EMA- -EFPIA M&S Workshop EFPIA M&S Workshop - - Session 3 - - PowerPoint PPT Presentation

EMA EMA-

• EFPIA M&S Workshop

EFPIA M&S Workshop -

• Session 3

Session 3 M&S examples that failed or succeeded to M&S examples that failed or succeeded to meet regulators meet regulators’ ’ expectations expectations Decisive support of Modeling & Simulation Decisive support of Modeling & Simulation for getting drug approval of non for getting drug approval of non-

• tested

tested dosing scheme : 2 examples dosing scheme : 2 examples

Valérie Cosson

• F. Hoffmann–La Roche Ltd

Position statement and Position statement and associated questions associated questions

Successful approval of non-tested dosing scheme using M&S techniques without further dedicated prospective studies



Would in general the EMA accept the principle of relying on M&S approaches to label an unstudied dose or dosing regimen?

• If yes, what information and evidence would be needed by

the EMA?



Would in general the EMA accept to increase the dose in a sub-population if the exposure remain within the investigated range?

• If yes, what information and evidence would be needed by

the EMA?

2

Background Background

What has triggered the changes in dose (and dose adjustment rules) compared to the original plan?



Changes of regulatory recommendation

• n endpoint

target range: the example of C.E.R.A (Continuous Erythropoietin Receptor Activator), a new erythropoietin stimulating agent (ESA) for the treatment

• f anemia in patients with chronic kidney disease

(CKD).

• BLA and MAA were submitted to both FDA and EMA

based on an hemoglobin (Hb) target range of 11 to 13 g/dL.

• After submission, FDA modified the Hb target range to

11 to 12 g/dL (as optimal target range) and avoid Hb > 13 g/dL for safety concern.

3

Background Background

What has triggered the changes in dose (and dose adjustment rules) compared to the original plan?



Less efficacy in an identified sub-population: the example of ribavirin in HCV genotype-1 patients with normal transaminases (ALT)

• A lower dose than the recommended one for HCV

genotype-1 infected patients with elevated ALT was used in patients with normal ALT

• Less efficacy i.e. sustained virologic response

(SVR) was

• bserved in this population compared to the patients

with elevated ALT

4

Rationale and objectives of the M&S Rationale and objectives of the M&S analyses analyses



In both examples, the knowledge of the exposure- response relationship was considered sufficient to rely on M&S approaches to investigate new doses



Clinical trial simulations were conducted to assess efficacy and safety clinical outcomes of non-tested dosing scheme (and dose adjustment) proposed in the SmPC (Summary of Products Characteristics)

5

Available Data for C.E.R.A. Available Data for C.E.R.A.



Data from 400 patients of 3 open-label, randomized, multicentre, parallel-group Phase III studies, AMICUS, MAXIMA and PROTOS



The PK assessment period in AMICUS was the 24-week correction

• period. The PK assessment period in both MAXIMA and PROTOS

was the 28-week dose titration period.



The Hb assessments were performed weekly in the three Phase III studies during the correction or titration periods.

6

Available Data for Ribavirin Available Data for Ribavirin



For model development, SVR and Hb data from genotype- 1 infected CHC patients with elevated ALT levels receiving a ribavirin treatment of 48 weeks were used:

• 817 patients for GAM development of SVR
• 1233 patients for GAM development of incidence of anaemia



For the assessment of dose in genotype-1 infected patients with normal ALT levels receiving a daily dose of 800 mg ribavirin for 48 weeks, SVR data from 138 patients and Hb data from 206 patients were used

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Methods Methods



Development of PKPD models using available data.



Evaluation of the predictive performance of the PKPD models by visual predictive check and posterior predictive check on defined metrics



Simulations to evaluate the efficacy and safety of alternative dosing scheme.

8

The Exposure The Exposure-

• Response Analysis for

Response Analysis for C.E.R.A. C.E.R.A.

Time [days] C.E.R.A. [ng/mL] 5 10 15 20 50 100 150 200 Hemoglobin [g/dL] 6 8 10 12 14 16

PROTOS: patient 2651

Time [days] C.E.R.A. [ng/mL] 5 10 15 20 50 100 150 200 Hemoglobin [g/dL] 6 8 10 12 14 16

PROTOS: patient 752

Time [days] C.E.R.A. [ng/mL] 5 10 15 20 50 100 150 200 Hemoglobin [g/dL] 6 8 10 12 14 16

PROTOS: patient 851

Time [days] C.E.R.A. [ng/mL] 10 30 50 50 100 150 200 Hemoglobin [g/dL] 6 8 10 12 14 16

MAXIMA: patient 1364

Time [days] C.E.R.A. [ng/mL] 10 30 50 50 100 150 200 Hemoglobin [g/dL] 6 8 10 12 14 16

MAXIMA: patient 4004

Time [days] C.E.R.A. [ng/mL] 10 30 50 50 100 150 200 Hemoglobin [g/dL] 6 8 10 12 14 16

MAXIMA: patient 2501

Time [days] C.E.R.A. [ng/mL] 10 20 30 40 50 100 150 200 Hemoglobin [g/dL] 6 8 10 12 14 16

AMICUS: patient 301

Time [days] C.E.R.A. [ng/mL] 10 20 30 40 50 100 150 200 Hemoglobin [g/dL] 6 8 10 12 14 16

AMICUS: patient 834

Time [days] C.E.R.A. [ng/mL] 10 20 30 40 50 100 150 200 Hemoglobin [g/dL] 6 8 10 12 14 16

AMICUS: patient 125

Observed and predicted Hb concentrations in individual patients selected from PROTOS, MAXIMA and AMICUS.

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The Exposure The Exposure-

• Response Analysis for

Response Analysis for Ribavirin Ribavirin



The higher incidence of anemia in patients with normal ALT is due to a difference in percentage of female patients (61% for normal ALT versus 33% for elevated ALT)

Dose/BW (mg/kg) Probability SVR 5 10 15 20 25 0.0 0.2 0.4 0.6 0.8 1.0

Probability SVR

Dose/BW (mg/kg) Likelihood HgB < 10 5 10 15 20 25 0.0 0.2 0.4 0.6 0.8 1.0

Likelihood Anemia

Likelihood of Anemia

1.0 0.8 0.6 0.4 0.2 0.0

Incidence Hb < 10 g/dL 25 25 20 15 10 5

Probability SVR

Dose/BW (mg/kg)

0.0 0.4 0.2 0.8 0.6 1.0

Probability SVR 5 20 10 15 Dose/BW (mg/kg)

Elevated ALT Normal ALT

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Model qualification Model qualification



The PKPD models are qualified to be used in simulation mode

30 35 40 45 50 55 60 50 100 150 200 250 SVR response (%) Replications

800 mg

30 35 40 45 50 55 60 50 100 150 200 250 SVR response (%) Replications

1000/1200 mg

5 10 15 20 50 100 150 200 250 Incidence HgB < 10 (%) Replications

800 mg

5 10 15 20 50 100 150 200 250 Incidence HgB < 10 (%) Replications

1000/1200 mg

Efficacy Safety Patients with elevated ALT Patients with normal ALT

Observation

Occurrence Hb>13 g/dL (IV)

C.E.R.A. Ribavirin

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40 60 80 Patients with at least one Hb>13 during first 28 w [%] AMICUS: 71 5 10 15 20 25 30 Number of replicates

M&S Results: Simulation of efficacy and M&S Results: Simulation of efficacy and safety of non safety of non-

• tested dosing scheme and dose

tested dosing scheme and dose adjustment rules of C.E.R.A. adjustment rules of C.E.R.A.



With 0.3 µg/kg/w IV or SC every 2 weeks, the median predicted

• ccurrence of Hb>13 g/dL

was decreased down to 41% and 26.5% respectively compared to 71% in AMICUS.



With 0.3 µg/kg/w IV and SC given every 2 weeks, the median response rate (percentage of patients with Hb11 g/dL and Hb from baseline 1 g/dL at least once during the first 24 weeks of treatment) was 92.5% and 83% respectively. The value in AMICUS was 93%.

0.3 µg/kg/w IV 0.3 µg/kg/w SC Median predicted incidence >13 g/dL 41.0 % 26.5% Median simulated response rate 92.5 % 83.0%

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M&S Results: Simulation of efficacy and safety of M&S Results: Simulation of efficacy and safety of non non-

• tested dosing scheme of

tested dosing scheme of Ribavirin Ribavirin



At 1000/1200 mg, the SVR in patients with normal ALT is predicted to be similar to patients with elevated ALT

800 mg 1000/1200 mg Elevated ALT 40% (36%-45%) 49% (46%-53%) Normal ALT 39% (34%-44%) 48% (42%-53%)



At 1000/1200 mg/day, the incidence of anaemia in patients with normal ALT is predicted to be higher than in patients with elevated ALT, especially in females

1000/1200 mg Females Males Elevated ALT 23% (19%-27%) 8% (6%-10%) Normal ALT 31% (24%-38%) 11% (7%-16%)

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Conclusions Conclusions

1.

The trial simulations have shown that new dosing scheme proposed in SmPC ensures good efficacy and manageable safety risk.

2.

Thanks to Modeling and Simulation techniques additional confirmatory trials could be avoided.

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Regulatory Feedback Regulatory Feedback



The new dosing scheme and dose adjustment for C.E.R.A. were approved by EMA and FDA



EMA accepted the changes in the label

• The dose of 1000/1200 mg Ribavirin

is not limited only to patients with elevated transaminases

• The risk of developing anemia is higher in the female

population

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Position statement and Position statement and associated questions associated questions

Successful approval of non-tested dosing scheme using M&S techniques without further dedicated prospective studies



Would in general the EMA accept the principle of relying on M&S approaches to label an unstudied dose or dosing regimen?

• If yes, what information and evidence would be needed by

the EMA?



Would in general the EMA accept to increase the dose in a sub-population if the exposure remain within the investigated range?

• If yes, what information and evidence would be needed by

the EMA?

16

Extended Questions Extended Questions



If the Sponsor demonstrates that:

• The pharmacology and the mechanism of action of the drug are

well known,

• The exposure-response relationships for efficacy and safety in the

target population are adequately characterized,

• The covariate effects are known,
• Enough confidence in the models to simulate response in a specific

sub-population within the range of previously studied exposure:

 All of the proof of the model robustness using classical technique (gof plots, SE, VPC, PPC…) are provided



In which cases

• The EMA would only rely on the simulations to label an unstudied

dose or dosing regimen ?

• The EMA would still ask to confirm in an additional study ?

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BOS4 : Extended Questions BOS4 : Extended Questions

Significant Benefit in life-threatening disease Prevention or delay of long term disease with high morbidity mortality Symptomatic treatment AEs that can be monitored and treated M&S only? M&S only? M&S only? Safety signals with clear predictive indicators M&S only? M&S only? M&S only? Safety signals without clear predictive indicators M&S + Additional data? M&S + Additional data? ??



In which cases

• The EMA would only rely on the simulations to label an

unstudied dose or dosing regimen ?

• The EMA would still ask to confirm in an additional study ?

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Efficacy Safety