optimizing patient enrollment in clinical trials

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…


Complexities of the Drug Development Process


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


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


Other Large Pharma and Biotech Companies

AstraZenecaNovartisBristol-Myers SquibbRocheWyethEli LillyAbbott LabsSchering PloughSchering AgBoehringer-Ingelheim

Amgen

Genentech

Serono

Biogen-Idec

Celgene

Genencor

Chiron

Icos

Millennium


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)


Process Chemistry (6 – 12 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


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).


Time to Approval is Decreasing

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.


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


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


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


Internet Applications for Today’s Clinical Trial

Sponsors and vendors have recognized the value of the internet for:

Patient RecruitmentMonitoringPatient EducationElectronic Data CaptureData Management


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


Patient Recruitment & the Internet

www.clinicaltrials.gov


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


Developing the Sponsor-CRO Partnership

Clinical Trial Team


Who is involved?

Remember the big picture

Collaborate early

Build relationships

Clear objectives

Regulatory

sites

Investigator

MediaSponsor

Subject

Advocacy

LegalCommercial


The Outsourcing Challenge

Create & develop productive strategic partnerships with external suppliers

Drive process improvement both externally and internally

Integrate internal and external processes


Why do we need to establish performance expectations with external suppliers?


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


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


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


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


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


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


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


Seek Metrics to Support Investigator Relationship Management

Pharma

R&D Office

CentralLaboratories

DataManagement

SafetyReporting

IRB

CRO

ProjectPhysician

CRA

Investigator


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?


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


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


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


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)



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


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



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


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


Roles and Responsibilities: Biogen IDEC

Co-sponsor with Genentech

Implementation team participation

Regulatory consultation

Funding through Genentech/Biogen IDEC collaboration


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


Roles and Responsibilities: Roche Affiliates

Post marketing safety reporting responsibilitiesKey customer managementInput regarding key investigator sites outside USParticipation in regional investigator meetings


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


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


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)


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?


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


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)


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)


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


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)


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


Questions ?


Celebrate & share success

Vadim Paluy, MD

[email protected]

(408) 621-4028

www.placetresearch.com

optimizing patient enrollment in clinical trials

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