Why do patients do better in clinical trials?

1
Why do patients do better in clinical trials?

• Dr Mark Hill MD FRCP
• Consultant Medical Oncologist
• Clinical Lead for Research
• Kent Cancer Network

2
Overview

• Definitions evidence base
• Types of clinical trial
• Rationale Fringe benefits
• Patient perspective
• Safeguards/GCP/Governance
• Quality
• NCRN
• Reporting implementation

3
Why do patients do better in clinical trials?

• Because I say so!
• Method by which new treatments are thoroughly
  tested
• Patients within trials are known to do better
• Dr E Grainger, Deputy Editor Lancet Oncology,
  ESMO Congress, Berlin, 2009
• Evidence hard to pin down- simple outcome
  measures biased by strict eligibility criteria
  and case control studies have never been done to
  a high standard
• Apple pie and motherhood

4
Definitions

• Patients
• Restricted to cancer patients
• 1 in 3 people in Western Countries will develop a
  malignant disease at some time in their lives,
  ergo
• Everyone has a relative with this diagnosis, ergo
• Patients Society at large
• Better
• Live longer?
• Improved quality of life?
• More support?
• More investigations?
• Feel more altruistic?

5
Clinical Trials

• Prognosis of cancer has improved steadily over
  the last 2 decades, coinciding with the increase
  in quality clinical trial activity
• Approx 1 improvement in survival per annum in
  Western countries
• Much of this improvement has come about by the
  application of clinical trial results, not only
  with drug therapy but also with RT and surgery (M
  Hill, Brighton, 2009)
• Tomorrows treatment today

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Types of Clinical Trial

• Observation
• Epidemiology, screening, genetics, qualitative
• Prevention
• Lifestyle, supplements
• Intervention
• Surgery
• Radiotherapy
• Drugs- Investigational Medical Products (IMPs)
• First in man
• Phase 1-4
• Randomised or not
• Placebo controlled/blinded or not
• Commercial or not (NCRI)

8
Drug Trials

• Phase 1
• Dose limiting toxicity, response not important,
  mixed tumour types, heavily pre-treated
• Phase 2
• May be randomised confirm toxicity, estimate
  response in single tumour type
• Phase 3
• Always randomised possibly placebo controlled or
  blinded, aim to quantify efficacy in single
  tumour type
• Phase 4
• Post marketing rare side effects

9
Understanding the Patient

• Why people participate in clinical trials
• Improved outcomes- therapeutic advance
• More surveillance
• Information
• Altruism
• Better support
• Hope

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Understanding the Patient

• Newly diagnosed patients may struggle with a
  number of difficulties
• Navigation around the clinical environment
• Loss of personal identity
• Apprehension regarding clinical trials
• New faces, new rules
• Levels of knowledge about disease and clinical
  research
• I dont want to be a guinea pig/ turn out like
  elephant man

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Understanding the Family

• Life disruption
• Worry about the patient
• Inability to "fix" the problem
• Financial burdens
• Overload
• Struggling to learn about the disease and its
  impact
• Learning to provide care

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Understanding the PatientThe bad news
consultation

• Settings
• Language
• Company
• Timing
• Support
• What next- ?Trial
• BSC
• Placebo controlled
• Phase 1

13
How to introduce a Clinical trial

• Become an expert patient communicator
• Basic skills
• Treating the whole person
• Realigning allegiances
• Understanding today's patient
• Listen and make time
• What you do and don't do matters
• Questions make the difference
• Language issues- verbal and non-verbal cues

14
How to introduce a Clinical trial

• Institutional attitudes make a huge difference
• New patient information
• Respectful presentation
• The truth about
• Randomization
• Money
• Side effects
• Life style

15
Fringe benefits

• Practical and emotional support- research nurses
• Additional surveillance- more tests and for
  longer will pick up delayed effects of treatment

16
Phase 1 Trials

• Response rate lt5, but offers hope to those not
  ready to give up
• Mainly considered an act of altruism
• Major commitment from patients impacting on
  quality of life in last few months- 4 Ts
• Toxicity
• Travel
• Time
• Tests

17
Phase 2 trials

• Access to new drugs with promise in a particular
  tumour type
• Examples include
• Imatinib (Glivec) for blast phase CML and GIST
  (2001)
• PARP inhibitors for triple negative breast cancer
  (2009)

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Triple Negative Breast Cancer (TNBC)

• ER-negative, PR-negative, and HER2 not
  overexpressed
• 15 of all breast cancers (170,000 cases
  worldwide in 2008)
• Aggressive natural history
• Higher rates of symptomatic visceral and brain
  metastases
• Median survival of 13 months after developing
  metastases
• 30 patients develop metastatic disease

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PARP Inhibitor Mechanism of Action
1. PLATINUM CHEMOTHERAPY Inflicts DNA damage via
adducts and DNA crosslinking
Pt
PARP1
Pt
BSI-201
4. REPLICATION FORK COLLAPSE Double strand DNA
break
PARP1
3. INHIBITION OF PARP1 Disables DNA
base-excision repair
Pt
PARP1
2. PARP1 UPREGULATION Base-excision repair of
DNA damage
Pt
Pt
BRCA1 BRCA2
CELL DEATH
CELL SURVIVAL
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Randomized Phase II Trial of BSI-201 plus
Gemcitabine/Carboplatin in Metastatic TNBC
Randomize
BSI-201 5.6 mg/kg d 1, 4, 8, 11 Gemcitabine
1000 mg/m2 Carboplatin AUC 2 d 1, 8 q3w
Restage every 2 cycles
Metastatic TNBC (n 123)
Gemcitabine 1000 mg/m2 Carboplatin AUC 2 d 1, 8
q3w

• Key inclusion criteria
• 2 prior chemotherapies for MBC
• No prior gemcitabine, platinum agent, or PARP
  inhibitor

Crossover to experimental arm allowed at
progression
Primary endpoints CBR (CR PR SD 6 months),
safety Secondary endpoints ORR, PFS, OS

• OShaughnessy et al. J Clin Oncol 2009
  27(suppl)793s (abstract 3)

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Randomized Phase II Trial of BSI-201 in
TNBCEfficacy
BSI-201 Gem/Carbo (n 42) Gem/Carbo (n 44) P Value (HR 95 CI)
Tumour Response
ORR 20 (48) 7 (16) .002
CBR 26 (62) 9 (21) .0002
Survival (n 57) (n 59)
mPFS 6.9 months 3.3 months lt.0001 (0.342 0.200-0.584
mOS 9.2 months 5.7 months .0005 (0.348 0.189-0.649)

• OShaughnessy et al. J Clin Oncol 2009
  27(suppl)793s (abstract 3)

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Progression-Free Survival
BSI-201 Gem/Carbo (n 57) Median PFS 6.9
months Gem/Carbo (n 59) Median PFS 3.3
months P lt 0.0001 HR 0.342 (95 CI,
0.200-0.584)
OShaughnessy et al. J Clin Oncol 2009
27(suppl)793s (abstract 3)
23
Overall Survival
BSI-201 Gem/Carbo (n 57) Median OS 9.2
months 8 Gem/Carbo (n 59) Median OS 5.7
months P 0.0005 HR 0.348 (95 CI,
0.189-0.649)
OShaughnessy et al. J Clin Oncol 2009
27(suppl)793s (abstract 3)
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Olaparib A novel, orally active PARP inhibitor

• A phase I trial identified olaparib (AZD2281
  KU-0059436) 400 mg bid as the maximum tolerated
  dose1 with a signal of efficacy in BRCA-mutated
  ovarian cancer2

• Most common toxicities CTCAE grade 1 and 2
  nausea and fatigue
• Significant PARP inhibition and tumor response at
  olaparib doses 100400 mg bid

1. Yap T et al. J Clin Oncol 200725(18S)abst
3529 2. Fong P et al. J Clin Oncol
200826(15S)abst 5510.
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Phase II Study of Olaparib in BRCA-deficient
Advanced Breast Cancer

• Patient population
• Stage IIIB/IIIC/IV
• Failure of 1 prior chemotherapy for advanced
  disease
• BRCA1 or BRCA2 mutation
• Single arm, sequential cohort trial design
• Cohort 1 (n 27) olaparib 400 mg po bid 28 day
  cycle
• Cohort 2 (n 27) olaparib 100 mg po bid 28 day
  cycle
• Primary endpoint ORR by RECIST
• Secondary endpoints included PFS and safety

• Tutt et al. J Clin Oncol 2009 27(suppl)803s
  (CRA501).

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Efficacy
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Phase 3 Trials

• Main method by which new cancer treatments are
  demonstrated to be an improvement on what has
  gone before, especially when magnitude of benefit
  is small
• Survival curves improving over time trial by
  trial- part of ongoing process
• Innumerable examples of patient benefit in
  experimental arm most significantly in adjuvant
  setting where lives are saved-
• 5-FU in colorectal cancer
• Herceptin in breast cancer
• Rituximab in NHL

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Phase 3 Trials

• Important negative studies
• Adjuvant irinotecan avastin in colorectal
  cancer
• High dose chemotherapy in breast cancer
• Even when there is a benefit from new treatment,
  only a proportion of participants will receive
  it- however
• Outcomes are still better in the control group
  compared to patients treated outside of research
  environment
• Trial centres offer higher quality care
• Evidence for this in off study population

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Quality measure

• Outcomes in Centres running trials and treating
  patients on similar protocols are generally
  better than historical controls
• Paediatric leukaemia
• Participation in trials improves quality of care
  of medical practitioners
• ONE trial of PPIs for GERD in general practice

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Phase 4Post-Marketing

• Rare side effects
• Unusual interactions
• Obvious patient benefit

31
Why do Research?

• Investment in research saves lives, and that is
  why the Government wishes to make Britain the
  best place for RD and innovation
• John Reid, Former Secretary of State for Health

Politics is not a bad profession. If you succeed
there are many rewards, if you disgrace yourself
you can always write a book Ronald Reagan, 40th
President of the United States
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Research Fraud

• Werner Bezwoda
• Falsified records of women on a trial of high
  dose chemotherapy for breast cancer conducted in
  the 1990s

33
Why do Research?

• Enshrined in Patients Charter and NHS Cancer
  plan Constitution
• right of patient to have access to clinical trial
• oncology centres have no choice!
• Best available treatments
• Quality measure
• Institutional Reputation
• Recruitment and retention
• Job satisfaction
• Culture

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NHS Constitution for England

• Research
• is a core part of the NHS
• enables the NHS to improve the current and future
  health of the people it services
• The NHS will do all it can to ensure that
  patients, from every part of England, are made
  aware of research that is of particular relevance
  to them
• The NHS is therefore putting in place procedures
  to ensure that patients are notified of
  opportunities to join in relevant ethically
  approved research and will be free to choose
  whether they wish to do so
• 21 Jan 2009

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Operating Framework for the NHS in England
2009-10
published in December 2008
18. High Quality Care for All the NHS must play
its full part in supporting health research.. All
providers of NHS care will need to increase their
participation on research. The national ambition
is to double the number of patients taking part
in clinical trials and other well-designed
research studies within five years. SHAs are
expected to ensure that NHS trusts work with the
NIHR Comprehensive Research Network locally to
contribute to this progressive increase.
36
Research Governance

• Method of maintaining quality assurance in
  clinical research
• Sets out principles, requirements and standards
• Defines mechanisms to deliver them
• Describes monitoring and assessment arrangements

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Why is it important?

• Improves research and safeguards the public by
• Enhancing ethical and scientific quality
• Promotes good practice
• Reducing adverse incidents and ensuring lessons
  learned
• Forestalling poor performance and misconduct

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Who is it for?
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Who is it for?

• Everyone involved in research
• Senior and junior
• All professional groups
• Primary-tertiary care/Social and public health
• i.e. those who
• Design studies
• Participate in trials
• Host or fund research
• Manage or undertake research
• You can run but you cant hide R Reagan

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The Rule Book(s)

• ICH-GCP International Conference on
  Harmonisation of Good Clinical Practice
  Guidelines (May 1996)
• Quality and Ethical standard for EU, Japan and US
  based on the Declaration of Helsinki
• EU Directive on Clinical Trials (May 2004)
• The approximation of the laws, regulations and
  administrative provisions of the Member States
  relating to the implementation of Good Clinical
  Practice in the conduct of clinical trials on
  medicinal products for human use'
• National Research Governance Framework (April
  2005)
• Outlines principles of good governance that apply
  to all research undertaken within the remit of
  the Secretary of State for Health

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Problems

• Some guidance open to interpretation esp. EU
  directive
• No fault indemnification
• Legal agreements between NHS bodies
• Complex and onerous approaches to Research
  Governance
• Delays in trial processing prior to commencement
• Infrastructure capacity
• Prioritisation of trials

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Key Players- National and Local

• Department of Health, NCRN (I), MRC, CTAAC
• Cancer Research Network
• RATs, DOGs
• Comprehensive Local Research Network
• MREC, LREC
• Hospital Trust R D Committee
• Departmental Trial Committee

43
National Cancer Research Networks

• 33 Local Research Networks covering England
• KMCRN
• includes 5 acute hospital trusts (pop. 1.7 M) but
  no medical school
• Recruitment to randomised trials league table
• 32nd in 2003 up to 8th in 2007
• Remained in top 10 since

44
Approving a new Trial

• Complex and comprehensive regulatory processes
• Scientific, ethical, financial, legal and
  infrastructure considerations

45
MRC/CRUK Joint Funding Mechanism
Independent Investigator/ Group
NCRI Study Group
Portfolio/
NCRI
CTAAC Outline Sift
Recruitment
DECLINE
International
ICAP
perspective
INVITE
REVISE
A P P R O V A L
therapeutic trials
screening trials
Int. studies (full protocol)
MRC Full Proposal
CTAAC Full Proposal
Decline
Resubmit
Fund
Resubmit
Decline
National Portfolio

• Assessment Criteria for CTAAC outline
  applications are as follows
• Clinical importance of the research question
• Scientific importance of the research question
• Adequacy of background and preliminary data
• Strength of study design, including statistical
  design
• Expected interest/appeal to patients and
  likelihood of adequate accrual
• Anticipated opening for trial in portfolio

Includes NCRN trials (no research costs) and
collaborations involving pharmaceutical
companies
46
Kent Medway Trials Infrastructure
Diagnostics
Approved
Local Assessment (KOC Clinical Trials Group)
Pharmacy
Chemotherapy
Not approved
P.I.s
Research Staff
Approved
Apply to CTU
Approved
Not approved
47
Registration and reporting

• Trial registries extremely important to ensure
  access to help to make sure trials are
  published- esp negative ones
• Reporting of results to patients and medical
  community
• Implementation of positive studies obviously
  critical

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Conclusion

• Entering a clinical trial means the experience of
  undergoing treatment for cancer is not lost
• there should be a reason why a patient is not
  offered entry into a study
• Participation in clinical trials is good for
• Patients
• Professionals
• Institutions
• Society at large