implementation of mams 1 mahesh parmar, feb-2010 practical implementation of multi-arm multi-stage...

Implementation of MAMS 1 Mahesh Parmar, Feb-2010

Practical Implementation of Multi-Arm Multi-Stage Trials

Mahesh ParmarDirector

MRC Clinical Trials Unit


Structure of presentation

1. MAMS Designs2. MAMS application in STAMPEDE3. Issues in implementation4. Conclusions


1. MAMS Designs



Why Multi-Arm, Multi-Stage trials?

• More often than not ‘new’ is not better

• Academia 624 NCI sponsored phase III trials (Arch. Int Med, 2008) ~30% of trials ‘statistically significant’ ~40% of trials ‘new’ therapy preferred

• Industry Agents successful at phase I: only 10-20% receive a

marketing authorisation Success rate of phase III trials ~30-40%


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


Principles of a New Strategy

• Need better mechanism than single arm phase II trial to decide

• Test as many new promising treatments as possible in the same timescale maximise potential for a “positive trial”

• Potential to discontinue unpromising arms quickly and reliably

• Start to randomise as quickly as possible

• Multi-Arm, Multi-Stage (MAMS) trials


Activity (phase II stages)

• Asks the question Are there reasons why we should not continue

testing this treatment?

• Testing for a lack-of-activity Emphasis not testing for activity but for lack-of-

activity or lack-of-sufficient-benefit


Activity phase II stages

• Assume definitive outcome measure is most clinically relevant eg overall survival in cancer trials

• In Activity Stages focus on an earlier outcome measure eg “failure-free survival” (FFS) in cancer trials


Multi-Arm, Multi-Stage Trials

R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient



R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Stage 1 accrual

Final analyses

Stage 3 accrual

Stage 2 accrual

Intermediate analyses 2




R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Final analyses

Stage 3 accrual

Stage 2 accrual





R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Final analyses

Stage 3 accrual

Stage 2 accrual




R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Yes

Yes

Stage 2 accrual

Final analyses

Stage 3 accrual




R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity

Insufficient activity


Yes

Yes

Stage 2 accrual

Final analyses

Stage 3 accrual




R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity



Yes

Yes

No

Stage 2 accrual

Final analyses

Stage 3 accrual




R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Sufficient activity

Sufficient activity


Yes

Yes

No

Stage 2 accrual

Final analyses

Stage 3 accrual




R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Sufficient activity

Sufficient activity


Yes

Yes

No

Yes

Yes

Stage 2 accrual

Final analyses

Stage 3 accrual




R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Sufficient activity

Sufficient activity


Yes

Yes

No

Yes

Yes

Stage 2 accrual

Control

Sufficient activity


Final analyses

Stage 3 accrual



R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Sufficient activity

Sufficient activity


Yes

Yes

No

Yes

Yes

Stage 2 accrual

Control

Sufficient activity


Yes

Yes

Stage 3 accrual

Final analyses



R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Sufficient activity

Sufficient activity


Final analyses

Yes

Yes

No

Yes

Yes

Stage 2 accrual

Control

Sufficient activity

(N/A)


Yes

Yes

No

Stage 3 accrual



R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Sufficient activity

Sufficient activity


Final analyses

Yes

Yes

No

Yes

Yes

Stage 2 accrual

Control

Sufficient activity

(N/A)



Yes

Yes

No

No

Stage 3 accrual



R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Sufficient activity

Sufficient activity


Final analyses

Yes

Yes

No

Yes

Yes

Stage 2 accrual

Control

Sufficient activity

(N/A)


Sufficient activity


Yes

Yes

No

No

Yes

Stage 3 accrual



R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Sufficient activity

Sufficient activity

Control

Primary analysis


Final analyses

Yes

Yes

No

Yes

Yes

Stage 2 accrual

Control

Sufficient activity

(N/A)


Sufficient activity


Yes

Yes

No

No

Yes

Stage 3 accrual

Primary analysis



R

A

N

D

O

M

I

S

E

Test 1

Test 2

Test 3

Test 4

Con-trol

Eligible patient

Yes

Yes

Yes

Yes

Yes

Stage 1 accrual

Control

Sufficient activity


Sufficient activity

Sufficient activity

Control

Primary analysis

Secondary analysis

Secondary analysis

Primary analysis


Final analyses

Yes

Yes

No

Yes

Yes

Stage 2 accrual

Control

Sufficient activity

(N/A)


Sufficient activity


Yes

Yes

No

No

Yes

Stage 3 accrual


Advantages of MAMS

• Fewer patients • Less overall time

Randomised from the start Concurrent (not sequentially) No delay between phase II and phase III Fewer applications for finance and approvals

• one grant application• one protocol• one CTA submission (per country)• one ethics submission (per country)• one R&D approval (per site)

Saves many years!


Advantages of MAMS

• Fewer patients • Less overall time• Increased flexibility• Reduced costs


2. MAMS application in STAMPEDE



0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

0-4

5-9

10-1

415-1

920-2

425-2

930-3

435-3

940-4

445-4

950-5

455-5

960-6

465-6

970-7

475-7

980-8

485+

Age at diagnosis

Nu

mb

er

of

case

s

0

200

400

600

800

1,000

Rate

per

10

0,0

00

popu

lati

on

Male cases

Male rates

• Most common male cancer UK diagnosis: 34,000 in 2005

UK deaths: 10,000 in 2006

Global deaths: 250,000 in 2000

• Rising rates of diagnosis Aging population, awareness, PSA

screening

• Modest treatment effect = big impact

Impact


• Urgent need to improve outcomes for men starting hormone therapy with prostate cancer Median survival ~4 years Median failure-free survival ~2 years

• No new therapies improving survival for this group of men for many years

Needs in prostate cancer


Design rationale

• Many interesting agents Different classes and modes of action

• No obvious reason to choose one Many used in later stages of disease Don’t want to choose arbitrarily

• Quicker and efficient to use MAMS design


Trial Design

R

A

N

D

O

M

I

S

E

Androgen suppression (AS)A

AS + zoledronic acidB

AS + docetaxelC

AS + celecoxibD

AS + zoledronic acid + docetaxelE

AS + zoledronic acid + celecoxibF

Control arm

R

A

N

D

O

M

I

S

E

Hormone Therapy (HT)A

HT + zoledronic acidB

HT + docetaxelC

HT + celecoxibD

HT + zoledronic acid + docetaxelE

HT + zoledronic acid + celecoxibF

Control arm


Trial Design Stages

Stage Outcome MeasuresPrimary Secondary

Pilot Safety Feasibility

Activity I-III Failure-free survival Overall survival(phase II) (PSA-driven) Toxicity

Skeletal-related events

Efficacy IV Overall survival Failure-free survival(phase III) Toxicity

Skeletal-related eventsQuality of life


Design Assumptions: for all stages

• Pairwise comparison of each research arm against control

• Hazard ratios for design

•10% improvement in FFS: 50 to 60% at 2 yr

Overall survival

Failure-free survival

Null (H0) 1.00 1.00

Alternative (HA) 0.75 0.75


Significance level and power

StagePrimary Outcome

Significance Level

Power

I FFS 0.50 95%

II FFS 0.25 95%

III FFS 0.10 95%

IV OS 0.025 90%

Overall - 0.013 85%

STAMPEDE Joint TSC/IDMC Meeting 35 Matt Sydes, 20-July-2009

Cutpoints in STAMPEDE

95% power

95% power

95% power


3. Issues in implementation



Groups to convince – 1

• Medical community Mostly seen by urologists Trial treatments need to be given by oncologists

• Would it appear complex in clinics? Or in MDT meetings?

• Previous multi-arm trials Excellent recruitment to: FOCUS – colorectal cancer – 5 arms ICON5 – ovarian cancer – 5 arms



• Men with prostate cancer Involved patient groups Two patients on Trial Management Group Very positive opinions Patient involvement has been excellent for trial

• Two-part PIS General information (few pages) – prior to randomisation Arm-specific information

• All before randomisation or• Only relevant one after randomisation (few pages)• Patient choice – as informed as patient would like to be



• Funding bodies• Regulatory and ethical committees• Hospital governance

• Potential for conservative reviewers No precedent for such approaches

• Approved – after a bit of ‘discussion’



• Industry partners 3 industry partners in STAMPEDE All keen on design because… Not primarily comparing their drugs head to head Efficient design Early “get-out” if agent not so beneficial

• More companies = more negotiations More contracts More time …


Recruitment

• How many patients are required?• Total N dependent on:

Observed accrual rates Observed event rates

• Do we have the predicted mix of patients? # arms recruiting in each Activity & Efficacy Stage

• Likely 2300 to 3600 patients Over 5.5 to 7.5 years

• Faster recruitment: Requires more patients Takes less time


STAMPEDE Accrual

0

300

600

900

1200

1500

1800

2100

Cum

ulat

ive

rand

omis

atio

ns

Oct

-05

Jan

-06

Jul-

06

Jan

-07

Jul-

07

Jan

-08

Jul-

08

Jan

-09

Jul-

09

Jan

-10

Jul-

10

Jan

-11

Jul-

11

Oct

-11

Date of randomisation

Observed Expected

There are many successful accrual scenarios for recruitment toSTAMPEDE in the Statistical Design Document. One is shown here.

Pilot phase Activity Stage I Activity Stage II


Pilot Phase

• Assessing safety & feasibility Particularly for the combination arms

• Target: 210 patients in 18 months Limited centres

• Completed: Oct-2005 to Spring-2007 On schedule

• IDMC recommended continuing all arms None stopped because of clear safety signals


Stage 1

• Completed ahead of schedule

• IDMC recommended continuation of all arms


Hurdles

1. Funding2. Finalising choice of drug3. Discussions with pharma4. Funding (revisited)5. EU Clinical Trials Directive6. Vioxx7. Increased number of stages8. Continuity of staff9. Pilot phase


Funding – main grant

• Outline Application to MRC – May 2001 Accept for Full Application Novel design & novel drugs vs conservatism Advised to submit to CTAAC instead New at time – for cancer trials, incl. MRC funds

• Outline Application to CTAAC – November 2001 Accept for Full Application

• Full Application to CTAAC – November 2002 Accepted for partial funding – Feb 2003 Agreements/funding needed from industry partners


Funding – industry partners

• Novartis – zoledronic acid Research grant Free drug Drug distributed to sites

• Sanofi-Aventis – docetaxel Research grant Discounted drug (buy 1, get 2 free) Sites to buy drug & claim back

• Pfizer – celecoxib Free drug Research grant, including distribution costs


Negotiations

• Discussions required in many trials• More difficult if many companies?

Different pace Different contracts Different comments on protocol

• Flagged plans for future discussions International expansion planned All agreements made with UK affiliates


Changes in CTU Personnel

Continuity

3 Project Leads

5 Trial Managers

7 Data Managers

3 Patients/Consumer representatives

3 Statisticians (including the original 2!)


Future hurdles

1. Recruitment rates2. Contracts revisited3. Moving through MAMS stages4. Dropping arms5. Completing recruitment6. Adding arms


5. Issues in intermediate analyses



Moving through stages

• IDMC review interim data Safety and activity data Recommendations to TSC and TMG

• Education & training For all committees Trust in relationships Hypothetical examples

Trials

Unit

Trials

Unit

DMC: Data Monitoring Committee

TSC: Trial Steering

Committee

Participating centres

DMC feedback to TSC & TSC response to DMC

via Trials Unit

DMC feedback to TSC & TSC response to DMC

via Trials Unit

Report from Trials Unit

Question & Feedback

Trial expert panels

Sponsor/ Funder

Report from Trials Unit

Question & Feedback

TMG: Trial Management

Group

TMG: Trial Management

Group


Moving through stages

• Face-to-face meeting between TSC and IDMC

• Discussion of different scenarios

• Agree a lengthy communication plan – including timelines Between IDMC and TSC To Centres To Participants To Regulators Changes in randomisation programme etc…


Dropping arms or agents

• If combination arm stopped for lack of sufficient effect Should “single” agent arm stop too?

• If single agent arm stopped for lack of sufficient effect Should combination arm stop too?

• Training and discussion


Adding new arms

• Could an extra arm be added? Promising agents could be added later! “Rolling trial” or “roundabout design”? Use same approach as for other arms, but delayed

• Implementing in STAMPEDE Considering abiraterone Application to CTAAC (CRUK) approved Company considering proposal

• Design should be appealing to funders and industry Pre-existing network of recruiting sites Saves ~3 years


6. Conclusions



Conclusions

• Multi-arm, multi-stage trials are Being done in a number of other cancer types Feasible Efficient Supported by patients, clinicians, funders,

companies

• STAMPEDE Is recruiting well Is running well

MAMS Trials for GSK 58 Mahesh Parmar, Nov. 2010

References – MAMS trials

• Royston P, Parmar MKB, Qian W Novel Designs for Multi-Arm Clinical Trials with Survival Outcomes, with an Application in Ovarian Cancer. Statistics in Medicine 2003;22: 2239 – 2256.

• Barthel FM-S, Royston P, Parmar MKBA menu-driven facility for sample size calculation in multi-arm, multi-stage randomised controlled trials with a survival-time outcome. The Stata Journal 2007 (submitted)

• Parmar MKBSpeeding up the Evaluation of New Agents in Cancer. J.Natl.Cancer Inst. 100 (17):1204-1214, 2008.


References - STAMPEDE

• Sydes MR, MKB Parmar, ND James et alIssues in applying multi-arm multi-stage (MAMS) methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials 10 (39), 2009.

• James ND, Sydes MR, Clarke NW et alSTAMPEDE: Systemic Therapy for Advancing or Metastatic Prostate Cancer -- A Multi-Arm Multi-Stage Randomised Controlled Trial. Clinical Oncology 20 (8):577-581, 2008.

• James ND, Sydes MR, Clarke NW et alSystemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial. BJU.Int 103 (4):464-469, 2009.


Software and wokshop

• Free software available Design MAMS trials Available from MRC CTU Implemented in Stata

• CTU Workshop in February 2011 Design and analysis of MAMs trials Advanced Issues in Design and Analysis of Trials

with Time to Event Outcomes


Other MAMS trials

• ICON 6 3-arm, 4-stage trial in 2nd line ovarian cancer

using progression-free survival as the intermediate outcome measure

• AML 16 5-arm, 2-stage trial in acute myeloid leukaemia


Conclusions

• MAMS trials are Feasible Efficient Supported by patients, clinicians, companies


Contacts

Matthew Sydes

E [email protected]

T +44 (0)20 7670 4798


Extra slides


Trial Initiation 6 trial arms

Pilot PhaseRecruit 210 patients

Recruitment continues to control arm + other

research arms in next stage

Due to safety issues or a lack of feasibility, accrual may stop to one or more research arms

IDMC review

Key IDMC = Independent Data Monitoring Committee

FFS = Failure Free survival

(Total ~210 pts)

Trial Stage - Pilot


Trial Stage - Efficacy Stage I

Efficacy Stage I

Recruit until 113 control arm FFS events (Total ~1200 pts)

IDMC review

Accrual may be stopped in any research arm for safety or lack of efficacy

HR=1.00






Trial Stage - Efficacy Stage II

Efficacy Stage II


IDMC review



Accrual may be stopped in any research arm for safety or lack of efficacy

HR=0.92Recruitment continues to

control arm + other research arms in next stage


Trial Stage - Efficacy Stage III



Efficacy Stage III


IDMC review

Accrual may be stopped in any research arm for safety or lack of efficacyHR=0.89




Trial Stage – Efficacy Stage IV

Efficacy Stage IV

Recruit until 405 control arm deaths (Total ~3200 pts)

Main Analyses

(1) Overall survival in arms recruiting in Efficacy Stage IV

(2) Secondary outcome measures in arms recruiting in Efficacy Stage IV

(3) All outcome measures in all 6 arms involved in trial (regardless of

when recruitment stopped)


Statistical Issues

• Pair-wise comparison of each research vs control

• Randomisation ratio (A:B:C:D:E:F) = 2:1:1:1:1:1 Two control arm patients for every research arm patients Efficient for power

• Randomisation centrally Computer based algorithm Minimisation with an additional random element 7 stratification factors for balancing groups

MAMS Trials for GSK 72 Matt Sydes, Oct-2009

Phase II studies of single agent

Phase II studies of combinations

Phase III trials of combinations

R1

R1

R1C

R2

R2

R2C

R3

R3

R3C

A – Traditional approach

B – MAMS design

Phase II studies of single agent

R1

R2

R3

C R1 R2 R3

MAMS: Phase II/III trial of combinations

Time

Notes

C = control arm; R1 = research arm R1; R2 = Research arm R2; R3 = research arm R3

Assumes that single agent studies would be carried out before combination studies

Assumes that phase II studies require smaller numbers of patients and so smaller number of centres. Therefore, phase II studies of different agents may be carried out concurrently

Assumes that phase III trials require larger numbers of patients and a network of centres that can only run one trial at a time: therefore, phase III trials of different agents must be carried out sequentially

MAMS design rolls phase II assessment of combinations into the same trial as the phase III assessment of effectiveness


Impact of accrual rates

Accrual/Year

Total pts Duration (yrs)

Difference in pts

Difference in length

350 2960 8.5 -451 20 months

500 3411 6.8 0 0

750 4046 5.4 635 -17 months

Assuming: median FFS=24m, median OS=48m, 6 arms recruiting at each stage


Assumptions in STAMPEDE

• Broad eligibility spectrum Patients starting hormone therapy

• Newly metastatic• New & locally advanced• Previously treated & relapsing

Assume more patients are M0 than M1 Failure-free survival (FFS): median = 2 years Overall survival (OS): median = 4 years


Traditional Approach

Phase II

Phase III

A B C

Multi-arm, Multi-stage

A B C

Phase II = 50 pts, Phase III = 600pts

4*50 + 4*300 = 1400

Traditional vs MAMS

50+600=650

+50=700+600=1300

+50=1350+600=1950

Total


Continue Stop

Estimated Treatment Effect (HR)

1.000.75 (Favours experimental) (Favours control)

1-sided 75% CI around 0.92

End of Stage

II if HR >0.92

A+B

B

A

x

x

x

Example

Stop A

Stop A+B

Stop B

Action?


Continue Stop




End of Stage

II if HR >0.92

A+B

B

A

x

x

x

Example

Action?

Continue A

Continue A+B

Continue B


Continue Stop




End of Stage

II if HR >0.92

A+B

B

A

x

x

x

Example

Requires exploration and intra-arm comparisons

Stop A

Stop A+B

Continue B

Action?


Continue Stop




End of Stage

II if HR >0.92

A+B

B

A

x

x

x

Example

Continue A

Continue A+B

Continue B

Action?


Continue Stop




End of Stage

II if HR >0.92

A+B

B

A

x

x

x

Example

Action?

Continue A

Continue A+B

Continue B


Activity phase II stages

• At any time should be more intermediate events than definitive events

– eg more FFS events than deaths (OS)

• Therefore, more power for intermediate outcome measure at any time

• Design assumes:– To see an effect on OS you have to see an effect on FFS– Just because you see an effect on FFS does not mean that you

will see an effect on OS


Advantages of MAMS

• Fewer patients • Less overall time



Phase II

Phase III

A B C

Multi-Arm, Multi-Stage

A B C


4*50 + 4*300 = 1400

Traditional vs MAMS

50+600=650+50=700

+600=1300+50=1350

+600=1950

Total



95% power

95% power

95% power


4. General issues in implementation

1. MAMS Designs2. MAMS application in STAMPEDE3. Issues in implementation4. General issues in implementation5. Issues in intermediate analyses6. Conclusions


No intermediate outcome?

• Design depends on the use of an intermediate outcome

• What happens if no such outcome exists?

• Use the primary outcome, earlier in time– Lack-of-benefit analysis useful anyway– Applying this to a number of ongoing trials


How many arms?

• Could be many arms– From 2 to 10 or more

• Consider – Accrual rates– Rationale for inclusion– Adjust randomisation ratio


Arms to compare

• Different drugs– Classes of agent– Combinations of agents

• Same drug– Dose levels– Duration– Initiation time– Method of administration

• Non-drug therapy


Adding new arms

• Could an extra arm be added?– Promising agents could be added later!– “Rolling trial” or “roundabout design”?– Use same rules as for other arms, but delayed

• Exploring in STAMPEDE

• Design should be appealing to industry– Pre-existing network of recruiting sites– GSK?


Stopping for efficacy?

• Stopping rules specified for lack-of-benefit

• No formal stopping rules for efficacy– Early data looking for sufficient evidence of activity to support

continued investment– Could draw in usual conservative early stopping guidelines


STAMPEDE TMG

Current TMG members

Nick James Karen Sanders

Noel Clarke Rachel Morgan

David Dearnaley Richard Gracie

Max Parmar Jim Stansfeld

Matt Sydes John Dwyer

Malcolm Mason

John Anderson

Rick Popert


How long to get here?

• Oct 2000 = first discussion• Nov 2000 = first formal meeting• Oct 2005 = first patient randomised

• Why so long?– Some issues of design ie MAMS-specific issues– Some issues of collaboration– Some issues beyond control


Hurdles

1. Funding


Hurdles

1. Funding2. Finalising choice of drug


Changes in drugs

1st mtg = Nov 2000 1st appln = May 2001

Hormone therapy Hormone therapy

Mitoxantrone (MTZ) MTZ+pred

Docetaxel Docetaxel + pred

Prednisolone -

Stilboestrol Stilboestrol + aspirin

Estramustine Estramustine + aspirin

?Bisphosphonates (factorial) ?Bisphosphonates

?Herceptin -

?ECF -

?Strontium -

?Epirubicin -


Changes in drugs

1st appln = May 2001 2nd appln = ???


MTZ+pred MTZ+pred OR

Docetaxel + pred Docetaxel + pred

Stilboestrol + aspirin Stilboestrol + aspirin OR

Estramustine + aspirin Estramustine + aspirin

?Bisphosphonates ?Bisphosphonates

?Iressa

?Atrasentan

?Celecoxib


Changes in drugs

2nd appln = ??? Final appln = Nov 2002


MTZ+pred OR -

Docetaxel + pred Docetaxel + pred

Stilboestrol + aspirin OR -

Estramustine + aspirin

?Bisphosphonates Zoledronic acid

?Iressa -

?Atrasentan -

?Celecoxib Celecoxib

Docetaxel + zoledronic acid

Celecoxib + zoledronic acid


Change in population

• Originally new M1 only• Expand to new M1 + new M0• Expand to new M1 + new M0 + relapsing


Hurdles

1. Funding2. Finalising choice of drug3. Discussions with pharma


Hurdles

1. Funding2. Finalising choice of drug3. Discussions with pharma4. Funding (revisited)5. EU Clinical Trials Directive


EU Clinical Trials Directive

• May 2004• Many uncertainties over sponsorship• Application for regulatory approval

– Put in before new system to get CTA-rollover– Easier in old system?– Less easy not for old system trials


Hurdles

1. Funding2. Finalising choice of drug3. Discussions with pharma4. Funding (revisited)5. EU Clinical Trials Directive6. Increased number of MAMS stages


Increased stages

• Planned as two-stage trial (plus Pilot)• IDMC to meet annually• Therefore, plan more interim hurdles• Increased from 2 to 4 stages

– Required new program– -stage2- to -stagen-– Revise protocol

• Revised again in Summer 2007– -stagen- to -nstage-– Small decrease in number of required events


Changes in trial personnel

Name Involvement

Nick James TMG (CI)

Noel Clarke TMG

David Dearnaley TMG

Max Parmar TMG

Matt Sydes TMG

Sarah Meredith Moved on

Sharon Naylor Moved on

David Kirk Retired (TSC)

Clare Moynihan Moved on


1. Recruitment rates

Accrual/Year

Total pts Duration (yrs)

Difference in pts

Difference in length

350 2960 8.5 -451 20 months

500 3411 6.8 0 0

750 4046 5.4 635 -17 months

Assuming: median FFS=24m, median OS=48m, 6 arms recruiting at each stage


Key points – 1

• For many diseases we have many potential new treatments

• Majority are likely to prove no more effective than control

• We need to change the question we ask– How do we improve outcomes as rapidly as possible for this

disease?


Key points – 2

• Intermediate outcome can be very helpful– Need not be true surrogate– Often assume larger effect size on intermediate outcome

• MAMS trials speed evaluation of new treatments by testing many treatments at the same time and using lack of benefit analyses

implementation of mams 1 mahesh parmar, feb-2010 practical implementation of multi-arm multi-stage...

Documents

multistage mams trials

implementation of mams

accrual stage

accrual final analyses

mams application

possible multiarm

cancer trials

accrual intermediate