Considerations IN Pharmacovigilance for Biosimilars · 2018-02-07 · 1 Considerations IN...

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Considerations IN Pharmacovigilance for Biosimilars

Dr. Shubhadeep Sinha, MD (Pharmacology, Mumbai)Vice-President &

Head- Clinical Development & Medical Affairs (CD&MA)Hetero Labs Limited, India

ISOPCON 2016, Agra, India19-OCT-2016

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• The views, opinions expressed in the following PowerPoint slides are those of the

individual presenter and should not be attributed to the conference organizers,

Hetero, its directors, officers, employees, volunteers, members, chapters, councils,

Special Interest Area Communities or affiliates, or any organization with which the

presenter is employed or affiliated.

• These are interpretations of the presenter and should not be used as reference in any

other presentations or discussions or in any publications or sharing or attributed to

any domestic or international, non-governmental, governmental or regulatory

agencies.

• These PowerPoint slides are the intellectual property of the individual presenter. To be

used by permission. All rights reserved.

Strictly Confidential

DISCLAIMER

AGENDA

1. Biosimilar News

2. Biosimilar Safety and Definitions

3. Biosimilar Pharmacovigilance Challenges - Manufacturing & Structure

4. Biosimilar Pharmacovigilance challenges – Product Naming

5. Biosimilarity and Pharmacovigilance Challenges- Interchangeability

6. Biosimilarity and Pharmacovigilance Challenges- Immunogenicity

7. Biosimilarity and Pharmacovigilance Challenges- Evolving Regulatory

Guidelines3 Strictly Confidential

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BIOSIMILAR NEW(S)

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AGENDA

1. Biosimilar News








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BIOSIMILAR AND SAFETY - DEFINITIONS

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BIOSIMILAR OR BIO-SIMILARITY MEANS: Similar biological or biosimilar

A biosimilar is a biological medicinal product that contains a version of the activesubstance of an already authorised reference product in the EEA, and

which has shown similarity to the reference product in terms of qualitycharacteristics, biological activity, safety and efficacy based on a comprehensivecomparability exercise

The biological product is highly similar to the reference product

not withstanding minor differences in clinically inactive components

There are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

Pharmacovigilance is defined by the World Health Organization as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems.”

Biosimilar or Biosimilarity

Pharmacovigilance

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BIOSIMILARITY AND PHARMACOVIGILANCE

Putting the two together has yielded a complex regulatory landscape with wide

variations and inconsistencies across countries and markets.

Difficult enough to build and maintain a robust PV program to meet regulatory requirements for small molecule drugs— and yet generic PV programs will not satisfy the requirements for Biosimilars.

Evolution is at different speeds and directions

FDA regulations with respect to biosimilars continue to evolve and continue to improve clarity with respect to pharmacovigilance.

European Medicine Agency has specific requirements for biosimilar pharmacovigilance (PV)—although the PV landscape continues to evolve in Europe, as well.

Companies developing biosimilars, need to be aware of several key issues with respect to

biosimilars that will impact their PV programs.

Challenges

AGENDA

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Manufacturing methods.

1. More complex than for conventional small-molecule drugs.

2. Small differences between manufacturing methods can significantly

impact a biosimilar’ s biological properties, purity and clinical

activity.

3. No guarantee that resulting biosimilar will be comparable to its

reference product

Challenges

Biotherapeutics’ structure & manufacturing underscore the importance of pharmacovigilance (PV)

• A complex production process

– Intrinsic variability

• A complex structure- difficult to make exact biological copy, hence “biosimilar”

• A potential for generating unwanted immune responses

– Potential for both rapid and delayed onset adverse reactions

• Potential impact of post-marketing changes

Specifically traceability is of ImportanceSpecifically traceability is of Importance

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• Microheterogeneity

– alternative disulfide pairings/disulfide shuffling, deamidation, (methionine) oxidation, crystallization of N-terminal glutamine residues, and partial enzymatic cleavage

• Aggregation

• Glycosylation

– Only a problem for glycosylated proteins

– Virtually impossible to replicate glycosylation

• Excipients

• Syringe

– A known source of problems

MANUFACTURED PRODUCT RELATED PROBLEMS

GLYCOSYLATION IN BIOLOGICAL DRUGS IS IMPORTANT FOR TWO MAIN REASONS:

• Glycan may affect many of the protein properties: pharmacokinetics (uptake and length of time in the body), bioactivity, secretion, in vivo clearance, solubility, recognition, and antigenicity

• Quantitative and qualitative aspects of glycosylation affected by production process in culture, including cell line, method of culture, extracellular environment, and protein itself

Comprehensive Characterization

• Physicochemical as well as biological

• Against multiple batches of innovator spanning a number of years

• Understand innovator variability

• Specification changes over life of product

• No label change

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The Solution: Characterization

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Product names.

Multiple distinct biosimilars in development, multiple manufacturers may be producing

same biosimilar—names not necessarily distinctive---traceability issues in c/o an ADR.

Even slight variations in the manufacturing process from one company to another may

have untoward consequences. It is critical to record complete batch information as part of

the PV program.

Product identification compromised across healthcare settings.

Both spontaneous adverse event reporting systems & active surveillance systems

depend on accurate identification of the product dispensed or given to patients, yet

there is great variability in how health professionals and patients refer to

medications in these settings.

Challenges

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AGENDA

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Interchangeability –

Generics and brand name products can be prescribed

interchangeably in most cases. Biosimilars—although comparable to

the innovator drugs—cannot.

“Automatic” interchangeability would require data showing that a

biosimilar produces equivalent clinical result in any given

individual.

Challenges

AGENDA

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Preapproval immunogenicity in the entire premarketing clinical study

population mandatory but not sufficient to rule out rare occurrences

Post-approval surveillance for immunogenicity and rare adverse

events may be needed and/or required over the long term, once a

biosimilar is on the market.

Such monitoring is expected across regulatory guidelines varying in

conditions from guideline to guideline.

Challenges- Immunogenicity

Safety Issue Explanation

tuberculosis with the use of

tumour necrosis factor (TNF)-a

inhibitors, especially Infliximab

and adalimumab

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 (containing polysorbate)

immunogenic response to endogenous

molecules, which occurred following changes in the manufacturing of epoetin alfa

Giezen et al. Drug Safety 2009

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Complexity of immunogenicity: Exaggerated pharmacology

3011/28/2016

3111/28/2016

3211/28/2016

Risk Based Approaches to Immunogenicity Testing

Risk = Probabilityharm x Severityharm

•Severity outweighs the probability of a risk occurring.

•The overall Risk Score depends on an assessment of the various

factors that influence immunogenicity

How many patients are

likely to mount an immune

response?

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What happens to the patient

if they mount an immune

response?

AGENDA

1. Biosimilar News








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Evolving guidelines. As guidelines for biosimilar approvals and PV evolve,

pharmaceutical companies will need to stay vigilant so that their PV

programs can rapidly adapt to evolving regulatory criteria.

Challenges

Key Regulatory Countries for Biosimilars

2000-2004 2008 2009 2010, 2016

2011, 2015, 2016

EuropeCanada

Australia Japan

United States(established

legal pathway)

Europe

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2012, 2016

India (CDSCO)

biosimilar guideline

11/28/2016

3711/28/2016

3811/28/2016

CLINICAL STUDY REQUIREMENTS

Design trials with right endpoints and right population

Difficulty in identifying sites and patients in Phase I and III

Can take a long time and a lot of patients

Phase IPhase I studies supporting dose(s) for targeted indications

Phase I Study:

•Healthy volunteers vs patients

•Ethics committee considerations•Part 1 - Initial safety and comparative PK arms (at labeled dose)•Part 2 - Comparative PK/PD, Immunogenicity and Safety/Efficacy run in parallel to Phase III study submissions•N>40 for Interim Analysis for PK/PD powering

Difficulties• Cross-over designs

• Sentinel dosing group for Phase I

Phase III

•Single Pivotal (therapeutic category)

• PK/PD assessments with shorter cycles

of therapy

•Immunogenicity determined with full

regimen of therapy

•“Interchangeability” not yet addressed

by FDA

Thank you for attention!

THANK YOU FOR ATTENTION!

Strictly Confidential 40

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Considerations IN Pharmacovigilance for Biosimilars · 2018-02-07 · 1 Considerations IN...

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