Biotherapeutics –How to manage complexity?

Dr. Thomas Schreitmueller, Head Regulatory PolicyF. Hoffmann – La Roche Ltd, Basel, Switzerland

Disclosure – Conflicts of Interest

• Employed by F. Hoffmann – La Roche Ltd.• The relationship reported above will not impact my ability to

present an unbiased presentation

2

The complexity of Biotherapeutics and the need for specific regulatory frameworks for

biosimilarsThe use of existing copies of biotherapeutic products that have not gone through an adequate development program is not recommended due to potential safety implications.

Biological products are highly complex – Generics approval pathways and practices do not apply

Adapted from: Steven Kozlowski; FDA

K

pyro-E

G

D

O

D

GO

D

pyro-E • Pyroglutamyl peptides

K

• C-terminal Lysine

D

D

D • Deamidation

O

O • Methionine oxidation

G

G• Glycation

• High mannose,G0,G1,G1,G2

• Sialylation

Modifications may result in approximately 108 potential variants

Biologics have the potential to induce an immuneresponse

Formation ofanti-drug antibodiesis the chief criterion for defining a biologic’simmunogenicity.

FDA. Guidance on Immunogenicity Assessment for Therapeutic Protein Products. 2014.

• All protein-based biologics have an immunogenic potential, i.e. they may be identified as ‘foreign’ by the patient’s immune system and cause an immune response.

• The consequences of such an immune reaction can range from transient appearance of anti- drug antibodies (ADAs) without any clinical significance to severe life-threatening conditions.

• Besides potentially causing immunogenicity-related adverse effects, ADAs may alter a biologic’s pharmacokinetic/pharmacodynamics properties and/or abrogate its therapeutic effect.

Immunogenicity can be defined as:The tendency of a biologic to induce an unwanted immune response or to induce immunologically related adverse events.

3. Packaging, Labelling and Distribution

2. Drug Product Process

1. Drug Substance Process

Biotherapeutics – Manufacturing Complexity

https://www.ich.org/products/guidelines.html

8

WHA 67/20 is calling for strengthening regulatory systems mentioning biotherapeutic product (BTP) the first time in a WHA resolution

In reference to national regulatory capacity, the World Health Assembly approved this resolution on promoting the establishment of multinational collaboration, work sharing and cooperation between national and regional regulatory authorities in complex technical areas such as the regulation of biotherapeutic products in order to potentially overcome these constraints.

67th WORLD HEALTH ASSEMBLY (WHA)/A67 R20

9

By approving this resolution, Member States recognized that access to biotherapeuticmedicines, including biosimilars, is important for patients in many countries and, through the resolution, urge all Member States to develop “solid, scientifically-based regulatory frameworks” and to use the World Health Organization (WHO) Guidelines as the foundation for these frameworks.

67th WORLD HEALTH ASSEMBLY (WHA)/A67 R21

WHA 67/21 is calling specifically for increasing access to biotherapeutic product (BTP) the first time in a WHA resolution

10

Recommendation of 16th

ICDRA meeting in 2014*:

“…to strengthen the capacity of NRAs to assess and monitor the quality, safety and efficacy of biotherapeutics during the complete life-cycle of the product…”

*WHO Drug Information Vol. 28, No. 3, 2014

In the ICDRA 2014 recommendations member states wanted more from WHO

The WHO regulatory framework for biotherapeuticproducts

•Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by recombinant DNA technology, WHO Technical Report Series, No. 987, Annex 4 pdf, 418kb

•Regulatory assessment of approved rDNA-derived biotherapeutics, Technical Report Series, No. 999, Annex 3pdf, 147kb

The WHO Guidelines on procedures and data requirements for changes to approved biotherapeutic products was adopted by ECBS in its 68th meeting in 2017. •Annex 3, TRS 1011pdf, 452kb

https://www.who.int/biologicals/biotherapeutics/biotherapeutic-products/en/

•Guidelines on evaluation of similar Biotherapeutic Products (SBPs), Annex 2, Technical Report Series No. 977, 2009pdf, 493kb

•WHO Questions and Answers: Similar Biotherapeutic Productspdf, 424kb

•Guidelines on evaluation of monoclonal antibodies as similar biotherapeuticproducts (SBPs), Annex 2, Technical Report Series No. 1004, 2016pdf, 221kb

ImplementationWHO Guidelines adopted by the ECBS 2009 have been instrumental in raising awareness of the complex scientific issues related to the licensing of similar biological products. Implementation of the guidelines has become an increasingly important tool in achieving regulatory convergence.

https://www.who.int/biologicals/biotherapeutics/similar_biotherapeutic_products/en/

The WHO regulatory framework for similar biotherapeuticproducts

The Basis of Biosimilarity is the «Totality of Evidence»as outlined in all relevant global regulatory guidelines incl. WHO and WHO reference countries

The use of existing copies of biotherapeutic products that have not gone through an adequate development program is not recommended due to potential safety implications.

S c i e n c e

Ana

lytic

al S

imila

rity

Pre-

clin

ical

Sim

ilarit

y

Clin

ical

Sim

ilarit

y

Phar

mac

ovig

ilanc

e

B i o s i m i l a r i t y

Prop

er Q

ualit

y Sy

stem

The Process Defines the Product

© Roche

DNA 1

Product 1

Product 2

Fermentation 1Purification 1

Purification 2

Fermentation 2

Cell line 1

Cell line 2

14

DNA 2

Amino acid sequence

Vector 1

Vector 2

The same amino acid sequence

(perhaps the same DNA sequence)

(Probably) A different DNA-vector A different

recombinant production cell

line

A different production process

Different analytical methods

Different process à different product

A second manufacturer uses...

Biosimilar

Quality

Cross reference

Non-Clinical

Clinical Cross reference

Cross reference –class specific

Safety and efficacyIntegrated Biosimilarity

Exercise –Quality, Safety and Efficacy

3.Clinical

2. Non clinicalin vitro testing

(+specific in vivo if needed)

1. Quality (analytical) comparison, functional

aspects e.g. binding

Biosimilar?

Biosimilar?

Biosimilar?

Originator

Totality of Evidence/Stepwise Approach

Note: Unwanted immunogenicity can occur with any biologic including biosimilars- this can only be evaluated clinically

Applying the biosimilar concept-stepwise and comparative

Establishment of Similar Biotherapeutic Product (SBP) Guideline has increased – driven by WHO efforts

The history of regulatory frameworks for biosimilars

17

2004

EMA Overarching biosimilar guideline

(revised 2014)

EMANon-clinical/ Clinical

guideline(revised 2014)

2010 2015

WHOGuidelines on

biosimilars(Annex 2)

2009

FDAAbbreviated

approval pathway for biosimilars

(351(k))

FDABiosimilarity

scientific/qualityconsiderations

2014

FDABiosimilarity clinical

pharmacology (draft)

2005 2012

EMAProduct-class

specific guidelines(link)

EMAOverarching quality guideline (revised

2014)

WHOGuidelines on mAb

biosimilars(draft)

2016

EMAGuideline on

biosimilar mAbs(non-clinical/

clinical)

General EU Guidelines:

Overarching Guideline (CHMP/437/04)“Guideline on Similar Biological Medicinal Products”

Non-clinical/clinical Guidance Quality Guideline

Insulin Somatropin G-CSF Epoetin IFN-α LMWH mAbs IFN-β Follitropin

Class-specific EU Guidelines: non-clinical/clinical aspects:

2006 2006 2006 2006 2009 2009 2012 2013 2013

Revision ongoing, draft GL

target Q1 2018

Revision ongoing-concept

paper target Q3 2018

Revision 2012

Revision 2015

Revised 2014

Revised 2015

Revised 2014

Revision 2016

Revision being

considered 2018 TBD

Revision planned-concept paper due

Q3 18

The EU regulatory frameworks for biosimilars

12 withdrawn prior to opinion

2 negative opinions

43 Positive opinions

3 withdrawn after

approval

39 hold a current

Marketing Authorisation

1 awaiting EC decision

14 Unsuccessful applications

Unsuccessful applications (withdrawals/negative opinion) suggest that the system is working as it is able to distinguish products that should not be approved from those that should.

57 Marketing Authorisation Applications

Biosimilars applications submitted to EMA, approved, withdrawn or rejected

WHO. Guidelines on biosimilars 2009. http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdfEMA. Overaching guideline on biosimilars 2014: CHMP/437/04 Rev 1. EMA. Guideline on immunogenicity 2007: EMEA/CHMP/BMWP/14327/2006.

FDA. Guidance on biosimilarity 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdfFDA. Guidance on quality 2015:Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product (PDF - 144KB)

FDA. Draft guidance, Q&A on BPCI Act 2015:Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry (PDF - 107KB)

Biosimilar regulatory framework comparison

Regulatory Framework

Similarity concept

Substitution/Interchange-

ability

Extrapolation across

indications

Immuno-genicity

Naming/Pharmacovigilance Reference Product

EMAConcept created by EU

Decided at member state level

Ok if scientifically justified for each condition

Needs to be studied in humans pre- and post approval

EU uses INN system and Trade Name to distinguishBiotherapeuticProducts while the US is using a 4-letter suffix with the non-proprietry name--------------PV is required for all products in EU, US and in accordance with WHO guideline-------------Requires adequate monitoring process to differentiate AEs in the marketplace –but is not specified

Reference product must be approved in the EEA but possible to use non-EEA authorized comparator

WHO

Follows EU principles; however, WHO has not issued product specific non-clinical or clinical guidelines

Not addressed in WHO guidance

Reference product must have been licensed on basis of a full dossier

FDASimilar concept to EU except no product specific guidance.

Interchange-ability is a higher standard than Biosimilarity

Data from non-US with acceptable bridge to the US licensed product

WHO-specific EMA-specific FDA-specific Common Guidance

FDA: Interchangeability General Principles

• Two step process requires:– Demonstration of biosimilarity to reference

product– Demonstration of interchangeability

• Interchangeability a higher standard;requires clinical studies demonstrating that the biosimilarproduct:

– Provides the same clinical result as the referenceproduct in any given patient

– Can be switched back an forth with thereference product without greater risk than the risk of using the reference product alone

• Interchangeable product may be substituted forthe reference product without intervention of thehealthcare provider

The Theory of Biosimilarity

The use of existing copies of biotherapeutic products that have not gone through an adequate development program is not recommended due to potential safety implications.

McCamish M and Woollett G. mAbs 2011;3(2):209-217.

The variability of the quality attributes of the reference product defines the acceptable variability of the bio-similar …

…resulting in biosimilar products that are highlysimilar to the reference product

Schellekens H et al. Eur J Hosp Pharm Pract 2004; 3:43-47.Brockmeyer C et al. Eur J Hosp Pharm Pract 2009; 15:34-40.

“Copy epoetins” from 8 different manufacturers (marketed outside US/EU)

Eprex® reference standard

Eprex®BS EPO 1 Eprex®BS EPO 2

Not similar to reference product No clinically relevant differences

The Practice of Biosimilarity

Infliximab approval (Flixabi®) in the EU

“Based on the CHMP review of data on quality, safety and efficacy, the CHMP considers by majority decision that the risk-benefit balance of Flixabi in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis in adult patients and Crohn’s disease and ulcerative colitis in adults and in children and adolescents aged 6 to 17 year is favourable and therefore recommends the granting of the marketing authorisation”

Evaluation Conclusion from CHMP

Adapted from CHMP assessment report EMA/CHMP/272283/2016

“In conclusion, the undersigned CHMP members consider the benefit/risk balance of Flixabi to be negative since biosimilarityto Remicade has not been established.”

DIVERGENT POSITIONS dated 1 April 2016 Flixabi EMEA/H/C/004020/0000

Agnes Gyurasics (HU)Daniel Brasseur (BE)Daniela Melchiorri (IT)Greg Markey (UK)Jana Schweigertova (SK)Jens Heisterberg (DK)Karsten Bruins Slot (NO)Koenraad Norga (COM)Kristina Dunder (SE)Nevenka Trsinar (SI)Outi MakiIkola (FI)Pieter de Graeff (NL)Fatima Ventura (PT)Robert Hemmings (COM)

• For Flixabi an increased incidence of ADA was observed both in the Phase 1 and the Phase 3 studies, and it has not been substantiated that the difference was an artefact due to – for example – problems with the interpretation with the immunogenicity assays that were used.

• In the Phase 3 trial, which was conducted in patients with rheumatoid arthritis, the efficacy of Flixabi, whilst meeting the pre-specified equivalence margins, was consistently, although not universally, estimated to be lower than that of Remicade.

• It is noteworthy that the Phase 3 study showed that the efficacy, regardless of treatment group, was significantly lower in ADA positive patients than in ADA negative patients.

• It is not possible with reasonable certainty to exclude that the estimated reduction in efficacy of Flixabi was the result of the higher incidence of ADA. In this regard,

Based on these differences the Flixabi® EPAR reveals a divergence of opinions on biosimilarity of European regulators:

DIVERGENT POSITIONS dated 1 April 2016 Flixabi EMEA/H/C/004020/0000

Complex Mode of Action of mAbs may involve various mechanisms

TargetCells

ComplementC1q

Effector cells: NK

cells, MΦs

C) Complement dependent cytotoxicity (CDC)

B) FcγR mediated Antibody dependent cellular cytotoxicity (ADCC)

A) Direct cell death

Dendritic cell

D) Adaptive cellular immunity

Activated T-cells

Examples non-clinical:

• The binding activities of some batches of SB2 were found to be slightly higher than the upper limit of the similarity range.

FcγRIIIa of SB2 114 -141% compared to 77 - 108% for EU Remicade

FcγRIIb of SB2 105 -120% compared to 99 - 104% for EU Remicade

FcRn of SB2 105 -120% compared to 88 - 105% for EU Remicade

Flixabi® EPAR : The analytical and non-clinical assessment indicated (significant) differences between the biosimilar and the reference product

Adapted from CHMP assessment report EMA/CHMP/272283/2016

Attributes(Analytical method) Result

Ratio of G0 (Oligosaccharide, (%))

Lower G0 translated to lower binding to FcγRIIIa binding

Ratio of FcγRIIIa binding(Relative binding, (%))

Data presented by Celltrion during CASSS CMC Strategy Forum Brazil, 2015

Remsima®: The analytical and non-clinical assessment indicated (significant) differences between the biosimilar and the reference product

Comparison of FcγRIII-binding of Remicade®, Remsima® and Flixabi® clearly indicates:

Biosimilars are (highly?) similar but not identical…

Remsima® Remicade® Flixabi®

% FcγRIII-binding100

Schematic representation not representing concrete values

…and is raising important questions

% FcγRIII-binding100

Schematic representation not representing concrete values

• Are Remsima® and Flixabi® similar?• Are longterm safety and efficacy profiles comparable?• Can patients simply be switched from Remicade® to

Remsima® to Flixabi®?• Can we simply apply automatic substitution?

Remsima® Flixabi®

The Practice of Biosimilarity –

The Consequences

Risk mitigation strategies – Crucial for all Biologics/ Biosimilars

MoreDefined

Uncertain

Label Populations

OptimizedIndividualized

Populations and Endpoints

Ben

efit/

Ris

kSi

mila

rity

How to bestManage thistransition?

What to consider?

PV/Benefit Risk Management Plans

Adapted from Thomas Lundgrenn (DIA QPPV Forum, 17-18 April 2013)

Pharmacovigilance is key for allbiologics

Regulatory guidanceon biosimilar naming and AE reporting

EMA

• Biosimilars are given the same INN asthe reference product.

• Brand name and batch number is required for reporting of suspected adverse reactions.

FDA • INNs of biologics are given an identifier (four- letter suffix) unique to each product.

Robust pharmacovigilance is important for detection of rare and/or unexpected safety issues.

FDA. Nonproprietary Naming of Biological Products - Guidance for Industry. 2017. EMA. Guidelines on good pharmacovigilance practices (EMA/529641/2016). 2016. EMA. What does the black triangle mean? 2013.

INN, international non-proprietary name

• Rare and/or unexpected safety issues often become apparent only after a medicinal product has been on themarket.

• All new biologics, including biosimilars, require “special monitoring” by the EMA to encourage reporting of suspected side effects (indicated by ”▼” on SmPC andPIL)

• Unique identifyers that distinguish products (e.g., biosimilars from their reference products) are a prerequisite for appropriate reporting of adverse events in the post-marketing setting.

Switching between the Reference Product and it’sBiosimilars will be a Scenario in clinical Practice

Treatment-experienced patientsSwitching a patient to a biosimilar when he or she is already on a treatment program with the reference product or vice versa

Treatment-naïve patients

Biosimilar is prescribed to treatment-naïve patients.

Renwick et al. Lancet Oncol. 2016 Jan;17(1):e31-8. FDA: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, April 2015

No clinically meaningful differences are expected, since approved biosimilars have undergone therapeutic equivalence evaluations in treatment-naïve patients.

Will require additional clinical evidence going beyond the biosimilarityassessment otherwise the consequences of switching are unknown.

Cantini et al. Failure of bio-IFX after switching fromre-IFX in Behçet’s disease patientsEur. J. Rheumatology 2017

• Behçet’s disease (BD) is a chronic, relapsing, systemic vasculitis ofunknown cause involving veins and arteries of all sizes. Eye andneurological inflammatory involvement (neuro-Behçet) representsevere clinical manifestations of BD that may lead to blindness orpermanent neurological deficits.

• Our experience with the 3 BD patients who were successfully treatedwith re-IFX and who experienced recurrence of uveitis and of neuro-Behçet soon after switching to bio-IFX appears to reinforce skepticismregarding the exchangeability and automatic substitution of referencere-IFX with the biosimilar drug.

• In the absence of a valid explanation, we could only hypothesize that the rapid failure of bio-IFX in our 3 patients might be related to the development of ADAs against IFX.

Cantini et al. Failure of bio-IFX after switching from re-IFX in Behçet’s disease patients , Eur J Rheumatol 2017

Medical Associations Considerations on Switching and Position on

Pharmacy-mediated Interchangeabiliy

Switching – ESMO

The Danish Medicine Council’s recommendations for rituximab1. New patients - rituximab naive:

The expert committee believes bx. rituximab can be used

2. Patients who previously have been treated with MabThera - and after a break in the treatment are to resume biological treatment:The expert committee believes that there are no significant arguments for not using bx. rituximab

3. Patients who are currently undergoing treatment with Mabthera: The expert committee believes that change of drug during the introduction treatment may create uncertainty in the dialogue with the patients. Also new side effects or progression - even if not caused by that change could complicate the situation for the patients - who already are in a difficult phase of their disease and treatment.The expert committee recommend NOT to change the treatment/drug in the introduction phase

Biosimilar Market Dynamics in the EU and Considerations for Sustainability

45

Sustainability for the Biologics/Biosimilars –A stong and focused regulatory system is key

46

47Adapted from: IQVIA Advancing Biosimilar Sustainability in Europe, A Multi Stakeholder Report, September 2018

A Multi-Stakeholder Definition of Sustainability for the Biologics/Biosimilars Marketplace

48

49Adapted from: IQVIA Advancing Biosimilar Sustainability in Europe, A Multi Stakeholder Report, September 2018

Tendering Scenarios – Impact on Sustainability

Conclusions

Conclusions I

• Regulations for biosimilars are globally harmonized in that:

– They do not accept the generics approach for biologics– They all demand comparative assessments against one

reference product registered as NBE– Expect analytical differences between the reference product

and the biosimilar product and thus– Suggest a stepwise similarity assessment including head to

head pre-clinical and clinical studies as well– Permit extrapolation when scientifically justified.– Require robust pharmacovigilance

• The decision on similarity is based on the «totality-of-the-evidence»

51

Conclusions II

Patients deserve the best available treatment for better outcomes and cure.

Biosimilars are a valid treatment option when approved according to properly implemented standards

Switching decisions by the treating physician should be based on the patient situation and on the availability of data from robust similarity and switching relevant assessments

Uninformed or enforced switching of patients should be avoided through proper procurement strategies and the respective management of formularies

53

Thank You !