Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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Evidence-based medicine is the systematic, scientificand explicit use of current best evidence in makingdecisions about the care of individual patientsTherapeutic evaluation of drugQuantification of benefitAppropriate method-dosage, duration, patient selectionSurveillance of adverse effects

clinical trialscohort studiescase control studies

ConductClinical

Trial

Disease

Population Drug

SpecificConcern

Cost vs Health Outcomes Grid

Effectiveness -

Effectiveness +

Costs -

Costs +

?Useless

Dominant

re we ready togive up oneffectiveness forlower costs?!

Costsmore butdoes less

Costs moreand doesmore

Costs lessbut doesmore

Costs less and does less

Based on: Appropriateness/Safety/ Efficacy and cost Genuine indication Minimum number of drugs Inexpensive and appropriate formulation Preferably oral route – avoid injections Monitor adverse drug Event Patient education related to drugs and disease

Approval of the product, new drugs should be closely monitoredfor their clinical safety once they are marketed. The applicantsshall furnish Periodic Safety Update Reports (PSURs) in order to-

Report all the relevant new information from appropriatesources;

Relate these data to patient exposure; Summarize the market authorization status in different

countries and any significant variations related to safety; and Indicate whether changes should be made to produce

information in order to optimize the use of the product.

Title & AbstractIntroduction

General statement of purposeComplete Preclinical results on animal studyClinical data if availableTime frame

Goals: Primary & secondary objectivesStudy Design:

Type of studyRecruitment criteria : Exclusion & Inclusion criteriaRandomisation criteria and Sample sizeDuration of study

Data Analysis:Case report forms, Statistical Analysis, Bibliography

Informed consent form:VoluntaryExplained in simple nontechnical languageTranslated in the native language of the subjectComprehensive information regarding the trials

Benefit of new therapy over existing onesAlternative treatments available

All possible adverse reactionsFreedom to withdraw from the trial

at any time,without giving any reason

Independent Competent 5 – 7 members; 5 required for quorum. Member Sec from same Institution Others: A mix of medical non-medical,

scientific & non-scientific including lay public Multidisciplinary & Multisectorial

To protect the dignity, rights & well being ofpatients / volunteersEnsure a competent review of the protocolAdvise on all aspects of welfare & safetyEnsure scientific soundness of the proposal

It is a prospective ethically designed investigation inhuman subject to objectively discover/verify/compare/ the results of two or more therapeutic

measures(drugs)Preclincal studiesmicrodosing studiesPhase I : First in man safetyPhase II : First in patientdose, dosage formPhase III : Efficacy, ADRsPost marketing surveillance or Phase IV : Evaluation inthe real clinical setting

ObjectivesTo assess a safe & tolerated doseTo see if pharmacokinetics differ much from animal to manTo see if kinetics show proper absorption, bioavailabilityTo detect effects unrelated to the expected actionTo detect any predictable toxicity

Inclusion criteriaHealthy volunteers : Uniformity of subjects: age, sex,nutritional status [Informed consent a must]Exception: Patients only for toxic drugs Eg AntiHIV, Anticancer

Exclusion criteriaWomen of child bearing age, children

MethodsFirst in Man : Small number of healthy volunteersFirst in a small group of 20 to 25Start with a dose of about 1/10 to 1/5 tolerated animaldoseSlowly increase the dose to find a safe tolerated doseIf safe in a larger group of up to about 50 –75No blindingPerformed by clinical pharmacologistsCentre has emergency care & facility for kinetics studyPerformed in a single centreTakes 3 – 6 months [ 70% success rate]

First in patient [ different from healthy volunteer]Early phase [20 – 200 patients with relevant disease]

Therapeutic benefits & ADRs evaluatedEstablish a dose range to be used in late phaseSingle blind [Only patient knows] comparison withstandard drug

Late phase [ 50 – 500]Double blindCompared with a placebo or standard drug

OutcomesAssesses efficacy against a defined therapeutic endpointDetailed P.kinetic & P.dynamic dataEstablishes a dose & a dosage form for future trials

Takes 6 months to 2 years [ 35% success rate]

Age: Pediatric,GeriatricGender: WomenPhysiology: Pregnancy, NursingPathological states: renal failure, hepatic failure,cardiac failure,BMI: obese, leanEthnicity/RaceVulnerability

Guidance for Industry, investigators andReviewers; Exploratory IND Studies, Jan2006,US FDA

Phase III A: up to NDA submissionEnd of Phase III A studies must include special patientpopulations and pharmacoeconomic data collectionAt least one placebo controlled trial

Phase III B:Ongoing at time of NDA submissionUndertaken after NDA submission but before NCE is marketed

New indications may be includedNew patient populations may be includedSpecial features explored e.g. drug interactions

20PLS-2012

ObjectivesTo assess overall and relative therapeutic value of the new drug

Efficacy, Safety and Special Properties

To determine optimal dosage schedule for use in General PracticeThe dosage schedule in C.T.’s should be as close as possible to

its anticipated clinical use

Data obtained is Major component of NDA submissions-Regulatoryinputs are important i.e. what comparative drug to useMarketing Department inputs i.e. information on most widely

Prescribed treatment

21PLS-2012

Large Sample Size: Multicentric, ↑VariabilityFewer exclusion criteria (stable concomitant disease allowed)Longer duration of treatment: Weeks/MonthsStudy design

ParallelCross over

Investigator’s BrochureStudy Protocol (Investigator’s meeting)

All investigators agree to followCase Record forms

Same at all centersStudy monitoring especially recruitment rateStudy monitors

Clinical research associatesDrug supplies

22PLS-2012

After Marketing Permission(Real World Use of the New D

Thousands/Lakhs of patients now use the drug

G.P.’s, Little medical supervisionCo morbidities/other drugs taken (Herbals)Non adherence to treatment rampant (> 50%)Long duration of treatmentSelf-medication rampant

- Prescription drugs- OTC drugs

PLS-2012 23

Phase IV C.T.: Special Characteristics

1. Very large sample size2. No or little supervision: Physician shopping3. Fewer data collected from each patient4. Fewer Exclusions (Contraindications only)5. Longer drug administrations6. Expensive7. Comorbidities and co-medications8. Non adherence to treatment: Common9. Self-medication common

PLS-2012 24

To obtain information on Unsupervised use of Registered Drugin the Community under daily routine conditionsPMS: Legally fulfill this Regulatory Requirement

Mandatory for Fast Track ApprovalsDoes not influence diagnostic/therapeutic procedures ofParticipating physicians. Uses Specific Record FormsEnrolled patients are not subjected to any disadvantage oradditional risk

Data collected provides an unbiased picture of daily routine Useof drug, allowing Realistic assessment of Benefit-Risk ratios

1. Comparative long term Benefit-Risk assessment

2. Drug usage in the community

3. QOL Assessment

4. Dose-refinement

5. Rare ADR’s and long term safety

6. Benefit-Cost assessment

7. Improvement in Primary End-points of disease

1. Spontaneous Voluntary Reporting2. Case Control Studies3. Intensive Hospital Monitoring4. Prescription Event Monitoring5. Literature Surveys6. Prospective population based studies for rare ADR’s7. Automated patient Data Banks

(Useful for retrospective studies)

CDSCO, HQ

National Coordination CentreIPC Ghaziabad, UP

SteeringCommittee

WorkingGroup

Signal Review Panel

Core Training Panel

Quality Review Panel

M O NAI

DT

RO R I N G

IMMUNIZATIONPROGRAMMES

PharmaceuticalIndustry ADRsoriginating inIndia

PROFESSIONAL BODIESHOSPITALSMEDICAL COLLEGES

StakeholdersPatients, Health CareProfessionals, PharmaIndustry

CDSCO ZONAL/SUBZONALOFFICES

North

GhaziabadChandigarh

SouthChennai,Hyderabad,Banglore

EastKolkata

WestMumbai

Ahmadabad

1

3

4

c

A

DE

B

PHARMACOVIGILANCE

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It is the pharmacological science relating to thecollection, detection, assessment, monitoring, andprevention of adverse reaction with Pharmaceuticalproducts.

It is the study of the safety of marketed drugs underthe practical conditions of clinical use in largecommunities

It is concerned with the development of science andregulation in the area of drug safety.

Restrictive inclusion/exclusion criteria limitsgeneralizability

Conflict between results observed in controlled experimentversus use in real life

Too expensiveSingle intervention, single-dose-though there is increasinguse of factorial designEthical considerationsBias in what interventions are studied and what studies arepublishedTranslation of large sample derived risks and outcomes toindividual patients

1. Not dependent on large resources or researchinfrastructure

2. Can be interesting, accessible and readily digestiblefor readers

3. Convey the ‘art’ of medicine4. Not all research questions are amenable to RCT5. An expedient way of communicating new ideas,

syndromes, treatments and adverse reactions

“All substances are poisons;there is none which is not a poison.The right dose differentiates a poison from a remedy.”

Paracelsus (1493-1541)

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