Optimizing Patient Enrollment in Clinical Trials Forum

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Optimizing Patient Enrollment in Clinical Trials
Forum
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Objectives

• Discuss enrollment strategies
• Highlight important factors
• Share ideas
• Maximize impact on outcome
• Create an Ideal CRO

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Complexities of the Drug Development Process
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Pharmaceutical and Biotechnology Cultures
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Drug Companies The Top Five

• Pfizer
• Parke-Davis, Warner Lambert, Pharmacia, Searle,
  Monsanto, Pfizer
• GlaxoSmithKline
• Burroughs Welcome Glaxo Glaxo-Wellcome
• Smith Kline French Beecham SKB
• Sanofi-Aventis
• Sterling-WinthropKodakSanofi SyntholoboSanofi-
  Syntholobo
• Hoechst Marion Roussel Rhone-Poulenc Rorer
  Aventis
• Merck
• Johnson Johnson

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Other Large Pharma and Biotech Companies

• Amgen
• Genentech
• Serono
• Biogen-Idec
• Celgene
• Genencor
• Chiron
• Icos
• Millennium

• AstraZeneca
• Novartis
• Bristol-Myers Squibb
• Roche
• Wyeth
• Eli Lilly
• Abbott Labs
• Schering Plough
• Schering Ag
• Boehringer-Ingelheim

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The Drug Discovery Process
Traditional Small Molecules MAb
RNAi
42-66 months 27-50 months 15-24 months
Total Discovery Time
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Clinical Development
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Time to Approval is Decreasing
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RECRUITMENT

• What is it all about?

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Laws governing clinical trial conduct

• Lasagnas law
• The prevalence of any disease under study
  drops
• dramatically immediately upon study
  initiation, returning
• to previous levels only once enrolment is
  complete
• Murphys law
• Everything that can go wrong will go wrong
• Giltinans law
• The expected quality of trial data obtained
  from a center where the P.I. is a
  thought-leader in the field is inversely
  proportional to the degree of exaltation of the
  P.I.

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What does recruitment mean?

• A fresh or additional supply of something
• A fresh supply or number of persons, either as
  additional to the previous number, or to make up
  for a decrease.
• To get or seek recruits
• More than the word suggests

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Target population

• THE PLANwhat to do and when
• Seek out information..tailor
• Patients
• Give main eligibility criteria
• Inclusion and exclusion criteria best specified
  as checkbox criteria
• Are lab values needed to establish eligibility?
  Central or local lab determinations?
• Minimize ambiguity when specifying who is
  eligible, especially in multi-center trials
• Therapy/Sites
• Flexibility-be accommodating
• Geography
• Time of Year
• Numbers
• Time.stay ahead of the game
• Early risk assessment/hurdles

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Basic design elements

• Control group (concurrent, other?)
• Gold standard randomized, double-blind,
  placebo-controlled trial
• Blinding (double, single-blind, open-label?
  precautions in implementation?)
• Randomization (allocation to treatments - how
  implemented?)
• Balance across key prognostic factors?
• Min/max representation of certain subgroups or
  participating study centers?
• Adequate sample size?
• Method for handling of dropouts/missing data
  specified? Unambiguously?
• Blinding is especially important in the case of
  subjective evaluation
• Balance across important prognostic factors

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Internet Applications for Todays Clinical Trial

• Sponsors and vendors have recognized the value of
  the internet for
• Patient Recruitment
• Monitoring
• Patient Education
• Electronic Data Capture
• Data Management

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Patient Recruitment by Internet

• Competition for participants (PIs and sites)
• Specific inclusion and exclusion criteria
  (screening)
• Multi-center, international studies
• Evidence requirements (e.g., heterogeneity)
• With its ability to reach a large population of
  potential subjects, the internet is a natural,
  important tool for recruitment for a number of
  trials
• Large number of websites have been developed

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Patient Recruitment the Internet
www.clinicaltrials.gov
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Summary

• Recruitment is more than word suggests
• Even studies that are easier to recruit for can
  run more efficiently with a plan and smooth
  implementation
• This means less time and money and more
  importantly.faster access to the drug by
  patients.
• Team Work..its not achieved alone
• Start early
• Plan, Implement, Measure Close

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Clinical Trial Team
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Who is involved?

• Remember the big picture
• Collaborate early
• Build relationships
• Clear objectives

Legal
Commercial
Advocacy
Media
Regulatory
Sponsor
Investigator
Subject
sites
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The Outsourcing Challenge

• Create develop productive strategic
  partnerships with external suppliers
• Drive process improvement both externally and
  internally
• Integrate internal and external processes

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Why do we need to establish performance
expectations with external suppliers?
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Strategic or Tactical Outsourcing?

• Strategic Outsourcing
• Outsource all data management to a single company
• In April 2003, Wyeth outsourced its clinical data
  management operations to Accenture, enabling
  Wyeths clinical staff to focus on more critical
  functions.
• The bold move aims to deliver equally bold
  results, including an 80 percent reduction in
  clinical trial cycle times and a 30 percent
  reduction in contracted costs.
• Tactical Outsourcing
• Outsource single development project to a single
  or group of CRO
• Transactional Outsourcing
• Contract a single project to a single CRO

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Maximising the Value of Outsourcing
Time
Cost
Risk
Quality
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Selecting CROs as a Competitive Bid Process

• Clinical trial management, data management, etc.
• Therapeutic/Indication knowledge
• Previous experience with similar drug class
• Company annual reports
• References, Testimonials
• Financial Background checks
• Staffing Levels/Turnover
• Quality of Personnel
• Geographic stretch
• Service Gaps
• Stability
• Access to Metrics
• Previous audit reports

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Project Specifications (Sponsors view)

• Specifications to be written in a manner to
  promote full and unrestricted competition by
  setting actual, minimum requirements
• Elements to consider when writing specifications
• Identify the essential characteristics of the
  service to be purchased
• Do not include unnecessary features
• Emphasize performance over design
• Do not allow them to be written by a CRO
• Should be quantifiable rather than qualitative
• Should be verifiable
• Do not overstate quality
• Metrics selected should create a common language
  among diverse team members

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Track Performance vs. Milestones
Sponsor
CRO
CRO
CRO
CRO
CRO
Study Planning
Study Start-up
Patient enrolment
Data Cleanup
Statistical analysis
Report writing
Analysis
Protocols
Sites
Patients
CRF Pages
Reports
Protocol Start
Protocol Approval
1st Patient entered
Last Patient entered
Last Patient complete
Database Lock
Analysis Complete
Report Approval
Drug Order - Drug Available
Query Resolution Time
Site enrolment
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POOR MONITORING Produces poor data causes delays
and costs time
INCORRECT ENROLLMENT FORECASTS Causes delays,
increases resources and cost time
Time Money
POORLY DESIGNED STATISTICAL ANALYSIS PLANS cause
database changes which cost time
BADLY WRITTEN REPORTS cause more reviews,
rewrites which cost time
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How to Measure CRO Success

• There are several areas equally applicable to all
  dimensions of outsourcing
• Finance/budget
• focus on cost management and cost delivery of
  services and work products
• Customer satisfaction
• focus on critical attributes that generate
  satisfaction with services and work products
  among internal business customers
• Dont be afraid to stop or change
• Work/product delivered
• focus on quantifying the amount of service or
  work product provided in a given time period
• Quality
• focus on the objective and measurable aspects of
  quality of services and products
• Continuous improvement
• Open to new ideas
• Time/schedule
• focus on critical service, product, and project
  time frames and the ability to deliver on time

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Seek Metrics to Support Investigator Relationship
Management
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What Does Pharma Expect From Outsourcing?

• Focus on Quality
• delivering expertise and knowledge that meet or
  exceed the quality standards demanded by product
  development teams and regulatory authorities
• Focus on Delivery
• Acting with an unwavering commitment to execution
  and delivery of development and business Key
  Performance Indicators
• Focus on Teamwork
• Creating dynamic, talented teams that work
  locally and globally, communicate openly
  internally and externally, are passionate about
  and enjoy what they do
• Focus on Leadership Innovation
• Leading by example, welcoming change, encouraging
  innovation, providing an environment of
  professional learning and development, and
  creating value for the product

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Summary

• The bid defence process provides an opportunity
  to establish performance expectations with CROs
• Metrics provide the roadmap
• starting point
• Where you need to improve (vision of future)
• Focus on Quality, Delivery, Time and Cost during
  the bid defense process
• Develop productive and performance enhancing
  relationships

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Just One Example A single Phase III randomized,
placebo-controlled, double-blind study of Rituxan
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Non-Hodgkin's lymphoma most commonly occurs in
the lymph nodes and is a cancer of the
B-cells Rituxan, a monoclonal antibody, binds to
the CD20 protein found on normal and cancerous
B-cells in vitro.
Rituxan recruits components of the body's immune
system (phagocytes, etc.) to destroy B-cells
Once Rituxan has cleared the body, normal B-cells
can begin to grow again
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Rituxan Clinical Development PlanChallenges and
Constraints

• Rituxan was marketed
• Accrual hurdle Patients/ physicians may opt for
  treatment off-study
• The specified patient population for the Phase
  III study is small
• Uncertainty re the frequency and clinical
  significance of anti-Rituxan antibodies (HACA) in
  this patient population

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Rituxan Phase III Feasibility Assessment

• Objective To establish the feasibility of
  conducting the proposed clinical trial
• A site survey process was implemented to collect
  data in the US and some other countries
  (Australia, NZ, Russia, Poland, Czech Republic)
• Telephone contacts were utilized in Sweden,
  Denmark, Canada, Italy and the UK
• Targeted site criteria Covance
  hematologist/oncologist database (US) and Roche
  key customers/investigators (ex-US)

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Rituxan Phase III Feasibility Assessment

• Conclusions (US)
• Significant numbers of investigators declined to
  participate in the feasibility assessment since
  they would be unable to conduct the trial at
  their sites (212/246, 86)
• However, all responding investigators (34, 14)
  felt that the trial was operationally feasible
  and would be interested in participating
• Recruitment projections estimated that it would
  take more than 12 months to complete enrollment
  (n75) at 34 US sites
• Assessment based on
  single-arm trial design

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Rituxan Phase III Feasibility Assessment

• Conclusions for other countries
• Much higher investigator acceptance of
  feasibility assessment and trial design (34/54,
  63)
• Involvement of sites outside the US will enhance
  enrollment but will increase operational
  complexity
• Assessment based on randomized pivotal trial
  design

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Site Selection

• 25 US sites targeted
• 20 sites targeted in other countries
• 4 Canada
• 5 Australia
• 2 New Zealand
• 4 Sweden
• 5 Italy
• 2 UK
• Expect enrollment gt Outside US US

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Roles and Responsibilities Genentech

• Co-sponsor with Biogen IDEC
• Authorship of study protocol and development of
  CRF
• IND holder, primary contact with US FDA
• Responsible for study operationalization
• Contract holder with CRO and study sites
• Drug manufacture, supply and distribution
• Safety reporting
• Medical monitoring (oversight and 1 US
  responsibility)
• Statistical analysis, final study report and sBLA
  filing

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Roles and Responsibilities Biogen IDEC

• Co-sponsor with Genentech
• Implementation team participation
• Regulatory consultation
• Funding through Genentech/Biogen IDEC
  collaboration

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Roles and Responsibilities Roche HQ

• Life cycle team decision to support
  Genentech/Biogen IDEC study conduct ex-US
• Communication with Roche Affiliate offices
• Future consideration of label expansion to
  countries outside the US

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Roles and Responsibilities Roche Affiliates

• Post marketing safety reporting responsibilities
• Key customer management
• Input regarding key investigator sites outside US
• Participation in regional investigator meetings

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Roles and Responsibilities Covance

• Execution of transferred obligations from
  Genentech
• Regulatory applications outside US
• Safety reporting to authorities outside US
• Site management
• Central labs, IVRS, drug distribution management
• Data management
• Medical monitoring in AU/NZ
• Execution of investigator meetings

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Roles and Responsibilities Connector-Medical

• Medical monitoring in EU
• Protocol exceptions
• Unblinding
• SAE review if required
• Participation in EU investigator meeting
• Site identification and feasibility assessment
  for Sweden / Denmark

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A Global Team
Covance
ROCHE
STUDY SITES
COVANCE
GENENTECH / IDEC
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Issues in International Research

• Prepared using materials of the Council for
  International Organizations of
• Medical Sciences (CIOMS is an international,
  non-governmental, non-
• profit organization established jointly by WHO
  and UNESCO in 1949)

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What types of things make a country/ community
especially vulnerable to harm or exploitation
from external scientific research?

• Economic disparity
• Authoritative/corrupt political system
• Lack of human rights protection
• Lack of individual autonomy (especially when this
  applies only to certain sectors)
• Lack of infrastructure for scientific/ ethical
  review
• Low education or literacy

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Some issues to consider.

• Who should provide consent for participation?
• Community leaders? Heads of household? Only the
  individual participant?
• What is sensitive information?
• Abortion in Russia vs. The Philippines
• Income
• In societies where life is very public...How can
  privacy be assured during data collection?
• How can you insure that consent is truly
  informed?
• Some of the basic principles may be difficult to
  convey/implement due to
• Limited autonomy
• Limited education
• Language barrier
• This cannot be used as a reason to forgo
  obtaining individual informed consent thus,
  creative informed consent processes should be
  developed

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With respect to clinical trials...

• Persons in underdeveloped communities should not
  ordinarily be involved in research that could be
  carried out reasonably well in developed
  communities
• Research should be responsive to the health needs
  and the priorities of the community in which it
  is to be carried out
• Local IRBs should be constituted in the same way
  that IRBs are constituted in the US (diversity
  and representation of relevant stakeholders
  researchers, health care providers, community
  representatives)

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FDA Vs. European Committees Concerns
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CLINICAL TRIALS Conducted by European
Organization for the Research and Treatment of
Cancer (EORTC)
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EORTC TODAY (I)

• Aims
• Improvement of cancer treatment and related
  problems
• Education to high quality clinical research
• How ?
• Multicenter - multinational and intercontinental
  cancer clinical trials
• Research projects on methods and practices for
• cancer clinical trials
• anti-cancer agents development
• cancer management procedures
• Dissemination of know-how courses - symposia -
  workshops

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EORTC TODAY (II)

• Network of more than 350 institutions from 31
  different countries
• /- 2,000 collaborators
• (clinicians, pathologists, researchers,...)
• /- 7,000 patients are entered each year in EORTC
  trials (database of more than 100,000 patients)
• /- 30.000 patients in follow-up
• /- 120 trials open to patients entry
• (Phase I -gt Phase III)

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PATIENT ACCRUAL IN EORTC CLINICAL STUDIES 2000
(6509 PTS)
Norway61 Estonia1 Czech Rep.37 Poland51 Slovak
ia45 Hungary26 Slovenia7 Croatia42 F.R.
Yugoslavia13 Bosnia3 Romania
11 Bulgaria15 Turkey75 Israel78 Egypt46
Sweden71 Denmark38 The Netherlands1484 U.K.
538 Belgium760 Italy413 Germany569 Greece27 A
ustria111 Portugal57 Spain219 France1166
Finland3

Argentina 6 Chile 28 Canada188 N.
Zealand5
Russia32 USA52 Malta10
Switzerland169
South Africa14 Australia34 Saudi Arabia4
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Questions ?
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Celebrate share success

• Vadim Paluy, MD
• vadpal_at_hotmail.com
• [phone]
• www.placetresearch.com
•