European regulatory guidelines for biosimilars
1Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland and 2Department of Renal Medicine, Morriston Hospital, Swansea, UK
Correspondence and offprint requests to: A. Wiecek, Department of Nephrology, Endocrinology and Metabolic Disease, Medical University of Silesia, Francuscka St 20-40, 40-027 Katowice, Poland. Email: awiecek{at}spskm.katowice.pl
 |
Abstract |
|---|
 Top Abstract IntroductionAre current regulations...EMEA structureEMEA guidelinesDiscussionReferences |
|---|
The impending arrival en masse of biosimilars on Western markets is placing drug regulatory agencies under pressure to realign their policies. Biosimilars require more rigorous assessments than traditional chemical generics. This is because of the molecular complexity of recombinant proteins, and the complexity of biological manufacturing processes. Small differences can arise in a recombinant protein product which are hard or impossible to detect with even state-of-the-art analytical techniques. Yet, these differences can have significant impact on the safety and efficacy of the drug. The European Medicines Agency (EMEA) has taken the lead in issuing guidelines, most of which are still under review. The guidelines advocate pre-clinical and clinical testing of biosimilars prior to market authorization, complemented by tailored pharmacovigilance plans. These guidelines provide a valuable base from which to develop in this evolving regulatory environment.
Keywords: biopharmaceuticals; biosimilars; EMEA; regulatory guidelines
|
Introduction |
|---|
|
TopAbstractIntroductionAre current regulations...EMEA structureEMEA guidelinesDiscussionReferences |
|---|
A generation of biotechnology-derived therapeutic agents are reaching the end of their patent lives, heralding the market entry of biosimilars. However, recombinant proteins are associated with a number of issues which distinguish them from traditional chemical drugs and their generics. Recombinant proteins are highly complex at the molecular level, and biological manufacturing processes are highly elaborate: they involve cloning, selection of a suitable cell line, fermentation, purification and formulation. In addition, the therapeutic properties of recombinant proteins are highly dependent on each step of the manufacturing process. The result is that different manufacturing processes yield a unique product, which may have a distinctive safety and efficacy profile (hence the name ‘biosimilar’ instead of ‘biogeneric’, which implies identity). A biosimilar may differ significantly from a reference brand product. Furthermore, such differences may not be detectable with even state-of-the-art analytical techniques. The only certain way to assess the safety and efficacy of a biosimilar is to conduct pre-clinical and clinical tests.
|
Are current regulations adequate? |
|---|
|
TopAbstractIntroductionAre current regulations...EMEA structureEMEA guidelinesDiscussionReferences |
|---|
Current European Union (EU) legislation is embodied in three documents, dating from 2001 onwards. The first covers items such as blood-derived products and vaccines [1], without referring specifically to biotechnology-derived drugs. Article 10 contains a paragraph which remains the object of contention: ‘The applicant shall not be required to provide the results of toxicological and pharmacological tests or the results of clinical trials if he can demonstrate: (i) either that the medicinal product is essentially similar to a medicinal product authorised in the Member State ... (ii) or that the constituent or constituents of the medicinal product have a well established medicinal use, with recognised efficacy and an acceptable level of safety, by means of a detailed scientific bibliography’. The first point importantly lacks a precise definition of ‘essentially similar’, while the second ignores the significant differences that can occur between manufacturing processes. An amendment in 2003 [2] describes recombinant proteins as a ‘new class of biological medicinal product’, but provides no further guidance. The last update, in 2004 [3], begins to broach the topic of biosimilars, stating ‘Biological medicinal products similar to a reference medicinal product do not usually meet all the conditions to be considered as a generic medicinal product mainly due to manufacturing process characteristics. When a biological medicinal product does not meet all the conditions to be considered as a generic medicinal product, the results of appropriate tests should be provided in order to fulfil the requirements related to safety (pre-clinical tests) or to efficacy (clinical tests) or to both’. Although this amendment recognizes the difference between biosimilars and classical generics, the document does not delve any deeper into the matter.
The European Medicines Agency (EMEA), a decentralized body of the EU, has taken the lead in bridging the gap. The EMEA's Committee for Proprietary Medicinal Products (CPMP), and its descendant, the Committee for Medicinal Products for Human Use (CHMP), have issued a number of guidance documents. The overarching document, CHMP/437 [4], sets the scene by recognizing that the generic approach no longer suffices where biosimilars are concerned. The other documents can be categorized according to their focus on quality or clinical issues, or their focus on changes to an existing manufacturing process or an entirely new process. An important distinction to be made in this regard is between ‘comparability’, which assesses products preceding and following a change in manufacturing process, and ‘similarity’, which assesses products from entirely different manufacturing processes, with a focus on safety and efficacy. The guidelines pertaining to changes in a manufacturing process have already been approved [4–6], although the document on quality issues will be superseded by the QE5 document from the ICH (International Conference on Harmonisation). The ICH seeks to harmonize regulatory processes across the US, Europe and Japan. EMEA guidelines relevant to new manufacturing processes for biosimilars are still under review [7, 8]. They are supplemented by a number of Concept Papers, which provide the basis for a case-by-case approach.
|
EMEA structure |
|---|
|
TopAbstractIntroductionAre current regulations...EMEA structureEMEA guidelinesDiscussionReferences |
|---|
European guidelines are being generated through consultation both within the EMEA and externally (Figure 1). Internally, the CHMP collaborates with a number of Working Parties (WP) through scientific advice and peer review. An important WP is the Biological WP (BWP) which operates closely with the Safety WP and Quality WP. The BWP's remit includes developing guidelines on quality and clinical requirements for biologics, and participation in the shaping of ICH guidelines. Externally, the EMEA/CHMP operates within a network including Scientific Advisory Groups (SAGs), the National Competent Authorities (NCAs) of EU Member States, patient groups, universities and academic societies. Finally, the EMEA welcomes and encourages input from practicing physicians. Together, these groups aim to reach a consensus on medicinal products containing biotechnology-derived active substances.
|
|
EMEA guidelines |
|---|
|
TopAbstractIntroductionAre current regulations...EMEA structureEMEA guidelinesDiscussionReferences |
|---|
Guidelines for changes in a manufacturing process
The guidelines for quality [6] and clinical [7] studies required after a change in a manufacturing process advocate a case-by-case approach. The quality checks depend on the nature of the recombinant protein and the nature of the manufacturing change. Whether pre-clinical or clinical studies are required depends chiefly on the results from the quality assessment, and particularly on the ability of analytical techniques to characterize the biological product. All variations must be tracked within the pharamacovigilance database for the product.
Guidelines for novel manufacturing processes (Biosimilars)
The relevant guidelines, yet to be approved, were published in 2005 [7, 8]. They reaffirm the principles which are applicable to innovator companies, e.g. the applicants should demonstrate the consistency and robustness of their manufacturing process. Studies for biosimilars always have to be carried out in comparison with the original reference product. They involve batteries of in vitro assays, impurity profiling, and clinical pharmacokinetic (PK) and pharmacodynamic (PD) studies. Generally, clinical efficacy trials will be warranted, complemented by immunogenicity tests using validated assays. As ever, a post-approval continued benefit-risk assessment (pharmacovigilance plan) is necessary.
Biosimilar-specific guidelines
The Concept Papers and their annexes provide guidance specific for certain biological products, and have been published for recombinant human insulin [9, 10], growth hormone (GH) [11, 12], granulocyte colony-stimulating factor (GCSF) [13, 14] and epoetin (EPO) [15, 16]. They provide specific details on the various studies which need to be carried out for biosimilars, both pre-clinical and clinical. Further, such Concept Papers will progressively appear according to demand.
The annexe to the insulin Concept Paper [9] places special emphasis on the comparative nature (relative to an innovator brand) of the studies. The PK properties of the biosimilar and the reference product should be assessed in a single-dose crossover study using subcutaneous administration. Provided that equivalence can be concluded from PK and PD data, there is no anticipated need for clinical efficacy studies. However, immunogenicity issues can only be settled by a clinical study with a comparative phase of at least 6 months, followed by pharmacovigilance procedures.
The annexe to the growth hormone Concept Paper [11] resembles the insulin annex, with a few noteworthy differences. Besides references to specific bioassays and PD markers, the main difference is that equivalent therapeutic efficacy between the biosimilar and the reference product should be demonstrated in at least one adequately powered, randomized, parallel group, confirmatory clinical trial. Treatment-naïve children with growth hormone deficiency are recommended as the target population, as they provide the most sensitive model.
The annexe to the EPO Concept Paper [15] outlines somewhat more stringent requirements, reflecting the greater molecular complexity of EPO compared with insulin or GH. At least two adequately powered, randomized, parallel group clinical trials are necessary. Safety data over at least 12 months from at least 300 patients treated with the biosimilar in the efficacy trials is considered sufficient to provide an adequate pre-marketing safety database, and to exclude excessive immunogenicity. Treatment-naïve patients (or patients who have not received EPO treatment for at least 3 months) with renal anaemia are recommended as the target population, as they provide the most sensitive model. As ever, a rigorous pharmacovigilance plan is required, and special attention should be paid to the possibility of antibody-induced pure red cell aplasia (PRCA).
|
Discussion |
|---|
|
TopAbstractIntroductionAre current regulations...EMEA structureEMEA guidelinesDiscussionReferences |
|---|
The market for biotechnology-derived medicinal products is evolving rapidly with the imminent entry of biosimilars. Recombinant proteins are associated with a host of complex quality, safety and efficacy issues, and biosimilars are associated with a number of uncertainties. Nevertheless, the EMEA has forged ahead in providing guidance for national regulatory bodies in Europe. The EMEA guidelines are, however, a work in progress, and readers should consult the EMEA web site (www.emea.eu.int) for the latest updates.
Some sections of the guidelines are still controversial. For instance, it is stated that comparative clinical trials can be foregone if the biosimilar can be characterized in detail by physicochemical and in vitro techniques, or alternatively that comparative PK/PD studies can replace clinical trials. The annex to the insulin Concept Paper echoes this: efficacy data need not be provided if equivalence can be concluded from PK and PD data. In contrast, the other three Concept Papers regard comparative clinical studies as a necessity. However, non-clinical studies cannot guarantee similarity, and therefore should not be allowed to replace clinical studies where biosimilars are concerned.
The emphasis on adequate screening for immunogenicity events is well-warranted, given the incidence of PRCA. Post-marketing monitoring is an essential component in tracking rare but serious adverse events like these. The guidelines state that immunogenicity analyses should be performed especially in cases where repeated administration is proposed. A useful addition to the guidelines would be to require branding of biosimilars, to allow optimal and accurate pharmacovigilance.
Currently, no legal framework exists in the US for the approval of biosimilars, and the FDA have released no guidance documents. The EMEA has provided a valuable base for EU legislation to evolve from. However, if we wish to ensure patient safety with the arrival en masse of biosimilars to the market, it is imperative that their unique characteristics be recognized. Accrued experience will then allow regulatory authorities to optimally match guidelines to the genuine risks and benefits associated with biosimilars.
Conflict of interest statements. A.W. has participated in meetings sponsored by Roche. A.M. has participated in meetings sponsored by Roche, Janssen-Cilag and Amgen.
|
References |
|---|
|
TopAbstractIntroductionAre current regulations...EMEA structureEMEA guidelinesDiscussionReferences |
|---|
- . The European Parliament and the Council of the European Union. (2001) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Official Journal of the European Union 67–128.
- . The Commission of the European Communities. (2003) Commission Directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use. Official Journal of the European Union 46–94.
- . The European Parliament and the Council of the European Union. (2004) Directives 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. Official Journal of the European Union 34–57.
- Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. CHMP/437/042005.
- Committee for Proprietary Medicinal Products. Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance. Non-clinical and clinical issues. EMEA/CPMP/3097/02/Final2003.
- Committee for Proprietary Medicinal Products. Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: quality issues. EMEA/CPMP/BWP/3207/00/Rev1 2003.
- Committee for Medicinal Products for Human Use. Guidelines on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. EMEA/CHMP/BWP/49348/200523 November 2005European Medicines Agency.
- Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/42832/2005.
- Committee for Medicinal Products for Human Use. Annex guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing recombinant human insulin. EMEA/CHMP/32775/2005.
- Committee for Medicinal Products for Human Use. Concept Paper, similar biological medicinal products containing recombinant human insulin. Annex to the guideline for the development of similar biological medicinal products containing biotechnology derived proteins as active substance: (Non) clinical issues. CHMP/Comparability Working Party/146710/2004.
- Committee for Medicinal Products for Human Use. Annex guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing somatropin. EMEA/CHMP/94528/2005.
- Committee for Medicinal Products for Human Use. Concept Paper, similar biological medicinal products containing recombinant human growth hormone. Annex to the guideline for the development of similar biological medicinal products containing biotechnology derived proteins as active substance: (Non) clinical issues. CHMP/Comparability Working Party/146489/2004 corr2004.
- Committee for Medicinal Products for Human Use. Annex guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on biosimilar medicinal products containing recombinant granulocyte-colony stimulating factor. EMEA/CHMP/31329/2005.
- Committee for Medicinal Products for Human Use. Concept Paper, similar biological medicinal products containing recombinant human granulocyte -colony stimulating factor. Annex to the guideline for the development of similar biological medicinal products containing biotechnology derived proteins as active substance: (Non) clinical issues. CHMP/Comparability Working Party/146701/2004.
- Committee for Medicinal Products for Human Use. Annex guideline on similar biological medicinal products containing biotechnology-Derived proteins as active substance: non-clinical and clinical issues: guidance on biosimilar medicinal products containing recombinant erythropoietins. EMEA/CHMP/94526/2005European Medicines Agency.
- Committee for Medicinal Products for Human Use. Concept Paper, similar biological medicinal products containing recombinant human erythropoietin. Annex to the guideline for the development of similar biological medicinal products containing biotechnology derived proteins as active substance: (Non) clinical issues. CHMP/Comparability Working Party/146664/2004.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Gottlieb Biosimilars: Policy, clinical, and regulatory considerations Am. J. Health Syst. Pharm., July 15, 2008; 65(14_Supplement_6): S2 - S8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Jelkmann Recombinant EPO production points the nephrologist should know Nephrol. Dial. Transplant., October 1, 2007; 22(10): 2749 - 2753. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||