interpreting clinical trials in nephrology: a regulator’s ... · kdigo controversies conference...

Interpreting Clinical Trials in Nephrology: A Regulator’s

Perspective

Romaldas Mačiulaitis

European Medicines Agency Lithuanian University of Health Sciences

KDIGO

KDIGO Controversies Conference on Challenges in the Conduct of Clinical Trials in Nephrology September 8-11, 2016 | Paris, France

Disclosure of Interests

The views presented in this presentation/these slides are those of the author and should not be understood or quoted as being made on behalf of the

European Medicines Agency and/or its scientific committees

No relevant disclosures.

2 Romaldas Maciulaitis, Regulatory view

KDIGO


Main Messages

•  The regulatory interpretation of clinical trials employed for research and development (R&D) purposes is highly overlapping with patient centered academic one and put into the context of public health and legal constrains

•  Efficacy and safety findings build the basis assessing benefits, risks, uncertainties and risk management during drug life-cycle

•  R&D in nephrology could benefit from academic input especially when generic knowledge is missing, consensus is needed, or real world data are unreliable, e.g., as in case of orphan conditions

•  Joint initiatives combining academic, industry and regulatory competences might solve unresolved, controversial and emerging R&D issues thus, meeting unmet regulatory needs

3

Romaldas Maciulaitis, Regulatory view

KDIGO


Outline

•  Clinical trials in a regulatory framework

•  Various methodological approaches testing AKI and CKD

•  Possible ways to manage controversial issues


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5

Constrains of Entering into Practice and Using of Drugs

Authorization

R & D

Payment

Prescription

Patient

Is drug benefit exceeding the risk(s) tn a certain patient group?

What biological and pharmaceutical features are most beneficial for therapeutic purpose?

What are the health and monetary consequences of the usage of the drug vs alternative treatment in a patiens group?

What are the potential benefits of the drug to my patient vs existing alternatives?

Will I use as it is directed, do I want and do I can to pay for this drug from my pocket?

Drug

ca

ndid

ate

Drug

Usa

ge

Maciulaitis 2013, based on WHO 2002 5


KDIGO


Clinical Trial in a Regulatory Framework

•  Clinical trial is a tool for R&D, drug approval and life-cycling:

•  Pre-authorization

•  Scientific Advise, including Biomarkers Qualification Procedures/Advises, Parallel advise with Health Technology Assessment Authorities

•  PRIME, Adaptive Pathway Authorization

•  Marketing authorizations (MA)

•  Full MA, Conditional MA, Exceptional MA, New indications

•  Post-authorization

•  Post Authorization Safety Study (PASS)

•  Post Authorization Efficacy Study (PAES) 6


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7

•  Learning vs, Confirming Paradigm in ICH E8)

Clinical Drug Development Paradigms

ICH E8 (1997) 7


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Approved

Not approved

Minimum acceptable efficacy

Maximum acceptable risk

Risk

Benefit

T.Salmonson, 2007

Drug Approval – a Binary Perspective


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R&D

Patient Care

Efficacy

Focused on responder analysis and mean values measuring by clinically meaningful endpoints

Focused on individual patient need, such as off-label use, including

downgrading contraindications

Safety

Risk should be clearly specified and manageable

B/R (+)

• Guided by targeted product profile during R&D

• Should be (+) at the time of Marketing Authorization

Usually more than just

binary decision


Clinical Trial for Drug Approval vs Patient Care

KDIGO


B/R – what "risks" to consider

The "clinical" relevance of: •  non-clinical findings •  lack of non-clinical data •  pharmacokinetic data •  lack of PK data •  known PD/clinical safety profile, including safety

specification •  unknown clinical safety profile

•  use the safety specification in the RMP, throughout entire life-cycle of the product

Based on T.Salmonson, 2007



KDIGO


B/R – what "risks" to consider

The "clinical" relevance of: •  non-clinical findings •  lack of non-clinical data •  pharmacokinetic data •  lack of PK data •  known PD/clinical safety profile, including safety

specification •  unknown clinical safety profile

•  use the safety specification in the RMP, throughout entire life-cycle of the product

Based on T.Salmonson, 2007

11

Flexibility is limited



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KDIGO Controversies Conference on Challenges in the Conduct of Clinical Trials in Nephrology September 8-11, 2016 | Paris, France 12


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R&D

Patient Care

Efficacy

Focused on responder analysis and mean values measuring by clinically meaningful endpoints

Focused on individual patient need, such as off-label use, including

downgrading contraindications

Safety

Risk should be clearly specified and manageable

B/R (+)

• Guided by targeted product profile during R&D

• Should be (+) at the time of Marketing Authorization

Usually more than just

binary decision


Clinical Trial for Drug Approval vs Patient Care

KDIGO


< text >

Nafea faa ipoipo (When will you marry me?) by Paul Gauguin,1892

Interchange By Willem de Kooning, 1955

~$300 mio ~$300 mio


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Outline


•  Various methodological approaches testing CKD and AKI



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Different Patient Cohorts to be Considered for the Design


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A

15 to

<60

GFR (ml/min)

60 to

120

>

120

RRT

D: persistent normofiltration C: normo-hyper-normofiltration

B: normo-hyper-normo-hypofiltr. A: normo-hypofiltration F: comorbid DKD

TIME

Adapted based on Maclsaac et al., AJCD (2014)

E: normo-AKI-normofiltration

Time of diabetes diagnosis

E.g.

, RA

DA

R,

NEP

HR

ON

-D

E.g.

, IR

MA

- 2

Romaldas Maciulaitis, Regulatory view 17

Tools distinguishing different historically comparable patient cohorts are needed, e.g., to predict evolution

(A or B but not C to E scenarios)

Several GFR Evolutions’ Scenarios in DKD

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A scenarios

Several Albuminuria Evolutions’ Scenarios in DKD

Nor

mal

Albuminuria

(AU)

Mod

erat

ely

in

crea

sed

D: persistent normo AU

B: normo-moderate AU

A: normo-moderate-severe AU

E: comorbid DKD

TIME

C: normo-moderate-normo AU


Tools distinguishing different historically comparable patient cohorts are needed, e.g., to predict evolution

(A or B but not C to E scenarios)

Seve

rely

in

crea

sed

E.g.

, IR

MA

- 2

E.g.

, RA

DA

R,

N

EPH

RO

N D

E.

g.,

AC

CO

RR

D


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A

Model GFR Evolutions’ Scenario in DKD 15

to <

60

60 to

120

>

120

RRT

TIME

Adapted based on Maclsaac et al., AJCD (2014)


The baseline and response BMs predicting baseline & true responses (soft and/or hard)

∆GFR = -25% ∆GFR = -30%

CKD stage 3

CKD stage 5D B: normo-hyper-normo-hypofiltration

E.

g., R

AD

AR

, N

EPH

RO

N-D

E.

g., I

RM

A - 2

GFR (ml/min)

Baseline response = pharmacodynamic response

HR after adjustment to relevant confounders


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Several GFR Evolutions’ Scenarios after AKI

Adapted based on Cerda et al., CJASN (2008)

GFR

<60

ml/m

in

GFR

>60

R

RT


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Prevention and Management of AKI

Primary prevention

Secondary prevention

Therapy

Adapted based on Cerda et al., CJASN (2008), Macedo et al (2014) Romaldas Maciulaitis, Regulatory view 21

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Various methodological approaches


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Relevance of clinical effect for the applied indication

– General issues on study design (e.g., single study, non-controlled design due to feasibility issues in case of orphan renal condition, limited study duration to detect clinically relevant progression)

– Choice of (primary) endpoints and validity of the endpoint measurement (e.g., omission of relevant hard endpoints, such as all cause mortality, mGFR vs eGFR controversies)

– Selected population (e.g., representativeness of certain CKD population, including specific/variable risks)

– Choice of comparator (e.g., in case of well established use)



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Concerns not allowing accurate conclusion on the

clinically relevant safety profile:

– Control of different regional ratios of ADRs reporting

– Clustering ADRs

– AESI (Adverse events of special interests, such as AKI)

– Long-term safety data

– Other



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– Choice of comparator (e.g., in case of well established use only)



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WILL STUDY BE ABLE TO PROVE AN IMPACT ON PROGRESSION or

NOT?


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Furht et al., 2011, KDIGO 2012 27


Different Time Might be Needed to See the Effect

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Li et al., 2012 28


Different Patterns of Disease Cours do Matter

Longitudinal Progression Trajectory of GFR Among Patients With CKD

KDIGO


Li et al., 2012 29


Data about natural histories and abilities to have eligible concurrent matched controls

might facilitate R&Ds

Linearity is not a necessary case

Longitudinal Progression Trajectory of GFR Among Patients With CKD

Different Patterns of Disease Cours do Matter

KDIGO


eGFR vs mGFR


KDIGO


GFR is shown for men (Panel a) and women (Panel b) of various ages, with the GFR measured as the urinary clearance of inulin.

Wesson 1969, KDIGO 2012 31

Normal Values for GFR by Age

+/- 15 - 20%


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KDIGO 2012 32

Non-GFR Determinants for SCr


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Gupta et al., 2012

Non-GFR Determinants for CysC Inflammation

Multivariable linear regression adjusted for age, sex, race/ethnicity, diabetes, hypertension, ACE/ARB use, and lipid-lowering drug use.


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Gupta et al., 2012 34



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Targonska-Stepniak, & Majdan, 2011 35



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Stevens et al., 2009 36

After adjustment for GFR and GFR measurement error, age, sex, and race.

Non-GFR Determinants for SCr & CysC

After adjustment for GFR and GFR measurement error.


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Shlipak et al., 2013 37

Accuracy of eGFR Varies


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Rule et al., 2013 38

Different Risks Scores Depending on the Method in General Community


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GFR DECLINE ONLY vs OTHER OUTCOMES


KDIGO


Adjusted Hazard Ratios for the Three Study Outcomes in the General-Population Cohort

Studies.

Shlipak et al., 2013 40

GFR Decline vs Other Endpoints


KDIGO


Matshushita 2010, KDIGO 2012 41

Relationship of eGFR and albuminuria with mortality



KDIGO


Levey et al., 2011, KDIGO 2012 42

Summary of continuous meta-analysis (adjusted RRs) for general population cohorts with ACR



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Outline


•  Various methodological approaches testing AKI and CKD



KDIGO


Harmonization of Approaches in CT

• Qualification procedures/advises (QP/QA)

•  Nephrotoxicity BM QP/QA in 2008; ADPKD BM QP/QA in 2015

• Dedicated multi-stakeholders forums/workshops

•  Done: GFR in 2014; Biomarkers QP in 2016; ADPKD in 2016

•  To be held: KDIGO in 2016 and others

• Guidance documents (GL), including from the regulators

•  GL on the clinical investigation of medicinal products to prevent development/slow progression of chronic renal insufficiency (2016)

•  GL on the clinical investigation of medicinal products for acute kidney injury (concept paper to be issued in 2016/2017)


KDIGO


EMA/CHMP / SAWP Reports

Qualification Procedures/Advises


KDIGO



Qualification Procedures/Advises

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GL to prevent/slow progression of CKD that was released for public consultation in 2014-2015

EMA Guidance Documents


KDIGO


Previously proposed wording in the drafted guidance document has been changed:

Primary endpoints “Primary prevention: The primary efficacy endpoint should be the prevention or

slowing of decline in the level of renal function, defined as either

- Time to occurrence of CKD 3 or - incidence rate of CKD 3 or higher or - reduction in development of clinically meaningful and stable

difference in GFR loss with or without prevention of increased proteinuria /

albuminuria“

GL to Prevent / Slow CKD Progression


KDIGO


Previously proposed wording in the drafted guidance document has been changed:

Primary endpoints “Primary prevention: The primary efficacy endpoint should be the prevention or

slowing of decline in the level of renal function, defined as either

- Time to occurrence of CKD 3 or - incidence rate of CKD 3 or higher or - reduction in development of clinically meaningful and stable

difference in GFR loss with or without prevention of increased proteinuria /

albuminuria“



KDIGO


Proposed wording in the drafted guidance document has been changed:

Primary endpoints “Secondary prevention: The goals of secondary prevention in CKD are (1) to slow GFR decline

and (2) to reduce proteinuria/albuminuria

The recommended primary endpoint is time to a predefined and justified loss in GFR, such as 50%. Other (lower) magnitudes of proportions, such as 40% decrease in GFR might be used, provided this magnitude is qualified for specific primary disease.

The composite of all cause mortality and renal loss (CKD 5D, see definitions) should always be reported and in case of advanced rapidly progressive disease should be considered as a co-primary endpoint with justified acceptance criteria.”



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Adjustments for certain diseases, e.g., ADPKD,

IgAN, Lupus Nephropathy



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Fick et al 1995

e.g., other candidate EPs for ADPKD


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Inker et al 2015

Interpretation of findings is not always straightforward

Early Change in Proteinuria as a Surrogate Endpoint for Kidney Disease Progression: An Individual Patient Meta-analysis. Individual Level Association


KDIGO


eGFR vs mGFR

55

Regulatory Assessment


KDIGO




“Whenever precise determination of GFR is considered essential, such as when the expected decline in GFR is slow, leading to studies over prolonged periods of time (years) or is very variable in case of assessing GFR using estimations, it is recommended that measured GFR (mGFR) is prioritised over estimated GFR (eGFR).

eGFR using validated equations e.g. the Modification of Diet in Renal Disease Study Groups’ (MDRD) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) may also be used to complement mGFR.”


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KDIGO


Proposed wording in the drafted guidance document:

Study duration For primary prevention the study duration should normally be

based on the predicted rate of deterioration and the stage of CKD of the cohort selected at entry (see also the Section 4.4.1). It is expected that studies in primary prevention might require a substantial time.

For secondary prevention, the same general principles as for primary prevention apply; the study duration could be adapted based on the expected rate of progression and stage of CKD at entry. In the case of slowly deteriorating CKD, focusing on moderately or severely impaired renal function is advised.“



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KDIGO







Clinically meaningful specific patient reported

outcomes (PRO)?

Flexibility should be justified



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Orangulator Based on “Times”, 2 Sept 2016

Regulatory tango Based on “Times”, 2 Sept 2016


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Conclusions

•  The regulatory interpretation of clinical trials employed for research and development (R&D) purposes is highly overlapping with patient centered academic one and put into the context of public health and legal constrains

•  Efficacy and safety findings build the basis assessing benefits, risks, uncertainties and risk management during drug life-cycle

•  R&D in nephrology could benefit from academic input especially when generic knowledge is missing, consensus is needed, or real world data are unreliable, e.g., as in case of orphan conditions

•  Joint initiatives combining academic, industry and regulatory competences might solve unresolved, controversial and emerging R&D issues thus, meeting unmet regulatory needs

66


KDIGO


Thank you

Q?

[email protected]

67

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