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
The Organisation for Professionals in Regulatory Affairs
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Thank you!
Sjaak Bot sbot@its.jnj.com
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