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Clinical TrialsDr Menaal Kaushal

JR IIDepartment of S.P.M.S. N. Medical College

Agra

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Types of Studies

Epidemiological Studies

Observational

Descriptive

Analytical

Interventional/ Experimental

RCT Field Trial

Community Trial

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Why Clinical Trials?

Gold standard with a Totality of Evidence: Lab Study- High Precision Epidemiological Study- High Relevance

Designed to elucidate Most Appropriate Treatment for the FUTURE PATIENTS

Should be done only in existence of CLINICAL EQUIPOISE

So, during enrollment the researcher must ensure Absence of THERAPEUTIC MISCONCEPTION among the participants.

Also ensure the non-existence of Oxymoron: THERAPEUTIC RESEARCH

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From Lab to Clinics to Community- the Developmental Process Funnel

Drug Discover

y

Pre clinical Phase I

FIH

Phase II

POCPhase

III

Post approval Trials- Phase IV

10,000 compounds

10- 15 yrs

$ 1 billion

1 compound

Bench to Bed Side Translational Blocks

T0- Discovery Science T1 Phase

Clinical/ Translational Research

NOT Clinical Trial

Borderline Trial Clinical Trial

T2 T3

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Pre Clinical Phase

Safety Testing- Toxicity and Physiological Response to the new Compound is assessed

Organs targeted include: Cardio- vascular

Neuro- muscular

Respiratory

+ Other Organs and systems depending on the compound’s action

Dose Dependence

Potential for Reversibility

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Toxicity studies

Acute Toxicity: determine overdose effects

Repeated Dose Toxicity: maximum

duration of clinical trial

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MRSD Determination

HED= animal’s NOAEL (mg/kg)* Wt (Animal) 1-

0.62

A 10 fold Safety margin is usually used, so:

MRSD= HED/ Safety factor

Maximum tolerated Dose (MTD) needs to be estimated where the Dose limiting toxicity has a certain probability

( )

Wt (Human)

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Dose Response Curve

Increasing Dose (mg/kg)------------>

Pro

bab

ility

of

ad

vers

e

even

ts P

(DLT

) --

----

----

>

0

1

0.33

MTD

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Phase I- FIH Trial

Healthy volunteers are given a single dose in a controlled environment (In- patient settings)

Volunteers usually paid

Risks are kept to be minimum

What needs to be assessed is: Safety Pharmacokinetics Pharmacodynamics Route and Rate of administration Fixing up the end points Physiologic effects in humans

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POC Study

Patients having the disease of interest, are

enrolled

Volunteers not paid

Moderate (or even serious) risks are acceptable

Done to assess: The Dose response

Safety

Pathophysiology

Limited observation about efficacy

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Steps in Conducting a Phase III Clinical Trial

Design Phase

Research Question- FINER Criteria, PICOT style

Study Designs

Ethical Considerations& GCP Guidelines

Registering with CTRI

Latest DGCA Guidelines- Video Record Every Consent

Sample Size, Clearly defined Inclusion- Exclusion criteria

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Steps in Conducting a Phase III Clinical Trial

Implementation Phase Randomization v/s Random Allocation

Blinding

Control- Standard Treatment v/s Placebo

Monitoring& DSMB- Interim Analysis

Analytical Phase ITT v/s Per protocol analysis

CONSORT Guidelines

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Research Question

FINER; PICOT

Following need to be considered: Effect Size Composite endpoints Surrogate End Points Study duration Secondary Questions Sub group Hypothesis Natural History Studies

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Study Designs

Two group parallel design- The Look ahead trial (T2DM obese pts on Diabetes support& education v/s active, intensive lifestyle modification)

Multi group parallel design- The Re-ly trial (Atr Fib pts on warfarin v/s dabigatran 110mg v/s dabigatran 150 mg)

Factorial design- The SUPPORT Trial (very premature neonates were randomized into Early surfactant v/s early CPAP and O2 Saturation 85% v/s 95%)

Cross over design- Pts can be compared on themselves. E.g. Hemophilia trial. No carry over between the two treatment periods- Rest period is needed

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The History Behind Ethics

Nuremberg Code- 1946

Declaration of Helsinki- 1964

Council for International Organizations

of Medical Sciences CIOMS- 1982

International Conference on

Harmonization – Good clinical practice

(ICH-GCP)- 1996

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Historical Perspectives

Council for International Organizations of Medical

Sciences (CIOMS) and WHO (1982) – International

ethical guidelines for biomedical research involving

human subjects Revised – 1993, 2002

International Conference of Harmonization – Good

clinical practice (ICH-GCP)-1996) International ethical and scientific quality standard for

designing, conducting, recording and reporting trials

involving human subjects.

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13 Principles of GCP

1. Ethics (Declaration of Helsinki)

2. Risk Benefit analysis

3. Trial subjects (rights and safety)

4. Investigational product (Information support study)

5. Scientifically sound

6. Compliance (IRB review)

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7. Qualified physician to provide medical care

8. Trial staff (trained in protocol)

9. Informed consent

10.Data (reporting, interpretation, verification)

11.Confidentiality

12.Good manufacturing practice of the investigational product

13.Quality Assurance of all aspects of protocol

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7 Components of the Ethics:

1.Social or Scientific value

2.Scientific Validity

3.Fair Subject Selection

4.Favorable risk- benefit ratio

5. Independent review

6. Informed Consent

7.Respect for potential and enrolled subjects

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Ethics in Trials

During Phase I Trials, 95% of the times,

participating patients do not benefit

from the Trial

The probability (chance) of having any

benefit 5%

Risk of fatal complication 5%

While there may be a significant chance of

benefit in Phase III Trial

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Risk- Benefit Ratio

Risk to Pt Benefit to

Pt

Risk to

Pt

Benefit

to pt

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Risk- Benefit Ratio

Risk to PtBenefit to PtBenefit to Society

+

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Informed Consent - Elements

Information Patient/subject information sheet

Comprehension Simple and understandable language Local language translations

Voluntariness

Consent

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Informed Consent

Community studies – Consent needed from Community – group consent Individuals

Children Parent/guardian Assent of child to his/her capability

Mentally Ill Close biological relative Legally authorized person Certificate from psychiatrist

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Importance Of Clinical Trials Registration

To ensure transparency , accountability and to increase public trust in the conduct of clinical research.

Clinical trial registration and results reporting would help ensure unbiased public records on safety and efficacy of drugs.

All clinical trials should be registered before the enrolment of the first patient and all results made publicly available.

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Registration of Trials Globally

At the 58th WHA held on 25th May 2005 WHO had set up of an International Clinical Trial Registry Platform (ICTRP), a one-stop search portal for searching registers worldwide.

The ICTRP recommended 20 key points as Trial Registration data Set that need to be publicly declared before the enrolment of the first patient.

In the 59th General Assembly of the World Medical Association, 2008, in its revision of the Declaration of Helsinki among other modifications, specifies that:

“Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject.”

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CTR- I

Till 2006, there was no national registry of clinical trials in India

On July 20, 2007, ICMR through its National Institute of Medical Statistics (NIMS) formed Clinical Trials Registry – India (CTRI) www.ctri.nic.in with financial support from DST and WHO.

The CTRI has additional data points over the ICTRP’s recommended 20 point data set:

Later these additional points were borrowed from CTR- I and were inculcated in the WHO’s ICTRP.

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Registration Data Set of the CTRI

1. Public Title of Study2. Scientific Title of Study,

Acronym, if any3. Secondary IDs, (UTN, Protocol

No etc) 4. Principal Investigator’s Name

and Address*5. Contact Person (Scientific

Query)6. Contact Person (Public Query)7. Source/s of Material or Monetary

Support8. Primary Sponsor9. Secondary Sponsor10. Countries of Recruitment11. Site/s of study12. Name of Ethics Committee and

approval status13. Regulatory Clearance obtained

from DCGI * Optional fields

14.Health Condition/Problem studied15.Study Type 16. Intervention and Comparator agent17.Key inclusion/Exclusion Criteria 18.Method of generating

randomization sequence*19.Method of allocation concealment*20.Blinding and masking*21.Primary Outcome/s 22.Secondary Outcome/s23.Target sample size24.Phase of Trial25.Date of first enrollment 26.Estimated duration of trial 27.Status of Trial28.Publication details*29.Brief Summary

Additional items of CTRI

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Clinical Trial Registry-India

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It is housed at the National Institute of Medical Statistics, ICMR, New Delhi.

Trial registration is purely online, paperless process and free of charge

The CTRI software application was modified and implemented on 15th March 2011.

Clinical Trials Registry – India

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Objectives of CTRI

To establish a public record system by registering all clinical trials on health products including: Drugs Devices Vaccines Herbal drugs

It makes the information available to both public and healthcare professionals in an unbiased, scientific and timely manner.

To create a complete, authentic and readily available data of all ongoing and completed clinical trials.

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Objectives of CTRI

To provide a corrective system against “positive results bias” and “selective reporting” of research results to peer review publication.

To increase awareness and accountability of all the participants of the clinical trials and also for public access:

Trial registration empowers the public and offer patients the choice of enrolling in a clinical trial to gain access to latest breakthrough treatment options.

To promote training, assistance and advocacy for clinical trials by creating database and modules of study for various aspects of clinical trials and its registration.

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Registration of clinical trials under CTR- I is recommended by:

1. Drugs Controller General (India): Made mandatory since June 2009

2. Editors of Indian Biomedical Journals;

3. Ethics Committees of various institutions, AIIMS, CMC, Sir Ganga Ram Hospital etc.

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DCGI Notification

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CTRI currently accepts registration of:

Prospective trials

Ongoing

Completed trials

Terminated trials

Registered trials are flagged as:

Trial registered prospectively

Trial registered retrospectively

Terminated trial registered

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Empowering patients

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Registering Trials during PG Thesis

CTRI encourages registration of trials being conducted as part of post-graduation thesis work This would help

Ensure ethical standards Prevent unnecessary duplicate research Raise the standard of research Enable better exchange of data and ideas

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PG Thesis registration

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Methodology

Enrollment Criteria

Ascertainment of Primary End

Point

Treatment A(Test)

Treatment B(Control)

Quality:AdherenceMissing Data

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Sample Size Calculations

n= 2 ṕ (1-ṕ) (Zα/2+Zβ)2/ Δ2

Where:Δ= pc- pt

ṕ= (pc+ pt)/ 2

At α= 0.05, Zα/2= 1.96

At β= 0.20, Zβ= 0.84

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Sample Size Calculations

n= 2 (Zα/2+Zβ)2/ log (λc/λt)2

Where:λ= survival probabilityAt α= 0.05, Zα/2= 1.96

At β= 0.20, Zβ= 0.84

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Randomization

Unrestricted Randomization: may produce

treatment groups of different sizes

Randomized Permuted Block

Stratified Randomized Permuted Block

Cluster Randomization

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Unrestricted RandomizationPro

babili

ty -

----

----

----

----

----

Number of heads from 20 tosses--------------------

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Rela

tive

effi

cien

cy

Proportion allocated to Treatment A

50%0% 100%

Relative Efficiency of Unbiased Allocation

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Randomized Permuted Blocks

ABAB AABB

BBAA BABA

ABBA

BAAB

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Blinding

Single Blind Trial

Double Blind Trial

Triple Blind Trial

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Analysis

Intent to treat

Modified Intent to treat

Per protocol Analysis On assigned Tt Fully compliant with study domain

As treated Analysis

Best Active- Interventional

Compromised Observational

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Analysis to Study Outcome

Binary (HTN or Normotensive)

Measurable (BP reading)

Time to event (at what time during the follow up, has the event occurred)

Other outcomes: No. of episodes (e.g. no of exaggeration episodes of asthma, while on treatment)

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CONSORT (Con solidated S tandards o f R eporting T rials) statement

Section/ Topic

Item No

Checklist Reported on Pg no

Title& Abstract

1a Identification as a randomised trial in the title

1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts)

Introduction 2a Scientific background and explanation of rationale

Background& Objectives

2b Specific objectives or hypotheses

Method

Trial Design 3a Description of trial design (such as parallel, factorial) including allocation ratio

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons

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Section/ Topic

Item No

Checklist Reported on Pg no

Participants 4a Eligibility criteria for participants

4b Settings and locations where the data were collected

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were actually administered

outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed

6b Any changes to trial outcomes after the trial commenced, with reasons

Sample size 7a How sample size was determined

7b When applicable, explanation of any interim analyses and stopping guidelines

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Section/ Topic

Item No

Checklist Reported on Pg no

Randomization

Sequence 8a Method used to generate the random allocation sequence

Generation 8b Type of randomisation; details of any restriction (such as blocking and block size)

AllocationConcealment mechanism

9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned

Implementation

10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions

Blinding 11a

If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how

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Section/ Topic

Item No

Checklist Reported on Pg no

11b If relevant, description of the similarity of interventions

Statistical Method

12a Statistical methods used to compare groups for primary and secondary outcomes

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses

Results

Participants (a flow diagram strongly recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome

13b For each group, losses and exclusions after randomisation, together with reasons

Recruitment

14a Dates defining the periods of recruitment and follow-up

14b Why the trial ended or was stopped

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Section/ Topic

Item No

Checklist Reported on Pg no

Baseline data

15 A table showing baseline demographic and clinical characteristics for each group

Number analyzed

16 For each group, number of participants (denominator) included in each analysis and whether the analysis wasby original assigned groups

Outcomes& estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and itsprecision (such as 95% confidence interval)

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended

Ancillary analysis

18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory

harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms)

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Section/ Topic

Item No

Checklist Reported on Pg no

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses

Generalizability

21 Generalisability (external validity, applicability) of the trial findings

Interpretation

22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence

Other information

Registration

23 Registration number and name of trial registry

Protocol 24 Where the full trial protocol can be accessed, if available

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders

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Flow chart

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References:

Textbook of Preventive and Social Medicine by K. Park

ctri.nic.in

Clinical Trials by Stuart J Pocock

edx.org/ harvard

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Thank You