Biosimilars in Germany: guidance of the Drug Commission of the German Medical Association

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Abstract:
Biosimilars have been available in Europe for more than 10 years, but their adoption in Germany has not been very successful. As their pharmaceutical quality, efficacy (particularly in extrapolated indications), safety (especially immunogenicity) and interchangeability with reference products have been controversially discussed by healthcare professionals, the Drug Commission of the German Medical Association developed a practical guidance for the therapeutic use of biosimilars.

Introduction

Biosimilars (biosimilar medicines) have been available in Europe for more than 10 years, which has made it possible to gain practical experience with these products, particularly in oncology, rheumatology and gastroenterology.

Nevertheless the adoption of biosimilars in Germany has not been very successful and still faces many concerns voiced by physicians about their pharmaceutical quality, efficacy (particularly in extrapolated indications), safety (especially immunogenicity) and interchangeability with the originator product [1]. These misconceptions cannot be explained medically or scientifically. The uptake of biosimilars in Germany has not been very high to date, as no approved biosimilar has achieved complete or at least high market penetration, even after 10 years of availability [2].

Position of the Drug Commission

In 2008, the Drug Commission of the German Medical Association (Drug Commission) released a statement about biosimilars, pointing out that they can be considered a therapeutic alternative to the reference (originator) products [3].

Given that the first biosimilar of a monoclonal antibody, i.e. infliximab (Remsima®, Inflectra®), was approved in 2013 and the patents of many bestselling biologicals have already expired or will expire in the next few years, German physicians will continue to be confronted with an ever-increasing number of biosimilars in the near future [4].

As the substitution of biosimilars at the pharmacy level is not permitted in Germany, physicians are in the key position to increase the use of biosimilars. Therefore, physicians’ information and education are the most critical factors impacting the integration of biosimilars into the treatment practice.

The Drug Commission has revised its statement to develop practical guidance for the therapeutic use of biosimilars. This guidance aims to acquaint clinicians with the concept of biosimilars. Furthermore, it provides an overview of the scientific principles guiding biosimilar development and regulatory requirements and also outlines the differences between biosimilars and generic medicines. The extrapolation procedure is also highlighted, as it seems that there is not a thorough understanding of it among all physicians. Topics such as pharmacovigilance and immunogenicity are also addressed [5].

Particular attention was paid to the interchangeability of reference products and biosimilars. Switching from the reference products to biosimilars in patients who have already been treated with a biological medicine has been introduced on the basis of available switch studies focused on efficacy and safety, which demonstrated no (significant) differences between the patients who were switched and those who were maintained.

Guidance summary

The Drug Commission summarized the central points of its guidance to respond to the most frequently voiced concerns about biosimilars. Understanding the specifics of biological and biosimilar medicines and their manufacturing process and approval is crucial for the assessment of biosimilars.

Biological medicines are large, complex molecules (proteins) produced in living organisms, mostly by biotechnology. As biological medicines are manufactured in living cells or organisms, the final products regularly have the same amino acid sequence, but an inherent degree of minor variability (microheterogeneity), e.g. in glycosylation [1, 6]. Every single batch of a biological medicine is highly similar, but not identical to the other batches of the same biological medicine. Minor variability is often seen after changes in the manufacturing process. In the case of Remicade® (infliximab), there have been more than 30 changes in the manufacturing process since its approval in the EU in 2002 [7]. The version of Remicade® which is currently available is therefore highly similar (biosimilar), but not identical to the Remicade® used in the pivotal studies.

Minor variability does not critically affect the efficacy and safety of biological medicines as long as it is within an acceptable range defined during the approval process. Minor variability is constantly monitored using analytical tests, which are usually more sensitive than clinical studies in terms of detecting structural and functional differences. Following changes in the manufacturing process, companies producing biological medicines must continuously ensure that the post-change batches are as efficacious and safe as the pre-change batches. To date, there have been no cases of a biological medicine with minor variability within the acceptable range resulting in differences negatively affecting clinical efficacy and safety [1]. The scientific principle of comparability is also applied for the approval of biosimilars.

A biosimilar is a biological medicine containing a version of the active substance of an already approved biological medicine (reference product). Biosimilarity is established based on the totality of evidence from physicochemical, structural and functional tests, as well as from clinical studies (comparability exercise) [8, 9]. The scientific principles used are the same as those applied to demonstrate comparability after a change in the manufacturing process of an already licensed biological medicine [8, 9]. The designation ‘highly similar’ marks the acceptable range for minor variability in biosimilars in the same way it does for every post-change batch of a reference product.

The first biosimilar in the European Union (EU) was approved in 2006. Over 10 years of clinical experience with biosimilars have not revealed any clinically meaningful differences between biosimilars and reference products in terms of clinical efficacy and the type, severity and incidence of side effects. In August 2017, there were 35 approved biosimilars in the EU and 24 of them are already available in Germany [10].

Drug Commission’s perspective: FAQs about biosimilars

1. Are there any differences between biosimilars and reference products with regard to quality, efficacy and safety?
Biosimilars are developed and approved in the EU according to scientifically sound principles and carefully monitored to ensure their pharmaceutical quality. The strict requirements for establishing biosimilarity are the same as those applied for demonstrating comparability after a change in the manufacturing process of already approved biological medicines. As the therapeutic efficacy and safety of biosimilars are comparable to the therapeutic efficacy and safety of their reference products, biosimilars offer a safe and efficacious alternative to originator biologicals. Functionally irrelevant differences (minor variability) are not higher within biosimilars than they are within different batches of reference products. Over 10 years after the approval of the first biosimilar in the EU, no important differences between biosimilars and reference products have been demonstrated.

2. Should biosimilars, when available, be given to treatment-naïve patients?
Biosimilars and reference products are therapeutically comparable. Biosimilars can be prescribed with consideration of the approved indications, the availability of an adequate mono-dose formulation to avoid costs associated with drug disposal and the availability of suitable pharmaceutical preparations (pre-filled pens or syringes or powder for solution for injection).

3. Should patients already treated with a biological medicine be switched to a biosimilar, when available?
With regard to switching between reference products and biosimilars, the Drug Commission adheres to its opinion from 2008. Switching is possible when followed by adequate clinical monitoring. The same clinical aspects taken into account for treatment-naïve patients should also be considered before switching. All switch studies have confirmed the therapeutic equivalence of biosimilars and reference medicines [11].

4. Should biosimilars be used in approved indications for which no clinical studies have been conducted?
The pivotal studies with biosimilars do not aim to establish the clinical efficacy of the active substance per se, as this has already been done for the reference product. Clinical studies are carried out to examine the biosimilar product and to ensure that there are no clinically meaningful differences between the biosimilar and the reference product which negatively affect efficacy, safety and immunogenicity. For this purpose, an indication of the reference product is chosen, which is most suitable for detecting any differences in therapeutic effect. The scientific principles of data extrapolation used for biosimilars approval are not a special arrangement for biosimilars, as extrapolation occurs also with other regulatory procedures as, e.g. when establishing line extensions. The comparability exercise used to evaluate the biosimilarity of a biological investigational medicinal product (IMP) is the same as that applied to establish comparability following changes in the manufacturing process of all biological medicines. Therefore, biosimilars can be considered therapeutically comparable to their reference products in all approved indications [9].

5. What should be taken into consideration when monitoring therapy with biosimilars?
There are basically no differences between the pharmacovigilance of biosimilars and their reference products. Spontaneous reporting of suspected side effects is crucial for the monitoring of the medicines’ safety. As biologicals are highly complex drugs manufactured in living cells resulting in a minor degree of variability, traceability is an important issue for both reference medicines and for biosimilars. If patients treated with biological medicines, regardless of whether they are originator biologicals or biosimilars, experience side effects, the brand name and batch number should be reported to guarantee the traceability of the product in the case of safety issues.

6. What should German statutory health insurance (SHI)-contracted physicians consider when prescribing biosimilars?
Twenty-four biosimilars are already available in Germany and can be prescribed by SHI-contracted physicians. Biosimilars are usually cheaper than reference products. It has already been shown that the availability of biosimilars strengthens economic competition in the pharmaceutical market and provides opportunities for cost reduction [12, 13]. This supports the financial sustainability of the national solidarity-based health insurance system in Germany. The prescribing of any given medicine in Germany must adhere to the efficiency principle based on § 12 SGB V (Social Code V, § 12). This also applies when prescribing biosimilars. In order to increase the uptake of biosimilars, regional target agreements were concluded. Regional biosimilar prescription quotas should assist German physicians to improve prescribing efficiency.

7. How could patients be involved when prescribing biosimilars?
A major point to consider when prescribing biosimilars or switching between reference medicines and biosimilars should be to ensure that the patients are well-informed. This is supported by independent publications, e.g. by the European Medicines Agency (EMA) or the European Commission [6]. To ensure patients’ adherence to therapy, it is crucial to respect and to address any fears and concerns they may have. Following the recommendations in this guidance will help to improve access to biological therapy and reduce costs. The decision to use biosimilars in treatment must be made by a physician. From the Drug Commission’s perspective, the use of biosimilars requires detailed patient information and consultation in addition to the consideration of approved indications, availability of an adequate mono-dose formulation and suitable pharmaceutical preparations. In light of the fact that a non-medical switch or an automatic substitution (which is not permitted in Germany) could not satisfactorily fulfil these requirements, the Drug Commission strongly rejects this procedure.

The future: perspectives and challenges

The mission of the Drug Commission is to provide physicians with independent, scientific information about medicines. By emphasizing the relevance of biosimilars for the sustainability of the healthcare system, the Drug Commission aims to assure German physicians of the benefits of biosimilars.

Biosimilars offer a safe and efficacious therapeutic alternative to originator biologicals. There is plenty of evidence supporting the use of biosimilars in clinical practice and there are no grounds to believe that the use of biosimilars carries more risk than the use of reference biologicals. To date, no data have been published revealing any disadvantages of biosimilars either when starting therapy or when switching patients from reference medicine to a biosimilar. Switch studies have not indicated any reasons for physicians not to prescribe biosimilars.

Biosimilars approved in the EU and used for years have proven to be safe and efficacious. Bridging the information gap on biosimilars should minimize unfounded fears and concerns among clinicians to assist them in making evidence-based, appropriate and cost-effective treatment choices for their patients. As healthcare costs are constantly rising in Germany, biosimilars offer an opportunity to reduce costs without compromising the right of German patients to efficacious and safe medicines in a national solidarity-based health insurance system. Assisting physicians to get acquainted with biosimilars could effectively and consistently deliver the best health care for patients while retaining physicians’ freedom to prescribe.

Competing interests: None.

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

Authors

Stanislava Dicheva, PhD, Arzneimittelkommission der deutschen Ärzteschaft, 1 Herbert-Lewin-Platz, DE-10623 Berlin, Germany

Professor Wolf-Dieter Ludwig, MD, PhD, Arzneimittelkommission der deutschen Ärzteschaft, 1 Herbert-Lewin-Platz, DE-10623 Berlin, Germany

References
1. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Giezen TJ, Gravanis I, Heim HK, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111-7.
2. Schwabe U, Paffrath D. Arzneiverordnungen 2015 im Überblick. In: Schwabe U, Paffrath D, editors. Arzneiverordnungs-Report 2016. Berlin: Springer-Verlag; 2016. p. 13-7.
3. Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ). Stellungnahme der Arzneimittelkommission der deutschen Ärzteschaft zu Biosimilars [homepage on the Internet]. [cited 2017 Oct 9]. Available from: http://www.akdae.de/Stellungnahmen/Weitere/20081209.pdf
4. Patent expiry dates for best-selling biologicals. Generics and Biosimilars Initiative Journal (GaBI Journal. 2015;4(4):178-9. doi:10.5639/gabij.2015.0404.040
5. Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ). Arzneimittelkommission der deutschen Ärzteschaft. Leitfaden ‘Biosimilars’, 1. Auflage (August 2017) [homepage on the Internet]. [cited 2017 Oct 9]. Available from: https://www.akdae.de/Arzneimitteltherapie/LF/Biosimilars/index.html
6. European Medicines Agency. European Commission. Biosimilars in the EU: information guide for healthcare professionals [homepage on the Internet]. [cited 2017 Oct 9]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf
7. Vezer B, Buzas Z, Sebeszta M, Zrubka Z. Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents. Curr Med Res Opin. 2016;32(5):829-34.
8. European Medicines Agency. Guideline on similar biological medicinal products. CHMP/437/04 Rev 1. 23 October 2014 [homepage on the Internet]. [cited 2017 Oct 9]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf
9. Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191-6.
10. European Medicines Agency. Multidisciplinary: biosimilar [homepage on the Internet]. [cited 2017 Oct 9]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c
11. Kurki P, van Aerts L, Wolff-Holz E, Giezen T, Skibeli V, Weise M. Interchangeability of biosimilars: a European perspective. BioDrugs. 2017;31(2): 83-91.
12. QuintilesIMS. The impact of biosimilar competition in Europe [homepage on the Internet]. May 2017 [cited 2017 Oct 9]. Available from: http://www.medicinesforeurope.com/wp-content/uploads/2017/05/IMS-Biosimilar-2017_V9.pdf
13. Improving access to biosimilars in low-income countries. Lancet. 2017;389(10082):1860.

Author for correspondence: Stanislava Dicheva, PhD, Arzneimittelkommission der deutschen Ärzteschaft, 1 Herbert-Lewin-Platz, DE-10623 Berlin, Germany

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2018 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Last update: 12/04/2022

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New product-specific bioequivalence guidance

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Abstract:
For harmonization of the authorization requirements for specific generic applications within the EU, consistent criteria were drafted for 16 active substances, which are out now for public consultation.

Submitted: 2 January 2014; Revised: 6 January 2014; Accepted: 7 January 2014; Published online first: 20 January 2014

Official draft guidance has recently become available for 16 new active substances that have either lost patent protection, will imminently lose it, or whose data-protection period has recently expired. The guidance establishes which criteria should be used when investigating the bioequivalence of a certain generic drug to its originator for these 16 substances.

The so-called product-specific bioequivalence guidance was published on 15 November 2013 [1], after development by the Pharmacokinetics Working Party (PKWP) of the European Medicines Agency (EMA), links to the published product-specific bioequivalence guidances (PSBEGS) can be found on the EMA website [2, 3].

By clearly stating which criteria should apply to these active substances, problems that have repeatedly led to questions and uncertainties during product development and application for marketing authorization can be avoided in the future.

Clearer guidance can sometimes resolve controversial issues: for example, establishing for distinct substances which strength of medicine is suitable and should be investigated in a bioequivalence trial; determining whether a study should be conducted in a fasted or fed state so that it is clear whether individuals participating in a trial should take medicines with food; or, instead of conducting a bioequivalence trial, a waiver using the biopharmaceutics classification system approach can be applied, which means that in vitro data will mainly suffice.

Product-specific bioequivalence guidance will make it clear for applicants whether the conventional bioequivalence criteria of 80–125% should apply, whether the 90–111% interval is required, or, in the case of highly variable drugs, a broadened acceptance margin of up to 70–143% may be chosen. Additionally, it will become clear if the parent of an active substance has to be measured in the plasma or the metabolite, or even both. It will also distinguish when it is appropriate to use healthy volunteers in a trial compared with patients.

The aim of product-specific bioequivalence guidance is to rationalize the criteria applied to substances in the authorization process, thereby giving companies more planning security when drafting an application, including the planning and carrying out of bioequivalence studies. It also gives the EU and all European national medicines authorities a single harmonized view on which criteria are deemed well founded and necessary for market authorization of generics with certain active substances.

Interested parties and stakeholders can forward comments on each of these active substances to pkwpsecretariat@ema.europa.eu on or before 15 February 2014.

The 16 published product-specific bioequivalence guidance substances are as follows:
– Capecitabine
– Carglumic acid
– Dasatinib
– Emtricitabine/Tenofovir
– Erlotinib
– Imatinib
– Memantine
– Miglustat
– Oseltamivir
– Posaconazole
– Repaglinide
– Sirolimus
– Sorafenib
– Tadalafil
– Telithromycin
– Voriconazole

As a member of EMA PKWP that drafted the guidance, I fully support this initiative, which is the first of its kind and highly essential for pharmaceutical companies. We are actively encouraging participation of stakeholders during the consultation process. Please use this opportunity to comment on the 16 draft guidelines.

Competing interests: None.

Provenance and peer review: Commissioned; internally peer reviewed.

References
1. GaBI Online – Generics and Biosimilars Initiative. EMA releases product-specific bioequivalence guidelines [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Jan 6]. Available from: www.gabionline.net/Guidelines/EMA-releases-product-specific-bioequivalence-guidelines
2. European Medicines Agency. EMA promotes consistent development of bioequivalence studies through product-specific guidance [homepage on the Internet]. 2013 Nov 11 [cited 2014 Jan 6]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/11/news_detail_001958.jsp&mid=WC0b01ac058004d5c1
3. European Medicines Agency. Clinical efficacy and safety: clinical pharmacology and pharmacokinetics [homepage on the Internet]. [cited 2014 Jan 6]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000370.jsp&mid=WC0b01ac0580032ec5

Author: Christoph Baumgärtel, MD, MSc, Department Head, Department Safety and Efficacy Assessment of Medicinal Products, Institute Marketing Authorisation of Medicinal Products & LCM, AGES MEA–Austrian Medicines and Medical Devices Agency, and Austrian Federal Office for Safety in Health Care (BASG), European Expert in Pharmacokinetics Working Party of EMA, Member of Austrian Prescription Commission, 5 Traisengassee, AT-1200 Vienna, Austria

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2014 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Last update: 14/02/2019

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Update on clinical practice guideline on the use of epoetin and darbepoetin in adult patients with cancer

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Abstract:
Chemotherapy-induced anaemia can be treated using erythropoiesis-stimulating agents (ESAs), but these can cause serious side-effects including tumour progression, venous thromboembolism, and shorter survival. Following extensive review of recent literature, the American Society of Clinical Oncology and the American Society of Hematology have updated their guidelines on the use of ESAs. New recommendations include minimising the use of ESA in patients receiving chemotherapy with curative intent.

Cancer patients with chemotherapy-induced anaemia have two treatment options for boosting their haemoglobin (Hb) levels: blood transfusion or the use of erythropoiesis-stimulating agents (ESAs). Both have advantages and disadvantages, so to help physicians navigate their way through treatment decisions, the American Society of Clinical Oncology and the American Society of Hematology have collaborated to update an earlier Clinical Practice Guideline on the use of epoetin and darbepoetin in adult patients with cancer [1].

The original publication of 2002 was updated in 2007 following the availability of more information on risks associated with ESAs. The latest (2010) update gives recommendations for the use of ESAs, and also summarises evidence on their effectiveness at reducing transfusions and increasing Hb and reviews the latest evidence on ESA-associated tumour progression, venous thromboembolism, and/or survival. It involved a literature review with one new individual patient data analysis, four meta-analyses, two systematic reviews, and 13 new reports of randomised controlled trials, including through searching MEDLINE and the Cochrane Collaboration Library.

The 2010 update is available, together with a patient guide and other clinical tools and resources at www.asco.org/guidelines/esa and www.hematology.org/guidelines/esa

Overall, the 2010 guideline confirms that ESA therapy is associated with shorter survival and/or increased risk of tumour progression and recurrence—in addition to the previously highlighted increased risk of thromboembolism. The 2010 guideline recommends that for patients receiving myelotoxic chemotherapy with an Hb level of less than 10 g/dL, physicians should discuss with them the potential risks and benefits of ESAs compared to the potential harms and benefits of transfusion. Transfusion carries a risk of serious infections and immune-mediated adverse events, but offers the benefit of a rapid rise in Hb levels. Patient preference should be taken into account in the final decision on treatment, the updated guideline cautions against using ESA under all other circumstances.

Specific recommendations

I General recommendation
The 2010 update includes the general recommendation that alternative causes of anaemia aside from chemotherapy or other underlying haemopoietic malignancy be explored before ESA treatment commences. Physicians should also aim to minimize the use of ESA in order to reduce the risk of thromboembolism, ‘particularly in patients with malignancy being treated with curative intent.’

The US Food and Drug Administration FDA labelling indicates the use of ESAs in patients receiving chemotherapy for palliative intent, in order to reduce the need for transfusions. FDA does not recommend treatment with ESAs for patients receiving curative chemotherapy because of an increased risk of mortality and thromboembolism. The 2010 update notes, however, that because the evaluation of risks versus benefits has not been done according to subgroups with different chemotherapy intent, i.e. curative versus palliative, clinical judgement is required to determine the goal of treatment for individual patients. The update states, ‘Clinicians are urged to exercise caution in considering ESA use in patients with malignancy being treated with curative intent. The Update Committee stresses the importance of including a detailed discussion between healthcare providers and their patients about the potential harms and benefits of ESA therapy.’

The 2010 update gives examples of diseases for which the treatment goal should be curative: testicular cancer, first-line therapy of Hodgkin’s disease, and early stage breast, lung, or colon cancer.

The 2010 update also summarizes the evidence showing both a statistically significant increased risk of mortality and thromboembolism, and the reduced need for transfusions, with ESA treatment.

II Special commentary on the comparative effectiveness of epoetin and darbepoetin
Regarding the comparative effectiveness of epoetin and darbepoetin, the position remains unchanged since 2007 that these agents are considered to be equivalent with respect to safety and efficacy.

IIIa Chemotherapy-induced anaemia: threshold for initiating ESA therapy
The 2010 update recommends, in accordance with FDA-approved labelling, the use of epoetin or darbepoetin in patients with chemotherapy-induced anaemia and whose Hb concentration has fallen to below 10 g/dL, in order to decrease the requirement for transfusions. The question of threshold, however, ‘merits further investigation’, as the 2010 Update Committee found evidence insufficient for recommending ESA treatment for patients with Hb concentrations higher than 10 g/dL, or any associated increase in harms associated with doing so.

IIIb Chemotherapy-induced anaemia: initiating when Hb is > 10 g/dL but < 12 g/dL
Clinical judgement is needed to decide when to commence ESA treatment in patients with anaemia whose Hb concentration is between 10 and 12 g/dL, as well as consideration of the risks, benefits, and goals of ESA treatment. The goal of such treatment remains the reduction of transfusions, rather than to improve quality of life, for which the evidence remains insufficient.

IV Thromboembolytic risk
The 2010 update confirms the 2007 guideline that the use of ESAs leads to a statistically significant increased risk for thromboembolism. The 2010 update, therefore, recommends that clinicians should carefully weigh the risk of thromboembolism in patients when prescribing ESAs.

V Starting and modifying doses
The 2010 update recommends following FDA guidelines, for example, starting epoetin at a dose of 150 U/g three times a week or 40,000 U weekly subcutaneously, and increasing or reducing the dose, or discontinuing, according to the outcome in terms of reduction of transfusions and Hb levels achieved.

VI Discontinuing therapy for no response
The 2010 update repeats the recommendations of 2007 that ESA treatment be discontinued in patients who do not respond within six to eight weeks.

VII Hb target
Given the evidence that ESA treatment leads to an increased risk in mortality, which has become more apparent since 2007, the 2010 update recommends that treatment aims to increase Hb to ‘the lowest concentration needed to avoid transfusions, which may vary by patient and by condition’. The available data do not identify a specific target Hb concentration for ESA therapy that is free from an increased risk of mortality.

VIII Iron monitoring and supplementation
As in 2007, the 2010 update suggests that patients should be monitored for iron status, including iron levels and iron-binding capacity, and treated with iron supplements where necessary. There is insufficient evidence to support intravenous iron therapy.

IX Anaemia in patients not receiving concurrent chemotherapy
As for the 2007 guideline, the 2010 update continues to recommend that ESA treatment should be limited to patients undergoing concurrent chemotherapy, and that treatment should be discontinued when patients complete their chemotherapy course.

X Treatment of anaemia in patients with non-myeloid haematologic malignancies who are receiving concurrent chemotherapy
As in 2007, the 2010 update recommends that before considering use of ESAs, physicians should first observe the outcomes of chemotherapy and/or corticosteroids in patients with myeloma, non-Hodgkin’s lymphoma, or chronic lymphocytic leukaemia. Treatment with ESAs should commence only if there is no increase in Hb in these patients.

In its conclusions, the 2010 update calls for additional research to ‘clarify the mechanisms of harm and, particularly, the groups of patients or circumstances of clinical use that are least associated with these risks’. The authors add, ‘This understanding is paramount to the ability of clinicians to extend the benefit of these drugs while reducing the risks.’

Competing interests: None.

Provenance and peer review: Article prepared based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Editor’s comments

These guidelines, is based on a comprehensive literature review, conclude that the particular erythropoiesis-stimulating agents mentioned can be considered equivalent choices.

Julie Clayton, PhD, GaBI Journal Editor

Reference
1. Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Somerfield MR, Temin S. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Oncol Pract. 2010 Nov;6(6):317-20. doi:10.1200/JOP.2010.000132

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2013 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Biosimilars in oncology: current and future perspectives

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EORTC continues to support the appropriate treatment of adult patients with G-CSF to prevent febrile neutropenia: guideline updates

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Abstract: 
The European Organisation for Research and Treatment of Cancer (EORTC) has updated its 2006 guideline on the use of granulocyte colony-stimulating factor (G-CSF) for the prevention of febrile neutropenia (FN), a sometimes fatal condition in which a loss of neutrophils in patients receiving chemotherapy leads to infections and fever. The guideline provides recommendations on the assessment of risk factors for FN, and the choice of G-CSF formulation.

Submitted: 4 February 2013; Revised: 6 February 2013; Accepted: 7 February 2013; Published online first: 12 February 2013

Background

Patients undergoing chemotherapy for cancer are at risk of developing febrile neutropenia (FN), a condition in which a loss of neutrophils leads to infection, fever and sepsis, and is fatal in 9.5 to 12.5 per cent of cases. Patients aged over 65, and those undergoing myelosuppressive therapy appear to be most at risk, and may have their chemotherapy delayed, or treatment doses reduced, to minimize the effects of FN. As a consequence, they are then more prone to treatment failure and poorer clinical outcome with regard to their cancer, particularly solid tumours and lymphoma.

Prophylactic treatment is available in the form of G-CSF, which boosts and replenishes the body’s supply of neutrophils. This preventive measure reduces hospital admissions, antibiotic use and the need for dose-reduction. Treatment can be with one of several approved forms of recombinant G-CSF, including filgrastim and its biosimilars, or the pegylated version of filgrastim. All three are considered equivalent in clinical efficacy and safety. Their use, however, requires caution, and needs to be limited to patients who are deemed to be most at risk of FN.

To help guide the decision-making process for managing patient treatment and care, EORTC set up a working party in 2005 to systematically review available data and derive evidence-based recommendations on the most appropriate way to use G-CSF in adult patients undergoing chemotherapy. This European Guidelines Working Party published its first set of recommendations in 2006. These guidelines were revised in 2010 following a new systematic review owing to several developments, including the understanding of the factors that predispose patients to the onset of FN, and the availability of new models for assessing risk [1].

Issues considered for the guideline updates

The updated guideline, which is intended to complement the previously published European Society for Medical Oncology (ESMO) guideline on the use of G-CSF for prevention of chemotherapy-induced FN in patients with cancer, takes into account a range of issues regarding different potential risk factors that affect the likelihood of patients developing FN.

Febrile neutropenia is defined as an absolute neutrophil count of < 0.5 x 109/L, or 1.0 x 109/L predicted to fall below 0.5 x 109/L within 48 hours, with fever or clinical signs of sepsis. Fever is defined as a rise in auxiliary temperature to > 38.5°C sustained for at least one hour.

Among the issues considered for the guideline update was the assessment of risk that a patient will develop FN. Risk factors which affect the likelihood of this include the tumour type, chemotherapy regime such as the type, frequency and dosage of chemotherapeutic agents, and patient-related factors such as whether they have experienced FN previously. Various risk indices are available for assessing who is most likely to develop FN, including that produced by the Multinational Association for Supportive Care in Cancer (MASCC) in which a score of 21 or above indicates low risk.

There is consensus that treatment with G-CSF should be given to a patient with solid tumour or lymphoma if their risk goes above a threshold of 20 per cent, according to guidelines from Canada, Europe (EORTC and ESMO) and USA (American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN)).

Another issue that clinicians have to contend with is whether or not to give prophylactic antibiotic medication instead of, or in combination with, G-CSF. Caution is generally stressed with regard to antibiotics owing to the need to minimize the development of antibiotic resistant infections. G-CSF may therefore appeal as an alternative way to minimize the risk of infections and fever in patients undergoing chemotherapy, but then clinicians must weigh up the potential adverse effects of G-CSF treatment. These include a small risk that patients may develop secondary cancer, such as myelodysplastic syndrome, acute myeloid leukaemia, or acute lymphoblastic leukaemia.

Updating the guideline involved a new review of literature published between 2006 and July 2009, on studies concerning adults aged 18 and over, with solid tumours or lymphoma, as well as evidence presented at meetings held between April 2006 and December 2009. EORTC also took into account the 2009 NCCN and 2006 ASCO guidelines.

Summary of the 2010 EORTC guideline updates

Recommendation 1: patient-related risk factors for increased incidence of FN and complications of FN
The updated guideline confirms that patients are at increased risk of FN if the patient:

  • is aged 65 years or over
  • is at an advanced stage of disease
  • has had previous experience of FN
  • has had prior chemotherapy or has intense chemotherapy scheduled.

The recommendations on the process of evaluating risk factors remain in line with previously published guidelines.

Recommendation 2: chemotherapy regimens associated with increased risk of FN
New targeted agents added to chemotherapy regimens can exacerbate myelosuppression and hence febrile neutropenia, for example, in patients with non-small cell lung cancer given cetuximab or bevacizumab. The updated guideline lists some of the various drug combinations that have a potentially elevated risk of FN and note that, ‘Consideration should be given to the elevated risk of FN when using certain chemotherapy regimens.’ Furthermore, they stress, ‘this list is not comprehensive and there may be other drugs or regimens associated with an increased risk of FN.’

Recommendation 3: G-CSF to support intensive chemotherapy regimens
Based on consistent findings in the more recent literature, the updated guideline continues to support the use of prophylactic G-CSF to facilitate the delivery of dose-dense (increased frequency) and dose-intense (increased dose) chemotherapy in an attempt to improve long-term clinical outcomes. This is particularly recommended when more frequent and intensive chemotherapy is likely to have survival benefits.

Recommendation 4: impact of the overall FN risk on G-CSF use
Recent literature confirms the benefits of G-CSF treatment for preventing FN in patients with a wide range of malignancies, including breast cancer and lymphoma. Physicians should assess the patient’s risk for FN case-by-case in order to make treatment decisions, taking into account patient-related risk factors, the chemotherapy regimen and associated complications and treatment intent. This should be done at the beginning of each treatment cycle. Recent studies confirm that G-CSF has clinical benefits for patients whose FN risk is equal to, or greater than, 20 per cent. The authors note, however, that this guidance is not intended to supersede national guidelines.

Recommendation 5: G-CSF in patients with existing FN
There are only a limited number of sufficiently powered studies on the effects of G-CSF treatment in patients with an ongoing episode of FN. The EORTC guideline update, in line with ASCO, continues to recommend that ‘Treatment with G-CSF for patients with solid tumours and malignant lymphoma and ongoing FN is indicated only in special situations. These are limited to those patients who are not responding to appropriate antibiotic management and who are developing life-threatening infectious complications (such as severe sepsis or septic shock).’

Recommendation 6: choice of formulation
The updated guideline recommends the use of filgrastim and lenograstim (daily injections) and pegfilgrastim (once per cycle administration) to prevent FN and FN-related complications, where indicated. Filgrastim biosimilars are also included in this recommendation.

In conclusion, the 2010 update of EORTC guideline aims to help optimise local protocols and patient management strategies in hospitals across Europe, in order to improve patient care and clinical outcomes.

Competing interests: None.

Provenance and peer review: Article prepared based on published scientific or research papers recommended by members of Editorial Board; internally peer reviewed.

Editor’s comments

The EORTC guideline is based on a comprehensive literature review, and concludes that all three G-CSF’s are considered therapeutic equivalent choices.

Julie Clayton, PhD, GaBI Journal Editor

Reference
1. Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocytecolony-stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 47 2011;47(1):8-32.

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2013 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Last update: 03/10/2016

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New CHMP guideline on immunogenicity of monoclonal antibodies

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Author byline as per print journal: Robin Thorpe, PhD, FRCPath; Meenu Wadhwa, PhD

Abstract:
The importance of monoclonal antibodies as a product class and the challenge of assessing unwanted immunogenicity for these products have prompted the drafting of a new CHMP (Committee for Medicinal Products for Human Use) guideline. The ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’ is intended as an annex to the existing general immunogenicity guideline. This guidance in conjunction with other relevant CHMP guidelines should assist manufacturers and regulators who are involved with producing or assessing marketing authorization applications for monoclonal antibody products.

Submitted: 4 February 2013; Revised: 6 February 2013; Accepted: 7 February 2013; Published online first: 12 February 2013

Unwanted immunogenicity remains a major concern for biological products including biosimilars. Assessing the immunogenicity of biologicals and the possible clinical consequences of this is a considerable challenge and requires carefully planned, prospective immunogenicity studies, conducted using appropriate patient groups. Regulatory guidance on this has been published by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) (Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins; EMEA/CHMP/BMWP/14327/2006). This guideline, which came into effect in 2008, has been used by manufacturers of biologicals and regulators especially at the marketing authorization stage of regulatory product approval. Although it has been generally well received, one criticism of it is that it is ‘too general’ and does not provide specific guidance for particular products or classes of products. The latter point is indeed true, as the guideline was intentionally drafted to provide general guidance relating to all biological products. Drafting guidelines dealing with immunogenicity issues for specific products is possible, but has been considered unnecessary or even undesirable. It would be a major task to produce specific guidelines covering the very wide range of biological products now being produced or in development and there would be much overlap in the content of many of the specific guidelines as several aspects of unwanted immunogenicity are common to all biologicals. But, in some cases there are issues that affect some products more than others or are different for different biologicals. Normally, this has to be dealt with on a case-by-case basis. However, in some cases for specific products or product classes, generalities pertaining to their immunogenicity may apply, which may merit the preparation of specific immunogenicity guidelines. One such large class of products is monoclonal antibodies (mAbs). This is clearly a very important class of biotherapeutics and in vitro diagnostics, for which there are several approved products in the EU and elsewhere; many more are in development.

In view of this situation, and following internal and external consultation, the decision was taken to draft a mAb specific CHMP immunogenicity guideline. This guidance, titled ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’ (EMA/CHMP/BMWP/86289/2010) has now been adopted by CHMP (again following public consultations) and came into effect in December 2012. It is intended as an addendum to the ‘Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins’ (EMEA/CHMP/BMWP/14327/2006), i.e. that it should be read in conjunction with the general guideline. The new guideline includes sections addressing problems experienced with screening and confirmatory assays used in assessing immunogenicity of mAbs (assays for antibody detection, presence of mAb product in samples for analysis, confirmatory assays and controls), assessment of the neutralising capacity of antibodies induced against mAbs and considerations on immunogenicity risk management of mAbs (risk identification, risk management and risk monitoring and mitigation). The guideline concentrates on specific issues, problems and technicalities that relate to mAbs and products that have similarities to mAbs, such as IgFc fusion proteins. However, some parts of the guideline contain useful information that can also apply to other biologicals. The new immunogenicity of mAbs guideline will apply to all mAbs, including biosimilar mAbs, but treats biosimilars as just a subclass of biologicals (which they clearly are) with no specific requirements from the immunogenicity perspective. This follows the approach taken in the ‘Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins’.

However, immunogenicity assessment for biosimilars does differ in one important aspect from immunogenicity assessment of stand-alone biologicals, as comparative immunogenicity, which is an essential element of the comparability studies, has to be assessed for the candidate biosimilar and the innovator (reference) product. Non-clinical and clinical issues relating to biosimilar mAbs are addressed in another new guideline, ‘Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues’ (EMA/CHMP/BMWP/403543/2010); which includes sections that address these aspects of immunogenicity for biosimilar mAbs. This guideline is specific to the mAb product class and therefore needs to be read alongside the ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’. Of note, the biosimilar mAb guideline does not reflect on the quality aspects of mAbs as a guideline dealing with this particular aspect is already in place (Guideline on development, production, characterization and specifications for monoclonal antibodies and related products; EMEA/CHMP/BWP/157653/2007) although this does not include any considerations for specific assessment of immunogenicity of biosimilars (this was not thought to be necessary at the time when the guideline was drafted). From the immunogenicity perspective, it is clear that the methodology and strategy for assessment of immunogenicity of biosimilar products including mAbs needs careful evaluation to ensure that this is appropriate for the required comparative assessment. In particular, it is important to ensure that screening procedures identify all patients who develop antibodies against the product that they receive, i.e. the candidate biosimilar or the reference product. This implies that at least screening assays need to be tailored to include the use of the biosimilar and the reference product as antigens (usually conducted as separate assays) and samples from treated patients are screened against the antigen relating to the product that they received. If the trials are double blind (as is normally required for mAbs), then this means that samples will have to be screened against both antigens, as the identity of the product that the patients have received is unlikely to be known at the time of screening. If this strategy is not adopted, it is possible that false negative results may be generated for some patients as one or more epitopes present on the biosimilar and reference products may not be shared. This aspect of immunogenicity assessment strategy is likely to receive considerable attention as more experience is gained with immunogenicity assessment of biosimilar products including mAbs. It is also important to understand the underlying causes of immunogenicity when comparing the incidence of immunogenicity. For example, it may be that differences observed with immunogenicity between a candidate biosimilar and the reference product are due to differences in impurity profiles due to a change in the expression system.

The new immunogenicity of monoclonal antibodies guideline stresses the importance of risk assessment for immunogenicity management, but emphasises the need to take account of the numerous factors that may contribute to immunogenicity, e.g. the production system used, the patient population treated, the clinical indication(s) selected for treatment and the antigen target of the mAb. It is not possible to assign a single ‘risk level’ for mAbs as a product class, as each product needs to be assessed on a case-by-case basis, taking account of all the risk factors.

For patients

Monoclonal antibody products are potentially very valuable medicines and several are approved for the treatment of a range of clinical problems. Many more such products are in development. Unwanted immunogenicity associated with mAb products can be a problem, occasionally resulting in adverse effects and more often a reduction in clinical efficacy. The new guideline described in this article will help manufacturers of mAb products in assessing unwanted immunogenicity of mAbs and will also aid regulators in their evaluation of mAb products for approval for marketing.

Competing interests: None.

Provenance and peer review: Commissioned; internally 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

Author for correspondence: Robin Thorpe, PhD, FRCPath, Head – Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2013 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Related article
ICH Q11: development and manufacture of drug substances–chemical and biotechnological/biological entities

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ICH Q11: development and manufacture of drug substances–chemical and biotechnological/biological entities

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Abstract: 
The International Conference on Harmonisation (ICH) has endorsed a new guideline concerning the development and manufacture of chemical and biotechnological/biological drug substances. The guideline harmonises the scientific and technical principles relating to the development and description of the drug substance manufacturing process to be included within the Common Technical Document (CTD) and submitted to regulatory authorities in the European Union (EU), Japan and USA. This question and answer is intended to provide the reader with a flavour of the background to the guideline and its relevance for biosimilar and generic drug substances.

Submitted: 7 July 2012; Revised: 26 July 2012; Accepted: 27 July 2012; Published online first: 1 August 2012

The need for an International Conference on Harmonisation (ICH) guideline on the development and manufacture of drug substances was endorsed by the ICH Steering Committee in October 2007. This recognised the absence of harmonised guidance for industry and regulatory authorities in this area and the need to consider how principles and concepts described in ICH guidelines Q8 (Pharmaceutical Development), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System) apply to the development of drug substance manufacturing processes.

The ICH Q11 guideline was drafted by an expert working group comprising representatives from regulatory authorities and the pharmaceutical industry in the European Union (EU), Japan and USA. Observers actively contributed to the discussions and included regulators from Canada, China, Singapore and Switzerland, the World Health Organization along with international groups representing biotechnology, generic and self-medication industry sectors.

The ICH Q11 guideline was endorsed by the Steering Committee on 1 May 2012 and was adopted in the EU by the Committee on Human Medicinal Products in May 2012.

This question and answer is intended for those with interest in the development and manufacture of drug substances, those involved in regulatory submissions for marketing authorisations in the EU and quality assessors in competent authorities. It is intended by way of introduction to the guideline. It assumes a general awareness of ICH quality guidelines. Readers should refer to the full text version and other ICH guidelines referred to in this article and available on the ICH website at www.ich.org/products/guidelines/quality/article/quality-guidelines.html

The authors of this article were members of the Q11 expert working group. Direct quotations from the guideline are the agreed position of the expert working group. Any other views or opinions expressed in this article are those of the authors and should not be attributed to the authors’ employers.

What is the purpose of ICH Q11?

The purpose of the guideline is to harmonise the scientific and technical principles relevant to the development and manufacture of drug substances and to provide guidance on the information to be included within the Common Technical Document (CTD) in support of marketing authorisation submissions. The guideline is intended to facilitate the submission of similar information in regulatory submissions within the ICH signatory regions (EU, Japan and USA) and may be helpful to pharmaceutical companies and regulators in other regions.

What is the scope of the guideline?

The guideline is applicable to new chemical drug substances and biotechnological/biological drug substances, as described in ICH Q6A and Q6B, respectively.

It provides guidance on information to be submitted in sections S2.2–S2.6 of the CTD. The guideline will be applicable to biosimilar molecules falling within the scope of Q6B. Although generic chemical substances were not included in the scope of the guideline, the principle of design of robust manufacturing processes through effective development and control, using the approaches described in the guideline, is also relevant for manufacturers of generic chemical substances.

Q11 is not intended as a guide to what to submit in applications during the clinical development of investigational medicinal products but the principles described may be taken into consideration during this time in order to provide information for inclusion in any later marketing authorisation submission.

Q11 does not provide guidance on how to comply with requirements for good manufacturing practice (GMP).

How does Q11 provide guidance for both biotechnological/biological and chemical drug substances?

The approaches to development of manufacturing processes are similar for both biotechnological/biological and chemical substances in respect of the need to define a robust commercial manufacturing process that consistently provides drug substance of defined quality. Both chemical and biotechnological/biological manufacturing processes are required to consistently produce high purity and potent molecular entities with processes designed to minimise and/or remove impurities. However, the limitations in analytical characterisation for biotechnological/biological substances necessitate a control strategy with greater emphasis on process controls as compared to chemical substances.

Q11 provides common principles for both chemical and biotechnological/biological substances but also provides specific guidance, for example, on drug substance starting materials for new chemical substances and what to submit for process validation studies for biotechnological/biological substances.

Does the guideline introduce additional regulatory expectations?

The guideline does not introduce new regulatory expectations. Different approaches may be taken to the development of a manufacturing process for a new drug substance. The ‘traditional’ approach continues to be acceptable. More systematic approaches to development along with quality risk management tools can provide greater understanding of sources of variability in the manufacturing process and flexibility in the application of the controls. Both ‘traditional’ and ‘enhanced’ approaches to development of the manufacturing process are acceptable and a combination of both approaches can also be used in process development.

Does ICH Q11 replace other ICH guidance on drug substances?

Generally applicable guidance concerning process development is given in ICH Q8, Q9 and Q10. ICH Q11 supplements existing ICH guidance and clarifies the application of concepts described in ICH Q8, Q9 and Q10, as relevant to drug substances. It supports approaches to process development in order to better understand and control sources of variability in the drug substance.

Does the concept of ‘design space’ as described in ICH Q8 apply to drug substances?

The definition of design space given in ICH Q8 is applicable for both chemical and biotechnological/biological drug substances. Movement within an approved design space would not require prior regulatory approval.

How should movement within a ‘design space’ be handled for biotech products?

The development and approval of a design space for some biotechnological/biological drug substances can be challenging due to factors including process variability and drug substance complexity, e.g. post-translational modifications. These factors can affect residual risk, e.g. potential for unexpected changes to CQAs (critical quality attributes) based on uncertainties related to scale sensitivity, which remains after approval of the ‘design space’. Depending on the level of residual risk, it may be appropriate for an applicant to provide proposals on how movements within a ‘design space’ will be managed post approval.

These proposals should indicate how process knowledge, control strategy and characterisation methods can be deployed to assess drug substance quality following movement within the approved ‘design space’. This could include proposals for ‘design space’ verification, as well as a risk-based approach to define stratified actions, e.g. routine testing only, addition of characterisation tests.

What guidance is included in ICH Q11 in respect of selection of the starting material for a chemical drug substance?

Harmonisation was reached on the high level considerations for designation of the starting material for a chemical synthesis manufacturing process and on the information to be submitted in the dossier. It is anticipated that multiple chemical transformation steps from precursor structural fragments will be included in the dossier. Steps that require control due to introduction or removal of impurities in the drug substance should be considered in the designation of the starting material for the drug substance. The design of a suitable control strategy and its execution within GMP provide the basis for consistent quality of the drug substance.

Does the definition of CQA stated in ICH Q8 apply to the drug substance?

The definition of CQA as described in ICH Q8 is relevant for both chemical and biotechnological/biological drug substance. A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Does Q11 recommend that all drug substance CQA are included in the drug substance specification?

The drug substance specification is only one part of a total control strategy and not all CQAs need to be included in the drug substance specification.

The control strategy should ensure that each drug substance CQA is within the appropriate range, limit, or distribution to assure drug substance quality. Different approaches can be envisaged to the management of specific CQAs, dependent on the knowledge of the relationship between process parameters and the particular CQA. This can include inclusion of a control for that CQA in the drug substance specification with compliance confirmed by testing each batch produced. Alternative approaches may include confirmation of compliance of a CQA using process controls applied upstream from the final drug substance with a control included for the CQA in the drug substance specification that is not tested on every batch. A further situation can be envisaged when a given CQA is controlled by the operating parameters of the process and ensured by process controls without including a control in the drug substance specification.

Can platform manufacturing data be used for biotechnologically-derived substances?

Significant experience gained through the use of a production strategy similar to those used by the same applicant to manufacture other drugs of the same type, i.e. platform manufacturing, is acknowledged in ICH Q11. Where appropriate, such prior knowledge can be used to leverage some development data and support evaluation/validation studies.

Does Q11 provide guidance on the number of batches required in drug substance process validation studies?

There is no ‘magic number’. The number of batches should comply with relevant guidances, e.g. ICH Q7, and can depend on several factors including but not limited to: (1) the complexity of the process being validated; (2) the level of process variability; and (3) the amount of experimental data and/or process knowledge available on the specific process.

To what extent are data generated with small-scale batches relevant to the validation of the commercial process for biotechnologically-derived substances?

The contribution of data from small-scale studies to the overall validation package will depend upon demonstration that the small-scale model is an appropriate representation of the proposed commercial scale. Data should be provided demonstrating that the model is scalable and representative of the proposed commercial process. Successful demonstration of the suitability of the small-scale model can enable manufacturers to propose process validation with reduced dependence on testing of commercial-scale batches.

Does Q11 provide guidance on changing the manufacturing process after approval of a marketing authorisation?

As indicated above, the concept of design space is applicable to drug substances. Following approval, changes within the defined ‘design space’ do not require regulatory approval.

Q11 also recognises that protocols for managing specific changes to the drug substance manufacturing process and intended to be implemented after approval, may be included for agreement with the regulatory authority during the assessment of the marketing authorisation application.

European legislative requirements for post-approval changes to marketing authorisations are applicable.

Further information on the regulation and detailed classification guidance are available on the European Commission website at ec.europa.eu/health/better-regulation-variations-regulations-developments_en.htm

Competing interests: None.

Provenance and peer review: Commissioned; internally peer reviewed.

Co-author

Kowid Ho, PhD, Unité des produits biologiques et issus des biotechnologies, Agence nationale de sécurité du médicament et des produits de santé, 143–147 Bvd Anatole France, FR-93285 Saint-Denis Cedex, France

Author for correspondence: Keith McDonald, MSc, MRPharmS, Group Manager, Licensing Division, Medicines and Healthcare products Regulatory Agency, 151 Buckingham Palace Road, SW1W 9SZ, London, UK

Disclosure of Conflict of Interest Statement is available upon request.

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Related article 
Generics substitution in primary care: summary of the Dutch community pharmacies guidelines

Last update: 12/03/2020

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Generics substitution in primary care: summary of the Dutch community pharmacies guidelines

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Abstract: 
Marketed medicines that have passed bioequivalence testing should in general be substitutable. However, for a variety of reasons, caution may be warranted, particularly with regard to narrow therapeutic index drugs and the indiscriminate use of biosimilars. The Royal Dutch Pharmacists Association (KNMP) has published professional guidelines for community pharmacies concerning generic substitution. The guidelines are based on scientific principles and provide a strong impetus for maintaining uniform professional standards. Here we present the main features of these guidelines [1].

Submitted: 23 February 2012; Revised manuscript received: 16 May 2012; Accepted: 23 May 2012

Background

The latest version of the guidelines was prompted by a renewed interest in generics substitution. The first edition of the guidelines was published following the introduction, in 1988, of a financial rule for pharmacists that offered them a fee of one-third of the price difference between a generic and a brand-name drug per substitution. This rule changed many times thereafter, but in year 2000 the interest in substitution rose again, partly for financial reasons and partly because ‘prescribing on generics name’ had been introduced. An updated version of the guidelines was deemed important for pharmacists as an instrument to weigh out the risks and benefits of substitution based on patient safety.

Definition of substitution

Generics substitution is defined as the mutual substitution of medicinal products having the same active ingredient, the same strength, and the same dosage form. Substitution of medicinal products with different dosage forms and therapeutic substitution is excluded from the scope of the Dutch guidelines.

Legislation

Every drug given marketing approval has been rigorously evaluated by licensing authorities and can be safely dispensed by any pharmacist. Legally, however, the pharmacist has to dispense only the prescribed product, and substitution requires the physician’s consent. This is especially relevant to branded products. In practice, in a local healthcare setting, this usually means that physicians and pharmacists reach agreements about substitution. When a drug is prescribed using a generic name, the pharmacist will dispense the most cost-effective formulation.

Bioequivalence

The decision on whether to substitute or not is determined by the degree of similarity of the products in question. For the market approval of generic drugs, pharmacokinetic bioequivalence studies are required. The European Medicines Agency (EMA) regards products as bioequivalent if the AUC ratio and Cmax results of comparative bioavailability studies produce a 90% confidence interval within 80.00–125.00% of the reference product. For narrow therapeutic index drugs the AUC limits are 90.00–111.11%, and similar Cmax is only required in specific situations [2].

However, for drug substitution, other factors may be involved besides pharmacokinetic bioequivalence, as explained in the guidelines.

Guidelines for generic medicine substitution in community pharmacies
When dispensing a licensed generic drug alternative for the first time, it is assumed to be as safe and efficacious for the patient as the innovator product.

However, when repeat dispensing is required for chronic use there may be situations–described in detail below–when caution is indicated before substitution:

  • Prescription of narrow therapeutic index drugs (NTI). The Dutch guidelines contain a list of NTI drugs, including digoxin, lithium, and transplantation drugs like ciclosporin and tacrolimus.
  • Prescription of drugs for which pharmacokinetic bioequiva-lence studies are not a good measure of interchangeability, such as oral drugs that have a local effect in the gastrointestinal tract, or inhalation medications with local effects in the lungs. Examples include: orally administered mesalazine, and inhalation of corticosteroids such as fluticasone.
  • Prescription of biologicals. Unlike synthetic small molecule drugs, biosimilars–generic versions of biological drugs–do not match the innovator product in composition, and their characteristics cannot be fully determined using laboratory analytical techniques. Classical bioequivalence studies have limited value in indicating equivalent efficacy and safety compared to the reference product. Product efficacy, safety and traceability are therefore additional, important issues for biologicals. The Dutch guidelines cover these issues with reference, for example, to filgrastim, epoetin and somatropin.
  • The recommendations for substitution of biologicals are as follows:
    • Based on scientific data substitution is not expected to cause problems if the route of administration and indication are the same as for the innovator product, on the basis that clinical tests have demonstrated comparable efficacy and safety between biosimilars and the innovator product. However, substitution is not recommended if it means a switch to a different route of administration for example, from subcutaneous to intravenous, for which the biosimilar has not been approved. This is because the immunogenicity of the biosimilar may vary from one route of administration to another. EMA does not formally recognise the safety of a biosimilar if its use involves a non-approved route of administration.
    • Substitution is not recommended for unapproved indications. While EMA leaves open the possibility that similarity between a biosimilar and the innovator product may also apply to other indications, these are omitted from the biosimilar’s drug approval dossier. The reasons are often unclear but may be found in the European public evaluation report (EPAR).
    • Random substitution without careful recording is not recommended owing to the risk of an immunogenic reaction. This can occur after a protracted period of time, and if it follows a substitution, it may not be clear which product has caused the adverse drug effect–the one used before or after substitution. Random substitution will compromise the reliable reporting of adverse drug effects.
  • In the case of patient-related factors, random substitution can affect adherence or the ratio of benefit to risk of the medicine:
    • Patient confidence in the medication can be undermined if the medicinal product looks different by, for example, its colour, or list of adverse reactions on the package insert. This is particularly relevant in disorders such as depression or psychosis, in which patients are sometimes distrustful of medication. A change in the external appearance of medicinal products or any change (real or imagined) in their action or adverse effects can damage patient adherence to treatment.
    • Random substitution can also affect the risk/benefit ratio in disorders for which the balance (dose versus efficacy and adverse reactions) of the therapy is critical, such as Parkinson’s disease or in transplantation patients.
    • When a patient has an intolerance for a certain excipient, substitution with a drug containing that excipient should be avoided, for example, the excipients wheat starch and parabens must be avoided in patients with celiac disease, and paraben allergies, respectively.
    • The medicinal product pack or an associated device can significantly affect its ease of use or compliance. Examples are inhalation medications, contraceptive pills or packs tailored to specific patient groups, such as Ledertrexate tablets for rheumatoid arthritis patients.

Additional considerations

When substitution is unavoidable, for example, when the innovator product is out of stock, the pharmacist should inform the patient properly, indicating the differences and similarities between the drugs in question. The patient should be warned not to take both drugs simultaneously and asked to monitor their drug responses in terms of efficacy and adverse reactions.

Generic products are tested for bioequivalence with the brand product as a reference. This means that the difference between two generic products can exceed the limit that is accepted for bioequivalence between a generic product and the reference product. If product A is bioequivalent with the reference product in the upper boundary of the AUC and product B in the lower boundary, these two generics versions are considerably different. Proper product information is mandatory in such a situation. The difference between two generics can be greater than the difference between a generic and a single reference product.

Although there may appear to be bioequivalence in a given small volunteer population, in practice, some patients experience problems following generics substitution. In most cases there is no satisfactory scientific explanation, but the patient’s responses to substitution should always be taken seriously.

In summary

Marketed medicines that have been tested for bioequivalence should in general be substitutable. However, caution in substitution is warranted in certain situations. To provide support to the pharmacy community, KNMP has issued a set of guidelines to promote a responsible substitution process in community pharmacies. This should help to maintain professional standards which in turn should help protect patients against harm caused by the effects of product substitution.

Editor’s note

The English version of the published Guideline for generic substitution is available for download on the KNMP website as well as GaBI Online.

A brief article detailing the process followed when drafting the guidelines is published on GaBI Online, available from: www.gabionline.net/Guidelines/Guidelines-for-substitution-of-generics-in-The-Netherlands

Competing interests: None. Dr Leonora Grandia declared that there is no competing interest in substitution besides being the author of the Guideline for generic substitution of KNMP. Professor Arnold G Vulto was involved in commenting on the draft guidelines.

Provenance and peer review: Commissioned; externally peer reviewed.

Co-author

Professor Arnold G Vulto, PharmD, PhD
Deputy Head Hospital Pharmacy, Professor of Hospital Pharmacy and Practical Therapeutics, Erasmus University Medical Center, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands

References
1. Guideline for generic substitution. KNMP The Hague, February 2012.
2. Guideline on the investigation of bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1/Corr**.
3. Guideline on similar biological medicinal products, CHMP/437/04, 2005.

Author for correspondence: Leonora Grandia, PharmD, Coordinator G-Standaard, Royal Dutch Pharmacists Association, PO Box 30460, NL-2500 GL The Hague, The Netherlands

Disclosure of Conflict of Interest Statement is available upon request.

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Last update: 22/06/2020

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