European Medicines Agency
7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
鼓励孩子的一段话
Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 13
E-mail: mail@emea.europa.eu a.europa.eu
London, 13 December 2007 Doc. Ref. EMEA/CHMP/BMWP/14327/2006
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE
(CHMP)
硬笔书法欣赏GUIDELINE ON IMMUNOGENICITY ASSESSMENT OF BIOTECHNOLOGY-DERIVED
THERAPEUTIC PROTEINS DRAFT AGREED BY BMWP
July 2006 ADOPTION BY CHMP FOR RELEASE FOR CONSULTATION January 2007 END OF CONSULTATION (DEADLINE FOR COMMENTS)
July 2007 AGREED BY BMWP
October 2007 ADOPTION BY CHMP
December 2007 DATE FOR COMING INTO EFFECT
April 2008
KEYWORDS Immunogenicity, unwanted immune respon, biotechnology derived
proteins, immunogenicity risk factors, assays, clinical efficacy and safety,
risk management
GUIDELINE ON IMMUNOGENICITY ASSESSMENT OF BIOTECHNOLOGY-DERIVED
THERAPEUTIC PROTEINS
TABLE OF CONTENTS
EXECUTIVE SUMMARY (3)
1.INTRODUCTION (3)
2.SCOPE (4)
3.LEGAL BASIS (4)
4.MAIN GUIDELINE TEXT (4)
4.1F ACTORS THAT MAY INFLUENCE THE DEVELOPMENT OF AN IMMUNE RESPONSE AGAINST A
THERAPEUTIC PROTEIN (4)
4.1.1 Patient- and dia-related factors (4)
跳远英文
4.1.2. Product related risk factors of immunogenicity (6)
4.2N ON-CLINICAL ASSESSMENT OF IMMUNOGENICITY AND ITS CONSEQUENCES (7)
4.3D EVELOPMENT OF ASSAYS FOR DETECTING AND MEASURING IMMUNE RESPONSES IN
HUMANS (7)
4.3.1 Assay strategy (7)
4.3.2 Antibody assays (7)
4.3.3Assay validation (8)
4.3.4 Characterisation of antibodies to a therapeutic protein (9)
4.4P OTENTIAL CLINICAL CONSEQUENCES OF IMMUNOGENICITY (10)
4.4.1Conquences on Efficacy (10)
4.4.2Conquences on Safety (10)
4.5I MMUNOGENICITY AND C LINICAL D EVELOPMENT (11)
4.5.1Rationale for sampling schedule and kinetics of the antibody respon (11)
4.5.2Conquences on pharmacokinetics of the product (12)
4.5.3Methodology aspects to asss comparability of immunogenicity potential as part of a
exerci (12)
comparability
4.5.4Immunogenicity in paediatric indications (13)
4.6R ISK MANAGEMENT P LAN (13)
REFERENCES (14)
ANNEX 1 FURTHER DETAILS ON METHODS FOR ASSESSMENT AND CHARACTERISATION OF IMMUNOGENICITY (15)
ANNEX 2 AN EXAMPLE OF A STRATEGY FOR ANTIBODY DETECTION AND CHARACTERISATION (18)
EXECUTIVE SUMMARY
The number of biological/biotechnology-derived proteins ud as therapeutic agents is steadily incre
asing. The products may induce an unwanted immune respon in treated patients, which can be influenced by various factors, including patient-/dia-related factors and product-related factors. This document contains background information concerning the potential caus and impacts of immunogenicity and provides general recommendations for the performance of a systematic immunogenicity asssment from a marketing authorisation perspective.
The predictive value of non-clinical studies for evaluation of immunogenicity of a biological medicinal product in humans is low due to inevitable immunogenicity of human proteins in animals. While non-clinical studies aimed at predicting immunogenicity in humans are normally not required, animal models may for example be of value in evaluating the conquences of an immune respon.
It is esntial to adopt an appropriate strategy for the development of adequate screening and confirmatory assays to measure an immune respon against a therapeutic protein. Assays may need to be capable of distinguishing neutralizing from non-neutralizing antibodies, and for u in pivotal clinical trials as well as in post-authorisation studies to be validated.
In the clinical tting, careful planning of immunogenicity evaluation should include data systematically collected from a sufficient number of patients. For a given product, sampling should pr
eferably be standardized across studies (e.g., sampling at baline, under treatment and follow up samples). The sampling schedule for each product is determined on a ca-by-ca basis, taking into account also the risks associated with an unwanted immune respon to patients. Data on the impact on efficacy and safety should be collected in order to fully understand the clinical conquences of the immune respon. Immunogenicity issues should be further addresd in the Risk Management Plan. The scope of this guideline covers a wide applicability. Thus, the concepts might have to be adapted on a ca-by-ca basis to fit an individual development programme. Applicants should consider the possibility to ek Scientific Advice from EMEA or from National Competent Authorities.
1. INTRODUCTION
Most biological/biotechnology-derived proteins induce an unwanted immune respon that is triggered by more than one single factor. This immunological respon is complex and, in addition to antibody formation, other events such as T cell activation or innate immune respon activation could contribute to potential adver respons.
The conquences of an immune reaction to a therapeutic protein range from transient appearance
of antibodies without any clinical significance to vere life-threatening conditions. Potential clinical conquences of an unwanted immune respon are a loss of efficacy of the therapeutic protein, rious general immune effects such as anaphylaxis, and, for therapeutic proteins ud for substitution, a potential cross-reactivity with the endogenous counterpart in ca it is still produced.
Many factors may influence the immunogenicity of therapeutic proteins. They can be considered to be patient-, dia- or product-related. Patient-related factors that might predispo an individual to an immune respon include: underlying dia, genetic background, immune status, including immunomodulating therapy, and dosing schedule. Product-related factors also influence the likelihood of an immune respon, e.g. the manufacturing process, formulation, and stability characteristics. Although data on possible unwanted immune reactions to therapeutic proteins are required before marketing authorisation, problems may still be encountered in the post-authorisation period. In the marketing authorisation application, the applicant should include a summary of investigations of immunogenicity in the respective overview ctions with full cross-reference to the data in the relevant modules. Depending on the immunogenic potential of the therapeutic protein and the rarity of the dia, the extent of immunogenicity data before approval might be limited. Further systematic immunogenicity testing might become necessary after marketing authorization, and may be included in the risk management plan.
2. SCOPE
The general principles adopted and explained in this document mainly apply to the development of an unwanted immune respon against a therapeutic protein in patients and how to systematically evaluate this. The guideline applies to proteins and polypeptides, their derivatives, and products of which they are components, e.g., conjugates. The proteins and polypeptides are mainly produced from recombinant or non-recombinant expression systems. Throughout this guideline, the term “therapeutic protein” is ud. This guideline should be read in conjunction with other relevant guidelines, e.g.:
• Guidelines on similar biological (biosimilar) medicinal products;
• Guidelines on comparability of biotechnology-derived medicinal products after a change in the manufacturing process.
For coagulation factors, plea, refer to the specific CHMP guidelines in this area (e references).
BASIS
3. LEGAL
This guideline has to be read in conjunction with the introduction and general principles (4) and part III of the Annex I to Directive 2001/83 as amended.
TEXT
GUIDELINE
4. MAIN
The conquences of an immune reaction to a therapeutic protein range from transient appearance of antibodies without any clinical significance to vere life threatening conditions. As a rule, therapeutic proteins should be en as individual products, and experience from related proteins can only be considered supportive. Also in this respect, concomitant medications and other patient-related factors like the underlying dia have to be taken into account, since the can also influence the clinical prentation of immunogenicity. Therefore, immunogenicity evaluation needs to be studied individually for each indication/patient population.
Evaluation of immunogenicity should be a multidisciplinary task, encompassing joint efforts of quality, non-clinical and clinical experts.
This document gives general recommendations and principles for developers and asssors of biotechnology-derived therapeutic proteins of how to approach immunogenicity evaluation from a marketing authorisation perspective. The scope of this guideline covers a wide applicability. Thus, the concepts might have to be adapted on a ca-by-ca basis to fit an individual development programme. For the justification of their approach to immunogenicity testing, Applicants should take into consideration both the risk for developing an unwanted immune respon, and the potential clinical conquences as outlined below. The approach taken for the design of the immunogenicity development concept should be fully justified, e.g. when omitting assays or immune respon measurements propod in this guideline. Applicants should consider the possibility to ek Scientific Advice from EMEA or from National Competent Authorities.
4.1 Factors that may influence the development of an immune respon against a therapeutic protein
4.1.1 Patient- and dia-related factors
北京市私立汇佳学校
Patient-related factors, which might influence the immune respon to a therapeutic protein, may include genetic factors, age of the patient, dia-related factors including other treatments, and previous exposure to similar proteins.
• Genetic factors modulating the immune respon
Genetic factors can alter the immune respon to a therapeutic protein and lead to inter-patient variability. Allelic polymorphism in the major histocompatibility complex (MHC), impacting on affinity and stability of the interaction between MHC molecules and antigenic peptides, and genes
encoding the T cell receptor of helper T cells may influence immune respons and immunological tolerance induction.
Immune respons may occur even if the amino acid quence of the therapeutic protein is fully human.
Other genetic factors influencing immunogenicity could be gene polymorphisms for cytokines that play a role in the fine-tuning of the immune respon (e.g. interleukin-10, TGF-beta etc.).
会计的岗位职责
• Genetic factors related to a gene defect
If the therapeutic protein is ud for substitution of an endogenous protein, reduced levels or even the lack of this protein may influence immunological tolerance, since for the patients the physiological antigen may reprent a neo-antigen.
• Age
The data from one age group cannot necessarily be projected to others since immune respon against a therapeutic protein can be an age-related phenomenon. Children may possibly have a different immune respon to the proteins. If the product is indicated in children, studies on immunogenicity should be carried out in this age group (e ction 4.5.4). If indicated in elderly, consideration should be given to a potentially altered immune respon.
• Dia-related factors
The patient’s underlying dia itlf can be an important factor in the context of developing an unwanted immune respon.
Some patients with chronic infections may be more prone to an immune respon, since their immune system is in an activated state.
In other conditions (e.g. malnutrition, advanced metastatic dia, advanced HIV dia, organ failure), an immune respon against a therapeutic protein might be less likely to occur due to an impaired immune system.
个人工作计划范文简短
尧舜禹的关系For some products, it has been reported that the development of an antibody respon can be different for different therapeutic indications or different stages of the dia. Therefore, immunogenicity normally needs to be studied parately for each dia or stage of the dia as part of the clinical studies.
• Concomitant treatment
Concomitant therapies may either decrea or increa the risk of an immune respon to a therapeutic protein. Typically, the immune reaction against a therapeutic protein is reduced when immunosuppressive agents are ud concomitantly. Consideration should also be given to previous treatments, that can modulate the immune reaction to a therapeutic protein and that have a long-term impact on the immune system. If clinical trials are performed in combination with immunosuppressants, a claim for u of the therapeutic protein in monotherapy must be accompanied by adequate clinical data on the immunogenicity profile in abnce of immunosuppressants, i.e. immunogenicity data from the combination with immunosuppressants are not relevant for the monotherapy tting.
• Duration, route of administration, treatment modalities
高中生议论文
Factors which may increa the immune respon to a therapeutic protein may be the route of administration, do, and the schedule of administration.
Products given intravenously may be less immunogenic than tho given subcutaneously or intramuscularly.
Short-term treatment only is usually less likely to be associated with immune respon than long-term treatment, and products given continuously are usually less immunogenic than tho given intermittently.
