biosimilar regulation from a clinical point of view bio...biosimilar regulation from a clinical...

Biosimilar regulation from a clinical point of view

– an update on immunogenicity and interchangeability

LIS-TNFBio seminar 2018Scandic Nidelven Hotel

Trondheim20.-21. mars

Venke Skibeli, PhD

Senior Advisor

Project leader Biosimilars / Clinical Assessor

Member of the CHMP - Biosimilar Working Party European Medicines Agency, London

[email protected]

Topics

o European regulation of biosimilars

o What are biosimilars?

✓ Regulatory aspects

✓ Immunogenicity of

biologicals

o Regulatory challenges

✓ Interchangeability

✓ Traceability2

Edvard Munch, The sick child, 1896

Venke Skibeli, PhD20.03.2018- LIS-TNFBIO 2018

Disclaimer

• The views expressed in this review are the personal views of VS and should not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

3Venke Skibeli, PhD20.03.2018- LIS-TNFBIO 2018

Biosimilars in the EU

➢ The EU has the highest number of biosimilar medicines approved, and extensive experience of their use and safety;

➢ The EU’s legal framework on biosimilars has been in place since 2004 and is used by other international regulators;

➢ Over the last 12 years, the EU monitoring system for safety concerns has not identified any relevant difference in the nature, severity or frequency of adverse effects between biosimilar medicines and their reference medicines.


Biologicals

Heparin- enoxaparin sodium

Insulin

Recombinant proteins

EnzymesInsulin

Purified blood products

Vaccines

Advanced therapies

Therapeutic proteins -Present basis for

development og biologicals


5

Biologicals are BIG!

➢ IgG

➢ Protein molecules are flexible, unstable and sensitive with regards to heat, pH, ion strength, oxidation, light

➢ Peptides may also be synthesized chemically = no biological ➢ Heparin – biological in the EU / regulated as a synthetic drug in the US/FDA


6

drug

Monoclonal antibody – MoAb structure

➢ IgG – immune globulin


7

SS

Batch variability

• „Non-identicality“ is a normal principle in biotechnology

• No batch of any biological is „identical“ to the others

• The „art“ is to demonstrate that the biosimilar is as close as possible to its reference product in all relevant functional and structural aspects,

8

What is a biosimilar?

From EMA - revised general guideline 2015:

• A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorisedoriginal biological medicinal product (reference medicinal product).

• A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise.


Can biosimilars be developed to any biological product?

1

0

• In principle, the concept of biosimilarity is applicable to any biological medicinal product.

• The success of developing a biosimilar will depend on the ability to produce a medicinal product which is similar to the reference medicinal product, and to convincingly demonstrate the similar nature of theconcerned products.


10

The Comparability Exercise

➢A technical expression

➢Shows that two biologicals are similar

1) Scenario 1: Change in the manufacturingprocess („pre- and post-change“ product from thesame manufacturer)

1) Scenario 2: A biosimilar is launced (compared tothe reference)

11 Venke Skibeli, PhD20.03.2018- LIS-TNFBIO 2018

Biosimilar epoetin-alpha (authorised in Europe)

Brockmeyer and Seidel, EJHP 2009

12

Biosimilarity – general aspects

Development and conclusion on biosimilarityis a step-wise approach

1.Step: quality level, to establish high similarity in a comprehensive comparability exercise

2.Step: non-clinical level, great importance offunctional assays to substantiate similar effects

3.Step: clinical level, lower sensitivity for demonstration of similarity, comparison should confirm biosimilarity as observed above

➢ If not, can it be explained (why, how) ?

➢ What additional data can minimise concerns ?

Ris

kof

failu

redecr

ease

s

Physiochemical and

functional assays

are the most

sensitive to

reveal subtle

differences

Biosimilarity is based on the “totalityof evidence”

Source: Cleveland clinic

Originator study Biosimilar study Demonstration of biosimilarityfollows the principles of

comparability testing (ICH Q5E) for pre- and post-change

manufacturing process


Basic principle for clinicaldevelopment of biosimilars• The aim of a biosimilar development programme is not to establish

benefit of a treatment for the patient

➢ this has been done before for the reference product!

➢The aim is to establish biosimilarity!

The „art“ is to demonstrate that thebiosimilar is as close as possible to itsreference product in all relevant functional and structural aspects, within current technical and scientificlimitations (inherent variability).

15

• This means:✓ The clinical study follows the idea that patients are

„models“

✓ The clinical study is selected to represent the most sensitive model to study differences

✓ Thus, trial design might be (entirely) different from the normal guideline principles !

✓ Scientifically not „abridged“, but rather „tailored“development

✓ For interchangeability, this means:▪ Specific data currently not requested in the EU, since

development focuses on comparability exercise itself▪ But „close similarity“ supports switching

Basic principles for clinical development ofbiosimilars


Tailored clinical programme

17

Demonstration of similarity, not patient benefit perse

▪ PK studies mandatory and preferably in healthysubjects

▪ Endpoints in clinical trials should be “sensitive” and study population homogeneous to detect potential drug-related differences in pharmacologicaleffects

▪ Clear shift to PD endpoints

Glucose infusion rate (in clamp studies) forinsulin

Anti FXa and anti FIIa activity for LMWH

Absolute neutrophil count (ANC) for G-CSF

Number of oocytes retrieved for follitropin(IVF)


Evolution of Biosimilars in the EU

2005 2006 2007 2008 2009 2010

Product-specific guidelines (new GLs and revisions)

Quality guidelineNon-clinical/Clinical guideline

Overarching guideline

2011 2012

mAb guideline,revision of overarching and general guidelines

Guidance

2013 2014 2015 2016

First biosimilar

somatropin

First biosimilareopoetin

First biosimilarfilgrastim

Product authorisation

First biosimilar mAb (infliximab)

and follitropinalfa

First biosimilar

insulin glargine

First biosimilar etanercept

and enoxaparin

sodium

First biosimilar

teriparatide, rituximab and adalimumab

2017

➢ FDA (US) approved their first biosimilar in 2015 Venke Skibeli, PhD20.03.2018- LIS-TNFBIO 2018

Biosimilar reviews are not „abridged“ or„accelerated“

Time to positive opinion issued bythe European Medicines Agency (days)

Schneider CK: Biosimilars in rheumatology: the wind of change. Ann Rheum Dis. 2013 Mar;72(3):315-8.(Data source: EPARs on EMA website)

19

Pharmaceutical documentation

• Biosimilar

• RMP

• S & E

• PK

• Nonclinical tests

• Analytical comparisons

Regulators and clinicians have different viewpoints

• Lack of confidence in

comparability

• Reliance on the experience

gained from manufacturing

changes

• Confidence in clinical trials

• Clinical trials as a part of the

comparability (totality of

evidence)

• Biosimilar is a new product

• Biosimilar contains a new

version of the active

substance of the reference

product


21

Immunogenicity

• It is impossible to predict ➢ the incidence of unwanted immunogenicity➢ the characteristics of the immune response➢ the clinical consequences and significance of

such immunogenicity

• Immunogenicity of biosimilars– is the reference product immunogenic?

➢ Impossible to predict an increase or decrease

• The Applicant has to include immunogenicity data when submitting the dossier

Monoclonal Ab

Growth hormone

insulin


European guidance for immunogenicity of therapeutic proteins1

Immunogenicity assessment of therapeutic proteinsEMEA/CHMP/BMWP/14327/2006 Rev. 1

•

➢ Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. (EMA/CHMP/BMWP/86289/2010) (2012)

1http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_0000

43.jsp&mid=WC0b01ac05800240cb 22

➢ Adopted by CHMP June 2017

➢ Effective from December 2017


Essentials from the new guideline

• Multidiciplinary Summary of immunogenicity

➢ Bringing in all aspects from production to treatment

• Risk assessment

➢ Justification of a risk based approach to immunogenicityneeded

• Assays

➢ The basis is the development of adequate screening and confirmatory assays

➢ Properly validated assays: Incidence of ADAs?

➢ Look for neutralisation/persistence

• Clinical correlation➢ integrated analysis of immunological, PK, PD, clinical

efficacy and safety data➢ clinical consequences – impact on PK, safety, efficacy

23


Immunogenicity of biosimilarinfliximab

Source: EPAR Remicade; PLANETRA study (Yoo DH, et al. Ann Rheum Dis. 2013 Oct;72(10):1613-20. © Christian Schneider


24

A risk based approach to immunogenicity

• Production of ADAs?

• What methods has been used?

• Validation of assays?

• Are the ADAs neutralising?

• Further characterisation of ADAs

➢Infusion-related reactions/

hypersensitivity

• Clinical correlation of ADA production

➢PK measurements

➢Clinical consequences➢Efficacy & safety

25

High risk - epoetin Low risk - alemtuzumab


Interchangeability, switching and substitution*

Interchangeability refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect. This could mean replacing a reference product with a biosimilar (or vice versa) or replacing one biosimilar with another. Replacement can be done by:

➢ Switching, which is when the prescriber decides to exchange one

medicine for another medicine with the same therapeutic intent.

➢ Substitution (automatic), which is the practice of dispensing one

medicine instead of another equivalent and interchangeable medicine

at pharmacy level without consulting the prescriber.

*) Definitions according to EMA/EC Information guidance for HCP from May 2017

26

• Immunogenicity is a frequently mentioned concern of switching tobiosimilars

➢ Not much evidence for these concerns (Kurki et al, 2017; Cohen et al, 2018, Mckinnon et al., 2018)

• Mostly switching studies have been performed, alternating studies are rare

➢ Alternating studies may increase following US guidance. (Draft guidance on interchangeability, January 2017)

➢ It all comes down to traceabilityRogers (2006), Nephrology (Carlton) 11(4):341-6; Mellstedt et al (2008), Ann Oncol19(3):411-9; Barosi et al (2011), Haematologica 96(7):937-42;

Scheinberg and Kay (2012), Nat Rev Rheumatol. 8(7):430-6; Gecse et al (2013), Gut 62(6):803-7

Switching of biologicals

Norwegian Medicines Agency – position on interchangeability


Biosimilar-meeting in the EU- Commission, May 5th 2017

Hans Ebbers (Project Leader of the Pharmacotherapeutic Group III at the Medicines Evaluation Board (MEB/CBG) in The Netherlands):

• According to Ebbers:

• Thus far there is no evidence that switching to/from biosimilars causes safety issues (Ebbers et al, 2012; Kurki et al, 2017)

➢Differences in efficacy/safety may be hard to establish

➢Hard to draw definitive conclusions from switching studies, other than a general reassurance that no problems have occurred as a result from the switch

➢If the key concern is immunogenicity, then anti-drug antibodies (ADAs) in relation to clinical outcomes or trough levels should be determined


Recent publication with EU colleagues

Conclusion: Biosimilarsin the EU are interchangeable

o More than 10 years of experience with biosimilars confirm their safe and effective use and support the scientific approach taken

o Rapid advances in the analytical sciences allowcomprehensive characterisation of increasinglycomplex molecules (e.g. mabs)

➢ If biosimilarity has not been shown at the quality level this cannot be overcome by clinical trials.

o Risk-based approach for in-vivo animal studies

o Since both EMA and FDA accept the use of a global referenceproduct in clinical studies (if a proper“bridge” has beenestablished), sponsors are striving for global development of their biosimilars

Biosimilars in the EU : Where are We Now ?


Expected benefits of biosimilars

32

▪ Biosimilars introduce competition on the market

▪ Tailored development programmes reduce developmentcosts

▪ Nevertheless, pharmaceutical quality, efficacy and safety (including immunogenicity) expected to be highly similar to reference product

➢ Increase in patient access to valuable and moderntreatment options and containment of health carecosts

From the EMA perspective:

Biosimilars approved in the EU are of good quality, are efficacious and safe in use!


Follow us

@legemiddelinfo legemiddelverket legemiddelverket.no

Thankyou !

[email protected]

biosimilar regulation from a clinical point of view bio...biosimilar regulation from a clinical...

Documents