Optimizing Patient Enrollment in Clinical

Trials Forum
 Objectives

Discuss enrollment strategies

Highlight important factors
Share ideas
Maximize impact on outcome
Create an Ideal CRO…

14 October 2004 Placet Research 2

 Complexities of the Drug
Development Process

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 Pharmaceutical and Biotechnology
Cultures

Pharma Biotech
Large Small
Stable Volatile
Tremendous resources Limited financial resources
(often < 2 years)
Small molecule drive Biologics
Focus on development Focus on discovery
Target
Drug

Risk averse Must take risks to compete

Est. Market cutoff -$500M Est. Market cutoff - $20M
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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-Winthrop+Kodak=Sanofi +Syntholobo=Sanofi-
Syntholobo
Hoechst Marion Roussel + Rhone-Poulenc Rorer = Aventis
Merck
Johnson & Johnson

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 Other Large Pharma
and Biotech Companies

AstraZeneca Amgen
Novartis Genentech
Bristol-Myers Squibb Serono
Roche Biogen-Idec
Wyeth
Celgene
Eli Lilly
Abbott Labs Genencor
Schering Plough Chiron
Schering Ag Icos
Boehringer-Ingelheim Millennium

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 The Drug Discovery Process

Traditional Small Molecules MAb RNAi

Target Identification

Early Research
Target Validation (6 – 12 months) RNAi Driven
Immunoprospecting Research
(6-12 months) (3 - 6 months)
Lead Identification Lead
Disc./Optimiz. Lead Optimization
(18 – 24 (3-6 months)
Lead Optimization months)

Animal Studies Animal Studies Animal Studies

Preclincal Development (12 – 18 months) (12 – 18 months) (12 – 18 months)

Manufacturing/Formulations Process Chemistry Production

(6 – 12 months) (6 – 12 months)

IND 42-66 months 27-50 months 15-24 months

Total Discovery Time
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 Clinical Development

Testing in Humans

Percent of Drugs
Number of Patients Length Purpose
Successfully Tested*
Ph. 1 20-100 Several months Mainly safety 70 percent

Ph. 2 Up to several hundred Several months Some short-term 33 percent

to 2 years safety but mainly
effectiveness
Ph. 3 Several hundred 1-4 years Safety, dosage, 25-30 percent
to several thousand effectiveness

 For example, of 100 drugs for which investigational new drug applications are submitted to FDA,
about 70 will successfully complete phase 1 trials and go on to phase 2; about 33 of the original
100 will complete phase 2 and go to phase 3; and 25 to 30 of the original 100 will clear phase 3
(and, on average, about 20 of the original 100 will ultimately be approved for marketing).

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 Time to Approval is
Decreasing

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RECRUITMENT
What is it all about?
 Laws governing clinical trial conduct

Lasagna’s law:
The prevalence of any disease under study drops
dramatically immediately upon study initiation, returning
to previous levels only once enrolment is complete

Murphy’s law:
Everything that can go wrong will go wrong

Giltinan’s 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 PLAN…what 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 Today’s
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 it’s 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

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www.clinicaltrials.gov
 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…..it’s not achieved alone
Start early
Plan, Implement, Measure & Close

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 Clinical Trial Team

Developing the Sponsor-

CRO Partnership
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 Who is involved?

Remember the big picture

Collaborate early
Build relationships
Clear objectives
Commercia
l Legal
Advoca
cy

Regulatory
Sponso Media
r

Subject Investigator
site
s
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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 Wyeth’s 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

Need to define value before we can manage it!

Need to quantify value before we can improve it!

Time

Risk Cost

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
(Sponsor’s 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

Protocols Sites Patients CRF Pages Analysis Reports

Study Planning Study Start-up Patient enrolment Data Cleanup Statistical analysis Report writing

Protocol Protocol 1st Patient Last Last Database Analysis Report

Start Approval entered Patient Patient Lock Complete Approval
entered complete

Drug Order - Drug Available Query Resolution Time

Site enrolment

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 POOR MONITORING INCORRECT
Produces poor data ENROLLMENT FORECASTS
causes delays Causes delays, increases resources
and costs time and cost time

Time = Money

POORLY DESIGNED BADLY WRITTEN REPORTS

STATISTICAL ANALYSIS PLANS cause more reviews, rewrites
cause database changes which cost time
which cost time

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 How to Measure CRO Success
There are several areas equally applicable to all dimensions of outsourcing:

1. Finance/budget
 focus on cost management and cost delivery of services and work products

2. Customer satisfaction
 focus on critical attributes that generate satisfaction with services and work products
among internal business customers
 Don’t be afraid to stop or change

3. Work/product delivered
 focus on quantifying the amount of service or work product provided in a given time period

4. Quality
 focus on the objective and measurable aspects of quality of services and products
 Continuous improvement
 Open to new ideas

5. 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

CRA

Project
Pharma
Physician

R&D Office CRO

Investigator

Central
IRB
Laboratories

Data Safety
Management Reporting

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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
 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 Plan
Challenges 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 (n=75)
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 > 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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 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)
 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
USA International Trials Europe
Frequent violations of Baseline characteristics All regulations created for marketing
eligibility criteria comparable across authorization but cover all types of
treatment groups? clinical trials
Serious violations of Dropout patterns Diversity and incompatibilities of national
eligibility criteria comparable across groups? regulations considerably slow down the
process
Poor compliance with Comparability of Costs for performing trials independently
dosing regimen/visit “completers” and early from the pharmaceutical company are
schedule dropouts? forbidding
Concomitant medication Study participants No real program to support clinical rese-
usage comparable across sites? arch at the European and national levels
Higher than expected Conclusions consistent
dropout rate across sites?
Technical glitches - e.g.
assay or measurement
difficulties; other data
problems
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 CLINICAL TRIALS
Conducted by European Organization for the Research
and Treatment of Cancer (EORTC)
 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 -> Phase III)
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 PATIENT ACCRUAL IN EORTC CLINICAL STUDIES 2000
(6509 PTS)

Sweden:71 Finland:3 Norway:61

Estonia:1
Denmark:38
Czech Rep.:37
The Netherlands:1484
Poland:51
U.K. :538 Slovakia:45
Belgium:760 Hungary:26
Italy:413 Slovenia:7
Germany:569 Croatia:42
Greece:27 F.R. Yugoslavia:13
Austria:111 Bosnia:3
Portugal:57 Romania: 11
Spain:219
Bulgaria:15
France:1166
Turkey:75
Argentina: 6
Chile: 28 South Africa:14 Russia:32 Switzerland:169 Israel:78
Canada:188 Australia:34 USA:52 Egypt:46
N. Zealand:5 Saudi Arabia:4 Malta:10
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 Questions ?

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 Celebrate & share success

Vadim Paluy, MD

vadpal@hotmail.com

(408) 621-4028

www.placetresearch.com

14 October 2004 Placet Research 57