Module 1 2021

25/06/2021

Life Cycle Management Regulatory issues and strategies

Sjaak Bot, VP Regulatory Affairs, Janssen EMEA

• Begin with the end in mind • But what is the end….?

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The opinions expressed are my own and not necessarily the opinions of the Janssen Pharmaceutical Companies of Johnson & Johnson, or any other organization or individual.

I am an employee and shareholder of Johnson & Johnson

Sjaak Bot VP, Head of EMEA Janssen Regulatory Affairs Janssen

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Learning Outcomes

 Post-approval life cycle management is often underestimated during the development phase

 With more and more early submissions based on limited data, post-approval life cycle management becomes a much more critical and high-burden activity  Life cycle management is a multi-disciplinary activity. Once a product is on the market, it is a challenge to get the right priority of all disciplines involved.  Regulatory Affairs is uniquely positioned to manage the life cycle management and to make sure that already in the pre-approval phase the post-approval requirements are sufficiently made clear.

Begin with the end in mind, but be aware that the end of development is only the beginning of the product-life

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Begin with the end in mind….

 … to ensure that the development of a new product addresses the future regulatory requirements for approval and will lead to a product that meets the patients needs.

 But what is the end? ● The successful approval of the product?

● The reimbursement, launch and the availability for patients? ● Or…. is that just the beginning of the life cycle of a product?

 During development R&D fully focusses on the initial approval ● most of the R&D teams (including RA) switch immediately to other projects.

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Life Cycle Management The new reality?

Today, the post-approval phase is much more demanding and much more regulated.

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Post-Approval Efficacy

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Post-approval Efficacy

 Extension of the indication to different diseases or to extend the treatment duration

 Usually planned

 After approval the target patient population is broadened and/or treatment duration extended .

 Planned, and/or

 A requirement imposed at the time of initial approval.

 In procedures like Conditional Marketing Authorization, Adaptive Licensing, PRIME (and US Breakthrough designation):  Post-approval data generation is required to get a better picture of the efficacy and safety in a specific patient population.  More often these data come from other, external sources (e.g. disease registries, Real World Data etc.)

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Post-Approval Efficacy Example: The volume of post-approval efficacy activities of a TNF-blocker*

Nail Psoriasis, Quality of Life

Paediatric PK

PsA structural damage, physical function

Shortened infusion time Moderate CD

Fistulizing CD maintenance

Crohn’ s Diseas e USCrohn’s Disease

RA anaemia

UC colectomy, hospitalizatio n, surgeries

Early progressive RA

RA joint damage

Paediatric UC

Ulcerative Colitis Psoriasis

RA physical function

1998 1999 2000 2001 2002 2003 2004

2006 2005 2007 2008 2009 2010 2011 2012

Rheumatoi d arthritis signs and symptoms

RA shortened infusion

CD time to response, dose escalation, mucosal healing, reduction of surgeries, hospitalization, and corticosteroid use

Luminal CD maintenance

RA dose escalation

Ankylosing spondylitis

Psoriati c Arthritis

1 st indication US EU indications

Paediatric CD

AS change of population

CD 3 rd to 2 nd line

* Ref: EPAR Remicade®

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Post-Approval Safety

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Post-Approval Safety

The past: A reactive process. • A decent process to ensure that side effects were reported, analyzed and put into the label when needed, was sufficient • Benefit / risk balance Today: a pro-active, strategic approach • Approvals based on limited data lead to uncertainties about safety. • (benefit + uncertainties) / (risk + uncertainties)

 The reaction of the regulators:  Formalization within the 2012 pharmacovigilance regulation including the establishment of the PRAC, the RMP and other measures to control the product safety and its uncertainties.

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The PRAC Pharmacovigilance Risk Assessment Committee; the EMA’s Committee responsible for assessing and monitoring the safety of human medicines.

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Risk Management is a continuous process throughout the lifecycle of a medicinal product.  Safety specification: - What we know, and what we do not know about the product’s safety profile (important identified and potential risks, missing information)  Pharmacovigilance plan: - Actions to increase our knowledge about the clinically relevant risks and to identify new Adverse Drug Reactions  Risk minimization measures: - Actions to minimize the risks of the product, including evaluation of the effectiveness of these actions

Risk identification

Risk characterization and monitoring

Actions effective?

Risk minimisation

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• Post-authorization safety studies, PASS, should be proposed to address the uncertainties in the safety profile of the product, usually the long-term safety. • Risk Minimization activities or measures are the activities that the company has to put in place to ensure that the patient is protected against unwanted and sometime unknown side effects. • For instance, warnings and precautions in the labeling or patient alert cards. • With the RMP being a part of the approval, the approach nowadays is more pro- active, risk-based and addressing uncertainties. • This approach should also be applied within companies • Teams with specific expertise • (Proactively) define the risk minimization measures and design the post-approval studies. Risk Minimization Measures

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Post-Approval Safety Example: The volume of post-approval safety label changes of a TNF-blocker*

Infections in the elderly

Cardiomyopathy, parasitic infections Sarcoidosis

TB, skin and subcutaneous tissue disorders

Invasive fungal infections, aspergilosis

Delayed Hypersensitivity

Invasive fungal infections

Opportunistic Infections

ILD, AEs with fatal outcome

Agranulocytosis, Pancreatitis

CD: 2 nd to 3 rd line therapy

Demyelinating disorders Oligosaccharides

Heart failure

Interstitial pneumonitis /fibrosis

HSTCL

Peripheral demyelination

Severe infections

Extrapulmonary TB

Vasculitis

HSTCL

Pregnancy

M A

1999 2000 2001 2002 2003 2004

2006 2005 2007 2008 2009 2010 2011 2012

HBV reactivation

Serum sickness, Pericardial effusion

Readministration

Pancytopenia Listeriosis

HBV

Hepatotoxicity

ADR frequencies

Multiorgan complications, opportunistic infections Paediatric malignancy, leukaemia

Malignancies in COPD

Transverse myelitis, Anemia, Hepatocellular damage

Safety in juvenile RA

New onset psoriasis, pustular psoriasis, hepatobiliary events

Malignancies

Pneumonia

* Ref: EPAR Remicade®

Viral infections, witching between biological DMARDs, neutropenia, hematologic reactions

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Post-approval efficacy and safety; A pro-active, strategic approach At the time of approval

• limited data and more uncertainties

• CHMP will ask for a commitment to generate post-approval data to address the uncertainties.

• CHMP final assessment depends on agreement on post-approval commitments, mostly on safety, but also efficacy

 Company strategy: be prepared to present “on the spot” company-approved scenarios, e.g. • … follow the patients more closely, with questionnaires, PSURS with a higher frequency….

• …. participate in an existing Real World Evidence program where patients-data can be compared to other treatments

• … set up an own registry in which you can control the data

• … but, ideally the CHMP would like to see a real, long term randomized double blind controlled trial.  Whatever the outcome, it is work for the years to come!

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Life Cycle Management The volume of post-approval efficacy + safety

Infections in the elderly

Sarcoidosis

Nail Psoriasis, Quality of Life

Paediatric PK

TB, skin and subcutaneous tissue disorders PsA structural damage, physical function

Cardiomyopathy, parasitic infections

Invasive fungal infections, aspergilosis

Delayed Hypersensitivity

Shortened infusion time

Invasive fungal infections

Agranulocytosis, Pancreatitis Fistulizing CD maintenance

Opportunistic Infections

ILD, AEs with fatal outcome

CD: 2 nd to 3 rd line therapy

Oligosaccharides

RA anaemia

Crohn’s Disease US

Moderate CD

Demyelinating disorders

RA joint damage

Heart failure Early progressive RA

Peripheral demyelination UC col ctomy, hospitalization, surgeries HSTCL

HSTCL

Interstitial pneumonitis /fibrosis RA physical function

Severe infections

Paediatric UC

Ulcerative Colitis Psoriasis

Crohn’s Disease

Extrapulmonary TB

Vasculitis

Pregnancy

1998 1999 2000 2001 2002 2003 2004

2005

2006

2007 2008 2009 2010 2011 2012

Readministration

HBV reactivation

Serum sickness, Pericardial effusion

HBV

Pancytopenia Listeriosis Rheumatoid arthritis signs and symptoms

Hepatotoxicity

RA shortened infusion

Luminal CD maintenance

Multiorgan complications, opportunistic infections CD time to response, dose escalation, mucosal healing, reduction of surgeries, hospitalization, and corticosteroid use ADR frequencies

Malignancies in COPD

Transverse myelitis, Anemia, Hepatocellular damage

Safety in juvenile RA

RA dose escalation

Ankylosing spondylitis

Malignancies

Pneumonia

New onset psoriasis, pustular psoriasis, hepatobiliary events

Psoriatic Arthritis

1 st indication US EU indications

Paediatric malignancy, leukaemia

Paediatric CD

AS change of population

CD 3 rd to 2 nd li e

Viral infections, witching between biological DMARDs, neutropenia, hematologic reactions

Every box represents a regulatory procedure, with a clinical report, a safety analysis, several summaries, a revised label etc. A truly multi-disciplinary team work and within a fixed timeframe.

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 The burden of Post-Approval Life Cycle Management is often underestimated by other R&D functions  In most companies, Regulatory Affairs is in charge to ensure that at any time during the life of a product the right priority can be given.  Imagine a simple safety variation to include a new side effect in the label.. Life Cycle Management a multi-disciplinary activity

● Analyses done by the safety, epidemiology, statistics…

● Involvement of Labeling, Medical Writing, Regulatory Operations … ● Submit the variation with the new label to the Health Authorities within 60 days after the initial safety signal. ● Ensure implementation in the PI

 A pro-active, strategic, forward looking leadership role of Regulatory Affairs is the key to success!

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Complex Life Cycle Management The new reality?

 Earlier submissions, limited data, more post-approval commitments.  With shorter development timelines, the burden of post- approval LCM becomes higher  Especially in the first years of the life cycle, new safety signal will be reported frequently and new indications are studies in parallel

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Learning Outcomes

 Post-approval life cycle management is often underestimated during the development phase

 With more and more early submissions based on limited data, post-approval life cycle management becomes a much more critical and high-burden activity  Life cycle management is a multi-disciplinary activity. Once a product is on the market, it is a challenge to get the right priority of the disciplines involved.  Regulatory Affairs is uniquely positioned to manage the life cycle management and to make sure that already in the pre-approval phase the post-approval requirements are sufficiently made clear.

Begin with the end in mind, but be aware that the end of development is only the beginning of the product-life

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Thank you!

Sjaak Bot sbot@its.jnj.com

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