The document discusses the regulatory framework and experiences related to monoclonal antibody submissions in the EU, highlighting the development, safety, efficacy, and immunogenicity of these biotherapeutics. It details the current state of monoclonal antibodies in various therapeutic areas, production statistics, quality issues, and the complexities of safety assessments during clinical trials. The conclusion emphasizes the importance of quality standards and comprehensive safety monitoring in the approval and post-marketing phases for monoclonal antibodies.

1. IFPMA/AIPM Biotherapeutics Workshop, Moscow
Regulatory experience with monoclonal
antibody submissions in the EU
15-16th
May 2013
Dr Alex Kudrin, Medical Assessor in Biologicals, MHRA, London, UK

2. Disclaimer
• This presentation is given in personal capacity and
represents only the author’s personal views and does not
represent policies or recommendations of MHRA, EMA,
FDA, any other companies and regulatory bodies
mentioned in this presentation.
• No confidential data is disclosed.
• All relevant references and links are from public domain.

3. Production of biologics
• A total of about 270 antibodies are currently in phase II-III
studies (120 are forecasted to be approved based on ~50%
attrition rate)
• Products in development for numerous therapeutic indications
and not only for conventional oncology and autoimmune
disorders
• Total production: 18 tonnes in 2009 – expected to reach 80
tonnes by 2020 (with at least 10% share of biosimilars: 10
tonnes)
• Yield of cell cultures will be improved 5-10-fold times
Ref: Olav Zulian, 2012

4. EU assessment of biologics

5. Mandatory scope for centralised procedure
• Recombinant produced biotechnology products, except for
some old biologics
• Biosimilars
• Advanced cell therapy products
• Genetherapy
• Orphan products
• Generics versions of centralised authorised products
• Products for diseases of public importance: oncology and
infectious diseases

8. Background on therapeutic MABs

10. MAB nomenclature
Source
stem
Suffix
o mAb
xi mAb
zu mAb
u mAb
Immunogenicity

11. Therapeutic indications for EU approved MABs
• Autoimmune diseases (e.g. Humira, Remicade or
Mabthera)
• Oncology (Avastin, Erbitux, Herceptin, Perjeta,
Adcetris)
• Passive immunotherapy for some infectious diseases,
e.g. Synagis for RSV
• Bone disorders: anti-RANKL for PMO (Prolia) and
SRE in cancer (Xgeva)
• In development: MABs for cardiovascular diseases,
Alzheimer’s disease, neurology indications, muscle
wasting etc.

12. Very potent
chemotherapeutic drug
• Tubulin polymerization inhibitors
• Maytansines (DM1, DM4)
• Auristatins (MMAE, MMAF)
• DNA damaging agents
• Calicheamicins
• Duocarmycins
• Anthracyclines (doxorubicin)
• Humanized monoclonal
Ab (IgG1)
• mAb with Fc
modifications (modulate
ADCC, CDC activity)
• Other mAb fragments
Linker stable in
circulation
Antibody-Drug Conjugate (ADC)
Schutten, 2012
>100 of ADC is in
development

13. Quality issues

14. Q5B Genetic Stability
Numerous Quality Guidelines Covering
Biotech Products
Cell Banks Process Drug Substance Drug Product
Q5D Cell Substrates
Q5A Viral Safety
Q6B Specifications
Q5C Stability
Q5E Comparability
EMEA/CHMP/BWP/157653/2007: Guideline on development,
production, characterisation and specifications for monoclonal
antibodies and related products

15. Characterisation is complex
• General characteristics
– Appearance, pH, particulates,
protein concentration
• Identity
– Peptide map, IEF,
glycosylation, charge profile
• Purity
– SDS PAGE, RP-HPLC,
CE-HPLC, SE-HPLC
• Potency
– Bio-assay
• C-terminal sequencing
• Amino acid composition
• Monosaccharide ratios
• Capillary electrophoresis
• Denaturing IEF with Western blot
• Circular dichroism
• Mass spectroscopy
• etc etc
Multiple methodologies used to characterise
quality attributes from different angles

16. Non-clinical issues

17. Safety
• Conventional approaches may not be appropriate
for biopharmaceuticals (ICH S6)
• Initial concerns = contamination with host cells and host cell
DNA
– Realization that safety concerns focused around exaggerated
pharmacology
• Two key issues
– Species selection
– Immunogenicity

18. Typical Toxicology Studies
• Single dose
• Repeat dose
–Generally 1-3 months for biotech products
–Short term use / acute life threatening – 2 wks
–Chronic use – 6 months
• Genotoxicity / Carcinogenicity
–Not required unless cause for concern
• Reproductive toxicity
–Case-by-case basis

19. Moving into FTIM
 Low relevance of NOAEL in
determination first dose in
humans;
 MABEL estimation using
desirable receptor
occupancy rates of <1-10%
using all available animal
and in vitro assay data
(human primary cell and
tissue cultures);
 Specific consideration to
informed consent
procedures and clarification
of high-level of risks
TGN1412 victim
Source: Muller and Brennan (2009) Safety Assessment and Dose Selection for
First-in-Human Clinical Trials With Immunomodulatory Monoclonal Antibodies:
Clinical pharmacology & Therapeutics 85: 247-258

20. Clinical issues: efficacy, safety,
immunogenicity and RMP

21. EMA clinical regulatory framework for MAB
• Non-clinical requirements follow ICH guidelines on biotechnology products
• Clinical guidance: no MAB specific guidelines
• Development is guided by guidelines on development of new drugs for
rheumatoid arthritis, cancer, multiple sclerosis etc.
• Early pre-phase II-III CHMP SA is encouraged
• General principles for establishing efficacy same as for NCEs
• Case by case, based on therapeutic indication and patient population
• Route of administration is typically parenteral.
• Phases of development often blurred due to patient populations targeted e.g
oncology
• Use of biomarkers is encouraged with co-development and validation of
diagnostic companion test
– Potential for highly targeted therapies e.g. HER2 (Herceptin); KRAS
(Vectibix and Erbitux)

22. Evaluation of the efficacy data
• The magnitude of the clinical effect (e.g. OS increase)
• The longevity of the effect
• Type of clinical benefits: disease modifying vs symptomatic
effects (e.g. radiographic data with anti-RA MABs)
• Effect on quality of life
• Effect on outcomes, e.g. effect on survival or CV-composite
endpoints
• Effect in different sub-populations and age groups
• Effect in subgroups stratified by biomarker

23. General principles in immunogenicity evaluation
• The assay should be in place from Phase I study
• Risk-driven evaluation of immunogenicity data
• Assay validated for sensitivity and specificity
• Screening, confirmation and neutralisation assays
• Justification of periodicity and timing of sampling
• Sensitive patient population and subgroup analyses (exposure
related, immunosuppression status related, across indications,
AE-related, loss of efficacy, PK/PD modelling)
• Monitoring of immunogenicity up to 12 month
• Commonly descriptive evaluation of immunogenicity

24. Examples of MAB-associated immunogenicity
MAB Indication Type Patients with
immune response
%
Infliximab RA, CD Chimeric 10-60%
Adalimumab RA, CD Human 12-25%
Natalizumab CD, MS Humanized Up to 30%
Trastuzumab Breast, gastric
cancer
Humanized 4%
Rituximab RA, lymphoma Chimeric 1.1-12.7%

25. Immunogenicity: assessment
–Deficiencies: assays are crude and not
sufficiently sensitive with false-negative results
–Lack of interpretation of the data, e.g. failure to
correlate Ab presence with any detrimental
clinical effect in individual patients (trough levels
of MAB, and ACR20)
–Clinical implementation of immunogenicity testing
during postmarketing period (has been done with
Remicade)

26. Safety
• Some serious and poorly understood risks:
• Infusion reactions with rituximab
• Opportunistic and serious infections
• PML with rituximab, natalizumab, efalizumab, etc.
• Tumorigenicity (lymphoma with adalimumab and
infliximab);
• Osteonecrosis of the jaw and atypical fractures with
denosumab
Risk management plan is
mandatory for any new
biotechnology products

27. Safety of biologics
• Singh et al. (2011) included 160 RCTs with 48,676 participants and 46
extension studies with 11,954 participants. The median duration of RCTs
was six months and 13 months for OLEs.
• Biologics as a group were associated with a statistically significant higher
rate of total AEs (OR) 1.28, 95% CI 1.09 to 1.50;
• Number needed to treat to harm (NNTH) = 22, 95% CI 14-60,
• Serious infections (OR, 1.37, 95% CI 1.04 to 1.82, NNTH = 108 95% CI, 50
to 989)
• TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143
to 14706).
• Infliximab was associated with a statistically significantly higher risk of total
AEs OR 1.55, 95% CI 1.01 to 2.35; NNTH = 13, 95% CI 8 to 505) and
withdrawals due to AEs compared with control (OR 2.34, 95% CI 1.40 to
4.14; NNTH = 10, 95% CI 5 to 30) – put in context of NNT (1.5).
Singh et al., 2011 Adverse effects of biologics: a network meta-analysis and
Cochrane overview (Review)

28. RMP examples: Infliximab and adalimumab
• Routine PV activities will be sufficient for a majority of
signals
• Education of prescribers and patients (including alert cards)
• If necessary, registries can be set-up if required on the basis
of existing registries with Remicade, Humira and Cimzia in
EU and US
• Pregnancy registries or PASS study

29. Case example: Natalizumab
• Natalizumab is approved for adult patients with relapsing forms of MS (EU)
• Currently around 150 PML cases reported with nearly 80,000 patients
receiving Tysabri worldwide, and >40,000 in the US
• PML is seriously disabling and potentially fatal ADR (>20%)
• Restricted prescribing and enhanced monitoring allows to reduce risk of
PML (based on TOUCH and Tygris data)
• JC serology assay recently introduced into US and EU labels allows
guidance on risk stratification (the highest in JC-positive patients who were
treated with Tysabri for >24 months and who also receive other
immunosuppressant therapy)

30. REMS / RMP: Natalizumab
• US: A restrictive prototype of TOUCH-MS or TOUCH-
CD REMS program are instituted
• EU Enhanced research monitoring TYGRIS registry
(5000 patients in EU and US)
• JC serology assay companion diagnostic assay as
per Tysabri SmPC
• Pregnancy register
• Industry led PML consortium (Roche, Pfizer, Biogen)

31. New EU pharmacovigilance directive 2010/84/EU)
 Some medicinal products are authorised subject to
additional monitoring. This includes all medicinal products
with a new active substance and biological medicinal
products, including biosimilars, which are priorities for
pharmacovigilance.
 Member states shall ensure, through the methods for
collecting information and where necessary through the
follow-up of suspected adverse reaction reports, that all
appropriate measures are taken to identify clearly any
biological medicinal product prescribed, dispensed, or sold
in their territory which is the subject of a suspected adverse
reaction report, with due regard to the name of the medicinal
product, and the batch number.

32. Typical clinical issues arising during EMA evaluation of
MABs
• The efficacy is insufficiently demonstrated (e.g. minor increase
in overall survival with oncology MABs or lack of consistency
between PFS/OS or lack of OS data)
• Narrow net benefit
• Risk confined to the drug and the type of ADRs: e.g. serious
infections, malignancies and MACE AEs with briakinumab
(anti-IL12) and not compatible with the proposed clinical use
(outpatient treatment of psoriasis)
• Important identified risks that are difficult to predict, control or
minimise (e.g. Raptiva withdrawal from EU in 2009 due to PML
issue (4 cases reported with incidence of 1:500 in psoriasis vs
1:800-1000 with Tysabri in MS)

33. CONCLUSIONS
• EU regulations on novel MABs is focused around Quality
issues
• Non-clinical guidance is drawn from ICH
• Clinical guidance is product group specific and shared with
NCE
• Safety requirements vary but safety databases are usually
extensive
• RMP and enhanced postmarketing surveillance are mandatory
with MABs

34. Questions and thanks for your participation