International Federationof Pharmaceutical Manufacturers & Associations

Pharmacovigilance Aspects of Biotherapeutic medicines:Nowadays and Perspectives

Dr Thomas Schreitmueller, F. Hoffmann - La RocheOn behalf of IFPMA Biotherapeutics Group

16 May 2013 © IFPMA 20131

Agenda

• Setting the scene– Changing regulations – a brave new world

• Pharmacovigilance Challenges related to Biotherapeutics– Biotherapeutics differ from chemically-synthesized

molecules – Immunogenicity– Exaggerated Pharmacology & Rare Events – Different regulatory pathways

• Traceability• Conclusions

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Pharmacovigilance today

• Systems developing at different rates, with different requirements

– Many countries still without strong pharmacovigilance systems

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

• 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

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New pharmacovigilance legislation adopted in the EU in December 2010 will promote and protect public health and save potentially thousands of lives each year by:•strengthening the European system for monitoring the safety and use of medicines•clarifying and simplifying tasks for the parties involved;•improving decision-making procedures and reducing administrative costs•strengthening communication and transparency on the safety of medicines

Patient SafetyChanging Regulations

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A brave new world of changing regulations:Understanding benefit-risk

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MoreDefined

Uncertain

Phase 3Trial

Population Label PopulationOff-label & Noncompliant

Population

OptimizeIndividualized

Population

PersonalizedHealth Care(biomarker,

Bioimaging, …)

Be

nef

it/R

isk

Efficacy-Effectiveness Gap

Lack ofcommunication

Lack ofexternal validity

How to BestManage ThisTransition?

Benefit Risk Management Plans

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

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;11:341-3463.Sharma BG. Manufacturing challenges for biosimilars – the process defines the product. EJHP Practice. 2007;13:54-56.

Biotherapeutics Small Molecules

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• One of the key factors that distinguishes both biotherapeutic and biosimilar medicines from low- molecular-weight pharmaceuticals and generic drugs is their capacity to elicit an immune response

• Immunogenicity is the production of host anti-bodies directed against a therapeutic (anti-therapeutic antibodies, ATA = anti-drug antibodies, ADA)

Challenge 2: Immunogenicity

16 May 2013 © IFPMA 20137 Chirmule et al, The AAPS Journal 2012

Approaches to address Immunogenicity

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Areas Potential clinical outcome

Safety • Hypersensitivity reactions • Receptor signaling related to cross-linking • Neutralizing activity of endogenous

counterpart

Efficacy • Neutralization • Impact PK • Change in biodistribution

None • Despite generation of antibodies, no discernible impact

Potential Consequences of Immunogenicity

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No predictability of Immunogenicityfrom preclinical to clinical

• Immunogenicity - The immunogenicity of mAbs is complex and there are a number of often poorly understood factors which make it difficult to predict with any certainty whether a therapeutic or diagnostic monoclonal antibody is likely to provoke a clinically relevant immune response*

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

Challenge 3: Exaggerated Pharmacology

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• The nature of safety problems identified after approval for biologicals is often related to the immunomodulatory effecte.g infections (Giezen et al. JAMA 2008)

• Adverse events are related to exaggerated pharmacology,e.g TB with Infliximab (Giezen et al, Drug Safety 2009)

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Exaggerated Pharmacology

Safety Issue Explanation

tuberculosis with the use of tumour necrosis factor (TNF)-a inhibitors, especially Infliximab

TNFa has a role in the immune response to the mycobacteria responsible for tuberculosis. Inhibition of TNFa will lead to an increase of the activity of the bacilli and cause disease

dramatically increased incidence of pure red cell aplasia in patients treated with one particular formulation of recombinant human epoetin

immunogenic response to endogenousmolecules, which occurred following changes in the manufacturing of epoetin alfa

Giezen et al. Drug Safety 2009

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Challenge 4: Different regulatory pathways

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Comprehensive pharmacovigilance and risk management planning needed for all biotherapeutics

• Even minor differences in the manufacturing process may affect the efficacy and/or safety profile– Innovator Products– SBPs may have potential for different safety profile than

innovator– 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.)

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Different regulatory pathwaysInterchangeability/Substitution

• Not all products will be approved for all indications

• Automatic substitution of biological products is not compatible with high levels of patient safety

• Right of the prescriber (physician) and of the patient to choose appropriate product based on proper and transparent information

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Different regulatory pathwaysImportance to “track & trace”

• Mix of biotherapeutics in use for the same treatment, some with the same INN

• Biotherapeutics with the same INN could have– Different posology– Different indications

How to track and trace the medicine which any given patient has received?

Identification Records Physician and patient awareness

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Acknowledged by the regulators: Increased emphasis on identification and tracking of biotherapeutics in pharmacovigilance systems

Article 102(e) of the Medicinal Products Directive 2011/83/EU, as amended by Directive 2010/84/EU, deals with the identification of medicinal products when reporting adverse events. Article 102(e) provides clarification specifically for biological medicinal products.

The Member States shall:

(e) 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, in accordance with Article 1(20), and the batch number [Emphasis added].

Example: New EU Requirement in EU

GVP Module VI requires MAH to follow up until batch number, brand name and active substance are known

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Traceability

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Issues in practice also emphasize importance of PV for biotherapeutics

• Biotherapeutics often used for chronic treatment– Switching therapies

• Physician and patient awareness• PV system requirements – necessary details to record

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

– Implications for effective pharmacovigilance• Frequency of switches• Managing track and trace, analysis

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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

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In Summary

• Due to their unique product characteristics and practices in prescribing and use, all biotherapeutics – innovator, SBPs and non-comparable biotherapeutics – require comprehensive pharmacovigilance guidance and systems

• Effective, global pharmacovigilance for patient safety requires that we:

1. Identify

Naming, distinguishable INN

2. Recordation /Reporting

Spontaneous reporting, Periodic reportsRobust dataPatient Records

3. Monitor and Assess

Safety signals identified, explored

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International Federationof Pharmaceutical Manufacturers & Associations

Thank you!

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