Registration studies
This presentation is the property of its rightful owner.
Sponsored Links
1 / 53

Registration Studies PowerPoint PPT Presentation


  • 48 Views
  • Uploaded on
  • Presentation posted in: General

Registration Studies. Registration studies – Phase III. Objectives To gain regulatory approval Robustness of trial and endpionts are paramount Design of trial can be discussed with regulatory agency To assess the efficacy of the drug compared to existing ‘gold standard’

Download Presentation

Registration Studies

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Registration studies

Registration Studies


Registration studies phase iii

Registration studies – Phase III

Objectives

  • To gain regulatory approval

  • Robustness of trial and endpionts are paramount

  • Design of trial can be discussed with regulatory agency

  • To assess the efficacy of the drug compared to existing ‘gold standard’

  • To assess the toxicity of the drug compared to existing ‘standard of care’

  • Collect QOL where appropriate

  • Collect relevant pharmaco-economic data


Phase iii studies patient selection

Phase III Studies – Patient selection

Regulatory authorities wish the population to be as homogenous as possible .

Specific tumour type

  • Stage, grade, target expression, geographical location increasingly important

  • Biomarkers may be mandatory

  • Good performance status

  • Any exclusion criteria based on population and any toxicities seen in earlier studies

  • Informed consent

  • Ability to read and write - QOL


  • Phase iii studies study design

    Phase III Studies – Study Design

    • Consider choice of endpoints- PFS, OS (RECIST, BIR)

    • Consider duration of therapy

    • Consider design

      • Parallel

      • Factorial

      • Crossover

    • Consider mode of randomisation - reduces selection bias

      • Equal/unequal

      • Stratification


    Phase iii studies study design1

    Phase III Studies – Study Design

    • Consider degree of blinding - reduces reporting bias

      • Open label studies are common

      • Single

      • Double

    • Sample size calculations

      • "Is my trial large enough to demonstrate a clinically significant difference between the groups if one is truly present?"


    Sample size calculation

    Sample size calculation

    • In oncology studies, this calculation determines the number of events, not the number of patients, required

    • Depends on:

      • Natural intra-patient variability - less important in oncology

      • Minimum difference between groups considered important by investigator

      • Acceptable levels of α and β

    • Remember effect of interim analyses


    Endpoints

    Overall Survival - time to death from any cause

    Progression-free survival - time to first observation of disease progression

    Time to treatment failure- time to first observation of disease progression, death or discontinuation

    Duration of response – time to first observation of response to progression / death

    Quality of Life- mainlyfor blinded studies.

    Endpoints


    Quality of life

    Quality of Life

    • 2 main instruments used

      • Functional Assessment of Cancer Therapy- General ( FACT-G)

      • European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire- C30 ( EORTC- C30)

    • Both modular set up with generic core questionnaires in combination with disease specific modules

    • Generic core includes:

      • Physical functioning and well-being, social functioning, social / family well-being etc


    Health outcomes

    Health Outcomes

    • Instruments commonly used and accepted:

      • SF-36

      • Health utility Index

      • EQ-5D

    • Increasing importance due to reimbursement / cost containment


    Basis for nda approval

    Basis for NDA Approval

    • Demonstration of efficacy with acceptable safety in adequate and well-controlled studies

    • Ability to generate product labeling that

      • Defines an appropriate patient population for treatment with the drug

      • Provides adequate information to enable safe and effective use of the drug


    Accelerated approval fast track priority review

    Accelerated Approval, Fast Track, Priority Review

    • Accelerated Approval

      • serious or life-threatening disease

      • demonstrable benefit over available therapy.

      • use of surrogate markers

      • mandated phase IV trials

    • Fast Track

      • life-threatening disease

      • potential to address unmet medical need

    • Priority review

      • drug would be a significant improvement compared to available drugs

      • Review of filing in 6 months


    Challenges for oncology drug regulations

    Challenges for Oncology Drug Regulations

    • New “targeted therapies”

      • Re-define definitions of diseases (based on mechanism of pathogenesis, genetics)

      • Greater efficacy in selected population may result in smaller patient populations

      • Novel surrogates to be validated

      • Dosing aimed at target rather than MTD

      • Dose studies, chronic administration


    The iressa story

    The IRESSA story


    Registration studies

    EGFR biomarkers were discovered late in the gefitinib development programme

    ISEL, INTEREST: Unselected trials in pre-treated setting

    ISEL

    Gefitinib registration Japan

    INTEREST

    IPASS

    2002

    2005

    2007

    2009

    EGFR protein expression

    IPASS: Clinically selected trial in first line setting

    EGFR gene copy number

    EGFR mutations


    The real challenge was to determine which tumours were really dependent on the egfr pathway

    Gefitinib

    Placebo

    The real challenge was to determine which tumours were really dependent on the EGFR pathway

    ISEL study: Median follow-up 7 months (range 3-15), 58% deaths

    Median, months

    1-year survival, %

    Log-rank HR (95% CI), 0.89 (0.77, 1.02); p=0.087Cox analysis, p=0.030

    Gefitinib

    5.6

    27

    Placebo

    5.1

    21

    Proportionsurviving

    1.0

    0.8

    0.6

    0.4

    0.2

    0.0

    0

    2

    4

    6

    8

    10

    12

    14

    16

    Time (months)

    1692

    1347

    877

    485

    252

    104

    31

    At risk

    Thatcher et al 2005


    Registration studies

    The dangers of dilution……..

    Probability of success in pivotal trial in the presence of a non-responsive subgroup

    Assumes responders have 33% effect and non-responders 0% effect,

    trial sized assuming all patients have a 33% effect


    Isel rigorously predefined subgroups showed a statistically significant increase in survival

    ISEL: Rigorously predefined subgroups showed a statistically significant increase in survival

    Never smoked (n=375)

    Ever smoked (n=1317)

    1.0

    HR 0.67; 95% CI 0.49, 0.92; p=0.012

    HR 0.92; 95% CI 0.79, 1.06; p=0.242

    Gefitinib

    0.8

    Placebo

    0.6

    Proportion surviving

    0.4

    0.2

    0.0

    0

    2

    4

    6

    8

    10

    12

    14

    16

    0

    2

    4

    6

    8

    10

    12

    14

    16

    Asian origin (n=342)

    Non-Asian origin (n=1350)

    1.0

    HR 0.66; 95% CI 0.48, 0.91; p=0.010

    HR 0.92; 95% CI 0.80, 1.07; p=0.294

    0.8

    0.6

    Proportion surviving

    0.4

    0.2

    0.0

    0

    2

    4

    6

    8

    10

    12

    14

    16

    0

    2

    4

    6

    8

    10

    12

    14

    16

    Time (months)

    Cox regression analysis

    Thatcher et al 2005


    Ipass phase iii study of gefitinib versus doublet chemotherapy in first line nsclc

    IPASS: Phase III study of gefitinib versus doublet chemotherapy in first line NSCLC

    Gefitinib250 mg/day

    1:1 randomization

    Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m2 3 wkly

    Endpoints

    • Patients

    • Adenocarcinoma histology

    • Never smokers or light ex-smokers*

    • PS 0-2

    • Provision of tumour sample for biomarker analysis strongly encouraged

    • Primary

    • Progression free survival (non-inferiority)

    • Secondary

    • Objective response rate

    • Quality of life

    • Disease related symptoms

    • Overall survival

    • Safety and tolerability

    • Exploratory

    • Biomarkers

      • EGFR mutation

      • EGFR gene copy number

      • EGFR protein expression

    • 1217 patients from East Asian countries

    *Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped 15 years agoand smoked 10 pack yrs

    Carboplatin/paclitaxel was offered to gefitinib patients upon progression

    PS, performance status; EGFR, epidermal growth factor receptor


    Ipass superior pfs and orr with gefitinib vs doublet chemotherapy pfs effect not constant over time

    IPASS: Superior PFS and ORR with gefitinib vs doublet chemotherapy; PFS effect not constant over time

    Probabilityof PFS

    Carboplatin /

    paclitaxel

    1.0

    Gefitinib

    N

    Events

    609

    453 (74.4%)

    608

    497 (81.7%)

    0.8

    HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001

    0.6

    5.874%48%7%

    Median PFS (months)4 months progression-free6 months progression-free12 months progression-free

    5.761%48%25%

    0.4

    Primary objective exceeded: Gefitinib demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS

    0.2

    0.0

    0

    4

    8

    12

    16

    20

    24

    Months

    At risk :

    Gefitinib

    609

    363

    76

    24

    5

    0

    212

    Carboplatin / paclitaxel

    608

    412

    118

    22

    3

    1

    0

    Objective response rate 43% vs 32% p=0.0001

    Primary Cox analysis and logistic regression with covariates; ITT population

    HR <1 implies a lower risk of progression on gefitinib


    Ipass gefitinib has a more favourable tolerability profile than doublet chemotherapy

    IPASS: Gefitinib has a more favourable tolerability profile than doublet chemotherapy

    Most common AEs (10% on either treatment) with >3% difference between treatments

    Gefitinib (N=607)

    Carboplatin/paclitaxel (N=589)

    #Absolute neutrophil count, white blood cell count, or haemoglobin worsened from baseline to CTC grade 3/4; gefitinib N=599, carboplatin / paclitaxel N=577 *Grouped term (sum of several preferred terms)


    Registration studies

    IPASS: EGFR mutation is a strong predictor for differential PFS benefit between gefitinib and doublet chemotherapy

    Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)

    Carboplatin / paclitaxel EGFR M- (n=85)

    Probabilityof PFS

    1.0

    EGFR M+HR=0.48, 95% CI 0.36, 0.64

    p<0.0001

    EGFR M-

    HR=2.85, 95% CI 2.05, 3.98

    p<0.0001

    0.8

    Treatment by subgroup interaction test, p<0.0001

    0.6

    0.4

    0.2

    0.0

    0

    4

    8

    12

    16

    20

    24

    Time from randomisation (months)

    M+, mutation positive; M-, mutation negative


    Mutation status causes conformational change and increased activation

    Mutation status causes conformational change and increased activation

    WT EGFR

    Mutant EGFR

    Ligand

    Extracellular domain

    Trans-membrane domain

    ATP

    Tyrosine kinase domain

    Tyrosine phosphorylation

    Ras-Raf-MAPK

    Proliferation

    Pi3K-AKT

    Survival

    EGFR internalisation

    Degradation/recycling

    EGFR signals longer

    at the cell membrane


    Registration studies

    IPASS: Superior quality of life and symptom improvement rates for gefitinib in EGFR mutation positive patients

    p<0.0001

    p=0.0003

    p<0.0001

    % patientswith sustained clinically relevant improvement

    p-values from logistic regression with covariates. Post-hoc analysis, EFQ populationClinically relevant improvement pre-defined as 6-point improvement for FACT-L and TOI;2-point improvement for LCS, maintained for at least 21 days.

    EFQ, evaluable for quality of life; FACT-L, Functional Assessment of Cancer Therapy-Lung; TOI, Trial Outcome Index; LCS, Lung Cancer Subscale


    Conclusions phase iii trial considerations

    Conclusions – phase III trial considerations

    • Patient selection

      • Activity in specific subsets

    • Study design

      • Experimental (& control!) arm – dose, duration of treatment

      • Frequency of evaluations

    • Study endpoints

      • Survival vs PFS?

      • Use of biomarkers?

      • Qol

      • Health economics

    • Post phase III plans

      • Early access

      • Phase IIIb/IV

      • Investigator Initiated Studies


    Registration studies

    STAMPEDE: Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy

    Sponsor number:MRC PR08ISRCTN number: ISRCTN78818544EUDRACT number: 2004-000193-31CTA number: 00316/0026/001-0001

    Slide set (abridged)


    Design rationale

    Design rationale

    STAMPEDE is multi-arm, multi-stage trial

    3 investigational drugs in original design

    Intergroup randomised controlled trial

    Using Multi-Arm Multi-Stage methodology

    MAMS design


    Design rationale1

    Design rationale

    Many interesting agents

    Different classes and modes of action

    Many used in later stages of disease

    Others new

    No clear reason to choose a particular one

    Many choices

    Don’t want to choose arbitrarily

    Want to assess all interesting agents

    Quicker and efficient to use MAMS design

    Start by test many agents

    Focus to more active agents using LOB analyses


    Why multi arm multi stage trials

    Why Multi-arm, Multi-stage trials?

    Typical (academic) Phase III trial

    Hundreds or thousands of patients

    5 to 10 years from idea to result

    Hundreds of research staff

    Cost millions in development

    Years of investment from the key players

    High chance of finding new treatment is not superior

    Whether to continue testing a new treatment?


    Mams vs traditional

    MAMS vs traditional

    T1

    Traditional Approach

    Multi-arm, Multi-stage

    T2

    Phase II

    T3

    C

    T1

    T2

    T3

    T4

    T4

    Phase II

    C T1

    Phase III

    C T3

    C T4

    Phase III


    Advantages of mams

    Advantages of MAMS


    Trial design stages

    Trial Design Stages

    StageOutcome Measures

    PrimarySecondary

    (Pilot)(Safety)(Feasibility)

    ActivityI-IIIFailure-free survivalOverall survival

    (phase II) Toxicity (safety)

    Skeletal-related events

    EfficacyIVOverall survivalFailure-free survival

    (phase III) Toxicity (safety)

    Skeletal-related events

    Quality of life


    Intermediate analysis potential outcomes

    Intermediate Analysis – Potential Outcomes

    Arms/Drugs might be dropped for Safety Reasons

    All patients on that arm/drug stop treatment

    Arms/Drugs might be dropped for lack of activity

    Patients on that arm/drug could continue treatment depending on the results seen

    TSC recommended that patients that were still being treated on celecoxib-containing arms stopped celecoxib. However, decision ultimately left to patient.


    Registration studies

    STAMPEDE DESIGN

    Slide set (abridged)


    Stampede original design

    STAMPEDE original design

    Man with high-risk prostate cancer starting long-term hormone therapy

    Trial IDs

    MRC PR08

    CRUK/06/019

    ISRCTN78818544

    NCT00268476

    Slide set (abridged)


    Registration studies

    STAMPEDE: A FLEXIBLE TRIAL

    Slide set (abridged)


    Flexibility

    Flexibility

    • Adaptive trial design

    • Uses lack-of-benefit analyses to focus accrual away from insufficiently active arm

    • Require evidence of activity to continue accrual

    • Accrual to both celecoxib-containing arms was stopped on IDMC recommendation at 2nd intermediate analysis

    Slide set (abridged)


    Flexibility1

    Flexibility

    • Can include new research arms

    • Use same intermediate hurdles for new arms

    • Compare against common control arm

    • New arm added in Nov-2011

      • Abiraterone Acetate

    • Further new arm planned for 2012

      • Local radiotherapy for M1 patients

    Slide set (abridged)


    Accrual

    Past accrual

    Possible future accrual

    Accrual

    2005

    2006

    2007

    2008

    2009

    2010

    2011

    2012

    2013

    2014

    2015

    2016

    2017

    • Following slides show accrual activity over time

    Follow-up

    Slide set (abridged)


    Accrual1

    Past accrual

    Possible future accrual

    Accrual

    2005

    2006

    2007

    2008

    2009

    2010

    2011

    2012

    2013

    2014

    2015

    2016

    2017

    A

    B

    C

    D

    E

    F

    Follow-up

    Slide set (abridged)


    Accrual initial plans

    Past accrual

    Possible future accrual

    Accrual: initial plans

    2005

    2006

    2007

    2008

    2009

    2010

    2011

    2012

    2013

    2014

    2015

    2016

    2017

    A

    ADT-alone

    B

    ADT + zoledronic acid

    C

    ADT + docetaxel

    D

    ADT + celecoxib

    E

    ADT + zoledronic acid + docetaxel

    F

    ADT + zoledronic acid + celecoxib

    Follow-up

    Slide set (abridged)


    Accrual end of pilot phase

    Past accrual

    Possible future accrual

    Accrual: end of Pilot Phase

    2005

    2006

    2007

    2008

    2009

    2010

    2011

    2012

    2013

    2014

    2015

    2016

    2017

    A

    ADT-alone

    B

    ADT + zoledronic acid

    C

    ADT + docetaxel

    D

    ADT + celecoxib

    E

    ADT + zoledronic acid + docetaxel

    F

    ADT + zoledronic acid + celecoxib

    Follow-up

    Slide set (abridged)


    Accrual end of activity stage i

    Past accrual

    Possible future accrual

    Accrual: end of Activity Stage I

    2005

    2006

    2007

    2008

    2009

    2010

    2011

    2012

    2013

    2014

    2015

    2016

    2017

    A

    ADT-alone

    B

    ADT + zoledronic acid

    C

    ADT + docetaxel

    D

    ADT + celecoxib

    E

    ADT + zoledronic acid + docetaxel

    F

    ADT + zoledronic acid + celecoxib

    Follow-up

    Slide set (abridged)


    Accrual end of activity stage ii

    Past accrual

    Possible future accrual

    Accrual: end of Activity Stage II

    2005

    2006

    2007

    2008

    2009

    2010

    2011

    2012

    2013

    2014

    2015

    2016

    2017

    A

    ADT-alone

    B

    ADT + zoledronic acid

    C

    ADT + docetaxel

    D

    ADT + celecoxib

    E

    ADT + zoledronic acid + docetaxel

    F

    ADT + zoledronic acid + celecoxib

    Follow-up

    Slide set (abridged)


    Accrual from nov 2011

    Past accrual

    Possible future accrual

    Accrual: from Nov-2011

    2005

    2006

    2007

    2008

    2009

    2010

    2011

    2012

    2013

    2014

    2015

    2016

    2017

    A

    ADT-alone

    B

    ADT + zoledronic acid

    C

    ADT + docetaxel

    D

    ADT + celecoxib

    E

    ADT + zoledronic acid + docetaxel

    F

    ADT + zoledronic acid + celecoxib

    G

    ADT + abiraterone

    Follow-up

    Slide set (abridged)


    Accrual plans from late 2012

    Past accrual

    Possible future accrual

    Accrual: plans from late 2012

    2005

    2006

    2007

    2008

    2009

    2010

    2011

    2012

    2013

    2014

    2015

    2016

    2017

    A

    ADT-alone

    B

    ADT + zoledronic acid

    C

    ADT + docetaxel

    D

    ADT + celecoxib

    E

    ADT + zoledronic acid + docetaxel

    F

    ADT + zoledronic acid + celecoxib

    G

    ADT + abiraterone

    M1 only

    H

    ADT + RT

    Follow-up

    Slide set (abridged)


    Stampede s future

    STAMPEDE’s future

    • Original research arms will stop accrual within 18m

      • Stop early at 3rd intermediate analysis for lack-of-benefit

      • Complete accrual to end of Efficacy Stage 4

    • Active, original research arms will present data in around 3 years

    • HT vs HT + abiraterone will recruit up to Nov-2014

    • HT vs HT + local RT will start in 2012

    • Further arms considered

    Slide set (abridged)


    Further reading

    Further Reading

    • Thatcher N et al, Gefitinib plus best supportive care in previously treated patients with refractory non-small-cell lung cancer: results from a randomisd, placebo controlled, multicentre study (Iressa Survival Evaluation in lung Cancer). Lancet 2005;366:1527-1537.

    • Chang A et al, Gefitinig (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: subset analysis from the ISEL study. J ThoracOncol 2006;1:847-855.

    • Kelloff GJ et al, New science-based endpoints to accelerate oncology drug development. Eu J Can 2005;41:491-501

    • Booth CM et al, Reflections on Medical Oncology: 25 years of clinical trials – where have we come & where are we going. J ClinOncol 2008;26(1):6-8

    • Gutierrez ME et al, Next generation oncology drug development: opportunities & challenges. Nat Rev ClinOncol 2009;6:259-265

    • Nathan DG. The Cancer Treatment Revolution, Wiley & Sons, Inc., 2007

    • Mukherjee S. The emperor of all maladies. A biography of cancer. Fourth Estate, 2010

    • James ND et al, Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage randomised controlled trial. Lancet Oncol 2012;13(5):549-558

    • Sydes et al, Flexible trial design in practice – stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials 2012;13:168


    Back up

    Back-up


    Randomization

    Randomization


    Clinical trial design

    Clinical Trial Design

    • Stratification: Categorizing subjects into subgroups by specific characteristics

      • Enables researchers to look into separate subgroups to see whether differences exist


    Stratification

    Stratification


    Fact g

    FACT-G


    Interim analyses

    Interim analyses

    • 1 analysis p=0.05

    • 2 analyses p=0.083

    • 3 analyses p=0.107

    • 10 analyses p=0.193

    • Designs exist to reflect this - extreme p values used for initial analyses to avoid loss of power


  • Login