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EMEA experience with endpoints for EMEA experience with endpoints - - PowerPoint PPT Presentation

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EMEA experience with endpoints for EMEA experience with endpoints for Oncology drug approval Oncology drug approval EMEA/CHMP Biomarkers Workshop 16 December 2005 Francesco Pignatti, MD Francesco Pignatti, MD The European Medicines Agency

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EMEA experience with endpoints for EMEA experience with endpoints for Oncology drug approval Oncology drug approval

EMEA/CHMP Biomarkers Workshop 16 December 2005 Francesco Pignatti, MD Francesco Pignatti, MD The European Medicines Agency (EMEA) The European Medicines Agency (EMEA) London London -

  • United Kingdom

United Kingdom

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Contents Contents

Endpoints commonly used in oncology Legal requirements

  • EMEA Experience with oncology drugs

EMEA Experience with oncology drugs

– –Endpoints in pivotal trials for registration

Endpoints in pivotal trials for registration

– –Common reasons for rejection

Common reasons for rejection

  • FDA Experience

FDA Experience

  • EU oncology guideline (

EU oncology guideline (New New) )

– –OS

OS v v PFS PFS

  • Summary

Summary

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  • From initial onset in a high risk population

From initial onset in a high risk population Reduction in the risk of disease Reduction in the risk of disease Protection against toxicity with no decrease in survival Protection against toxicity with no decrease in survival

  • Patient Benefit (palliation, improvement in symptoms)

Patient Benefit (palliation, improvement in symptoms)

  • Tumor (usually based on imaging results)

Tumor (usually based on imaging results) Response Response

  • Onset or worsening of disease related symptoms

Onset or worsening of disease related symptoms

  • Tumor (usually based on imaging results)

Tumor (usually based on imaging results)

  • Progression

Progression-

  • free

free

  • Disease

Disease-

  • free

free

  • Overall

Overall Survival Survival

Clinical trial endpoints commonly used in oncology

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Legal requirements Legal requirements

  • Randomized controlled clinical trials (if possible)

Randomized controlled clinical trials (if possible)

  • Versus placebo and versus an established

Versus placebo and versus an established treatment (as appropriate) treatment (as appropriate)

  • Minimize bias and uncertainty

Minimize bias and uncertainty

  • Authorisation

Authorisation refused if medicinal product refused if medicinal product

  • Efficacy insufficiently substantiated or lacking

Efficacy insufficiently substantiated or lacking

  • Harmful

Harmful

  • …

…

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ICH E8 and E9 ICH E8 and E9

  • Confirmatory

trials Confirmatory trials should demonstrate should demonstrate clinical benefit clinical benefit

  • The primary endpoint

The primary endpoint

  • Should

Should provide the most clinically relevant provide the most clinically relevant and convincing evidence and convincing evidence

  • Valid and reliable measure of some

Valid and reliable measure of some clinically relevant and important treatment clinically relevant and important treatment benefit benefit

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SLIDE 6

The EMEA experience The EMEA experience

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16 (64%) 16 (64%) Cytotoxic agent Cytotoxic agent a

a

2 (8%) 2 (8%) Endocrine agent Endocrine agent c

c

7 (28%) 7 (28%) Monoclonal antibody, Monoclonal antibody, biopharmaceuticals biopharmaceuticals b

b

N = 25 N = 25

EMEA Experience: Approved New Agents EMEA Experience: Approved New Agents

a – Alimta,Caelyx, DepoCyte, Foscan, Glivec, Hycamtin, Litak, Myocet, Panretin, Paxene, Targretin, Taxotere, Temodal, Trisenox, Velcade, Xeloda b – Avastin, Beromun, Erbitux, Herceptin, MabCampath, Mabthera, Zevalin c - Fareston, Faslodex Pignatti et al. Crit Rev Oncol Hematol. 2002 May;42(2):123-35. Chaplin et al. ESMO 2004. Pignatti, DIA Annual Meeting 2005.

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Approved Approved Indications Indications Site of primary and endpoints Site of primary and endpoints

13 (28%) PFS, RR 13 (28%) PFS, RR 13 (28%) OS, PFS, RR 13 (28%) OS, PFS, RR 5 (11%) RR 5 (11%) RR 5 (11%) OS 5 (11%) OS 3 (6%) OS, RR 3 (6%) OS, RR 3 (6%) OS, PFS, RR 3 (6%) OS, PFS, RR 3 (6%) PFS, RR 3 (6%) PFS, RR 1 (2%) RR 1 (2%) RR 1 (2%) OS 1 (2%) OS Hematological Hematological malignancy malignancy Breast Breast Sarcoma Sarcoma Lung cancer Lung cancer Colorectal Colorectal Brain cancer Brain cancer Ovarian Ovarian Head and neck Head and neck Prostate Prostate

N = 47 Endpoints N = 47 Endpoints Indications: includes new drug application and extensions of indication

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Design of pivotal trials (N=47 approved Design of pivotal trials (N=47 approved indications indications) )

Reason for accepting design Reason for accepting design n n Endpoint Endpoint Design Design OS OS PFS PFS RR RR PFS PFS RR RR 9 9 14 14

  • utstanding activity
  • utstanding activity

AND AND no established treatments no established treatments 4 * 4 * Phase III Phase III RCT RCT 2 2 18 18 Phase II Phase II

RR: 22 (47%) PFS: 16 (34%) OS: 9 (19%) RR: 22 (47%) PFS: 16 (34%) OS: 9 (19%)

* variation of established drugs

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Pivotal trials: primary endpoints and design Pivotal trials: primary endpoints and design

(N=48 approved indications)

1995-1999 (N=20) 2000-2004 (N=28) Endpoint OS 2 (11%) 6 (21%) PFS 3 (16%) 11 (39%) RR 15 (79%) 11 (39%) RCT 11 (55%) 19 (68%)

2 4 6 8 10 12 1995 2000 Submission (Year)

  • No. of indications

RR OS/PFS RCT

Note: Ongoing applications excluded Abbreviations: OS overall survival, PFS progression-free survival, RCT randomized controlled trial

DIA Annual Meeting 2005.

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Rejected Rejected / withdrawn indications (N=13) / withdrawn indications (N=13)

OS OS RR RR RR RR Endpoint Endpoint Reason for rejection Reason for rejection n n Design Design 2 2 non randomised non randomised AND AND no outstanding activity no outstanding activity

  • no effect

no effect

  • wrong comparator

wrong comparator

  • dose justification

dose justification

  • low level of response

low level of response

  • inadequate control

inadequate control

  • target /size of population

target /size of population

  • dose justification

dose justification 6 6 Phase III Phase III 5 5 Phase II Phase II

Eur J Clin Pharmacol. 2002 Dec;58(9):573-80.

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FDA experience FDA experience

  • What endpoints have been used in oncology

What endpoints have been used in oncology registration studies? registration studies?

  • Presentation/Publication:

Presentation/Publication: J J Clin Clin Oncol

  • Oncol. 2003 Mar 15;21(6):1066

. 2003 Mar 15;21(6):1066-

  • 73

73

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Primary Endpoints for New Molecular Entities Primary Endpoints for New Molecular Entities

Accelerated Regular Response Rate 93% 53% Survival 0 % 12% Time to Progression 7% 20% Symptom benefit 0% 12% Other 7% 32%

  • S. Hirschfeld, presentation to the CBER Office of Cellular Tissue and Gene Therapy

seminar on November 16 Talarico, et al. ASCO 2005

Proportion of clinical studies used to support approval using various endpoints

Note: Totals are not 100% due to multiple endpoints.

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EU oncology guideline EU oncology guideline

“Guideline on Evaluation of Anticancer “Guideline on Evaluation of Anticancer Medicinal Products in Man” (July 2003) Medicinal Products in Man” (July 2003) http://www.emea.eu.int/pdfs/human/ewp/020595en.pdf http://www.emea.eu.int/pdfs/human/ewp/020595en.pdf

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Non Non-

  • cytotoxic compounds

cytotoxic compounds

  • Non

Non-

  • cytotoxic compounds

cytotoxic compounds ⇒ ⇒ Very heterogeneous Very heterogeneous group group

  • Antihormonal

Antihormonal agents, agents, antisense antisense compounds, compounds, signal transduction, signal transduction, angiogenesis or cell angiogenesis or cell cycle inhibitors, immune modulators cycle inhibitors, immune modulators … …

  • Toxicity may not be an appropriate endpoint in

Toxicity may not be an appropriate endpoint in dose and schedule finding trials dose and schedule finding trials

  • ORR: may not be an appropriate measure of anti

ORR: may not be an appropriate measure of anti-

  • tumor

tumor activity activity

  • Use of predefined PD targets

Use of predefined PD targets

  • Biological validation

Biological validation

  • Confirmation of PD

Confirmation of PD-

  • efficacy

efficacy

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Revision 3 of the anticancer guideline Revision 3 of the anticancer guideline

  • Non

Non-

  • cytotoxic Compounds:

cytotoxic Compounds: Focus on exploratory studies Focus on exploratory studies

  • Phase I, dose and schedule finding trials

Phase I, dose and schedule finding trials

– – Endpoints, healthy subjects studies

Endpoints, healthy subjects studies

  • Phase II, therapeutic exploratory studies

Phase II, therapeutic exploratory studies

– – Use of TTP instead of response rate

Use of TTP instead of response rate

– – Randomised phase II studies

Randomised phase II studies

– – Within patient comparisons

Within patient comparisons

  • Phase III, confirmatory studies (all types of agents)

Phase III, confirmatory studies (all types of agents)

  • Interim analyses / data maturity

Interim analyses / data maturity

  • OS as primary endpoint, not RR

OS as primary endpoint, not RR

  • Possible:

Possible: PFS when clinically relevant, s PFS when clinically relevant, symptom control ymptom control

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OS or PFS? OS or PFS?

  • OS provides strong evidence of efficacy (mortality)

OS provides strong evidence of efficacy (mortality)

  • PFS if it measures clinical benefit (not a good

PFS if it measures clinical benefit (not a good surrogate for OS) surrogate for OS)

  • Symptomatic progression

Symptomatic progression v.

  • v. radiological only

radiological only

  • Use PFS when further lines of therapy modify OS

Use PFS when further lines of therapy modify OS

  • Use OS when PFS

Use OS when PFS ≈ ≈ OS, or major differences in OS, or major differences in toxicity toxicity

  • What is the smallest clinically relevant and

What is the smallest clinically relevant and convincing effect in terms of PFS? convincing effect in terms of PFS?

  • Many methodological issues to avoid bias

Many methodological issues to avoid bias

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Alternative primary endpoints? Alternative primary endpoints?

  • TTP, TTF or EFS generally not adequate

TTP, TTF or EFS generally not adequate

  • Other measures of patient benefit (e.g. limb

Other measures of patient benefit (e.g. limb-

  • saving surgery, access to BMT)

saving surgery, access to BMT)

  • Tumour markers (e.g., M

Tumour markers (e.g., M-

  • protein) may be

protein) may be used to define PD (together with other used to define PD (together with other variables) variables)

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Summary/Conclusions Summary/Conclusions

  • Strict legal requirements/guidelines to demonstrate

Strict legal requirements/guidelines to demonstrate benefit benefit

  • Wrong design or lack of efficacy the most important

Wrong design or lack of efficacy the most important reason for rejection reason for rejection

  • Flexible assessment of designs and endpoints

Flexible assessment of designs and endpoints

  • RR when outstanding activity, no treatment

RR when outstanding activity, no treatment available available

  • From OS to other measures of benefit

From OS to other measures of benefit

  • Non cytotoxic agents

Non cytotoxic agents

  • Focus on exploratory studies

Focus on exploratory studies

  • Role of CHMP scientific advice

Role of CHMP scientific advice

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Acknowledgements Acknowledgements

Eric Abadie Eric Abadie Myriam Chapelin Myriam Chapelin Steven Steven Hirschfeld Hirschfeld Bertil Jonsson Bertil Jonsson Michel Marty Michel Marty