed the development of a global biological qualifier (BQ) for biological medicines. This would provide a unique identifier for all biological active substances that are assigned an INN; but whereas the INN is a common and public non-proprietary name for a given active substance, the BQ would be applied to a particular manufacturer’s active substance. The BQ would not be part of the INN and it is envisaged that it would enhance identification, prescribing, dispensing and pharmacovigilance of biological medicines.
A draft scheme for such a BQ was published on the WHO website in July 2014 with comments requested from stakeholders by 19 September 2015 [8]. It emphasized that the BQ would not be part of the INN, would be a voluntary scheme, would be applicable to all biological substances, would uniquely identify the manufacturer or the manufacturing site, would be overseen by the WHO INN Expert Group and would be administered by the WHO INN Secretariat. It was proposed that the qualifier itself would consist of a four-letter code generated randomly and would avoid vowels to avoid inappropriate words; this would have the capacity to generate 160,000 unique codes. The draft scheme highlighted that the BQ would be valuable for physicians and nursing staff, pharmacists, regulatory authorities, health authorities and patients.
The Executive Summary of the 59th INN Consultation held 14–16 October 2014 provides feedback from stakeholders on the draft BQ scheme [9]. Over 100 comments were received from a mix of stakeholders, with opinions being expressed both for and against the proposal. Overall it appeared that two-thirds of commentators including those in industry, academics and patient groups expressed some level of agreement. Pharmacist associations were noted as generally not being in favour. The Summary further noted that negative comments appeared to arise from misunderstandings, with a particular area of confusion being the role of the BQ.
A revised draft of the BQ proposal was posted on the WHO/INN website in June 2015 [10]. The new draft emphasises that the BQ is to be applied to all biological active substances that can be assigned INN and not just to biosimilars. A major change in the revised scheme is that the original proposal to apply the BQ to a specific manufacturing site has been withdrawn and instead the BQ applicant ‘is foreseen to be a corporate body that makes or manages the making of a single substance by a single process controlled by the same quality substance globally’. Thus, an active substance manufactured at more than one site (by a single process controlled by the same quality substance globally) will have the same BQ as long as the substance from the different sites is deemed comparable by the regulatory authority(ies) involved. In the event that they are not deemed comparable, a separate BQ would be applied, but the two BQs would be hyperlinked in the WHO BQ database. The nature of the code – a random four-letter code – remains the same, whilst useful tables illustrating how a hypothetical BQ would apply are provided in the updated proposal.
In summary, this proposal would be an entirely new global nomenclature scheme for biological active substances. Will it be used, and by whom? Does it have advantages over existing nomenclature and traceability systems including the INN, the brand name/trade name, the company name, lot or batch numbers, and in the US the national drug code? Whilst there has been good support for the BQ, not all organizations are in favour of it [11]. WHO held a Biological Qualifier Regulatory Forum on 30 March 2015 and a Front Page Meeting with INN Stakeholders on 16 June 2015. Clearly, there is continuing debate over the need for and the format of a novel global BQ.
The INN process is organized and administered at WHO by the INN Secretariat; the INN Expert Group comprises an international group of experts in drugs and drug nomenclature and is responsible for the assignment of INN and the development of INN policy.
Acknowledgements
The author is grateful to Dr Robin Thorpe for critical reading of the manuscript.
Disclaimer
Any views presented in this paper are those of the author only and do not necessarily reflect the position of WHO, the INN Secretariat or the INN Expert Group.
Competing interest: None.
Provenance and peer review: Commissioned; externally peer reviewed.
References 1. World Health Organization. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. 2013 [homepage on the Internet]. 2013 Oct 29 [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/StemBook_2013_Final.pdf 2. World Health Organization. International Nonproprietary Names (INN) for biological and biotechnological substances (a review) [homepage on the Internet]. 2014 Dec 11 [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/BioRev2014.pdf?ua=1 3. World Health Organization. Guidelines on evaluation of similar biotherapeutic products (SBPs) [homepage on the Internet]. 2010 Jun 4 [cited 2015 Jul 2]. Available from: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf 4. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). CHMP/437/04 Rev 1. 23 October 2014. Guideline on similar biological medicinal products [homepage on the Internet]. 2014 Oct 30 [cited 2015 Jul 2]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf 5. Thorpe R, Wadhwa M. Terminology for biosimilars–a confusing minefield. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):132-4. doi:10.5639/gabij.2012.0103-4.023 6. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Narayanan G, et al. Biosimilars-why terminology matters. Nat Biotechnol. 2011;29(8):690-3. 7. Dolinar RO, Reilly MS. Biosimilars naming, label transparency and authority of choice – survey findings among European physicians. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):58-62. doi:10.5639/gabij.2014.0302.018 8. World Health Organization. Biological Qualifier. An INN Proposal. Revised draft July 2014 [homepage on the Internet]. 2014 Jul 30 [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/bq_innproposal201407.pdf?ua=1 9. World Health Organization. 59th Consultation on International Nonproprietary Names (INN) for Pharmaceutical Substances. Geneva, 14–16 October, 2014. Executive summary [homepage on the Internet]. 2015 Mar 13 [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/59th_Executive_Summary.pdf?ua=1 10. World Health Organization. Biological Qualifier. An INN Proposal Revised draft June 2015. [homepage on the Internet]. [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/bq_innproposal201506.pdf.pdf?ua=1 11. BioPharma. Markets & Regulations. European group criticizes proposed WHO, FDA biosimilar naming schemes. 13 Apr 2015. [cited 2015 Jul 2]. Available from: http://www.biopharma-reporter.com/Markets-Regulations/European-group-criticizes-proposed-WHO-FDA-biosimilar-naming-schemes
Author: James S Robertson, PhD, Member of the WHO INN Expert Group
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Abstract:
The backlog in medicines registration in South Africa is a result of the implementation of pro-generics policies without strengthening the regulator to handle the substantial increase in registration applications that followed. Despite the backlog, more than enough generics are registered to promote price competition and ensure access to affordable medicines.
Submitted: 25 February 2015; Revised: 10 April 2015; Accepted: 11 April 2015; Published online first: 24 April 2015
Background
The Medicines Control Council (MCC) of South Africa has been under considerable pressure to increase the rate of medicines registration and has been accused of delaying patients’ access to affordable and essential medicines. A study commissioned by the Minister of Health in 2006 to investigate the slow pace at which medicines were being registered ascribed it to a lack of skilled human resources, poor infrastructure and inefficient regulatory processes. It was thought that the MCC processes did not keep pace with developments in the pharmaceutical industry. Although these factors certainly contributed to the backlog in medicines registration, which developed at the MCC, it seemed unlikely that they could have been the cause since the MCC, prior to 2005, was viewed as a highly efficient organization and did not have a backlog. In this review we followed the history of medicines registration and application submissions from 2000 to 2012 to determine whether the development of the backlog was a gradual process, which could have been due to factors mentioned above, or a sudden occurrence that may have been precipitated by one or more critical events, such as a change in policy or relaxation of standards for registration. We have found that the backlog originated with the implementation of policies to promote the availability and access to generics but without anticipating, and providing for, the impact this would have on the resources of the MCC. The new policies caused a flood of application submissions to the MCC, which was not equipped in terms of manpower or administrative processes to handle the substantial increase in submissions. In spite of the backlog, the claim that it compromised access to affordable generic medicines appears unfounded since our analysis for a group of tracer medicines showed that only 54% of registered medicines were being marketed and that a maximum of only five brands account for 80% or more of the market for a particular medicine.
Introduction
In 2006, the South African Minister of Health appointed a ministerial task team (MTT) to review the MCC of South Africa and to make recommendations for the establishment of a new medicines regulatory authority. This was prompted by complaints from pharmaceutical companies [1, 2], private clinical research organizations [3, 4] academic clinical research groups [5] and civil society organizations [6, 7] that delays and the backlog in medicines registration were harming patients’ access to affordable medicines. The MTT report was published in 2008 and recommended that the MCC be replaced by a new regulatory agency to be funded on a 50% cost recovery basis from industry [8]. The proposed new agency that will be known as the South African Health Products Regulatory Authority (SAHPRA) was scheduled for implementation in April 2013. However, the Act has since been further amended to include provisions for SAHPRA to be a public entity with an independent board chaired by a Chief Executive Officer (CEO) and a stronger governance structure than in the previous draft. The latest version of the draft amendments to the Bill (Bill 6 of 2014) was tabled in parliament in February 2015. No date has since been specified for when SAHPRA will be established [9, 10].
Among the shortcomings in the MCC and its secretariat, the Medicines Regulatory Affairs (MRA), identified in the MTT report, were: a shortage of in-house skilled human resource capacity and its dependency on external reviewers employed at academic and research institutions (in-house staff turnover is high as many migrate to industry); lack of an efficient electronic document management system to track applications as they progress through the regulatory system; and a shortage of funds to improve infrastructure and attract and retain competent staff.
Since the MTT report did not examine how or when the backlog originated [8], we undertook a review of the data on the number of applications submitted for registration and the number of registration certificates (marketing authorization certificates) issued by the MCC between 2000 and 2012. The premise was that if the two remained closely correlated over this time period it would suggest that there was no real crisis at the MCC and that it could cope with its regulatory workload. A gradual divergence in correlation over time would imply that the regulatory processes, resources and infrastructure were not keeping pace with the developments in the local pharmaceutical industry. If a sudden break or divergence occurred at a specific time during the review period it would signal the occurrence of a critical event such as a change in policy.
In order to determine whether the current rate of registration by the MCC could potentially impede access to medicines we compared the availability of the number of branded generics of eight tracer medicines in the total South African market, i.e. the combined private and public sector markets, with the number of brands registered for each of the eight tracer medicines.
Selection criteria for tracer medicines
The criteria used to select the tracer medicines included: a) diseases that are prevalent in South Africa [11]; b) treatment established according to standard treatment guidelines; c) inclusion on the Essential Medicines List (EML); and d) the Millennium Development Goals (MDGs) of the United Nations, which deal specifically with health (MDG 4: to reduce child mortality; MDG 5: to improve maternal health; and MDG 6: to combat HIV/AIDS, malaria and other diseases). One medicine to treat each of the following conditions was selected: bacterial infections (ciprofloxacin); tuberculosis (rifampicin); human immunodeficiency virus (HIV) infection (lamivudine); diabetes (metformin); hypertension (amlodipine); atherosclerosis (simvastatin); maternal health (oxytocin); and depression (fluoxetine). It is important to note that although many of the medicines selected may be widely used in the treatment of the conditions for which they are registered, that they are not necessarily representative of the entire pharmaceutical market in South Africa. Consequently, generalizing the findings to other medicines or pharmacological classes requires caution.
The backlog in medicine registrations
By 2010 the backlog in registrations was estimated to be in excess of 3,000 applications
[12, 13]. Prior to 2005, the number of applications received and registration certificates issued were in equilibrium. From 2005 the number of applications submitted more than doubled whereas the number of certificates issued remained approximately the same, see Figure 1.
The relatively constant rate at which certificates were being issued from 2000 to 2011 was because additional staff were not appointed to meet the high demand for registration of new products. This shortcoming was also identified by the MTT in its report [8]. The increase in certificates issued after 2011 was due to the recruitment of temporary technical and administrative staff in 2009, with funding from the UK Department for International Development (DFID). It takes around 24 to 36 months from the start of a dossier review until a registration certificate is issued; hence, the increase in product approvals was only seen in 2012.
Pro-generics policy and the backlog in approvals
The large increase in submissions since 2005 is due to the introduction of pro-generics policies, which includes the mandatory generics substitution policy and fast track registration policy. The increase includes applications submitted via routine and fast track pathways.
In 1997 the Medicines Act was amended (Act 90 of 1997) with the aim of making medicines more affordable and accessible. The amendments included provisions for, amongst others, a transparent pricing system, parallel importation of innovator medicines from countries where they are sold for less than in South Africa, and generics substitution to promote the use of generic medicines, i.e. the progenerics policy. The legislation was challenged in early 1998 by 41 pharmaceutical companies [14] resulting in a delay in its implementation until 2003 when the legal challenge was withdrawn [15]. Not all of the policies were introduced; the generics substitution policy was implemented in 2003 whereas policies on pricing such as the single exit price (SEP) was introduced in 2004. Other amendments to the Act (pharmacists dispensing fee) were implemented in 2014.
Apart from the generics substitution provision made in 2003, the Department of Health (DoH) also introduced a fast track registration policy at that time, not only for new chemical entities (NCEs) considered essential for national health and which may not be on the EML, but also for all medicines on the EML [16], the majority of which are generics [17]. This contrasts with the fast track policy of the Food and Drug Administration (FDA) in the US, which is restricted to investigational new drugs designed to fill an unmet medical need [18].
Table 1 shows the number of registrations per year by product type, i.e. NCEs, biological and generic medicines and the number of fast track and duplicate registrations. The data were obtained from the Operations and Administration Directorate of the MRA. Between 2007 and 2012, registration of generic medicines outnumbered that of NCEs (more than 17-fold) and biological medicines (more than 60-fold). More generic medicines were registered through expedited review (fast track) than NCEs. Some generics manufacturers submit two or more copies of the same dossier under different tradenames. Each of these applications is for a separate registration certificate for a product and each product is considered independent. The numbers in parentheses indicate the number of such duplicate or multiplicative applications.
The practice of certain companies to register the same product under different trade names reflects both the very low cost to the company of registering medicines in South Africa (less than Euros 3,000 for a generic medicine [19]) and the commercial advantage they stand to gain when they licence or sell one of the duplicates (if they registered the product under two different names) to another company. This practice, known as ‘dossier farming’, is well known in the industry but is under researched and seldom reported in the literature.
The backlog in medicines registration may, thus, have been caused by the large number of generics submissions which followed soon after the implementation of mandatory generics substitution (pharmacists are required by law to dispense the generic drug, unless the patient, or the patient’s doctor, expressly refuses the substitution, or the price of the generic drug is higher than that of the branded product). This was compounded by legislative requirements for the expedited review of medicines on the EML (most of which are generics) and the lack of control over the number of generics applications for the same innovator medicine that can be submitted by a single company. The question that arises is whether the uncontrolled registration of generic medicines can be justified in terms of promoting access to affordable medicines. If a large number of generics in the market continually drive down the cost of medicines through competition, then the MCC should endeavour to acquire the necessary resources to increase its efficiency and shorten review times. However, if there is no price advantage to the public after a certain number of generics of an innovator product becomes available, then it may be necessary to review the current policies governing the registration of generic medicines.
Does the backlog impede the accessibility and availability of affordable medicines?
The pro-generics policy is intended to promote competition; the theory being that as more competitors enter a market, prices of products will fall [20]. Thus, registering a large number of generic brands of a particular medicine should drive down the price of that medicine. The question is whether the current backlog prevents both important medicines from coming onto the market and reduces competition and, hence, availability of affordable medicines.
Using IMS data for each of the tracer medicines we analysed the percentage market share (as measured by annual sales value in both private and public markets) for each branded product (generic and innovator) from 5% or less to more than 40%. The highest market share for a brand for most tracer medicines was between 40% and 50%. The number of registered brands and brands under review for each medicine was also included in the analysis to show the relationship between current (number of registered brands) and future (number of registered brands plus brands under review) product availability for each medicine, see Table 2.
The data show that two to five brands for each medicine account for 80% or more of the market value. Approximately 70% of marketed generics have a market share of less than 5% and only 54% of all registered generic brands are actually being marketed. This suggests that for most of the tracer medicines, with the exception of oxytocin, more than enough branded generics have been registered to ensure robust competition in their markets. Their markets have in fact become oversaturated since more than 40% of the registered products are not being marketed. Exceptions would be medicines, such as lamivudine and rifampicin where changes in treatment guidelines for HIV and tuberculosis (TB) may render some products obsolete. For example, in South Africa the intention is to transition all HIV patients to fixed-dose combinations (FDCs) containing tenofovir, emtricitabine and efavirenz or tenofovir, lamivudine and efavirenz [21]. Other antiretrovirals (ARVs), such as lamivudine, whether available in FDCs with other ARVs or as single agent products, may eventually be phased out. Oxytocin represents a special case since there are only three brands registered with none in the registration pipeline awaiting registration. The local market for oxytocin products is very small, just over US$2.8 million in 2012, and the product is only used in the hospital setting in South Africa. This, coupled with the need for cold chain storage, probably discourages local companies from including oxytocin formulations in their product portfolio. This contention is supported by more than 50 oxytocin formulations for human use that are available in the world market [22]. The limited availability of oxytocin products is thus more due to market failure than competition. The MCC should therefore prioritize registration of oxytocin products, should it receive applications, to ensure greater access.
Rifampicin is another case where the data do not follow that for the other tracer medicines. Changes in the treatment guidelines for TB may have made some FDC products containing rifampicin obsolete, which would account for them not being marketed. This would be further impacted by the development of resistant TB, an issue which is particularly pertinent in South Africa with its high incidence of the disease [11]. New FDC formulation with rifampicin should, thus, also be prioritized for registration by the MCC.
In the US, Reiffen and Ward (2005) used regression analysis to estimate the effect of the number of generics entries on the pre-expiry price of the original branded product for 31 drugs [23]. The authors also used price data obtained from IMS Inc. They found that a negative relationship existed between price and the number of generics entries and that the negative effect of increased competition on prices continues at least until the fifth firm enters the market but is not likely to be important after the eighth firm has entered. In other words, after eight generics, prices are unlikely to decline further since the average generics price will now approach the long-run marginal cost of production. South Africa had a population of 48.8 million in 2012 compared with the US population of 316.4 million [24]. Our market is thus smaller than that of the US and consequently one could expect that five generics would ensure sufficient competition in a market for prices to decline significantly from that of the innovator prior to patent expiry. Our findings appear to support this, since five generics competitors dominated the market for most of our tracer medicines.
The large percentage of generic drug products for some of our tracer medicines, which are currently not being marketed, could be due to market saturation. Thus, for some medicines (those for which there are already many generics in the market) it is likely that the backlog does not impede effective competition or, by extension, access to affordable medicines.
Although there is currently no formal mutual recognition agreement between the MCC in South Africa and the regulatory authorities of countries in the Southern African Development Community (SADC), companies may seek to register their products with the MCC in South Africa in order to obtain faster registration in neighbouring countries that have minimal regulatory capacity. For example, Namibia has, since 2010, granted abbreviated reviews for registration of essential medicines that are registered by Medicines Regulatory Authorities with which the Namibia Medicines Regulatory Council (NMRC) aligns itself, such as the MCC of South Africa, provided that the pharmaceutical
manufacturing site complies with current Good Manufacturing Practices (cGMP) and a complete dossier in terms of the applicable registration application format is submitted. (Gaeseb J, Registrar of Medicines, Namibia Medicines Regulatory Council, Ministry of Health and Social Services, Namibia. Personal communication. 6 November 2014).
The proliferation of pharmaceutical products, particularly in developing country markets, either through importation or local manufacture, places a tremendous burden on small and poorly resourced regulatory agencies. There is, thus, a need to review the legislation underpinning the registration process to include a medical needs clause, so that medicine registration can be prioritized on that basis. Provision should also be made to ensure that there is enough competition in the market to make medicines affordable.
Revisit pro-generics policy in the context of medical need
When suffi cient competition for an offpatent medicine exists in the market, regulatory backlog for registering further generics of that product will not have an appreciable effect on market competition, price or availability, and therefore not on access. It is only when competition is limited or non-existent, that the backlog may have those effects. Thus, the claims of industry that the backlog in registration applications of generic medicines impedes access to affordable medicines are generally not supported by our data. Our findings suggest that the backlog could be the result of government implementing progenerics policies without first providing the MCC and MRA with additional resources to handle the substantial increase in generic medicine registration applications that followed. It is important that these policies be reviewed so that further registration applications for products that are already widely available do not prevent generics of critical medicines from gaining speedy access to the registration system, while ensuring robust competition. It may be necessary to consider introducing a policy that will limit the number of generics for a specific medicine to prevent oversaturation of its market. The finding that a large proportion of generics for certain medicines are not marketed suggests that, in these cases, further generics may not lead to greater access.
The South African Government has committed itself to the establishment of a new medicines regulatory authority. The new authority, SAHPRA, is intended to be better resourced in terms of staff and infrastructure and is, therefore, likely to cost the public purse more to operate than the MCC, even if the fees to the industry will be significantly higher than the fees currently levied by the MCC. The scope of the new authority is to be expanded to include regulation of medical devices and complementary medicines. However, there is concern that if the primary motivation for SAHPRA is to register medicines regardless of need, it will serve the interests of the pharmaceutical industry more than that of the public. The industry will receive the benefi ts of shorter timelines while the burden in the form of tax payers’ funds to support the larger agency will be borne by the public. Another concern is that SAHPRA could expose itself to industry capture should it become dependent on funds sourced from industry to pay for its operational costs. When the funding formula for SAHPRA is thus determined it is essential that the regulator never be placed in a situation in which it might lose its independence, i.e. not to industry or to government [25, 26].
Conclusion
The findings from our analysis of the backlog in registration applications and market dynamics of generic drug products, although limited to only eight medicines, allow us to make a few tentative recommendations. Firstly, the National DoH should review its policy on expedited review, which currently applies to all generic medicines on the EML, and consider developing a medical needs clause to restrict this registration pathway to NCEs, new biologicals or new formulations for critical medicines, e.g. FDCs of ARVs. Fast track reviews for generics should be limited to the first five to eight applications received from different companies prior to expiry of the patent on the original. These should be reviewedconcurrently, if possible, so that they can enter the market more or less at the same time to effect significant price reductions through competition, thereby, making the medicine more affordable. This will link the expedited review pathway for registration not only to medical, but to economic need as well. Clone applications, i.e. a copy or exact duplicate of the originator and marketed by the manufacturer or applicant of the originator medicine but with only the labelling (including the brand name) being different, should be excluded from this provision. This is because the innovator applicant has the advantage of submitting such applications at any time before the patent on its original brand expires and can also market the clone before the expiry date of the originator brand in anticipation of imminent generics entry. Secondly, MCC should consider cancelling the registration of products after two years if they have not been marketed (sunset clause), unless the company can provide adequate justification for retaining registration beyond this period.
This recommendation stems from the observation that a high percentage of generics for certain medicines are not marketed after registration. The finding suggests that companies do not conduct adequate market research before submitting applications for registration to assess the viability of their products. One of the reasons could be the low cost for registering a generic drug in South Africa (US$2,260) compared with countries, such as Canada (US$38,006) and Australia (US$73,900). The resources spent on evaluating an application for a product that is eventually not marketed could have been applied to other regulatory activities, such as the regulation of medical devices, which are currently not controlled by the MCC because of resource constraints. Thirdly, generic medicines companies should be discouraged from submitting several applications for the same medicine under different trade names unless this can be justified from a public health perspective. This is because companies may be trading in registration certificates (dossier farming) at a significant premium to what they spent on obtaining registration with the MCC. Finally, we recommend that the new regulatory agency, SAHPRA, not be placed in a position in which it will become overly reliant on industry fees to fund its operations as this may compromise its independence and lead to industry capture.
Acknowledgements
The authors are grateful to IMS Health Inc for generously providing the market share data and the Medicines Regulatory Affairs for providing data on product registrations and registration applications. The authors would also like to thank Dr Petra Sevcikova, Ms Karen Maigetter, Professor Roger Jeffery and Professor Richard Laing for their valuable comments.
Disclaimer
The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the Medicines Control Council of South Africa or one of its committees or working groups.
Funding sources
This paper results from research funded by the European Union Seventh Framework Programme Theme: Health-2009-4.3.2-2 (Grant no. 242262) under the title ‘Accessing Medicines in Africa and South Asia [AMASA]’ (http://ec.europa.eu/research/health/public-health/public-health-andhealth-systems/projects/amasa_en.html). The project team includes partners at the University of Edinburgh (UK), Foundation for Research in Community Health (India), University of Ghent (Belgium), Mbarara University of Science and Technology (Uganda), Makerere University (Uganda), Queen Mary University London (UK), Swiss Tropical and Public Health Institute at the University of Basel (Switzerland) and the University of the Western Cape (South Africa).
Competing interest: The authors declare that they have no competing interests.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Henry MJ Leng1, PhD
David Sanders1, MRCP
Professor Allyson M Pollock2, MBChB, FFPH, MRCP (Ed), MRCGP
1School of Public Health, University of the Western Cape, Private Bag X17, Bellville, 7535, South Africa
2Centre for Primary Care and Public Health, Queen Mary University of London, London E1 2AB, UK
References 1. Kahn T. Cipla slumps on MCC delays. Business Day Live. 2012 Oct 18 [cited 2015 Apr 10]. Available from: http://www.businessday.co.za/articles/Content.aspx?id=167676 2. Kahn T. Litha forced to shut down cardiac unit. Business Day Live. 2012 Aug 8 [cited 2015 Apr 10]. Available from: http://www.bdlive.co.za/articles/2012/03/20/litha-forced-to-shut-downcardiac-unit 3. Buthelezi L. Drug listing delays laid at door of MCC. Accessed 3 August 2012. Available: http://www.mm3admin.co.za/documents/docmanager/2D5ED792-878C-4371-9575-8281A96BBB26/00031267.pdf 4. Kahn T. Blow to SA drugs sector as red tape snares trials. Business Day Live. 2012 Aug 8 [cited 2015 Apr 10]. Available from: http://www.businessday.co.za/articles/Content.aspx?id=174618 5. Thom A. MCC blocking access to lifesaving meds – HIV. Health-E News. 2010 Mar 4 [cited 2015 Apr 10]. Available from: http://www.healthe.org.za/news/article.php?uid = 20032666 6. Geffen N. Medicines Control Council needs new leaders. Quackdown. 2012 Jul 17 [cited 2015 Apr 10]. Available from: http://www.quackdown.info/article/medicines-control-council-needs-new-leaders/ 7. Thom A. Change at the MCC – too little, too late? Health-E News. [cited 2015 Apr 10]. Available from: http://www.health-e.org.za/2010/05/28/changeat-the-mcc-too-little-too-late/ 8. Report of the Ministerial Task Team on the restructuring of the Medicines Regulatory Affairs and Medicines Control Council and recommendations for the new Regulatory Authority for Health roducts
of South Africa (2008). Available from: oldgov.gcis.gov.za/documents/download.php?f=81967 9. Gray AL. Our medicines regulatory authority: plans for reform in South Africa. NSP Review. 2012;3. [cited 2015 Apr 10]. Available from: http://www.nspreview.org/2012/10/03/our-medicines- regulatory-authorityplans-for-reform-in-south-africa/ 10. Kahn T. SA step closer to new medicines regulator. Business Day Live. 2014 Mar 3 [cited 2015 Apr 10]. Available from: http://www.bdlive.co.za/national/health/2014/03/03/sa-step-closerto-new-medicines-regulator 11. Coovadia H, Jewkes R, Barron P, Sanders D, McIntyre D. The health and health system of South Africa: historical roots of current public health challenges. Lancet. 2009;374(9692):817-34. 12. Thom A. The MCC mess. Health 24. 2010 May 28 [cited 2015 Apr 10]. Available from: http://www.health24.com/Medical/Meds-and-you/Using-medicines/The-MCC-mess-20120721 13. Project Conclusion Report. MCC/MRA backlog task team. 2010 Oct [cited 2015 Apr 10]. Available from: http://www.sarrahsouthafrica.org/LinkClick.aspx?fi leticket=AW7KP7zEHKM%3d&tabid=2339. 14. Department of Health. Defending the Medicines Control Amendment Act. 2 March 2001. Pretoria: Department of Health 15. Berger J. Negotiating the new medicines regulatory framework: some basic facts and observations. The South African Journal of HIV Medicine. 2004;5(2):38-40. 16. Republic of South Africa. Health Department. Medicines Control Council. General information guideline. 2008 [homepage on the Internet]. [cited 2015 Apr 10]. Available from: www.mccza.co.za. 17. Republic of South Africa. Department: Health. National EML [homepage on the Internet]. [cited 2015 Apr 10]. Available from: http://www.health.gov.za/index.php/component/phocadownload/ 18. U.S. Food and Drug Administration. Fast track, accelerated approval and priority review. Accelerating availability of new drugs for patients with serious diseases [homepage on the Internet]. cited 2015 Apr 10]. Available from: http://www.fda.gov/For-Patients/Approvals/Fast/default.htm 19. Medicines and Related Substances Act, 1965. Schedules. Fees payable in terms of the Act. Government Gazette. 2012;569(35857). 20. Bagwell K, Lee GM. Number of fi rms and price competition. [cited 2015 Apr 10]. Available from: http://www.stanford.edu/~kbagwell/papers/Bagwell%20 Lee%20s%20021214.pdf 21. Davies NECG. Advice document. Fixed-dose combination for adults accessing antiretroviral therapy. S Afr J HIV Med. 2013;14(1 Suppl):41-3. 22. Drugs.com. Oxytocin [homepage on the Internet] [cited 2015 Apr 10]. Available from: http://www.drugs.com/international/oxytocin.html 23. Reiffen D, Ward MR. Generic drug industry dynamics. The Rev Econ Stats. 2005;87(1):37-49. 24. The world in fi gures: countries. The World in 2012. The Economist: 2012;97-105. 25. Stigler GJ. The theory of economic regulation. The Bell Journal of Economic and Management Science. 1971;2(1):3-21. 26. Abraham J. The pharmaceutical industry as a political player. Lancet. 2002;360(9344):1498-502.
Author for correspondence: Henry MJ Leng, PhD, School of Public Health, University of the Western Cape, Private Bag X17, Bellville, 7130, South Africa
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Notwithstanding the scientific and regulatory differences between generic and biosimilar medicines, the European Medicines Agency/Committee for Medicinal Products for Human Use has consistently applied a ‘same active substance’ approach to both.
Submitted: 28 November 2014; Revised: 20 January 2015; Accepted: 27 January 2015; Published online first: 30 January 2015
It is often stated that biosimilars are ‘similar but not identical’ to their reference product, or more generally, that two biological medicinal products cannot be identical [1, 2]. Although this statement may be correct from a purely scientific – especially biochemical – viewpoint, it is not correct from a regulatory point of view.
The European legal definition of a biosimilar is convoluted. Article 10.4 of the Directive 2001/83/EC [3] does not give a straightforward definition, but states: ‘Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, 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, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided.’
This legal article mainly describes what a biosimilar is not (it is not a generic), and that ‘appropriate results of tests and trials’ must be submitted; however, a clear definition is not provided. The legal definition of a biosimilar is somehow dependent on the legal definition of a generic, which requires a generic to have the same qualitative and quantitative composition in active substances, the same pharmaceutical form, and being bioequivalent with the reference product.
In actual regulatory decision-making, a biosimilar has the ‘same active substance’ as its reference product. As we will argue below, the actual decisions from European Union (EU) regulators demonstrate that this requirement applies to both generics and biosimilars.
It is important to realize that in this context ‘sameness’ is not a scientific concept. Two products will never be ‘the same’ or identical, if one looks hard enough for differences. This also applies to generics, especially when the source of the drug substance is different. If state-of-the-art physicochemical analysis techniques are employed, some (minute) difference(s) in product-related substances/impurities will always be found. Based on such differences a well-equipped analytical laboratory will be able to differentiate between common painkillers with the same active substance, but from different sources.
Sameness is a regulatory concept; it implies that the two products contain the same active substance within the meaning of the Directive. This legal sameness has real-world implications.
Firstly, it means that the active substance in the two products must comply with the same monograph of the European Pharmacopoeia or another pharmacopoeia, if such a monograph exists. Compendial monographs will use the International Nonproprietary Name (INN) as the identifier if an INN is available. Finally, neither a generic nor a biosimilar may contain a new active substance; because this would violate the regulatory and compendial principles outlined above. The regulatory system is internally consistent in this respect.
The second consequence of regulatory sameness is that no clinically meaningful differences exist between two products. Although this is not explicitly stated, it is the cornerstone of the generic/biosimilar approach: because, if a product is generic/biosimilar) to the originator†, clinical data can be extrapolated and their (clinical) benefit–risk is the same.
Recent US regulations for biosimilars state this clinical aspect more explicitly: Biosimilarity means that the biological product is highly similar to the US-licensed reference biological product notwithstanding minor differences in clinically inactive components; and that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency of the product [4].
Although EU regulators have not explicitly written down in the guidance that a biosimilar must have the ‘same qualitative and quantitative composition in active substances’ as the reference product, this principle is consistently used in regulatory decision-making. Available EU guidance is consistent with this requirement: more importantly, it is systematically applied in practice. This is exemplified by the EPAR (European public assessment report) ‘Summary for the public’ for the first biosimilar, Omnitrope (somatropin), which unequivocally states that the approved biosimilar has the same active substance as its reference product [5].
For somatropin and other non-glycosylated proteins the situation is basically the same as for generics: the active substance is the same and small differences are only observed in the excipients and product-related substances/impurities.
For glycosylated proteins, there will be batch-to-batch variability in the percentages of the different glycosylated forms, both within reference and biosimilar products. An active substance can be deemed ‘the same’ from a regulatory point of view, if this variability in glycosylation pattern is the same, i.e. if the glycosylation patterns have been overlapping. As a consequence, the two active substances are expected to have the same INN, because the aim of the INN system has been to provide health professionals with a unique and universally available designated name to identify each pharmaceutical substance [6]. If two active substances are the same, from a regulatory point of view, then the INNs will have to be the same. We note that the INN system may contain rare inconsistencies in this respect, due to the use of the Greek letter suffix to differentiate glycosylation patterns. For example, Retacrit (epoetin-zeta) is deemed biosimilar to Eprex (epoetin-alfa)‡. We feel that such inconsistencies, whilst sometimes unavoidable, should not be promoted by the liberal use of these suffixes. In this respect, we feel that the currently proposed addition of Biological Qualifiers (BQs) to the INN may obfuscate the original intention of the INN. This additional BQ suffix overlaps with the trade name and may be misinterpreted as meaning that the active substance is not the same [7].
Two reasons seem to cause that the ‘same active substance’ requirement is neither recognized nor correctly understood. First, as discussed above, the difference between the scientific and regulatory meaning of ‘same’ is not always appreciated. Second, the terms active substance and the drug substance, which have overlapping but different meanings, are sometimes mixed.
The European legal definition of generic uses the term active substance in the sense of ‘active ingredient with pharmacological activity’, in line with the definition of active substance in the European Pharmacopoeia [8]. On the other hand, drug substance is bulk material that can be composed of the desired product, product-related substances, and product- and process-related impurities [9].
To put it more illustrative: the active ingredient somatropin refers to a 191 amino acid protein, which can bind to a specific receptor. The drug substance somatropin may also refer to a stainless steel drum containing a frozen aqueous solution, of which the protein somatropin is actually only a few per cent by weight§. The concept of active substance has in decision-making for biosimilar unambiguously been used referring to the active ingredient and not to the drug substance.
In conclusion, European regulators have applied a consistent policy regarding assessment and approval of biosimilars. The cornerstone of this policy is that the active substance of a biosimilar must be ‘the same’ from a regulatory and clinical viewpoint, and should display ‘no relevant differences’ from a scientific viewpoint. We feel that it is important to communicate this message clearly to all stakeholders.
Author’s note
†In pre-2004 legal language such a product would be essentially similar to the originator.
‡The EPAR of this specific product states that the active substance is similar, which does not reflect any scientifically relevant difference in glycosylation pattern, but only the difference in INN-suffix.
§Further confusion is added due to the everyday usage of the term ‘API manufacturers’; these should be called ‘drug substance manufacturers’ in ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) terminology.
Competing interests: The authors declare that they have no competing interests.
Provenance and peer review: Not commissioned; externally peer reviewed.
Co-authors
Peter MJM Jongen1,2 Barbara J van Zwieten-Boot1 Marcel HN Hoefnagel1, PhD
1College ter Beoordeling van Geneesmiddelen-Medicines Evaluation Board (CBG-MEB) 500 Graadt van Roggenweg, NL-3531 AH Utrecht, The Netherlands 2National Institute for Public Health and the Environment, Ministry of Health, Welfare and Sport (RIVM), Bilthoven, The Netherlands
References 1. Schellekens H. Biosimilar therapeutics–what do we need to consider? NDT Plus. 2009;2(Suppl 1):i27-i36. 2. MHRA. MISG panel & forum topic proposal. Executive summary [homepage on the Internet]. 2015 [cited 2015 Jan 20]. Available from: http://www.mhra.gov.uk/home/groups/es-policy/documents/websiteresources/con2030475.pdf 3. European Commission. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 [homepage on the Internet]. 2015 [cited 2015 Jan 20]. Available from: http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf 4. U.S. Food and Drug Administration. Information for healthcare professionals (biosimilars) [homepage on the Internet]. 2015 [cited 2015 Jan 20]. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241719.htm 5. European Medicines Agency. European Public Assessment Report (EPAR) Omnitrope. EPAR summary for the public [homepage on the Internet]. 2008 Apr 14. [cited 2015 Jan 20]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000607/WC500043689.pdf 6. World Health Organization. Guidance on INN [homepage on the Internet]. 2015 [cited 2015 Jan 20]. Available from: http://www.who.int/medicines/services/inn/innquidance/en/ 7. The Inn crowd. Nat Biotechnol. 2013;31(12):1055. doi:10.1038/nbt.2760 8. European Directorate for the Quality of Medicines & HealthCare (EDQM). European Pharmacopoeia 8th Edition [homepage on the Internet]. [cited 2015 Jan 20]. Available from: https://www.edqm.eu/en/edqm-homepage-628.html 9. European Medicines Agency. Note for guidance on specifications: test procedures and acceptance criteria for biotechnological products. CPMP/ICH/365/96. September 1999 [homepage on the Internet]. 2006 Mar 7 [cited 2015 Jan 20]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002824.pdf
Author for correspondence: R Martijn van der Plas, Beoordelaar, Farmacologische, Toxicologische- en Biotechnologische Beoordeling, College ter Beoordeling van Geneesmiddelen, 500 Graadt van Roggenweg, NL-3531 AH Utrecht, The Netherlands
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
The attractiveness of the biosimilar regulatory pathway is threatened by so-called biobetters. This paper provides definitions and an overview of recent developments.
Submitted: 27 October 2014; Revised: 7 November 2014; Accepted: 12 November 2014; Published online first: 25 November 2014
Concerning the biosimilar landscape, the European Medicines Agency (EMA) was among the first institutions to offer a legal basis and regulatory guidance for biosimilar development. Since 2004, the available guidance documents have flourished and evolved to ensure high standard biosimilar medicines for patients throughout the European Union (EU). Biosimilar medicines seemed to be the ideal solution for healthcare representatives in fear that a growing number of highly expensive biologicals would sooner or later crash their systems and leave the costs of high-end treatment to the patient. Additionally, biosimilars, like generics, were considered innovation drivers, urging developers to focus on novel targets rather than stick with established top sellers.
After the first guideline was in place, the new concept was taken up with varying speed and varying success. While some markets were quick on uptake of biosimilars, other countries seemed more hesitant to incorporate the novel concept into daily practice [1]. It took time, but in 2013, biosimilar development started to gain momentum, with the positive CHMP (Committee for Medicinal Products for Human Use) opinion to Celltrion’s Remsima (infliximab) – the first biosimilar monoclonal antibody – developed from a South Korean Company. Even more encouragingly, within the EU, Remsima was able to obtain all major indications of originator Remicade by extrapolation. To date, 19 biosimilar medicines have a valid marketing authorization, and many more are waiting in the pipelines. More and more European markets jumped on the biosimilar bandwagon resulting in Italy overtaking Germany as the biggest European biosimilar market [1]. Biosimilars can be considered a success story – yet they are in fierce competition with a different player, which is from a European regulatory perspective, no player at all – the ‘biobetters’.
The term ‘biobetter’ was presumably invented by Mr GV Prasad, CEO of Dr Reddy’s Laboratories, at a bio-investor’s conference in Mumbai, India, in 2007 and has been excessively used ever since, possibly to a degree, where there is no unified definition for this marketing term [2].
While biosimilars, as the term suggests, aim to establish similarity to a known biological, biobetters seek superiority in one or various aspects of their clinical profile. While working against the same target protein, biobetters include structural changes, bi-functional targeting (with or without a biosimilar core) or an improved formulation that may result in an expected improvement in safety and/or efficacy [3].
Sharing the same target and being an improved version of a known biological sets biobetters apart from so-called ‘me-too biologicals’, which, without being structurally based on each other, share the same target, e.g. anti-TNFα monoclonal antibodies.
An interesting example of a biobetter, which could possibly reduce the impact of potential biosimilar candidates is the development of Roche’s obinutuzumab (Gazyvara), an anti-CD20 monoclonal antibody, which has shown superior efficacy in the treatment of chronic lymphocytic leukaemia (CLL) compared to its ‘originator’ rituximab (MabThera, Roche). Gazyvara gained EU marketing authorization for previously untreated CLL in 2014 – before biosimilar candidates of rituximab managed to finish their development programmes. However, it remains to be proven if Gazyvara can demonstrate a more favourable benefit/risk ratio than rituximab in other indications than CLL and to what extent it will replace MabThera, as well as putative biosimilar rituximabs, in the future.
While no special regulatory pathway for biobetters exists, a biobetter will always be treated as a product with new active substance from a regulatory perspective, some ‘short cuts’ might remain for biobetter developers. Knowing your target can reduce R & D costs, prior related drugs may help with choices of biomarkers and safety monitoring will most likely focus on known side effects of the already established target pathway. Furthermore, if a biobetter gains a marketing authorization, this may lead to market exclusivity, even if no patent protection will be issued. Sometimes, biobetter development is even used as a defence strategy of originator companies, to protect their market niche against possible biosimilar candidates via line extensions, as in the case of a subcutaneous formulation of Roche’s trastuzumab, which gained positive marketing authorization in 2013 shortly before Roche’s Herceptin (intravenous trastuzumab) patent expired in 2014.
Apart from the lack of new targets, the rise of biobetters can partly be attributed to certain regulatory pitfalls in the European biosimilar regulatory framework. For instance, the sensitive issue of interchangeability has, to date, not been addressed by EMA because interchangeability is tightly connected to substitution which is a national issue. In the absence of national legislation and guidelines, the decision if and under which circumstances interchangeability could be established remains with to individual doctors, especially in the context of hospital tendering processes [4]. Hence, it remains unclear whether, like generic drugs, biosimilars will be prescribed interchangeably with their originator in the near future.
To keep the biosimilar concept attractive for companies, regulatory guidance needs to evolve to more thoroughly address most urging regulatory questions in order to ease global developments. In line with this, the concept of extrapolation of indication has further been elaborated in a recent article issued by members of EMA’s Biosimilar Medicinal Products Working Party, specifying circumstances under which extrapolation to all originator’s indications can be possible [5]. Furthermore, in 2013 the new draft of EMA’s overarching biosimilar guideline opened the door to waiving clinical studies in biosimilar development under specific circumstances, e.g. for structurally more simple biological medicinal products, which in the future will have to be further specified to help companies in planning their biosimilar development programmes [6].
In conclusion, in a highly regulated market, such as the EU, the biosimilar concept stands a fair chance to continue posing an attractive regulatory pathway for drug developers, compared to developing ‘biobetters’ via a full application, thereby fulfilling the rising need for cheaper biological medicinal products. Regulatory guidance will further have to evolve, to keep biosimilars competitive against biobetters and to avoid pitfalls in their development.
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
References 1. Rickwood S, Biase SD. Searching for terra firma in the biosimilars and non-original biologics market. IMS Health, 2013.
2. DePalma A. Will biobetters beat biologics? October 2011 [homepage on the Internet]. [cited 2014 Nov 10]. Available from: http://social.eyeforpharma.com/forecasting/will-biobetters-beat-biologics
3. Dolinar RO, Reilly MS. The future of biological therapy a pathway forward for biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(1):36-40. doi:10.5639/gabij.2013.0201.014.
4. European Medicines Agency. Questions and answers on biosimilar medicines (similar biological medicinal products). EMA/837805/2011. 27 September 2012 [homepage on the Internet]. [cited 2014 Nov 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf
5. Weise M, Kurki P, Wolff-Holz E , Bielsky MC, Schneider CK . Biosimilars: the science of extrapolation. Blood. 2014 Oct 8. pii: blood-2014-06-583617. [Epub ahead of print]
6. European Medicines Agency. Draft guideline on similar biological medicinal products. CHMP/437/04 Rev 1. 22 May 2013 [homepage on the Internet]. [cited 2014 Nov 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf
Author:René Anour, DVM, Senior Clinical Expert, Department Clinical Assessment Safety & Efficacy, Institute Assessment & Analysis, Austrian Medicines & Medical Devices Agency (AGES), Austrian Federal Offi ce for Safety in Health Care (BASG), 5 Traisengasse, AT-1200 Vienna, Austria
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
‘Non-binding recommendations’ from regulatory bodies are in place for evaluation and production of generic liposomal doxorubicin injection. However, how these nano-sized generics (‘nanosimilars’) should be characterized and evaluated, and particularly when the ‘reference listed product’ is no longer in production are among the major issues. We discuss these issues with respect to complexity of liposomal structure and vesicular population heterogeneity, and the challenges facing ‘nanosimilars’.
Submitted: 9 January 2014; Revised: 27 January 2014; Accepted: 28 January 2014; Published online first: 10 February 2014
Doxil (owned by Johnson & Johnson through its subsidiary Janssen) is the trade name of doxorubicin HCl liposome injection. Doxil is indicated for HIV-related Kaposi’s sarcoma in patients with low CD4 count and extensive mucocutaneous or visceral disease as well as for the treatment of patients with advanced ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy [1]. The original patent for Doxil expired in 2009 [1]. However, there is an exclusivity extension for Doxil (an orphan designation until 17 May 2014) in combination with bortezomib (Velcade) for use in patients with multiple myeloma.
Doxil is a sophisticated multi-component nano-sized formulation and its biological performance is controlled by a complex array of interrelated physicochemical properties including liposome composition, vesicular size (curvature), morphology and surface characteristics, the internal environment, e.g. volume, pH, sulfate and ammonium ion concentration [1, 2]. The sheer complexity and the know-how of Doxil design, development and production, should indeed, offer market exclusivity and reduce the threat of generics competition even after patent expiration [3].
Since mid-2011, Doxil is in short supply, arising from voluntary shutdown of a third-party manufacturer (Ben Venue Laboratories, Bedford, Ohio, USA). Despite continued efforts to return the Ohio facility to working order, decision was made to permanently cease production by the end of 2013 [4]. Johnson & Johnson is now looking for an alternative site for producing Doxil [4]. However, in February 2013, the US Food and Drug Administration (FDA) approved a ‘nanosimilar’ version of Doxil (Lipodox) made by Sun Pharma Global FZE, a subsidiary of India’s Sun Pharmaceutical Industries Ltd [5]. Lipodox is not approved to treat patients with multiple myeloma, as this exclusivity agreement is still intact [4].
Are Doxil and Lipodox similar? Recently, FDA generated a draft document containing ‘non-binding recommendations’ for evaluation of generic injectable poly(ethylene glycol)-grafted (PEGylated) liposomal doxorubicin formulations [6]. It is well known that the biophysical characteristics of liposomes can modulate their biological performance, which include vesicular stability and circulation times, enhanced permeability and retention at solid tumours, drug-release rates (at the target site) and toxicity [1]. Although, these attributes have been addressed in the regulatory draft recommendations, precision biophysical characterization of drug-loaded vesicles is a daunting task [7]. A generic liposomal formulation may show similar morphological structures (lamellarity), mean average hydrodynamic vesicular size and electrophoretic mobility profiles to that of the reference listed drug (RLD). However, the vesicular suspension (whether RLD or generic drug) may be heterogeneous with respect to many physicochemical properties. Some vesicular populations may differ from others in terms of lipid bilayer stress and defects, aspect ratios (since on doxorubicin loading and precipitation the vesicular shape usually changes from spherical to an oblate spheroidal shape) and vesicular scattering intensity (even among vesicles of the same size/aspect ratio), and surface hydrophobicity/hydrophilicity. These issues are often not addressed in liposome production, but could play serious roles in liposomal ‘nanosimilar’ manufacturing and biological performance. Furthermore, a liposomal ‘nanosimilar’ may differ from the RLD in terms of the number of suspended vesicles in the vial, although the mean vesicular size (spherical equivalent) and encapsulated drug content (and drug-to-lipid ratio) may be the same between the two formulations. Here, dosing of the generic drug formulation, in terms of equivalent doxorubicin or doxorubicin/g lipid, may be the same as the RLD product, but not necessarily in terms of the number of administered vesicles. Accordingly, a generic doxorubicin HCl liposome injection may not be qualitatively the same as the RLD, i.e. Doxil. The above-mentioned changes, however, may not have a dramatic impact on vesicular circulation times (at least on the first injection), but may control the kinetic of drug release at tumour sites as well as affecting immune responses on infusion [7]. These biological differences, presumably, can only be observed in large and carefully planned studies. Indeed, small changes in liposome number will affect the total available surface area exposed to the blood, and subtle changes in liposomal surface properties can translate to large changes in the overall surface considering the large number of vesicles that are introduced into the systemic circulation. These changes, for instance, may affect the frequency of infusion-related reactions, where inadvertent complement activation is a causal factor [8]. Complement system is the first line of defense against intruders, recognizing danger primarily through pattern recognition [9]. Minor differences in liposome surface curvature, defects and characteristics can incite complement differently and through the binding of antibodies as well as different complement-sensing molecules to include C1q, mannose binding lectin, ficolins and properdin [9, 10]. Further complexity may emerge from the presence of complement activating aggregated contaminants in clinical formulations as well as vesicular structural transformation (resulting from vesicular heterogeneity) in contact with the blood that could elicit immunological reactions [9]. Indeed, morphological evidence for the presence of low-curvature oval, elongated or irregular liposomes and aggregate already exist for Doxil, which are believed to affect complement activation and consequential responses [11]. Other complications could still arise from potential differences in immunogenicity, which can only be observed in large population studies.
There are ongoing debates as how to evaluate generic or ‘nanosimilar’ liposomes for injection [12–14], but unavailability of the RLD product (Doxil in this case) is of concern for comparative purposes. After all, this is not about conventional bioequivalence approaches applied to a generic low molecular weight drug, which is sufficient to demonstrate comparable content, purity and clinical pharmacokinetics. With liposomes, the vesicular properties control the pharmacokinetics of the encapsulated drug as well as the toxicity profile [15]. Accordingly, various techniques must be adopted to examine key physicochemical parameters between generics and RLD products and identify vesicular population differences and systems’ heterogeneity. What are needed are advanced and sophisticated characterization tools that can provide better definition of vesicular (or nanoparticle) morphology heterogeneity, size and surface heterogeneity within a typical suspension as well as technologies that can yield more homogenous drug-loaded vesicular populations [7]. In the absence of such evaluations an independently developed liposomal formulation may not have identical pharmaceutical quality attributes as the RLD product and therefore cannot be considered interchangeable in the absence of designated clinical studies. A responsive regulatory framework is therefore needed and may be applicable to broader regulation of future products of nanotechnology [16].
Competing interests: None. Professor S Moein Moghimi acknowledges financial support by the Danish Agency for Science, Technology and Innovation (Det Strategiske Forskningsråd), reference 09-065746.
Provenance and peer review: Commissioned; externally peer reviewed.
Co-author
Z Shadi Farhangrazi, PhD, Biotrends International, Denver Technological Center, Greenwood Village, Colorado, USA
References 1. Barenholz Y. Doxil®—the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117-34. 2. Hamad I, Moghimi SM. Critical issues in site-specific targeting of solid tumours: the carrier, the tumour barriers and the bioavailable drug. Expert Opin Drug Deliv. 2008;5(2):205-19. 3. Moghimi SM, Peer D, Langer R. Reshaping the future of nanopharmaceuticals: ad iudicium. ACS Nano. 2011;5(11):8454-8. 4. Inman S. OncLive. Doxil availability once again in question. 2013 Oct 9 [cited 2014 Mar 3]. Available from: http://www.onclive.com/web-exclusives/Doxil-Availability-Once-Again-in-Question 5. U.S. Food and Drug Administration. FDA News Release. FDA approval of generic version of cancer drug Doxil is expected to help resolve shortage [homepage on the Internet]. 2013 Feb 4 [cited 2014 Mar 3]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm337872.htm 6. U.S. Food and Drug Administration. Draft guidance on doxorubicin hydrochloride. February 2010 [homepage on the Internet]. 2013 Oct 28 [cited 2014 Mar 3]. Available from: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorInformation/Guidances/UCM199635.pdf 7. Moghimi SM, Hunter AC, Andresen TL. Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective. Annu Rev Pharmacol Toxicol. 2012;52:481-503. 8. Szebeni J, Muggia F, Gabizon A, Barenholz Y. Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: predication and prevention. Adv Drug Deliv Rev. 2011;63(12):1020-30. 9. Moghimi SM, Farhangrazi ZS. Nanomedicine and the complement paradigm. Nanomedicine: Nanotechnol Biol Med. 2013;9(4):458-60. 10. Moghimi SM, Andersen AJ, Ahmadvand D, Wibroe PP, Andresen TL, Hunter AC. Material properties in complement activation. Adv Drug Deliv Rev. 2011;63(12):1000-7. 11. Szebeni J, Bedocs P, Rozsnyay Z, Weiszhár Z, Urbanics R, Rosivall L, et al. Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome. Nanomedicine: Nanotechnol Biol Med. 2012;8(2):176-84. 12. European Medicines Agency. 1st International Workshop on Nanomedicines. Summary report. EMA/538503/2010. 2010 Oct 21 [homepage on the Internet]. 2010 Oct 22 [cited 2014 Mar 3]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2010/10/WC500098380.pdf 13. Schellekens H, Klinger E, Mühlebach S, Brin JF, Storm G, Crommelin DJ. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol. 2011;59(1):176-83. 14. Gaspani S, Milani B. Access to liposomal generic formulations: beyond AmBisome and Doxil/Caelyx. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(2):60-2. doi:10.5639/gabij.2013.0204.053 15. Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin Pharmacokinet. 2003;42(5):419-36. 16. Hamburg MA. FDA’s approach to regulation of products of nanotechnology. Science. 2012;336(6079):299-300.
Author for correspondence: Professor S Moein Moghimi, PhD, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen Ø, Denmark
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Two biosimilar TNF-alfa monoclonal antibody (mAb) products were approved for clinical use in the European Union on 10 September 2013, following a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) in July 2013. The products, with trade names Remsima and Inflectra (INNs infliximab) contain an identical mAb. This approval shows the feasibility of using the biosimilar pathway for mAbs and paves the way for further biosimilar mAb products.
Submitted: 9 January 2014; Revised: 27 January 2014; Accepted: 28 January 2014; Published online first: 10 February 2014
Monoclonal antibodies (mAbs) have great potential for clinical use in vivo. Their specificity and ability to be produced to bind to almost any antigen of clinical interest has established them as potentially probably the largest class of biotherapeutics. Many are now approved for clinical use, many more are in various stages of clinical development and some are considered ‘blockbuster’ high income products. It would therefore seem reasonable to develop biosimilar mAbs, at least for the higher-usage products.
While it was previously considered that the molecular complexity and relatively large size of mAbs may limit the feasibility of using the European Union (EU) biosimilar approach for them [1], this has now been proven to be not the case, as the first two biosimilar mAb products were approved for use in the EU by the European Commission on 10 September 2013, following a positive opinion in July 2013 by the Committee for Medicinal Products for Human Use (CHMP). The two products, with trade names Remsima and Inflectra have used the TNF-alpha mAb Remicade as the reference product and the marketing authorizations are held by Celltrion and Hospira, respectively. All three mAbs have the same INN (infliximab), which reflects their similarity. However, the biosimilars do show some differences in glycosylation and so, according to the INN ‘rules’ a Greek letter could have been added as an identifier as a second word of the INN, but this option was not considered. The CHMP view was that the small differences in glycosylation were not clinically significant, based on the clinical trial data.
Both Remsima [2] and Inflectra [3] contain an identical mAb and are the same in their pharmaceutical form, strength, composition and route of administration but the packaging size varies.
Despite the approval of both biosimilar mAbs in September 2013, a Remicade patent extension has prohibited their sale in the EU although not elsewhere (Remsima has been marketed in South Korea for some time post approval as a biosimilar by the (then) Korean FDA in July 2012). Resolution of the patent issues will allow the biosimilars to be marketed in the EU later this year or in 2015; precise dates for this will differ between states and also could be affected by other considerations, such as marketing factors.
As per EU biosimilar requirements, the approval application included a detailed and thorough characterization of the mAb and an exhaustive quality comparison of the biosimilar with the reference product using state-of-the art methods. This was complemented by comparative non-clinical and clinical studies in a sensitive model to establish and confirm clinical biosimilarity. This comparability exercise data taken together provided an overall ‘proof’ of biosimilarity and assurance that the safety and efficacy profile of the biosimilar versions matches that of the reference product. This is stressed in the European Public Assessment Report (EPAR) for Remsima [2] which states ‘The Agency’s Committee for Medicinal Products for Human Use (CHMP) decided that, in accordance with EU requirements, Remsima has been shown to have a comparable quality, safety and efficacy profile to Remicade’. Therefore, the CHMP’s view was that, as for Remicade, the benefit outweighs the identified risks. The Committee recommended that Remsima be approved for use in the EU for all therapeutic indications of Remicade. Similar is the case for Inflectra [3].
The very important and often misunderstood issue of clinical comparability is also addressed by quoting data in the EPAR [2], i.e. ‘Remsima was studied to show that it is comparable to the reference medicine, Remicade. Remsima was compared with Remicade in one main study involving 606 adults with rheumatoid arthritis. Patients received either Remsima or Remicade in addition to methotrexate for 30 weeks. The main measure of effectiveness was the change in symptoms (measured by ACR20). After 30 weeks of treatment Remsima was as effective as Remicade, with around 60% of patients responding to treatment with either medicine’. The EPAR also contains statements relating to other key similarities found for the biosimilar and reference product, e.g. pharmacokinetics. No unexpected safety issues occurred, and immunogenicity was very similar to that observed for Remicade. For further information, see the EPARs at www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000240/human_med_001023.jsp&mid=WC0b01ac058001d124
It should be stressed that Remsima and Inflectra have been thoroughly characterized to show their biosimilarity to Remicade. Unfortunately, this is not the case for what are claimed to be ‘biosimilar mAbs’ marketed in some non-EU countries, for example, China and India. This problem has been highlighted before [4], but is still continuing as reports describing limited assessment of poorly compared products are still referring to these products as ’biosimilars’ although they are clearly not such according to EU (and WHO) definitions [5].
The EU approval of the two biosimilar mAb products not only demonstrates the feasibility of using the biosimilar pathway for relatively large, complex molecules, but also sets a precedent for other biosimilar mAb products to follow. We should expect several more biosimilar mAbs in the near and medium future. Perhaps a biosimilar trastuzumab will be next?
But the real challenge for biosimilar mAbs, at least in the EU will be market penetration. Pricing and uptake of Remsima and Inflectra throughout the EU will be interesting from this important perspective. Equally, improved communication with physicians [6], payers and patients on the rigorous regulatory approval process should facilitate an increase in the uptake of these types of products.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
Co-author
Meenu Wadhwa, PhD, Cytokines and Growth Factors Section, Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK
References 1. Schneider CK, Kalinke U. Toward biosimilar monoclonal antibodies. Nat Biotechnol. 2008;26(9):985-90. 2. European Medicines Agency. Assessment report – Remsima [homepage on the Internet]. 2013 Sep 30 [cited 2014 Jan 27]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002576/WC500151486.pdf 3. European Medicines Agency. Assessment report – Inflextra [homepage on the Internet]. 2013 Sep 30 [cited 2014 Jan 27]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002778/WC500151490.pdf 4. Thorpe R, Wadhwa M. Terminology for biosimilars – a confusing minefield. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):132-4. doi: 10.5639/gabij.2012.0103-4.023 5. Tan Q, Guo Q, Fang C, Wang C, Li B, Wang H, et al. Characterization and comparison of commercially available TNF receptor 2-Fc fusion protein products. MAbs. 2012;4:761-74. 6. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Giezen TJ, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111-7.
Author for correspondence: Robin Thorpe, PhD, Deputy Editor-in-Chief, GaBI Journal
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
As the number of innovator biologics and biosimilars increases worldwide, a growing debate has focused on how these products should be named. The simple concept of a name can have significant impact on prescribing, dispensing, and adverse event reporting processes and, consequently, patient safety.
Submitted: 2 January 2014; Revised: 10 January 2014; Accepted: 11 January 2014; Published online first: 24 February 2014
Biosimilars have now been on the market in the European Union for more than six years, and several other jurisdictions have approved biosimilars as well. Biosimilars are poised to enter the US market as soon as 2014, and more countries are developing approval pathways for biosimilars each year. As part of the discussion of the regulatory and scientific issues surrounding biosimilars, attention has increasingly turned to how all biologicals should be named and, in particular, whether biosimilars should have non-proprietary names that distinguish them from the reference product and from other biosimilars.
Background on biosimilar naming conventions to date
Thus far, the approaches to biosimilar naming have been somewhat inconsistent and are becoming more complex. The World Health Organization (WHO) has historically assigned biosimilars International Nonproprietary Names (INNs) that are the same as those of the reference products. However, a biosimilar could elect to use a Greek letter suffix to indicate potential differences in glycoforms when compared to the reference product [1]. National health authorities generally do not require a biosimilar applicant to submit an application to the WHO International Nonproprietary Name Committee for evaluation.
Biosimilars in Europe have generally (but not always) shared the non-proprietary names of their reference products. For example, Silapo (epoetin zeta) has a distinct non-proprietary name from its reference product, Eprex/Erypo (epoetin alfa) [2]. Remsima (infliximab), in contrast, shares the same non-proprietary name as its reference product, Remicade (infliximab) [3].
As regulators, physicians, and patients have gained experience with biosimilars and manufacturers have begun developing more complex biosimilars like monoclonal antibodies, support has grown for giving them distinct non-proprietary names, i.e. names that distinguish biosimilars from their reference products and from each other. For example, Australia’s Therapeutic Goods Administration (TGA) recently issued guidance requiring that the non-proprietary name of a biosimilar be composed of: (1) the reference product non-proprietary name; and (2) a biosimilar identifier, consisting of the prefix ‘sim’ and a three letter unique identifier code. According to TGA, this unique identifier code would be issued by the WHO International Non-proprietary Name Committee [4].
Japan also requires that biosimilars of complex protein products bear unique non-proprietary names. The naming convention there requires the biosimilar to use the non-proprietary name of the reference product, plus ‘biosimilar’ and a number indicating the order in which the biosimilar was approved in Japan, e.g. 1, 2, 3 [5, 6].
In the absence of a specific biosimilar naming scheme mandated by statute, US Food and Drug Administration (FDA) is in the process of developing its policy on biosimilar naming. Meanwhile, the agency recently approved full, non-abbreviated applications for three biologicals bearing non-proprietary names with distinctive prefixes: tbo-filgrastim, ziv-aflibercept, and ado-trastuzumab emtansine. FDA reasoned that distinct names would facilitate post-market safety monitoring and help minimize the potential for medication errors (by reducing the risk of a patient receiving a product different than what the physician intended and by reducing confusion among healthcare providers who may consider same names to mean that products are clinically indistinguishable) [7].
The current lack of global uniformity of non-proprietary naming of biosimilars may weaken the INN system, and the inconsistency could lead to confusion among stakeholders, including prescribers, pharmacists, patients, and the broader scientific community. WHO is now in the process of considering a scheme in which a unique identifier would be added to the non-proprietary name of a biosimilar, in order to distinguish it from the reference product and from other biosimilars [1].
Distinct non-proprietary names for all biologicals, including biosimilars, are essential to promoting the public health by helping to facilitate: (1) transparency and clear identification of a product; and (2) efficient and accurate pharmacovigilance.
Clear identification of biological products
Depending on the pharmacy laws and practices of a jurisdiction, shared non-proprietary names may increase the potential for automatic substitution at the pharmacy or lead to unintended switching from one product to another where a physician intended to prescribe a specific product. A physician may choose to prescribe a specific product for any number of reasons, including because individual patients may have been stabilized on a particular product. But in jurisdictions where prescribing by brand name is prohibited or discouraged, if non-proprietary names are shared across biologicals, including biosimilars, patients may end up receiving products that are different from those intended by physicians. This lack of transparency can pose threats to patients and the physician-patient relationship. Further, some countries base their procurement tenders on non-proprietary name, a practice that may lead to patients being switched (sometimes repeatedly) among non-interchangeable products that share the same name.
In addition, three recent surveys of prescribers in the US and European Union suggest that some physicians believe a shared non-proprietary name implies two products are structurally identical [8–10]. Shared names may therefore muddle prescriber choice by giving the impression that a biosimilar is identical to its reference product and identical to other biosimilars that share the same reference product, neither of which is the case. A biosimilar, by definition, is similar but not identical to the relevant reference product. Moreover, biosimilars will not undergo comparability testing with regard to other biosimilars. Without ensuring differentiation in naming among biosimilars, physicians or other stakeholders may be led to believe that different biosimilar products are identical to one another based solely on their individual biosimilarity to the reference product. In this way, shared non-proprietary names may inhibit physician understanding of the nature of biosimilars and may thwart physician efforts to ensure a patient receives the intended product.
Efficient and accurate pharmacovigilance
Effective post-market surveillance, and ultimately corrective actions to address safety concerns, hinges on the ability to efficiently and accurately identify potential safety signals and the product(s) responsible. The complexity of biological products and their sensitivity to even seemingly minor manufacturing changes and to environmental conditions means that, in some cases, it is not possible to fully predict the effect of a manufacturing change before it is implemented. It also means that clinically meaningful differences between biosimilars and their reference products sometimes may be detected only, or indeed may emerge, after biosimilar approval. It is therefore critical to be able to efficiently identify any adverse events associated with a specific biological after it reaches the market.
Spontaneous reports of adverse events often do not include meaningful product-identifying information beyond a product’s non-proprietary name [7, 11], and electronic payer databases vary in the extent to which they collect product-specific data. Shared non-proprietary names across products thus often result in the pooling of adverse events associated with multiple products, potentially masking a change in adverse events with respect to one product but not others as well as impeding the ability to identify the product(s) responsible for a safety signal [12].
In contrast, the distinct name approach currently under consideration by WHO would appropriately indicate that two related products are, in fact, related. But it would also indicate that two biologicals are distinct and help to reduce the potential for misattribution of adverse events. Because two products would share a common ‘core’ portion of the non-proprietary name, this policy would also allow for the aggregation of data to assess class-wide safety issues.
Conclusion
WHO should thus develop policies requiring distinct non-proprietary names for biosimilars to best serve the interest of public health. Swift action is critical. Although biosimilars have a rapidly expanding global footprint, the number of approved biosimilars is still limited enough that a new approach for naming biologicals, even if applied only prospectively, will result in significantly improved consistency. WHO should also investigate the use of distinct non-proprietary names for all biologicals. These policies would not require drastic changes to existing naming processes or prescribing and dispensing systems, but would reduce the potential for misattribution of adverse events and would improve product identification and transparency. These goals are becoming more critical as the number of approved biologicals increases. In the coming years, many new biologicals will enter the market, and some will be biosimilar, some may be interchangeable, and some will not undergo any comparability testing with another biological. A consistent, clear naming policy is critical to preventing confusion.
In addition to WHO, national regulatory authorities will play key roles as well. First, because WHO does not itself have the authority to make the INN process mandatory, national regulatory authorities should help facilitate global consistency by adopting policies that encourage all biological applicants to apply for an INN from WHO. Second, coordination between WHO and national regulatory authorities is also critical. Applicants are more likely to apply for an INN if the process is efficient and does not interfere with applicant review and approval timelines by national regulatory authorities. Finally, even if WHO adopts a unique identifier approach, this policy will have little effect if the identifier is not used on prescriptions, patient records, product labelling and advertising, adverse event reports, and other records. National regulatory authorities can therefore play a key role in educating healthcare professionals, manufacturers, and other stakeholders on the importance of including the unique identifier in all contexts.
Other tools should be used to complement these efforts and may help ensure the clear identification of biologicals and effective pharmacovigilance. For example, the use of distinct brand names may also help to distinguish between products. All biosimilar products in the European Union have had a distinct product name, and many stakeholders have suggested that the use of distinct brand names for biosimilars will eliminate the need for distinct non-proprietary names. However, not all jurisdictions have the authority to require that products bear a brand name. For example, in the US, FDA does not have explicit statutory authority to require that all biosimilars use a distinct brand name. There are also some jurisdictions that prohibit or discourage prescribing certain products by brand name, and many others – including the US – that do not mandate prescribing by brand name, so the use of distinct non-proprietary names becomes critical.
In addition, it is critically important to educate patients, physicians, and other stakeholders on the importance of reporting more product-identifying information in adverse event reports and prescribing and dispensing records, such as brand name, non-proprietary name, manufacturer name, and lot number.
Biologicals are revolutionizing healthcare, and biosimilars may offer additional options for patients. But in order for these products to offer the greatest benefit to patients, we must be able to accurately identify them and efficiently track any applicable adverse events. In this way, the simple concept of a name is critical to protecting patients around the world.
Competing interests: Ms Alexander is an employee of AbbVie, Inc. She has no conflict of interest that is directly relevant to the content of this manuscript.
Provenance and peer review: Not commissioned; internally peer reviewed.
References 1. World Health Organization. 56th Consultation on International Nonproprietary Names (INN) for Pharmaceutical Substances. Geneva, 15–17 April 2013. Executive Summary. September 2013 [homepage on the Internet]. 2013 Oct [cited 2014 Jan 9]. Available from: http://www.who.int/medicines/services/inn/56th_Executive_Summary.pdf 2. European Medicines Agency. Silapo: EPAR – Scientific Discussion. January 2008 [homepage on the Internet]. 2008 Jan [cited 2014 Jan 9]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000760/WC500050914.pdf 3. European Medicines Agency. Assessment Report: Remsima. 27 June 2013 [homepage on the Internet]. 2014 [cited 2014 Jan 9]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002576/WC500151486.pdf 4. Australian Government. Department of Health. Therapeutic Goods Administration. Evaluation of biosimilars. 30 July 2013 [homepage on the Internet]. 2014 [cited 2014 Jan 9]. Available from: http://www.tga.gov.au/industry/pm-argpm-biosimilars-00.htm#.Usn2XjOA3Dd 5. Arato T. Recent regulations of biosimilars in Japan. Pharmaceuticals and Medical Devices Agency. 47th Annual Meeting, DIA 2011; 2011 Jun 19–23, Chicago, USA. Available from: http://www.pmda.go.jp/regulatory/file/english_presentation/biologics/B-E1arato.pdf 6. Derbyshire M. Biosimilar development and regulation in Japan. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(4):207-8. doi:10.5639/gabij.2013.0204.055 7. U.S. Food and Drug Administration. Public Health Service. Department of Health and Human Services. FDA Biological Product Naming Working Group, FDA Memorandum, BLA 125294 – [xxx]-filgrastim. 2 August 2012 [homepage on the Internet]. [cited 2014 Jan 9]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125294Orig1s000NameR.pdf 8. Industry Standard Research. Alliance for Safe Biologic Medicine – Prescriber survey [homepage on the Internet]. 2012 Aug 31 [cited 2014 Jan 9]. Available from: http://safebiologics.org/resources/wp-content/uploads/2012/09/ASBM-Survey-1.pdf 9. Alliance for Safe Biologic Medicines. ASBM presents new European survey findings on biosimilars and the importance of nonproprietary naming [homepage on the Internet]. 2013 Nov 22 [cited 2014 Jan 9]. Available from: http://safebiologics.org/resources/2013/11/asbm-presents-new-european-survey-findings-on-biosimilars-and-the-importance-of-nonproprietary-naming 10. Prescriber Survey. ZS Associates on behalf of AbbVie. 2013. Data on file at AbbVie. 11. Biosimilar medicines and safety: new challenges for pharmacovigilance. WHO Drug Information. 2009;23(2):87–91. Available from: http://apps.who.int/medicinedocs/documents/s16240e/s16240e.pdf 12. Lietzan E, et al. Biosimilar naming: how do adverse event reporting data support the need for distinct nonproprietary names for biosimilars? FDLI’s Food and Drug Policy Forum. 2013;3(6):1-20.
Author: Emily A Alexander, JD, Director of US Regulatory Affairs, Biologics Strategic Development, AbbVie Inc, Building AP31, 1 North Waukegan Road, North Chicago, IL 60064, USA
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Biological product quality is susceptible to unexpected manufacturing issues, and the resulting variation may impact the safety or efficacy of these medicines and increase risks to patients. These risks can be managed more effectively by manufacturers’ adoption of the culture and practices of high reliability organizations and by their sharing of quality risk management information.
Submitted: 5 August 2013; Revised: 18 September 2013; Accepted: 19 September 2013; Published online first: 2 October 2013
The manufacture of therapeutic biologicals is constantly evolving science. Early naturally sourced biologicals were extracted and purified from animal tissues, cadavers, or donated blood with attendant risks of unwanted immune responses or infection with source-derived viruses. Early recombinant biologicals contained impurities from the manufacturing process that were sometimes associated with immunogenicity [1].
Many of these risks have been mitigated through modern bioprocessing technology but the manufacture of biologicals today still faces significant challenges: how can we ensure that biological medicines maintain their high quality, from batch to batch, and are supplied without interruptions to patients who may require long-term therapy to manage their medical conditions?
Biologicals are sensitive to manufacturing process conditions, handling and changes
Most biological medicines are manufactured using living cells that have been engineered to produce therapeutic proteins in large quantities. As these proteins are very sensitive to their conditions of synthesis and handling, a series of critical culturing and purification steps is required to produce a consistent, high quality active ingredient. The complexity of this process and the precision of required control require careful design and strict adherence to procedures as any changes introduced in the process can potentially influence the quality of the final product, including the structure, function and purity of the active ingredient [2].
The complexities of manufacturing biologicals also apply to biosimilars, which are approved on the basis of demonstrating highly similar quality, safety and efficacy to originator biologicals. In attempting to copy the originator product biosimilar manufacturers must independently design their own cell cultures and production steps. This is because the source materials, including the cell lines and the processes by which the original biologicals are made are confidential and may be protected by intellectual property laws, making exact replication of the steps extremely difficult, and typically resulting in structural differences between the products [3].
While many structural differences have no clinical relevance, it is possible that differences in protein folding, structural modifications (such as glycosylation), batch composition, and even the product container may have unexpected impact to the safety or efficacy of the product. For example, a product container contributed to a trend in immunogenicity for EPREX/ERYPO (sold in the EU) starting in 1998. The immunogenicity trend manifested as a sharp increase in the incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease and was ultimately traced to the effects of organic compounds leaching into the pre-filled syringes from uncoated rubber stoppers used by the manufacturer of EPREX/ERYPO. Due to the subtlety of the effect and the latency of the onset of PRCA (in some cases up to nine months after initiation of treatment) it took several years to identify and mitigate the effect of the organic leachate by changing to coated rubber stoppers [4]. Despite this discovery, new cases continue to emerge, generally in clusters. It is believed that the clusters were associated with protein aggregates potentially caused by a variety of factors including drug substance stability, improper handling, or interactions with container leachates [5].
The PRCA incident illustrates the importance of managing unexpected manufacturing events because the issue was not detected before patients were exposed to the impacted product. In many cases, manufacturing issues have been detected and investigated before the product was distributed to patients. These successful examples of managing unexpected events are known to individual manufacturers and to regulatory agencies, but are rarely publicized. Some examples that have been published include:
Changes in glycosylation patterns due to altered cell culture conditions [6]
Altered rates of biochemical modifications to the protein backbone after switching raw material supplier [6]
Turbidity in pre-filled syringes due to interaction of metal leachate with the protein product [7]
A hard-to-detect microbial contaminant that managed to evade cell culture medium filtration and testing programmes [8]
Presence of an impurity in the raw material used for a pegylated protein product [9]
Lack of compliance with cGMP (current good manufacturing practices) affects quality and reliable supply
Manufacturing and quality control issues like those just described can potentially impact patient safety and result in a loss of confidence in the quality of biologicals, but they can also impact to other products manufactured in the facility and cause product recalls and drug shortages, any of which can have profound effects on the company, customers, the biotech industry, providers and patients.
Regulatory agencies in the EU and US have recently emphasized the implications of this dynamic [10, 11]. Officials from the US Food and Drug Administration recently published an article describing quality management failures as a factor in sterile injectable drug shortages:
‘… drug shortages are first and foremost driven by the inability of various firms to maintain production because of the failure of quality management in facilities that produce the finished dosage form of the drug …’,
— J Woodcock and M Wosinska, Center for Drug Evaluation and Research for the US Food and Drug Administration [11].
Although FDA authors refer to the relationship of quality management to shortages of sterile injectable drugs, the issues cited are also relevant to the manufacture of biologicals. Biologicals share some of the same quality control issues with sterile injectables in that the final products are filled in facilities subject to similar stringency of control; but biologicals are, if anything, more susceptible to quality issues due to their relatively high sensitivity to multiple manufacturing steps. The rapidly increasing array of innovative biologicals and biosimilars could increase the chances of unexpected quality issues. These risks can be mitigated with investments in process and facility design, quality control systems, and management oversight, all of which can increase manufacturing reliability. While current market forces may not reward investments in quality and reliability, FDA may explore mechanisms to change this dynamic:
‘… FDA could support the buyers and payers in their purchase and reimbursement decisions by providing them with meaningful manufacturing quality metrics. This general approach has been successfully used in many other settings where quality is difficult to observe or quality signals are difficult to interpret. Restaurant grades, HMO scorecards or even a US Pharmacopeia stamp on vitamins are just a few among many tools that utilize this concept …’ [11].
Recognition of high quality operations could also apply to the biologicals industry, and industry can anticipate this with increased investment in quality systems and sharing of best practices among peer manufacturers.
Sharing best practices in manufacturing and quality
The bioprocessing industry currently shares information about manufacturing challenges and product quality risks via congresses and publications. Regulators often contribute to this by sharing anonymous case studies and by encouraging companies to publish novel findings. For example, after learning of a number of examples of unexpected product quality impact from chemicals leaching from primary containers, FDA published a compilation of these case studies along with recommendations for best practices to evaluate such risks [12]. In furtherance of this objective, Amgen published its experience with a tungsten residual during final production that led to rejection of product during visual inspection [13].
To a large extent this type of sharing focuses on phenomenon with an element of scientific novelty, and it is less common for companies to publish manufacturing challenges and investigations that lack such novelty or that could raise legal issues. This void can be partially filled through participation in technical consortia where case studies and best practices can be shared less formally. Such consortia exist. For example, Rx-360 was established in 2009 to share best practices with raw material and component sourcing in an increasingly global supply chain [14]. With regard to competitive concerns, we would draw a clear distinction between best practices that ensure patient safety and other proprietary information that might, for example, speed production, reduce costs and/or improve output.
High reliability organizations offer a model for the industry
Risks to product quality can be managed with focus on traditional GMP compliance and quality management, but manufacturers can also benefit from the practices of high reliability organizations (HROs). HROs invest in and engage well-trained and experienced support staff and advocate for management cultures that reward, ‘… in-depth analysis of unexpected results, robust risk assessments, and timely and effective implementation of mitigation measures’ [6]. HROs exist where high performance is needed despite overwhelming potential for error and disaster. Examples of HROs in other fields include: nuclear power plants, aircraft carriers, emergency rooms, air traffic control stations, first responder protocols, and wilderness firefighters [15]. While regulators increasingly expect biologicals manufacturers to adapt risk management programmes including some of these behaviors, HROs set a standard for integration and prioritization of these practices that, if more widely adapted, could improve the industry’s reliability and reputation – and further protect patients.
In addition to building a high reliability manufacturing culture, organizations can invest in a comprehensive strategy to reduce supply risks. Such a strategy could include multiple components [16, 17]:
Prevention, e.g. compliance with or exceeding cGMP standards
Technology, e.g. ensuring quality of raw materials using latest detection methods
Inventory, e.g. ensuring adequate stock of drug in the event of natural disaster
Diversification, e.g. multiple plants qualified for drug manufacture
In addition, a successful HRO will educate technical support staff to help orient and inform them so they can respond most effectively to unexpected manufacturing issues and incorporate findings into ongoing risk management. Critical background information includes the product’s history, the current manufacturing environment and any analogous situations that may have been encountered within the company or by other manufacturers. The response team should have senior-level support and have access to the external resources they need, e.g. consultants and analyses; and be authorized to examine every component of the manufacturing process, including in-house laboratories and manufacturing facilities and external vendors and suppliers, with the goal of conducting a focused and thorough investigation on the root causes of the unexpected event and identifying corrective actions [6].
Manufacturers that consistently strive to exceed minimum standards, that invest in supply risk mitigation, and that willingly adapt best practices shared by industry peers could benefit from an enhanced reputation as reliable suppliers.
Conclusion
Biosimilars, like all biologicals, are complex medicines produced in living cells and are highly sensitive to their manufacturing and processing conditions. Because of their complexity and sensitivity biologicals are at increased risk of quality issues compared with traditional drugs and generics, and this can affect the efficacy and safety of these treatments. Active participation in industry consortia where best practices can be shared among peers and a corporate focus on reliability of manufacturing can help minimize the risk and impact of unexpected quality issues, to the benefit of patients and companies.
Acknowledgement
Editorial assistance was provided by Mr Alex Brownstein of BioScience Communications, New York, NY, USA, whose work was funded by Amgen Inc.
Competing interests: Dr Gustavo Grampp and Dr Sundar Ramanan are employees of Amgen Inc and own stock in Amgen Inc.
Provenance and peer review: Not commissioned; externally peer reviewed.
Co-author
Sundar Ramanan, PhD, R & D Policy, Amgen Inc, One Amgen Center Drive, Thousand Oaks, CA, USA.
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document/document_detail.jsp?webContentId=WC500135113&mid=WC0b01ac058009a3dc 11. Woodcock J, Wosinska M. Economic and technological drivers of generic sterile injectable drug shortages. Clin Pharmacol Ther. 2013;93(2):170-6. 12. Markovic I. Evaluation of safety and quality impact of extractable and leachable substances in therapeutic biologic protein products: a risk-based perspective. Expert Opin Drug Saf. 2007;6(5):487-91. 13. Jiang Y, Nashed-Samuel Y, Li C, Liu W, Pollastrini J, Mallard D, et al. Tungsten-induced protein aggregation: solution behavior. J Pharm Sci. 2009;98(12):4695-720. 14. Rx-360: an International Pharmaceutical Supply Chain Consortium [homepage on the Internet]. 2013 [cited 2013 Sep 18]. Available from: http://www.rx-360.org/Home/tabid/38/Default.aspx 15. Weick KE, Sutcliffe KM. Managing the unexpected: resilient performance in an age of uncertainty. 2nd ed. San Francisco: Wiley; 2007. 16. Mica A, Green L. Drug availability: considerations for the hospital pharmacist. Eur J Hosp Pharm. 2012;19:160-1. 17. Mica A, et al. Steps to ensure adequate supply of biological medicines: considerations for the healthcare provider. Generics and Biosimilars Initiative Journal (GaBI Journal) 2013;2(3):136-43. doi:10.5639/gabij.2013.0203.038.
Author for correspondence: Gustavo Grampp, PhD, Director, R & D Policy, Amgen Inc, 4000 Nelson Road, MS AC-27-B, Longmont, CO 80503, USA
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Dr Brian Godman reviews the paper by Markovic-Pekovic et al. regarding recent reforms in the Republic of Srpska. These include prescribing restrictions where concerns with the value of products and measures to obtain low prices for generics, which is important given the rhetoric.
Submitted: 11 June 2013; Revised: 13 June 2013; Accepted: 17 June 2013; Published online first: 24 June 2013
Pharmaceutical expenditure has risen rapidly in the past decade, rising by more than 50% in real terms between 2000 and 2009 among OECD countries [1–5]. This has been driven by well-known factors including ageing populations, rising patient expectations and the continued launch of new premium priced drugs [1–6]. This has resulted in multiple supply- and demand-side measures across Europe to maintain the ideals of comprehensive and equitable health care [1–5]. Supply-side measures incorporate those to lower generics prices. They include prescriptive pricing policies, compulsory international nonproprietary name (INN) prescribing, compulsory generics substitution, transparency in the pricing and distribution of generics and reference pricing (ATC Level 5) with patients covering the additional costs themselves for a more expensive product than the referenced one. Demand-side initiatives incorporate those to encourage the prescribing of generics versus originators and patented products in a class or related class. They include guidelines, formularies, academic detailing, prescribing targets, financial incentives as well as prescribing restrictions [1–5]. The Republic of Srpska, which is one of the two constitutive entities of Bosnia and Herzegovina with a population of 1.43 million, is no different [7].
A reference price system was introduced for generics in the Republic of Srpska in May 2008, with the Health Insurance Fund (HIF) only reimbursing the lowest priced molecule. Patients are required to cover the additional costs themselves for a more expensive molecule than the current reference priced one [7]. This is similar to a number of other European countries [8]. Demand-side measures captured under the 4Es [2, 9] include: Education: Formularies, standard treatment guidelines and encouraging INN prescribing through e-prescribing initiatives; Engineering: Pharmacists obliged to offer patients the cheapest product once generics are available, monitoring the performance of healthcare institutions against prescribing and financial targets; Economics: Financial measures to encourage rational prescribing including INN prescribing; 100% co-payment if the indication prescribed for a drug is different to the permitted one; Enforcement: Rejection of the cost of prescriptions by HIF if the indications are different to the permitted ones (payment either by the pharmacist or patient) [7]. This includes prescriptions with missing indications.
There was decreasing expenditure/defined daily dose (DDD) in each of the three classes studied (proton pump inhibitors (PPIs), statins and renin-angiotensin inhibitor drugs) of up to 82% between 2004 and 2010. This was less for the PPIs as they were only reimbursed in 2008 with the new pricing system for generics. The various measures restricting the prescribing of angiotensin-receptor blockers (ARBs) to patients experiencing unwanted side-effects from angiotensin converting enzyme inhibitors (ACEIs), and only on specialist recommendation, were successful with ARBs constituting only 1.7% of total renin angiotensin inhibitor drug utilisation in 2010 [7]. This was appreciably lower than seen in Austria and Croatia, which also restricted ARB prescribing [5]. This suggests the greater monitoring of ARB prescribing in the Republic of Srpska further reduced their utilization.
Reimbursed expenditure/DDD for omeprazole, simvastatin and enalapril, as well as fixed dose combination (FDC) ACEIs, were similar in the Republic of Srpska to a number of European countries and regions with varying population sizes [7]. There were also similar precentage reductions in expenditure/DDD for the statins and enalpril in the Republic of Srpska compared with other European countries [7]. This, together with the recent findings from Lithuania [10], provides further evidence to counteract claims that countries with smaller populations have difficulties obtaining considerable price reductions for generics [10, 11]. This is an important observation as resource pressures grow with more standard drugs becoming available as generics [1–3].
A number of further measures are planned in the Republic of Srpska following this analysis. These include potentially restricting more expensive generic esomeprazole and pantoprazole to second line; alternatively prescibing targets for omeprazole and lanzoprazole as a percentage of all PPI prescriptions. In addition, potentially restricting the prescribing of FDC ACEIs to patients who have reached their blood pressure target on a combination of single ACEIs and diuretics and pertinent FDC ACEIs are available and reimbursed [7].
In conclusion, this study shows that a country with a small population can introduce a range of supply- and demand-side measures to enhance prescribing efficiency in classes where the products are similar in all or nearly all patients. As a result, providing a stimulus to other European countries to continue to introduce additional measures to maintain comprehensive and equitable healthcare in their countries.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. Godman B, Bennie M, Baumgärtel C, Sovic Brkicic L, et al. Essential to increase the use of generics in Europe to maintain comprehensive healthcare? Farmeconomia: Health Economics and Therapeutic Pathways. 2012;13 (Suppl 3):5-20. 2. Godman B, Wettermark B, Bishop I, Burkhardt T, Fürst J, et al. European payer initiatives to reduce prescribing costs through use of generics. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):22-7. doi:10.5639/gabij.2012.0101.007 3. Godman B, Abuelkhair M, Vitry A, Abdu S, et al. Payers endorse generics to enhance prescribing efficiency; impact and future implications, a case history approach. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):69-83. doi:10.5639/gabij.2012.0102.017 4. Godman B, Shrank W, Andersen M, et al. Comparing policies to enhance prescribing efficiency in Europe through increasing generic utilization: changes seen and global implications. Expert Rev. Pharmacoecon Outcomes Res. 2010;10(6):707-22. 5. Voncina L, Strizrep T, Godman B, Bennie M, et al. Influence of demand-side measures to enhance renin-angiotensin prescribing efficiency in Europe: implications for the future. Expert Rev Pharmacoecon Outcomes Res. 2011;11(4):469-79. 6. Garattini S, Bertele V, Godman B, Haycox A, Wettermark B, Gustafsson LL; Piperska Group. Enhancing the rational use of new medicines across European health care systems. Eur J Clin Pharmacol. 2008;64(12):1137-8. 7. Markovic-Pekovic V, Ranko Škrbic R, Godman B, Gustafsson LL. Ongoing initiatives in the Republic of Srpska to enhance prescribing efficiency: influence and future directions. Expert Rev Pharmacoecon Outcomes Res. 2012;12(5):661-71. 8. Dylst P, Vulto A, Simoens S. Reference pricing systems in Europe: characteristics and consequences. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):127-31. doi:10.5639/gabij.2012.0103-4.028 9. Wettermark B, Godman B, Jacobsson B, Haaijer-Ruskamp F. Soft regulations in pharmaceutical policy making: an overview of current approaches and their consequences. Appl Health Econ Health Policy. 2009;7(3):137-47. 10. Garuoliene K, Godman B, Gulbinovic J, Wettermark B, Haycox A. European countries with small populations can obtain low prices for drugs: Lithuania as a case history. Expert Rev Pharmacoecon Outcomes Res. 2011;11(3):343-9. 11. McKee M, Stuckler D, Martin-Moren J. Protecting health in hard times. BMJ. 2010;341:c5308.
Author: Brian Godman, BSc, PhD, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK; Liverpool Health Economics Centre, University of Liverpool, Liverpool, UK
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
GaBI Journal is an independent and peer reviewed academic journal. GaBI Journal encompasses all aspects of generic and biosimilar medicines development and use, from fundamental research up to clinical application and policies.
