Upload
raviprakash-k
View
111
Download
0
Tags:
Embed Size (px)
Citation preview
Optimizing Patient Enrollment in Clinical Trials Forum
14 October 2004 Placet Research 2
Objectives
Discuss enrollment strategies
Highlight important factors
Share ideas
Maximize impact on outcome
Create an Ideal CRO…
14 October 2004 Placet Research 3
Complexities of the Drug Development Process
14 October 2004 Placet Research 4
Pharmaceutical and Biotechnology Cultures
Pharma BiotechLarge 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
14 October 2004 Placet Research 5
Drug Companies: The Top Five
PfizerParke-Davis, Warner Lambert, Pharmacia, Searle, Monsanto, Pfizer
GlaxoSmithKlineBurroughs Welcome + Glaxo = Glaxo-WellcomeSmith Kline French + Beecham = SKB
Sanofi-AventisSterling-Winthrop+Kodak=Sanofi +Syntholobo=Sanofi-SyntholoboHoechst Marion Roussel + Rhone-Poulenc Rorer = Aventis
MerckJohnson & Johnson
14 October 2004 Placet Research 6
Other Large Pharma and Biotech Companies
AstraZenecaNovartisBristol-Myers SquibbRocheWyethEli LillyAbbott LabsSchering PloughSchering AgBoehringer-Ingelheim
Amgen
Genentech
Serono
Biogen-Idec
Celgene
Genencor
Chiron
Icos
Millennium
14 October 2004 Placet Research 7
The Drug Discovery Process
Traditional Small Molecules MAb RNAi
Target Identification
Target Validation
Lead Identification
Lead Optimization
Preclincal Development
Manufacturing/Formulations
IND
RNAi Driven Research
(3 - 6 months)
Animal Studies(12 – 18 months)
Early Research(6 – 12 months)
Lead Disc./Optimiz.
(18 – 24 months)
Animal Studies(12 – 18 months)
Process Chemistry (6 – 12 months)
Animal Studies(12 – 18 months)
Immunoprospecting(6-12 months)
Lead Optimization(3-6 months)
Production (6 – 12 months)
42-66 months 27-50 months 15-24 months Total Discovery Time
14 October 2004 Placet Research 8
Clinical Development
Testing in Humans
Number of Patients Length PurposePercent of Drugs Successfully Tested*
Ph. 1 20-100 Several months Mainly safety 70 percent
Ph. 2 Up to several hundred Several months to 2 years
Some short-term safety but mainly effectiveness
33 percent
Ph. 3 Several hundred to several thousand
1-4 years Safety, dosage, effectiveness
25-30 percent
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).
14 October 2004 Placet Research 9
Time to Approval is Decreasing
RECRUITMENT
What is it all about?
14 October 2004 Placet Research 11
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.
14 October 2004 Placet Research 12
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
14 October 2004 Placet Research 13
Target population
THE PLAN…what to do and when Seek out information…..tailorPatientsGive main eligibility criteria Inclusion and exclusion criteria best specified as ‘checkbox’ criteriaAre lab values needed to establish eligibility? Central or local lab determinations?Minimize ambiguity when specifying who is eligible, especially in multi-center trialsTherapy/Sites Flexibility-be accommodatingGeographyTime of YearNumbersTime….stay ahead of the gameEarly risk assessment/hurdles
14 October 2004 Placet Research 14
Basic design elements
Control group (concurrent, other?)“Gold standard”: randomized, double-blind, placebo-controlled trialBlinding (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
14 October 2004 Placet Research 15
Internet Applications for Today’s Clinical Trial
Sponsors and vendors have recognized the value of the internet for:
Patient RecruitmentMonitoringPatient EducationElectronic Data CaptureData Management
14 October 2004 Placet Research 16
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
14 October 2004 Placet Research 17
Patient Recruitment & the Internet
www.clinicaltrials.gov
14 October 2004 Placet Research 18
Summary
Recruitment is more than word suggestsEven studies that are easier to recruit for can run more efficiently with a plan and smooth implementationThis means less time and money and more importantly….faster access to the drug by patients.Team Work…..it’s not achieved aloneStart earlyPlan, Implement, Measure & Close
14 October 2004 Placet Research 19
Developing the Sponsor-CRO Partnership
Clinical Trial Team
14 October 2004 Placet Research 20
Who is involved?
Remember the big picture
Collaborate early
Build relationships
Clear objectives
Regulatory
sites
Investigator
MediaSponsor
Subject
Advocacy
LegalCommercial
14 October 2004 Placet Research 21
The Outsourcing Challenge
Create & develop productive strategic partnerships with external suppliers
Drive process improvement both externally and internally
Integrate internal and external processes
14 October 2004 Placet Research 22
Why do we need to establish performance expectations with external suppliers?
14 October 2004 Placet Research 23
Strategic or Tactical Outsourcing?
Strategic OutsourcingOutsource 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 OutsourcingOutsource single development project to a single or group of CRO
Transactional OutsourcingContract a single project to a single CRO
14 October 2004 Placet Research 24
Maximising the Value of Outsourcing
Need to define value before we can manage it!
Need to quantify value before we can improve it!
Time
CostRisk
Quality
14 October 2004 Placet Research 25
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
14 October 2004 Placet Research 26
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 qualityMetrics selected should create a common language among diverse team members
14 October 2004 Placet Research 27
Track Performance vs. Milestones
Study Planning Study Start-up Patient enrolment Data Cleanup Statistical analysis Report writing
Protocols Sites Patients CRF Pages Analysis Reports
ProtocolStart
ProtocolApproval
1st Patiententered
LastPatiententered
LastPatientcomplete
DatabaseLock
AnalysisComplete
ReportApproval
Drug Order - Drug Available
Site enrolment
Query Resolution Time
Sponsor CRO CRO CRO CROCRO
14 October 2004 Placet Research 28
Time = Money
POOR MONITORINGProduces poor data
causes delays and costs time
INCORRECTENROLLMENT FORECASTS
Causes delays, increases resourcesand cost time
POORLY DESIGNED STATISTICAL ANALYSIS PLANS
cause database changeswhich cost time
BADLY WRITTEN REPORTScause more reviews, rewrites
which cost time
14 October 2004 Placet Research 29
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
14 October 2004 Placet Research 30
Seek Metrics to Support Investigator Relationship Management
Pharma
R&D Office
CentralLaboratories
DataManagement
SafetyReporting
IRB
CRO
ProjectPhysician
CRA
Investigator
14 October 2004 Placet Research 31
Focus on Qualitydelivering expertise and knowledge that meet or exceed the quality standards demanded by product development teams and regulatory authorities
Focus on DeliveryActing with an unwavering commitment to execution and delivery of development and business Key Performance Indicators
Focus on TeamworkCreating 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
What Does Pharma Expect From Outsourcing?
14 October 2004 Placet Research 32
The bid defence process provides an opportunity to establish performance expectations with CROs
Metrics provide the roadmapstarting pointWhere 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
Summary
Just One Example… A single Phase III randomized, placebo-controlled, double-blind study of Rituxan
14 October 2004 Placet Research 34
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
14 October 2004 Placet Research 35
Rituxan Clinical Development PlanChallenges and Constraints
Rituxan was marketedAccrual hurdle: Patients/ physicians may opt for treatment off-study
The specified patient population for the Phase III study is smallUncertainty re the frequency and clinical significance of anti-Rituxan antibodies (HACA) in this patient population
14 October 2004 Placet Research 36
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)
14 October 2004 Placet Research 37
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 participatingRecruitment 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
14 October 2004 Placet Research 38
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
Rituxan Phase III Feasibility Assessment
14 October 2004 Placet Research 39
Site Selection
25 US sites targeted20 sites targeted in other countries
4 Canada5 Australia2 New Zealand4 Sweden 5 Italy2 UK
Expect enrollment > Outside US : US
14 October 2004 Placet Research 40
Roles and Responsibilities: Genentech
Co-sponsor with Biogen IDECAuthorship of study protocol and development of CRFIND holder, primary contact with US FDAResponsible for study operationalizationContract holder with CRO and study sitesDrug manufacture, supply and distributionSafety reportingMedical monitoring (oversight and 1° US responsibility)Statistical analysis, final study report and sBLA filing
14 October 2004 Placet Research 41
Roles and Responsibilities: Biogen IDEC
Co-sponsor with Genentech
Implementation team participation
Regulatory consultation
Funding through Genentech/Biogen IDEC collaboration
14 October 2004 Placet Research 42
Roles and Responsibilities: Roche HQ
Life cycle team decision to support Genentech/Biogen IDEC study conduct ex-USCommunication with Roche Affiliate officesFuture consideration of label expansion to countries outside the US
14 October 2004 Placet Research 43
Roles and Responsibilities: Roche Affiliates
Post marketing safety reporting responsibilitiesKey customer managementInput regarding key investigator sites outside USParticipation in regional investigator meetings
14 October 2004 Placet Research 44
Roles and Responsibilities: Covance
Execution of transferred obligations from GenentechRegulatory applications outside USSafety reporting to authorities outside USSite managementCentral labs, IVRS, drug distribution managementData managementMedical monitoring in AU/NZExecution of investigator meetings
14 October 2004 Placet Research 45
Roles and Responsibilities: Connector-Medical
Medical monitoring in EUProtocol exceptionsUnblindingSAE review if required
Participation in EU investigator meetingSite identification and feasibility assessment for Sweden / Denmark
14 October 2004 Placet Research 46
Covance
ROCHE
GENENTECH / IDEC
STUDY SITES
COVANCE
Issues in International ResearchPrepared 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)
14 October 2004 Placet Research 48
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
What types of things make a country/ community especially vulnerable to harm or
exploitation from external scientific research?
14 October 2004 Placet Research 49
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 PhilippinesIncome
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 autonomyLimited education Language barrier
This cannot be used as a reason to forgo obtaining individual informed consent: thus, creative informed consent processes should be developed
14 October 2004 Placet Research 50
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)
14 October 2004 Placet Research 51
FDA Vs. European Committees Concerns
USA International Trials Europe
Frequent violations of eligibility criteria
Baseline characteristics comparable across treatment groups?
All regulations created for marketing authorization but cover all types of clinical trials
Serious violations of eligibility criteria
Dropout patterns comparable across groups?
Diversity and incompatibilities of national regulations considerably slow down the process
Poor compliance with dosing regimen/visit schedule
Comparability of “completers” and early dropouts?
Costs for performing trials independently from the pharmaceutical company are forbidding
Concomitant medication usage
Study participants comparable across sites?
No real program to support clinical rese-arch at the European and national levels
Higher than expected dropout rate
Conclusions consistent across sites?
Technical glitches - e.g. assay or measurement difficulties; other data problems
CLINICAL TRIALS Conducted by European Organization for the Research
and Treatment of Cancer (EORTC)
14 October 2004 Placet Research 53
EORTC TODAY (I)
Aims :Improvement of cancer treatment and related problemsEducation to high quality clinical research
How ? Multicenter - multinational and intercontinental cancer clinical trials Research projects on methods and practices for
cancer clinical trialsanti-cancer agents developmentcancer management procedures
Dissemination of know-how : courses - symposia - workshops
14 October 2004 Placet Research 54
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)
14 October 2004 Placet Research 55
Sweden:71Denmark:38The Netherlands:1484U.K. :538Belgium:760Italy:413Germany:569Greece:27Austria:111Portugal:57Spain:219France:1166
PATIENT ACCRUAL IN EORTC CLINICAL STUDIES
2000 (6509 PTS)
Argentina: 6 Chile: 28 Canada:188 N. Zealand:5
South Africa:14Australia:34Saudi Arabia:4
Finland:3
Russia:32USA:52Malta:10
Norway:61Estonia:1
Czech Rep.:37Poland:51
Slovakia:45Hungary:26Slovenia:7Croatia:42
F.R. Yugoslavia:13Bosnia:3
Romania: 11
Bulgaria:15Turkey:75
Israel:78Egypt:46
Switzerland:169
14 October 2004 Placet Research 56
Questions ?
14 October 2004 Placet Research 57
Celebrate & share success
Vadim Paluy, MD
(408) 621-4028
www.placetresearch.com