17. Gino Grampp - Amgen

International Federation

of Pharmaceutical

Manufacturers & Associations

Biotherapeutic medicines and

pharmacovigilance

Dr Gino Grampp, Amgen

On behalf of IFPMA Biotherapeutics Group

20 November 2013 © IFPMA 2013 1

Agenda

• Setting the scene

– Changing regulations – a brave new world

• Pharmacovigilance challenges related to

biotherapeutics

• Identification and traceability

© IFPMA 2013 2 20 November 2013

Pharmacovigilance today

• Systems developing at different rates, with different requirements

– Many countries still without strong pharmacovigilance systems

– INN system for biotherapeutics weakening, different approaches to naming at national levels

– Need for robust PV systems and consistent approach to naming to allow countries to leverage global PV data

• Focus on the development of comprehensive pharmacovigilance systems including:

– Need to establish basic pharmacovigilance guidance to ensure patient safety

– Improving identification, naming of products, record keeping

– Increased emphasis on robust adverse event collection/reporting, surveillance, signal detection and evaluation

– Focus on risk in context of benefit

• Important to take the entire prescription/dispensing/using/ADR reporting chain into consideration for traceability

3 © IFPMA 2013 20 November 2013

Policy-makers are emphasizing enhanced

pharmacovigilance of biotherapeutics


European Community 2011 PV Legislation1

“The Member States shall:

(e) Ensure […] that all

appropriate measures are taken

to identify clearly any biological

medicinal product prescribed,

dispensed, or sold in their

territory…”

FDA is Considering Policies for the U.S.2

“The FDA process for biosimilars

must include product specific

safety monitoring […] and

appropriate strategies must be

developed to ensure the

implementation of robust,

modern pharmacovigilance

programs for biologics.”

1. Article 102(e) of the Medicinal Products Directive 2011/83/EU, as amended by Directive 2010/84/EU.

2. Kozlowski S et al. N Engl J Med. 2011;365:385-388.

Challenge 1: Biotherapeutics differ from

chemically-synthesized molecules in both

complexity & sensitivity

Image Source: Tim Osslund photographer (Amgen staff); Amgen Usage Rights: Unlimited world-wide usage rights for an unlimited time. Images

not to scale.

1. Prugnaud JL. Similarity of biotechnology-derived medicinal products: specific problems and new regulatory framework Br J Clin Pharmaco l.

2007;65:619-620;

2. Roger SD. Nephrology. 2006;11:341-346

3. Sharma BG. Manufacturing challenges for biosimilars – the process defines the product. EJHP Practice. 2007;13:54-56.

Biotherapeutics Small Molecules


Challenge 2: Immunogenicity

• One of the key factors that distinguishes biotherapeutic

medicines from low-molecular-weight pharmaceuticals is their

capacity to elicit an immune response

• Immunogenicity is the production of host antibodies directed

against a therapeutic (anti-drug antibodies, ADA)

• Rates of immunogenicity vary by product and condition of use

(from <1% to >50%)1,2

• ADAs may have no clinical impact, may impact bioavailability,

or may impact safety and efficacy1,2,3


1. Koren, E., et al. (2002). “Immune Responses to Therapeutic Proteins in Humans - Clinical Significance, Assessment and Prediction.” Current Pharmaceutical

Biotechnology 3(4): 349-360.

2. Purcell, RT and Lockey, RF. (2008). “Immunologic Responses to Therapeutic Biologic Agents.” Journal of Investigational Allergololgy & Clinical Immunology

8(5): 335-342

3. Chirmule, N., et al. (2012). "Immunogenicity to Therapeutic Proteins: Impact on PK/PD and Efficacy." The AAPS Journal 14(2): 296-302.

Challenge 3: Complex pharmacology

7

Hansel et al, Nat Rev Drug Discov. 2010 © IFPMA 2013

• Complex biotherapeutics (e.g. monoclonal antibodies) can

modulate immunological functions through multiple mechanisms

• The nature of safety problems identified after approval for

biologicals is often related to the immunomodulatory effect e.g.

infections (Giezen et al. JAMA 2008)

7 20 November 2013

Challenge 4: Limited predictability of

analytical and preclinical to clinical

Analytical and preclinical studies cannot reliably predict

immunogenicity, pharmacology or safety of biotherapeutics

• Immunogenicity: currently animal models cannot predict clinical

immune response to impurities (e.g. protein aggregates)1,2

• Pharmacology: animal models cannot reliably predict structural

effects on pharmacology (PK and PD)3

• Safety: Off-target and immunomodulatory effects are often species

specific

– Eg. Cytokine storm occurring in healthy volunteers treated with the superagonist

anti-CD28 monoclonal antibody TGN1412 (TeGenero)4

© IFPMA 2013 8

1.EMA Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use

2. Ponce et al. Regulatory Toxicology and Pharmacology 54 (2009) 164–182

3. Carter. Nat Rev Immunol. 2006;6:343-357.

4. Sathish et al. Nat Rev Drug Disc. 2013;12:306-324

20 November 2013

Challenge 5: Different regulatory pathways

Originator

Biotherapeutic

• Novel product, generally with patent protection

• Marketing authorisation through full regulatory dossier

Similar Biotherapeutic Product (SBP)

• Product highly similar to an originator biotherapeutic that has already been authorized (reference medicinal product)

• Subject to a tailored regulatory data package establishing biosimilarity through comprehensive comparability exercise

Non-comparable Biotherapeutic

• Product that is not approved in accordance with the WHO SBP guidelines, e.g.

• Product developed on its own and not directly compared and analyzed against a licensed reference product

• May or may not have been compared clinically

• Can be subject to regulatory approval, but in some settings of a more abbreviated nature

• Products with unclear approval standards


Original

Biotherapeutic SBPs

What is an SBP (aka “biosimilar”)? • As their name implies, SBPs are “similar” but not identical versions of their innovative

reference biotherapeutic product (RBP)

• Whereas producing generic versions of off-patent chemically-synthesized medicines

is relatively easy, producing an SBP is far more complicated due to the complex

molecular structure and the unique manufacturing process required for

biotherapeutic medicines

• Due to their manufacturing process and complexity, all SBPs differ from the

originator product and from each other and therefore regulatory assessment should

ensure that the inevitable differences do not lead to clinically meaningful differences.

1. Neiderwieser D, Schmitz S. Biosimlar agents in oncology/haematology; from approval to practice. Eur J Haematol. 2011 Apr;86(4):277-88

10 20 November 2013 © IFPMA 2013

Different regulatory pathways -

Implications for pharmacovigilance

• Many countries now have regulatory pathways for biologics and biosimilars which are

aligned with WHO related guidelines

– However, some jurisdictions have stand alone pathways defined differently

– For example, stand alone pathways for related biologics, but without comparability

• This results in multiple sources of biotherapeutics in use for the same treatment,

some with the same INN

– E.g. Interferon beta-1a, interferon beta-1b

• Biotherapeutics using the same INN could have

– Different posology

– Different indications

– Different safety profiles


How to identify and trace the medicine which any given

patient has received?

Identification

Records

Physician and patient awareness

Comprehensive pharmacovigilance and

risk management planning needed for

biotherapeutics

• Even minor differences in the manufacturing

process may affect the efficacy and/or safety profile – Originator Products

– SBPs may have potential for different safety profile than originator

– Non-comparable biotherapeutics - different safety and efficacy

profiles compared to other biotherapeutics of the same product

class possibly due to lack of comparability information, i.e. unknown

whether and which physicochemical differences exist (Weise, M., et al.)2

• Biotherapeutics often used for chronic treatment

– Switching therapies can confound pharmacovigilance,

especially in the case of latent immunogenicity2


1. Wiese M et al. Biosimilars – why terminology matters. Nat. Biotech. 2011;29:690-693

2. Wieser C, Rosenkranz A. Clin. Kidney J. 2013;6:164–182

Example: Important differences in

Interferon beta-1a

© IFPMA 2013 13

Presented by Regina Buffels, Biogen Idec, World Biosimilar Congress EU, London 2012

and Adapted from Meager et al. J of Interferon and Cytokine Research 2011;31:383-392

• Published reports show differences in purity and potency among originator and

non-comparable versions of interferon beta-1a

• Recall non-comparables have not been assessed through WHO-aligned SBP

pathway

Purity by SDS-PAGE Potency by In vivo Bioassay

Originators Non-comparables

20 November 2013

Do interferon beta-1a differences matter?

Interim analysis of an observational study • MATRIX phase 4 study performed in 2 Latin American countries

comparing antibodies (NAbs), PD markers, and treatment-related events

in originator (A) and non-comparable (B) IFN-beta

• Enrolment targets: 90 MS patients per arm, with 1-3 years prior exclusive

use of either A or B

Presented by Regina Buffels, Biogen Idec, World Biosimilar Congress EU, London 2012

Abstract by C. Cuevas at 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 10-13 October 2012, Lyon, France

Some study findings:

• Low enrolment due to common

pharmacy substitution of (B) for (A)

• NAbs not detected – probably due to

low patient numbers

• PD marker higher in cohort A

(P<0.01)

• Flu like symptoms higher in cohort A (P<0.01)


Traceability

© IFPMA 2013 15

Systems should encourage recording details beyond INN

(e.g. brand name, unique identifier, batch number, etc)

20 November 2013

IFPMA supports the goal of the INN

system

• IFPMA continues to share WHO's goal in preserving the objectives of the INN

system:

• Unique and universally-available designated name for each active substance to be marketed

as a pharmaceutical

• Clear identification; and

• Safe prescribing and dispensing

• Biotherapeutic medicines need to be identifiable throughout the prescribing

and dispensing processes to promote patient safety

• In practice this is not occurring with the current INN system

• IFPMA welcomes WHO action on this issue to promote a globally harmonized &

distinguishable naming system for biotherapeutics to promote clear identification and

effective track-and-trace of each distinct biotherapeutic medicine

• IFPMA supports publication of a proposal for implementation of a distinguishable INN for

all biotherapeutics, including a unique product identifier

© IFPMA 2013 16

In Summary

• Due to their unique product characteristics and

practices in prescribing and use, all biotherapeutics –

originator, SBPs and non-comparable biotherapeutics –

require comprehensive pharmacovigilance

guidance and systems

Nomenclature Systems Advocacy

1. Identification

Brand name

prescribing and/or

distinguishable INN for

biotherapeutics

2. Reporting & analysis

Spontaneous reporting;

Multiple identifiers

Periodic reports

Safety signals identified,

explored

3. Build Support

Education;

Active participation with

stakeholders


• Regulatory authorities can support effective pharmacovigilance

through:

International Federation

of Pharmaceutical

Manufacturers & Associations

Thank you!


Industry support for unique identifier

Presented by IFPMA at Open Session to Stakeholders: 57th Consultation on International Nonproprietary Names (INN) for Pharmaceutical Substances, October 22, 2013

Tracking and tracing biotherapeutics

– challenges for the INN system

• INN plays a central role in:

– National pharmacovigilance and traceability systems

– National systems for substituting medicines

• Limited control over use of existing INNs

– Applicant decides if new INN wanted/required

– If existing INN is chosen, National Regulators need to ensure

implementation of WHO naming system

• Under current WHO criteria, possible for multiple

biologics to have the same INN with different clinical

characteristics

• As a result: no clear INN differentiation between

similar products

20 16 May 2013 © IFPMA 2013

Technology

17. Gino Grampp - Amgen