DRUG TRAIL IN CVS

CONDUCT OF A DRUG TRAIL IN CARDIOLOGY

I.TAMMI RAJU

• Introduction– History– Definition– Types– guidelines

• Equipoise• Protocol• Core elements

– Study population, enrollement, recruitment, randomisation,active drug.

– Phases of trails– Data collection & statistical analysis

• Consort statement.

overview

• Introduction• Despite many decades of advances in diagnosis and

management,CVD remains the leading cause of death in developed & developing countries.

• Therapeutic recommendations in cardiovascular medicine are no longer based on nonquantitative pathophysiologic reasoning but instead are evidence-based.

• The practice of evidence-based medicine occurs when clinical decision making involves the incorporation of the best avail-able research evidence together with the clinician’s expertise and consideration of local or individual circumstances and the patient’s preferences regarding therapies and outcomes.

• One needs to be able to efficiently sift through the evidence and then be able to appraise the quality of that evidence before deciding how much weight to give it in terms of clinical decision making.

• Thus, the design, conduct, analysis, interpretation, and presentation of clinical trials are a central feature of the professional life of the contemporary cardiovascular specialist

• Definition

• A clinical trial is defined as a prospective scientific experiment that involves human subjects in whom treatment is initiated for the evaluation of a therapeutic intervention.

• The Code of Federal Regulations (CFR) defines a clinical trial as the clinical investigation of a drug that is administered or dispensed to, or used involving one or more human subjects

Historical aspects of clinical trails

Historical Highlights of Drug Trials

• 1909: Paul Ehrlich - Arsphenamine

• 1929: Alexander Fleming - Penicillin

• 1935: Gerhard Domagk - Sulfonamide

• 1944: Schatz/Bugie/Waksman – Streptomycin

• By 1950, the British Medical Res. Council developed a systematic methodology for studying & evaluating therapeutic interventions

DIFFERENT TYPES OF CLINICAL TRIALS BASED ON PURPOSE

• TYPE OF STUDIES BY THE WAY THE RESEARCHERS BEHAVE

Non-experimental (Observational)– Case report– Case series– Cross-sectional (survey)– Case-control– Prospective, observational (cohort)

Experimental– Randomized, clinical trial (RCT)

• The 3 most common designs are – uncontrolled clinical trials- weakest level – nonrandomized controlled trials, and – RCTs.

• For uncontrolled trials, no concurrent comparison group exists .

• In nonrandomized controlled trials, a concurrent comparison group does exist, but patients are allocate to this group by a nonrandom process.

• In an RCT, individuals are randomly allocated to 2 or more treatment groups, which usually include a standard treatment group and one or more experimental groups.

Classification by Study Design

Classification by Study Objective and Phase

• Advantages of Clinical Trials• Overall, clinical trials serve a multitude of

functions that include the– determination of a maximum tolerated dose,– formulation of the basis for drug approval by the FDA, – definition of standard therapeutic management.– Often provides the strongest evidence in support of

cause-effect relationships– Basis for clinical and public health policy

• Examples of clinical trial goals include assessing the safety and (relative) effectiveness of a medication or device:– On a specific kind of patient .– At a different dose (e.g., 10-mg dose instead of 5-mg

dose)– For a new indication– Is more effective for the patient's condition than the

standard therapy– Relative to two or more already approved/common

interventions for that disease .

DRUG TRAIL IN CVS

• ADVANTAGES• Small but important effect • potential for increased

recruitment and Enhance generalizability of the results

• extensive quality control• contributions of multiple

investigators with complementary expertise

• Bring new treatment to the community

• DISADVANTAGES • relate primarily to cost and

to logistical aspects of coordinating research across multiple units.

• SINGLE-CENTER TRIALS tend to be less expensive and cumbersome than multicenter trials, but the center must assume responsibility for all aspects of trial conduct, including quality control,data management, and data analysis.

• Sample size difficult.

Why Multicenter Trials?

Case-control studies and registry observations are integral to epidemiologic and outcomes research, are not

strictly clinical trials, and so will not be included here.

• GUIDELINES FOR CONDUCTING CLINICAL TRIALS:

GCP Guidelines- International Conference on Harmonization

• The objective of ICH GCP Guidelines is to provide a unified standard for European Union, Japan and United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in the jurisdiction.

• Published by the FDA in Federal Register in May, 1997• Adopted by all parties as GCP standard (considered law in

European Union; considered “final guidance” in the US)• Based on the Declaration of Helsinki

• This regulatory harmonization is achieved by developing guidelines. These guidelines are divided into four categories as follows: – Q – Quality Guidelines: Defining relevant thresholds for impurities

testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management.

– S – Safety Guidelines: ICH has produced a comprehensive set of safety guidelines to uncover potential risks like carcinogenicity, genotoxicity and reproductive toxicity.

– – E – Efficacy Guidelines: The work carried out by ICH under the

Efficacy heading is concerned with the design, conduct, safety and reporting of clinical trials.

– M – Multidisciplinary Guidelines: Those are the cross-cutting topics which do not fit uniquely into one of the Quality, Safety and Efficacy categories. It includes the ICH medical terminology (MedDRA) and the Common Technical Document (CTD)

CLINICAL TRIAL IN INDIA• India became a member of WTO in 1995 and agreed to

adhere to Product & Process Patent regime from 2005.

• India provides excellent environment for CT:– in terms of Less Cost, – Speed.

• Around 25 contract research organisations (CROs) and almost all multinational pharmaceuticals companies have started full-fledged clinical trials in India since last three years.

• Further, the amendment to Schedule Y of the Drugs and Cosmetics Act in February 2005 , now allows MNC s to conduct simultaneous trails in India and abroad

• TRIAL REGULATIONS IN INDIA• DCGI under CDSCO has the Prime responsibility for

Regulating CTs in India.

• Indian GCP Guidelines are in line with WHO, ICH, USFDA, and European GCP Guidelines as well as ICMR Code.

• Drugs & Cosmetics Act 1940, & Schedule Y tells the requirement and guidelines on Clinical Trials for Import & Manufacture of New Drug in India

• ICMR code includes statement of general & specific principles on research using human subjects in biomedical research.

GOOD CLINICAL PRACTICE

Elements of GCP• Sponsor• Investigator• IRB• Investigator Brochure• Essential documents• Clinical trial protocol and protocol amendments

SPONSORS FOR CLINICAL TRIALS • takes the responsibility for the Initiation, Management,

and/or financing the Clinical Trial – Pharmaceutical and Biotechnology companies – which

must prove the safety and effectiveness of their medicines before they can be marketed

– National Institutes of Health (NIH) – which are funded by the US Government.

– Other government agencies. – University Medical Schools & Hospitals, or any other

medical research centers. – Some non-profit organizations and even individual or

group of physicians .

• CRO is the Organization Contracted by the Sponsor to Perform One or More of Sponsor’s Trial related Duties and Functions.

• Investigator • Investigator is responsible for the Conduct of a Clinical Trial

at a SiteQualified to perform study should have Appropriate education,

training and experience to assume responsibility and should provide evidence of such qualifications.

Investigator’s Brochure

• For investigational drug trials• Summary of significant physical, chemical, pharmaceutical,

pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information that is relevant to the investigational product

• Relevant animal and clinical studies, adverse events, etc.

• Ethics Committee ensures prtection of Rights, Safety, and Wellbeing of the Subjects involved and to provide Public Assurance of the Protection

• Study Subjects ( Patients ) are Individual who Participate in the Study Voluntarily.

• The researchers send the data to the trial sponsor, who then analyzes the pooled data using statistical tests.

• ESSENTIAL DOCUMENTS• Essential Clinical Trial Documents individually and

collectively evaluates the conduct of a Trial & Preserves the integrity of the Data.

• These Documents demonstrate the Compliance of the Investigators and Sponsors/ CRO with GCP & all applicable Regulatory Requirements.

• They include, Base Records, Laboratory Data, CRFs, Randomization Key, Other Investigational Records, EC-NOC, DCGI-NOC, ICF, CRO-Sponsor Agreement.

• Institutional Review Boards [IRBs]/IEC

• Rely on integrity of Investigator but outside groups also have oversight

• Participants’ rights protected by [IRBs]/IEC

o An IRB is defined as: "any board, committee or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of biomedical research involving human subjects"

IRB/IEC responsible for such tasks: • Develop and issue written procedures • Review research for risk/benefit analysis & proper

protection of subjects• Issue written notice of approval/disapproval to the

Investigator• Review and respond to proposed protocol changes

submitted by the Investigator• Review reports of deaths, and serious and unexpected

adverse events received from the Investigator• Conduct periodic continuing review of the study, study

risks, selection of subjects, privacy of subjects, confidentiality of data, and the consent process

REVIEW OF ETHICS COMMITTEE OPERATIONS

• EC must have written SOP on its Compositions, Functions & Operations.

• The Chairman of EC should be from outside of the Institution ( Non Affiliated member ).

• The Quorum of EC should have min. 5 Members ( Medical Scientist / Pharmacologist, Clinician, Social Scientist , Legal Expert, Lay person. )

• No CT should be initiated at any Site without obtaining written NOC from the respective EC.

• If any Investigator or Study team Member is a part of EC, they should abstain from voting on their research proposal

• All serious & unexpected ADR should be reported to EC within 7 working days of their occurrence.

• EC should maintain its records for at least 5 years after the completion / termination of the study

• Equipoise is an ethical concept in the design and conduct of clinical trials.

• we can only conduct clinical trials in areas of uncertainty and can only continue as long as the uncertainty remains.

• Thus, for an RCT it is unethical to initiate a clinical trial that does not include the “standard treatment” as 1 of the therapy arms, if such a standard exists, and it is unethical to include a therapy arm that is known to be inferior to any other treatment.

Equipoise

3 ethical principles guide clinical research:• Respect for Persons: Treatment of person as autonomous• Beneficence: Issue re: potential conflict between good of

society vs. individual• Justice: Treatment of all fairly & all equally share benefits

& risks

Ethics of Clinical Trials:Protection of Participants

DRUG TRAIL IN CVS

• Voluntary informed consent• Experiment must be for the good of society, & results not

obtainable by other means• Experiment should be based upon prior animal studies • Physical & mental suffering & injury should be avoided• No expectation that death/disabling injury will occur from

the experiment• Risk vs. benefit• Only scientifically qualified persons to be involved• Subject can terminate her/his involvement

10 Key Points

• ADMINSTRATIVE STUCTURE• steering committee: usually is made up of a study chair and

other selected (or elected) representatives from the investigators and sponsor.

• Steering committee members develop the protocol, lead the trial, and publish the results when the trial is complete.

• Data coordination center is responsible for the management and quality control of the trial data, as well as for interim or final analyses of the results and monitoring safety, and efficacy data

Central Laboratory

STUDY TEAM AT TRIAL SITE• Study Team at Trial Site include Investigator, Co-Investigator,

Study Coordinator, Nurse, Pharmacist.

• Unblinded Personnel (Coordinator/Nurse/Pharmacist) are required in blinded Trials for dispensing the Trial Medications to the Study Subjects

• Clear delegation of duties to the study team members is essential for the smooth execution of a clinical Trial.

Individual Member of the Study Team can be delegated specific Trial Duties such as:

• Administration of ICF• Recruitment of Subjects• Correspondence with EC / CRO / Sponsors• Stoarge, Dispensing & Accountability of Drugs• Completion of Source Documents• Completion of CRF• Medical Management of the Trial Subject• Reporting of SAE ( Adverse Events )• Escalations, Resolutions, Management of Deviations• Logistics Management• Resolution of Data Enquiries• Patient’s Visit Scheduling, Protocol Compliance & Follow Up• Maintenance of Site Master File.• Compliance with GCP & Regulatory Guidelines• Tracking of Payments / Study Grants

Idea OF new drug

Reviews from the experts(Sponsor or CRO)

First planning meeting (basic design features)

Second planning meeting (draft protocol)

Final protocol (ethical and scientific, signed by a statistician)

Evaluation (scientific review, IRB, funding)

Implementation

Final analysis and publication

Development of a Clinical Trial

• A pilot experiment, also called a pilot study,• A small scale preliminary study conducted in order to

evaluate feasibility, time, cost, adverse events, and effect size (statistical variability) in an attempt to predict an appropriate relevant sample size and improve upon the study design prior to performance of a full large-scale quantitative research project.

• To avoid time and money being wasted on an inadequately designed project.

Core Elements of a Clinical Trial• Research Question• Hypotheses-Clinical Relevance• Core Design• Study Participants• Recruitment• Allocation-Randomisation • Masking (Blinding)• Treatment Groups• Data• Analytical Issues-Statistical Methodology• Interpretation of Results

• 1.Constructing the Research Question • A hypothesis is the best guess as to what the answer to the

study question might be. It should ideally be based on knowledge of the published literature and preliminary work and, hence, be an informed guess. 

• FINER Criteria for a Good Research Question• Feasible Interesting Novel Ethical Relevant

Core Elements of a Clinical Trial

• The hypothesis • Regardless of the design of the trial, it is essential that

investigators provide a statement of the hypothesis being examined, using a format that permits biostatistical assessment of the results

• Typically, a null hypothesis (HO) is specified (e.g., no difference exists between the treatments being studied) and the trial is designed to provide evidence leading to rejection of HO in favor of an alternative hypothesis (HA; a difference exists between treatments).

• Selection of Endpoint of Clinical Trial -Two major approaches

• net clinical benefit, net clinical outcome, or NACE • The balance of benefit and risk associated with a new

treatment may be described • Such terms typically combine elements of efficacy and

safety (e.g., cardiovascular death, nonfatal myocardial infarction [MI], nonfatal stroke, nonfatal major bleed) and provide clinicians with a summary statement about what to expect from a new treatment

• surrogate endpoint• Another approach is to use a a substitute for measuring

more traditional clinical outcomes. • Surrogate endpoints are attractive to investigators because

they are often measured on an interval (continuous) scale and can lead to trials with a smaller sample size

• CLINICAL TRIAL PROTOCOL • The protocol is the trial's 'operating manual' and ensures

that all researchers perform the trial in the same way on similar patients and that the data is comparable across all patients.

• Because the trial is designed to test hypotheses and rigorously monitor and assess outcomes, they can be seen as an application of the scientific method, specifically the experimental step.

• 7days-6months!!!• 4-50 pages long

• Written agreement between:– the investigator– the participant, – and the scientific community

• Legal documents for – FDA and other regulatory bodies

• To procure funding

Functions of Clinical Trial Protocol

• Study Participants-• Ideal ‘Accessible’ Population

– high risk for disease– candidates for treatment– representative of target population– feasibility considerations

• recruitment• follow-up• high quality data

• Sample size:• Larger the sample size (the larger the n), the more

confident we will be in trusting the conclusion• Effect of a particular intervention being studied is very

small, a large n would be needed to be certain of detecting it.

• Calculation of sample size-based on anticipated event rates in study population and clinically relevant differences in rates anticipated between two arms of trial.

• Enrollment Criteria Inclusion Criteria• – characteristics of accessible populationExclusion Criteria

– – considerations related to:– • adherence to therapy– • follow-up– • safety– • ethics

DRUG TRAIL IN CVS

• Recruitment• Most challenging • From an accessible

population, which is a subset of the target population

• They also must secure approval from their institutional review board for their recruitment plans.

• In most trials, the number of contacted people who actually enroll is small.

• Informed consent• Informed consent is a legal process in which a recruit is

instructed about key facts before deciding whether to participate. Researchers explain the details of the study in terms the subject can understand. The information is presented in the subject's native language.

• The document includes details such as its purpose, duration, required procedures, risks, potential benefits and key contacts.

• The participant then decides whether to sign the document. • The document is not a contract, as the participant can

withdraw at any time without penalty.

Run-In Design

Screen & Consent

Run-In Period with

placebo

STUDy

Unsatisfactory

Dropped

B

A

Note: It is assumed that all patient entering the run-in period are eligible and have given consent

Satisfactory

• Allocation-Randomization• A scientifically valid comparison between 2 treatment

groups depends on the groups being alike as much as possible, with the only exception being the specific treatments under investigation.

• The best way to achieve such a balance is by the use of randomization in which a chance mechanism determines the treatment assignment.

• Randomization will ensure that a specific treatment assignment is not known in advance to either the clinician or the patient.

• Randomization has 3 important influences that explain why it is considered the standard for trial design:

• (1) it reduces the likelihood of patient selection bias that may occur either consciously or unconsciously;

• (2) it enhances the likelihood that comparable groups of subjects are compared, especially if the sample size is sufficiently large; and

• (3) it validates the use of common statistical tests such as the x2 test for comparison of proportions and Student’s t test for comparison of means.

The Basic Randomized Controlled Trial

• BLINDING/MASKING

• Only when both the patient and caregiver are unaware of the treatment assignment can their desire for a favorable outcome not potentially bias the results of the trial..

Open label

Single blind

Double blind

Tripple bind

Participant × × ×

Investigator × ×

Data interpreter

×

• Selection of Active Treatment and Dosage• Before a company initiates testing in humans), it must

conduct extensive experiments in animal and human cells and in live animals (Preclinical Trial)

• If this stage of testing is successful, the company files an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) to request permission to conduct clinical trials.

• Selection of dosage is an inexact science, often driven by phase 1 or 2 dose-response studies followed subsequently by results of phase 3 trials.

Phase 0 - Preclinical• Preclinical animal studies• Looking for dose-response

• Phase I• These trials are designed to obtain the following

information: – Safety – Determine the most significant adverse events

in human subjects. – Tolerability – The safe dose range is determined by dose

escalations .– Pharmacokinetics –the effects body on the drug

molecule – Pharmacodynamics – The effects of the drug on the body

• The tested range of doses will usually be a fraction of the dose that caused harm in animal testing. Phase I trials most often include healthy volunteers

• Types of Phase 1 trials: – SAD – Single Ascending Dose – MAD – Multiple Ascending Dose – Food Effect – Effects of food substances on the

absorption of the drug

Single ascending dose

• Based on tradition, not so much on statistical theory

• Dose escalation to reach maximum tolerated dose (MTD)

• Dose escalation often based on Fibonacci Series

1 2 3 5 8 13 . . . .

Phase I Design

1. Enter 3 patients at a given dose2. If no toxicity, go to next dosage and repeat step 13. a. If 1 patient has serious toxicity, add 3 more

patients at that does (go to 4)b. If 2/3 have serious toxicity, consider MTD

4. a. If 2 or more of 6 patients have toxicity, MTD reached (perhaps)b. If 1 of 6 has toxicity, increase dose and go back to step 1

Designed to find dose where 1/3 of patients experience dose limiting toxicity (DLT)

Standard escalation design tends to underestimate target dose

• Multiple ascending dose• Multiple ascending dose studies are conducted to better

understand the pharmacokinetics and pharmacodynamics of multiple doses of the drug.

• In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body.

• The dose is subsequently escalated for further groups, up to a predetermined level.

• Phase II• Once range of doses is determined, the next goal is

biological activity or effect• Phase II trials are performed on larger groups (100-300) and

are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients.

• Genetic testing is common, particularly when there is evidence of variation in metabolic rate.

•  When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.

• Phase II studies are sometimes divided into Phase IIA and Phase IIB.– Phase IIA is specifically designed to assess dosing

requirements (how much drug should be given).– Phase IIB is specifically designed to study efficacy (how

well the drug works at the prescribed dose(s)).– Some trials combine Phase I and Phase II, and test both

efficacy and toxicity.• Goal

– Screen for therapeutic activity– Further evaluate toxicity

• Trial design-– case series– RCT

• Typical Gehan Design

– That is, want to check if drug likely to work in at least 20% of patients

1. Enter 14 patients2. If 0/14 responses, stop and

declare true drug response 20%3. If 1+/14 responses, add 15-40

more patients4. Estimate response rate & C.I.

• Phase III -the "pre-marketing phase" • This phase is designed to assess the effectiveness of the

new intervention and thereby, its value in clinical practice•  The percentage of Phase II trials that proceed to Phase III,

as of 2008, is 18%.•  Phase III studies are randomized controlled 

multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment.

• Comparative Studies• Experimental Group vs. Control Group• Establishing a Control-placebo or active standard

therapy 1. Historical2. Concurrent3. Randomized

• Randomized Control Trial (RCT) is the gold standard– Eliminates several sources of bias

Phase III Design

• Placebo -controlled trial- the control treatment is a placebo.• A placebo (inert substance) is preferable to “no treatment”

without a pill for two reasons. • The placebo effect -the act of taking a pill or receiving a

treatment may exert some benefit apart from the active ingredient.

• Second, use of a placebo pill should minimize the risk for unblinding participants and data collectors if the placebo is identical or very similar in appearance, taste, and smell to pills with active therapy

On international realm, 1999 “Declaration of Helsinki” revised to address use of placebos:

• Placebos not ethical in virtually all studies that involve diseases with PROVEN tx

• Remain ethical in trials where no proven tx.

DRUG TRAIL IN CVS

Issues in Clinical Trials: Use of Placebo Trials

• Active controlled trial-

• Given the burgeoning supply of new treatments in the cardiovascular armamentarium, more and more trials compare the test therapy to a standard therapy.

DRUG TRAIL IN CVS

• A new treatment used in a series of subjects

• Outcome compared with previous series of comparable subjects

• Non-randomized, non-concurrent

• Rapid, inexpensive, good for initial testing of new treatments

• Two sources of historical control data:

• Literature Subject to publication bias

• Data base•Tend to exaggerate the value

of a new treatment

Historical Control Study

DRUG TRAIL IN CVS

• Not randomized• Patients compared, treated

by different strategies, same period

• Advantage– Eliminate time trend– Data of comparable

quality• Disadvantage

– Selection Bias– Treatment groups not

comparable

Concurrent Controls

• Patients assigned at random to either treatment(s) or control

• Considered to be “Gold Standard”• Stratified Randomization• patients are formed into risk groups (strata) based on 1

or more prognostic factors, and a separate randomization is conducted for each strata.

• When the treatment assignment groups are then summed over the various strata, the end result is a forced balance of these overall treatment groups according to the factors used to form the strata.

Randomized Control Clinical Trial

1. Generalizable Results?– Subjects may not represent general

patient population – volunteer effect

2. Recruitment– Twice as many new patients

3. Acceptability of Randomization Process– Some physicians will refuse– Some patients will refuse

4. Administrative Complexity5. Interefere doctor – patient relationship.

Disadvantages of Randomized Control Clinical Trial

• Parallel• Cross Over• Factorial• Equivalence/Non-

inferiority

Commonly Used Phase III Designs

• The most common type of design is a parallel-arm trial with two or more groups.

• In such a design, participants remain assigned to their randomized group until the end of follow-up. Parallel-arm trials are relatively easy to understand, especially the basic two-group (arm) trial.

• An alternative is the crossover design, in which individuals are randomly assigned to a sequence (comparison treatment followed by new treatment, or vice versa). Crossover trials can be performed when the outcome is reversible, such as BP

PARALLEL-ARM CROSSOVER DESIGN

• Factorial Design • In a factorial design, multiple

treatments can be compared with control within a single trial through independent randomizations .

• More practical for CVD patients.

• Each intervention should be evaluated individually against control and the possibility of interaction between the factors should be evaluated, because the validity of comparisons within each factor depends on the absence of interaction.

• Factorial designs may not be appropriate if there is an a priori reason to anticipate interactions (e.g., resulting from related mechanisms of action

DRUG TRAIL IN CVS

EQUIVALENCE & NON –INFERIORITY TRAILS

• Regulatory submission • Once a drug has proved satisfactory after Phase III trials,

the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life.

• That is provided for review to the appropriate regulatory authorities in different countries for approval and to market the drug by sponser.

• Phase IIIB studies• It is common practice that certain Phase III trials will

continue while the regulatory submission is pending at the appropriate regulatory agency.

• This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase.

• Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases to obtain additional safety data, or to support marketing claims for the drug.

• Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines through a New Drug Application (NDA) containing all manufacturing, pre-clinical, and clinical data.

• In case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market.

• While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as FDA (USA), or the EMA (European Union),

• PHASE 4 CLINICAL TRIALS (Therapeutic use studies). • Post Marketing Surveillance Trial. • Involve the safety surveillance (Pharmacovigilance) and

ongoing technical support of a drug after it receives permission to be sold.

• Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug interactions ).

• The main rationale behind conducting Phase IV trials is – In prior clinical trials, up to Phase 3, patients are

selected and limited in number – Conditions of use in trials differ from those in clinical

practice – Duration of trials is limited – Information about rare but serious adverse reactions,

chronic toxicity, use in special groups (such as children, the elderly or pregnant women) or drug interactions is often not available.

Clinical Trials

Preclinical testing

FILE

IND

at

FDA

Phase I Phase II Phase III FILE

NDA

at

FDA

FDA Phase IV

Years 3.5 1 2 3 2.5 12 Total

Additional post marketing testing

Test population

Lab and Animal Studies

20 to 80 healthy volunteers

100 to 300 patient volunteers

1000 to 3000 patient volunteers

Review process/ Approval

Success rate

5000 compounds evaluated

5 enter trials 1 approved

The entire process of a drug from lab to this point may take approximately 12 to 18 years (but not always), often costing

over $1bn.For Every 10,000 – 30,000 drug molecules screened, only 1

reaches to the Market.

• Phase V• Phase V is a growing term used in the literature of 

translational research to refer to comparative effectiveness research and community-based research; it is used to signify the integration of a new clinical treatment into widespread public health practice.

• CDM (Clinical Data Management) is an integral part of the clinical trial process, which ensures the validity, quality, and integrity of data collected from trial subjects to a database system for statistical analysis & draw conclusions regarding the effectiveness, safety, and clinical benefit / risk of the drug product under investigation.

• The CDM process includes: – Case Report Form (CRF) development – Database development and validation – Data entry, query, and correction – Data quality assurance – Data lock, archive, and transfer.

Clinical Data Management)

• Events in a clinical trial may be measured on a nominal (dichotomous), categorical, or interval (continuous) scale.

• Clinical trials reports should use descriptive statistics, graphic displays, and estimates of the precision of the observations appropriate for the scale of measurement being used in the trial.

• Always have a clear plan on how to collect data-- design and pilot questionnaires, case report forms.

STATISTICS

DATA COLLECTION / MANAGEMENT

Statistical significance and power

• Statistical significance is based on the Type I or Alpha error– the probability of rejecting the null hypothesis when

it was true (saying there was a relationship when there isn’t one)

– usually we accept being wrong <5% of the time, or alpha=0.05

– Setting alpha depends on how important it is that we not make a mistake in our conclusion.

• The Type II or Beta error is the probability of accepting the null when it was false– saying there is no relationship when there is one– power is 1-B, and 80% or 90% (beta error of 10% or

20%) is conventional.

• Measures and Detection of Treatment Effect • A common assessment in a cardiovascular trial is

comparison of the proportion of patients experiencing a dichotomous event (e.g., dead versus alive) .

• When the outcome is an undesirable response and the data are arranged as investigational group compared with control group, a relative risk (RR) or odds ratio (OR) of less than 1 indicates benefit of the investigational treatment

• Interpretation of the treatment effect should take into account the absolute risk of the outcomes.

• The absolute risk difference (ARD) is the difference in events in the treatment group and the control group, and is particularly useful when expressed as the number of patients that must be treated (N = 1/ARD), or number needed to treat (NNT), to observe the beneficial effect in one patient.

• The p-value, or alpha error most commonly indicates the precision of the result, with a low p-value corresponding to a precise result.

• A t-statistic, Chi-square value gives the relative magnitude of a relation.

• The higher the magnitude of the above statistics, the more precise or stronger is the relationship between the explanatory variable (s) and the outcome of interest.

Measures of Precision of Effect

• The estimate of where the true value of a result lies is expressed within 95% confidence intervals, which will contain the true relative risk or odds ratio 95% of the time .

Precision of Effect: The Confidence Interval

Detection of treatment effects in clinical trials. Factors related to trial design (top) and to the patient and drug being investigated (bottom)

are shown. The interplay of these factors influences the ability to detect a treatment effect in a clinical trial.

Fallacies in Presenting Results: Statistically vs. Clinically Significant?

• Having a large sample size can virtually assure statistically significant results even if the correlation, odds ratio, or relative risk are low

• Conversely, an insufficient sample size can hide (not significant) clinically important differences (higher beta error or concluding no difference when there is one)

• Statistical significance directly related to sample size and magnitude of difference, and indirectly related to variance in measure

• Clinical versus Statistical Significance• Clinical significance pertains to the magnitude of benefit

that would be sufficient to change practice or public health policy

• Statistical significance-pertains to the probability that the observed result occurred bychance alone; it commonly is expressed as a P value. Statisticalsignificance depends on both the magnitude of benefit and the sample size

• CONSORT (Consolidated Standards Of Reporting Trials)

• Minimum set of recommendations for reporting randomized trials.

• It offers a standard way for authors to prepare reports of trial findings, facilitating their complete and transparent reporting, reducing the influence of bias on their results, and aiding their critical appraisal and interpretation.

• The most recent version of the Statement—the CONSORT 2010 Statement—consists of a 25-item checklist and a participant flow diagram, along with some brief descriptive text.

• The checklist items focus on reporting how the trial was designed, analyzed, and interpreted.

CONSORT - Consolidated Standards of Reporting Trials

• An official journal for the Society for Clinical Trials• The first issue was published in the May of 1980.• Aim and scope:

– Basic Design – Operating features– Organization– Analysis

• Current editor (1999-) James D. Neaton

Controlled Clinical Trial A Journal

If We areTaking Part in Research Studies:

Questions to Ask• What is study

about?• What are the goals?• Study sponsor?• Participant input

into protocols? • Inclusion criteria?• Benefits & risks

• Is there an incentive?• How protected from

harm?• What is required: #

study visit & what occurs?

• What happens after study is over?

• How results will be disseminated?

DRUG TRAIL IN CVS

Overview of Clinical TrialStudy

Design

DesignStudy

Documents

Notification to Regulatory

Authority

Investigator Selection

Ethics Committee

Review

ApprovalLetter

Investigator Meeting

SiteInitiation

PatientEnrollment

Monitoring

DataManagement

Follow upVisits

End of Trial

Statistical Review

FinalReport

ConclusionWell-designed and rigorously conducted trials

provide extremelyuseful information that can inform or guide,

clinicalpractice.