acceleration of clinical trials dr jani

E-mail: [email protected] 1, 15-Apr-11© Dr. R.H.Jani

Best practices & Techniques to Accelerate the

Trial Process

Dr. Rajendra H Jani

Senior Vice President, Clinical R&D

Cadila Healthcare Limited

Zydus Cadila House

TPS 5, Plot 360, Service Road

Vile Parle (E)

Mumbai- 400057E-mail: [email protected], [email protected]

mailto:[email protected]



Accelerate the Trial Process

• Examining the current trends in Clinical trials

• Analyzing trials for different phases of a project

• Deploying dynamic research approaches – Clinical trial designs

& systematic and random errors

• Best Practices to accelerate in Clinical trial -Implementing global

technique


Examining the current trends in Clinical trials


Comparison of Clinical Trial Density

Region CountryNumbers of

Studies

Global 103914 100%

America 60734 58.44%

Canada 7979 7.68%

USA 57464 55.29%

Europe 26228 25.24%

Germany 7134 6.86%

France 6132 5.90%

UK 5301 5.10%

Asia 16975 16.33%

China 2043 1.96%

India 1546 1.48%

clinicaltrial.gov 6th March 2011


Density of Clinical Trials

Density of actively recruiting clinical sites, Clinicaltrial.gov on 6th March 2011


Clinical Trial Density in India

Density of actively recruiting clinical sites in India, Clinicaltrial.gov on 6th March 2011


Clinical Trial Density in China


Analyzing trials for different phases of a project


Clinical studies: Phases of development

• Phase 0: A new concept of Micro-dosing

• Before the permission to market, a potential new drug candidates passes through three well defined clinical development phases; Phase I, II and III.

– Phase I is the earliest study usually conducted in healthy humansvolunteers and divided into early and late phase I studies

– Phase II studies are conducted in patients with the target diseaseand are also known as Proof of Concept or exploratory studiesusually.

– Phase III also known as confirmatory trials and aim at conclusively proof of efficacy and safety

– Phase IV are conducted in patients, usually at the post-marketingstage, to assess long-term safety and/or investigate rare adverseeffects.


Clinical trials: Phase I

• Early Phase I

– Single dose escalation

– Multiple dose escalation

– Pharmacokinetics

– Pharmacodynamic (sometimes)

– Maximum tolerated dose (MTD),

– gender effects and

– food effects.


Clinical trials: Phase I

• Late Phase I trial-

– Definitive pharmacokinetics / pharmacodynamic

– Bioavailability with range of formulations

– Interaction studies with

• Drug - food and

• Drug – drug

– Metabolic disposition

– Drug PK/PD/Metabolism in

• Hepatic impairment

• Renal impairment

– Pharmacokinetic in special groups; children and elderly


Clinical trial: Phase II

– Phase II studies are conducted in patients with the target

disease and are also

• known as Proof of Concept or

• exploratory studies

• First in patient trials

– Objectives of phase II studies is to-

• determine appropriate dose levels,

• investigate safety, and

• assess any signs of efficacy.

• The studies usually are relatively small in terms of

sample size, and they may or may not include

randomization, double-blinding, and control groups.


Clinical trials: Phase III

• Phase III studies are -

– Conducted in large numbers of patients to confirm the

efficacy and safety

– Confirmatory studies for PoC

– Sample size are determined from PoC results

– Statistical power

– Comparative


Clinical trials – a case study

Exenatide

(Eli Lilly /

Amylin

Liraglutide

(Novo Nordisk)

Industry sponsor 93 32

Sponsored By originator 68 32

Phase 1 Total 7 6

Healthy

Volunteers 3 3

India 0 0

Diabetes 5 3

Phase 2 Global 12 6

India 0 1

Phase 3 Global 31 19

India 7 6

Phase 4 Global 7 1

India 1 0

Compiled from Clinicaltrials.gov on 6th March 2011


Dynamic qualitative & quantitative research

approaches


Qualitative vs quantitative research

• Qualitative research is concerned with finding the answer to

questions which begin with

– why?

– how?

– In what way?

• Quantitative research is concerned with questions about:

– how much?

– How many?

– How often?

– To what extent?


Qualitative Vs Quantitative Research

• Qualitative:

– Participant observation

– Case study

– Structural observation

– Content analysis of

documents

– performance data

– Focus groups

– Example:

• What stops people

giving up smoking?

• Quantitative

– Randomized clinical trial

– Cohort

– Case-Control study

– Example:

• What proportion of

smokers have tried to

give up?


Qualitative Vs Quantitative Research

• Qualitative

– Title:

• Pregnancy outcomes in foreign-born and US-born women.

– Objective:

• To compare pregnancy outcomes between foreign-born women and women born in the United States.

– Method:

• Retrospective cohort study of all deliveries at Grady hospital in Atlanta between 1991 and 2000.

– *Authors: Forna F, Jamieson DJ, Sanders D, Lindsay MK.

Int.J.Gynecol.Obstet.2003;83:257-65

• Quantitative

• Title:

– The acceptability of injectable contraceptive by women in India

– Objective:

• To find out the reasons why there is such a low acceptability of methods of injectable contraception

– Method:

• The project will be conducted as a survey and some focal group discussions will be held.

• A total of 1200 women will be interviewed, 600 will be of the urban area and 600 from the rural areas.


Acceleration of Clinical trials through

Clinical trial designs


Clinical trials: Various designs

• Open comparative

• Comparative:

– Open or double blind

– Randomized

– Crossover

– Parallel

– Prospective

– Observer blind


Clinical trials: Blinding

• CLINICAL TRIALS – BLINDING (MASKING):

– Blinding refers to the situation in which the patients do not

know the treatment identity.

– A double-blinded study:

• the investigators and patients are blinded to treatment

identity, which eliminates assessment bias.

– An observer blind study:

• It is not possible to design a masked trial in some

situations, e.g., surgical trials.

• In such situations, the researchers who administer the

treatments should be distinct from those who collect the

data.


Clinical trials: Crossover design

• Some trials may invoke a crossover design in which patients

serve as their own controls. For example,

– subjects may undergo an experimental therapy for six weeks

and then “cross over” to the control therapy for another six

weeks (or vice versa).

• Crossover designs are appealing because

– the patients serve as their own controls.

– require a much smaller sample size than a “parallel” design.

• Crossover designs is suitable for chronic diseases or

pharmacokinetics studies in healthy volunteers

• sample of patients, so that variability will be lower.


Clinical trials: Crossover design

Limitations:

• Not suitable for an acute condition e.g., common cold, where condition may resolve itself within a short period of time, so there is nothing that the second treatment can do.

• A disadvantage of a crossover design is the potential for “carryover” effects, i.e., the treatment administered during the first period may carry over into the second treatment period.

• Criteria that are more restrictive will yield a homogeneous

• This will require a smaller target sample size, but recruitment will be difficult.

• Another drawback is that the results of the study may not be generalizable to other types of patients with the disease (lack of external validity).


Active Control Trials

• Many clinical trials compare two or more active therapies, rather than

comparing an active therapy with placebo.

• Issues that need clarifying include:

– How should the confidence interval for demonstrating non-

inferiority be determined?

– What data should be used to estimate the effect of the control

agent (e.g., all prior studies?)

– How should they be weighted?

– What drugs should be included as the active control?

– How should inconsistent results (i.e., size of treatment effect) from

prior studies of the active control be approached?

– What are appropriate sample size requirements in non-inferiority

and active-controlled studies?


Adaptive Trial Designs

• Adaptive trial designs allows modifications aspects of the trial after its initiation

– It allows the rectification of inappropriate assumptions

– Examples of the modifications are-

• Sample size re-estimation

• Early stopping due to efficacy or futility

• Adaptive randomization

• Dropping inferior treatment group

• Consensus and clarification is needed on questions such as:

• When can extra trial arms be dropped?

• When can an early marker be used to choose

• which treatment to carry forward or to choose a subset for analysis?

• When is it valid to modify randomization based on results, for example, in a combined phase 2/3 cancer trial?

• When is it valid and under what situations can one stage or phase of a study be combined with the second stage or phase?


Biomarkers : Enrichment Clinical Trial Designs


How do we know that a Biomarker is valid?

• What is a valid biomarker?

– A biomarker that is measured in an analytical test

system with well established performance

characteristics and for which there is an established

scientific framework or body of evidence that elucidates

the physiologic, toxicologic, pharmacologic, or clinical

significance of the test results.

– http:// www. fda. gov/ cder/ guidance/ 6400fnl. pdf


First Wave of Biomarkers

• Galactomannan detection in-

– broncho- alveolar lavage fluid as marker for invasive

pulmonary aspergillosis.

– blood as a biomarker for invasive aspergillosis.

• Preclinical Biomarkers of Nephrotoxicity (PSTC)

• Circulating Tumor Cells as biomarkers to aid in therapeutic

decision- making in metastatic breast cancer.


Biomarkers for Oncology

Drug Theraputic Area Biomarker Label Sections

Arsenic Trioxide Oncology

PML/RARα

translocation

Boxed Warning, Clinical Pharmacology, Indications

and Usage, Warnings

Busulfan Oncology

Philadelphia

chromosome Clinical Studies

Capecitabine Oncology DPD Contraindications, Precautions, Patient Information

Cetuximab (1) Oncology EGFR

Indications and Usage, Warnings and Precautions,

Description, Clinical Pharmacology, Clinical Studies

Cetuximab (2) Oncology KRAS

Indications and Usage, Clinical Pharmacology,

Clinical Studies

Dasatinib Oncology

Philadelphia

chromosome

Indications and Usage, Clinical Studies, Patient

Counseling Information

Erlotinib Oncology EGFR Clinical Pharmacology

Gefitinib Oncology EGFR Clinical Pharmacology

Imatinib (1) Oncology C-Kit

Indications and Usage, Dosage and Administration

Clinical Pharmacology, Clinical Studies

Imatinib (2) Oncology

Philadelphia

chromosome

Indications and Usage, Dosage and Administration,



Biomarkers for Oncology

Drug Theraputic Area Biomarker Label Sections

Irinotecan Oncology UGT1A1

Dosage and Administration, Warnings, Clinical

Pharmacology

Lapatinib Oncology Her2/neu


Patient Counseling Information

Mercaptopurine Oncology TPMT

Dosage and Administration, Contraindications,

Precautions, Adverse Reactions, Clinical

Pharmacology

Nilotinib (1) Oncology

Philadelphia

chromosome

Indications and Usage, Patient Counseling

Information

Nilotinib (2) Oncology UGT1A1 Warnings and Precautions, Clinical Pharmacology

Panitumumab (1) Oncology EGFR

Indications and Usage, Warnings and Precautions,


Panitumumab (2) Oncology KRAS


Clinical Studies

Rasburicase Oncology G6PD Boxed Warning, Contraindications

Tamoxifen Oncology Estrogen receptor

Indications and Usage, Precautions, Medication

Guide

Thioguanine Oncology TPMT Dosage and Administration, Precautions, Warnings

Trastuzumab Oncology Her2/neu

Indications and Usage, Precautions, Clinical

Pharmacology


Biomarkers : Enrichment Clinical Trial Designs

• Trastuzumab:

– Enrichment design-

• Diagnostic test is used to restrict eligibility for Her 2 +

breast cancer patients for the trial

• Drug is effective on Her 2+ patients which constitute 15-

25% of the breast cancer population

• Standard randomized trials would require large sample

size to detect diluted effects of trastuzumab.


Clinical trial

Random and systemic errors


Clinical trials: Random and systemic errors

• Objectives of any trial is to estimate not only intended and unintended effects, but also magnitude of such effects.

• Inaccurate estimates prove costly, either through-

– discontinuation of a good potential candidates or

– selection of wrong

• Systemic errors are

– reduced through precision and unbiasness

– Brought in by-

• Literature

• Study sample selection

• Measurement of exposures,

• outcomes (and covariates) analysis

• Interpretation


Clinical trials: Bias

What is bias?

Systemically wrong estimate of parameter of interest

Amount by which an estimate differs from true values

Any process tending to lead to results differing systemically from truth


Clinical trials: Some of possible source of bias

Bias

Study Design

Analysis

InterpretationMeasurement

Study conduct

Confounding

Selection


Clinical trials: Bias from study conduct

• With any systemic allocation procedure bias is possible,

perhaps-

– Hospital numbers; outdoor, indoor and emergency

– Date of presentations; weekdays vs. holidays

– Prognostic factor associated with allocation criteria

• The difference in results from any systemic allocation

procedures instead of differences in efficacy of treatment

• Above confounding factor


Clinical trials: Bias from confounding

Confounding factor is-

Associated with

treatment

Correlates with

outcomeExposure (treatment) Confounder Disease (Outcome)


Clinical trials: Bias from analysis

Attrition biases

Dropouts from the groups before the intervention is completed

Losses to follow-up


Clinical trials: Measurement biases

• Invasive

• Non invasive

• Governed by ethical issues & cost

Methods Investigations

• Sensitive (Responsive)

• Reliable (Repeatable)

• Practical

Methods of Measurement

• Provide practicability

• Validity becomes controversial

Surrogated marker


Clinical trial: Bias from interpretation

Blinding

Non-comparative trials

Confusion on statistics

• Preferred, revealed by pattern of response

• Hardly possible

• Observer blinding?

• Test of significance

• Methods of analysis


Best Practices to accelerate in Clinical trial


Regulatory-Trial Process-Technology

Clinical Trial

process

Reengineering

Technology

Improves

the performance

Regulatory

Influences trial

process

Emerging

Industry

Best Practices


Best Practice and technology for the acceleration of the

clinical trials

• Project managements

– Regulatory approaches

– Investigators’ selection

– Logistics

– Clinical trial management

– Electronic Data Capturing

– Clinical Data Management


Investigator Recruitment

• Early involvement of investigators to help to shape the protocol

for feasibility of recruitment

• Agreement

• Assessing the site’s ability to meet protocols requirements

• Better access to site recruitment

– Wider use data mining, assessment and screening

• Patient accrual vs cost

• Multiple prong approach to patient recruitment-

– Data Mining

– Local publicity

– Collaboration for tracing mobile patients


Clinical Trial Management

• Near real-time visibility of project status across all studies

whether in-sourced or outsourced, active or inactive

• Warning systems to identify problems or non-compliance early

• Better sponsor access to potential project team resources

• Continued outsourcing to CROs, using very defined

performance metrics


Clinical Data

Management

• eCRF, eCTD and CDISC standards are widely accepted leading

to “bridge development” to/from legacy systems

• Leveraging existing

– EDC and electronic patient reported outcomes (ePRO),

– expanding eSource collection methods and

– improving active analysis of trial and clinical data to identify

administrative, safety, or efficacy issues early


Data Analysis

• More near real time reporting and analysis occurring during

trials (adaptive designs, patient adoption rates, site selection,

etc.)

• Workflow tools used to streamline and document the process for

easy repeatability and increased reuse of statistical programs


Clinical Supplies

• More use of integrated processes and systems for effective

manufacturing, inventory, and distribution of small and large

orders

• Continued use of IVRS and a growing use of Radio Frequency

Identification (RFID) technologies to support better tracking and

scheduling


Regulatory and Safety

• Faster and more effective participation via Improved cross-

functional workflow

• management and database mining

– Use of database mining tools

– Shortened durations for document preparation and

submissions through use of integrated databases/systems

• Global pharmacovigilance function that develops and

implements risk management systems, including signal

detection and signal management


Thank You

This presentation is the property of Dr. Rajendra H Jani, Senior Vice President Clinical R&D, Zydus Cadila Healthcare Limited.

Views expressed in this presentation is of the author and not of the company. Under no circumstances the information contained in this presentation should be

quoted, distributed, copied, reproduced or retrieved, in part or whole, in any form, written, verbal and/or electronic format without the expressed permission

from:

Dr. Rajendra H Jani, Senior Vice President & Clinical R&D, Cadila Healthcare Limited, Zydus Cadila House, Service Road, Vile Parle (E),Mumbai-40057,

India,

Phone: +91-22-26186052, Fax: +91-22-26181735, E-mail: [email protected] or [email protected]


acceleration of clinical trials dr jani

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