5Phase I Clinical Studies First in man or normal healthy volunteer studies?Designed to determine all critical clinical safety issues for the drug.if you double the dose do you double the blood concentration?effect of fooddifferences between gender and age
6Phase IIa Clinical Studies Establish the science of the drug in the patients for which the drug is intendedConfirm the mechanism of action of the drug in the target condition or diseaseEstablish safety in patients with the target condition or diseaseDetermine the dosage range in patients to manage the condition or diseaseUsually confined but not always
7Drug Development Statistics Drug discoverers file patentPatent exclusivity (no generics) = 17 yearsDrug development time = yearsApplication review = yearsMarket exclusivity = yearsDrug development cost = $250 M - $400MTarget income/drug/year = $250 M - $1B
8Investigational New Drug - IND - Key milestone in drug development!Signals that the company believes the drug can safely be administered to humans.Once an IND is filed with the FDA, the company can start their first human study in 30 days; unless the FDA stops the study.
9Drug Development Standards Good laboratory practices (GLP) Non-clinical safety studiesGood manufacturing practices (GMP) Production operations Drug Formulation Quality controlGood clinical practices (GCP) Clinical studies Phases I to IV
10Drug Development Expensive & time consuming Race to market patent life is 17 years (no competition)$1M - $3M /day for first to marketSafety of the drug is thoroughly tested in laboratory animals and people.Efficacy of the drug has to be statistically proven efficacious in patients.MRO’s are important in this process.
12GCP - ICH DefinitionA standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.ICH - GCP Glossary (Final draft, May 1996)
13Good Clinical Practice (An Operational View) To: preventdetectcorrectdocumentCareless errorsViolationsFraud / MisconductEthical problems
14GCP - Objectives Ethics: Rights of patients Safety: Protection of patientsEfficacy: Utility of the product
15Registration Authorities Notification - Of starting - Of stopping - Adverse eventsAuthorizationSponsorPreparation of documentsPharmaceutical productsData managementDecisions on adverse eventsPreparation of reportsFiling and archivingAudit of systems and dataMonitorProtocol, Inv. brochureOn site visits informationAmendmentsto protocolClinical Laboratory- Equipment- Personnel- CertificationQualityInvestigator- Availability- Knowledge (product, protocol)- Trained team- Acceptance of monitoring- Acceptance of audit & inspectionEthics Committee - Independence- Composition- Written approval- DocumenteddecisionSevereAdverseEventsWrittenApprovalProductInformationConsentCompliancewith protocolPatientsRef: A. and T. Spriet, Good Practice of Clinical Drug Trials, Karger, Ed. 1992
16GCP in Medical Research Document ! Document ! Document !“If it is not written,it does not exist.”Dr. Lisook (FDA)Div. of Scientific InvestigationsOffice of Compliance
17Adverse Events (AEs) Adverse experience (AE) Adverse drug event (ADE) Adverse drug reaction (ADR)Adverse drug experience (ADE)Adverse reaction (AR)Side effect (SE)Undesirable reaction (UR)Unfavorable effect (UE)But not identical !
18Adverse EventsSigns - findings eg. BP, temperature, skin rashes or bruises etc.Symptoms - a change in function as abd. Pain, nausea, headache, lightheadednessLaboratory Finding - incr. or decr. Abn.Inter-current Illness - cold, URI etc.Study Condition - caused by blood draw or ambient temperature
19Adverse Event (AE) Defined Any untoward medical occurrence in a patient or clinical investigation subject who is administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.ICH - GCP GlossaryDraft 7 (March 31, 1995)
20Adverse Experience vs. Adverse Drug Reaction (FDA Concept) Adverse drug reaction (ADR) is an adverse experience (AE) that is probably / possibly / remotely a reaction to a drug. (Concept of drug-relation.)
21Adverse Experience: Attributes Frequent / RareBenign / SeriousPredictable* / UnpredictableExpected / UnexpectedEarly occurrence / Late occurrence* Related to pharmacology / class
22Adverse Drug Reaction: Types Type AType BPharmacologically predictableDose-dependentIncidence and morbidityMortalityTreatment+HighLowAdjust dose-LowHighStopAfter M.D. Rawlins and J.W. Thompson “Textbook of Adverse Drug Reactions”
23Adverse Events Severity Seriousness . Severity Intensity of an event (mild - moderate - severe)Seriousness Global evaluation of an event in terms of major consequences for life.
24Quality AssuranceAll those planned and systematic actions necessary to provide adequate confidence that a product or service will satisfy requirements for “Quality You Can Count On”.
25Quality Assurance “minimize correction through early detection” The goal of a QA is to“minimize correction throughearly detection”byMonitoring studies and forecasting QAcheckpoints to more efficiently utilize resources and minimize delays
26Standard Operating Procedures “SOPs” What are theyHow are they definedHow important are they
27SOPs - Defined A set of pre-established written procedures for: - The organization, The conduct, The data collection, The documentation, and - The verification ..…of a clinical trial
28SOPs - DefinedA set of pre-established written procedures to ensure that the rights and integrity of the trial subjects are thoroughly protected and to establish the credibility of data and to improve the ethical, scientific, and technical quality of trials.
29Standard Operating Procedures “SOPs” WHO does WHAT, WHERE, and WHENNOTWHY or HOWInstructionsTrainingPolicy
30Standard Operating Procedures To establish consistencyTo optimize time / manpowerTo enhance teamworkTo protect the subject / patientTo assure compliance with GCPTo assure worldwide acceptanceTo ensure quality of the data
31International Conference on Harmonization (ICH) What is itHow does ICH affect what we do
32ICH: Efficacy Groups (GCP) (1) E1A: Extent of population exposure forclinical safetyE1B: Prospective/retrospective studies ofdatabases on population exposureClinical safety data management (ADE) :E2A: Expedited reporting: def./standardsE2B: Expedited reporting: format of reportsE2C: Periodic safety updates
33ICH: Efficacy Groups (GCP) (2) E3: Clinical study reports:format/contentsE4: Dose-response informationfor registrationE5: Ethnic factors in acceptability offoreign clinical dataE7: Clinical trials in special populations:Geriatrics
34ICH: Efficacy Groups (GCP) (3) E6: Good Clinical Practices:consolidated guidelineE6A: Addendum: Investigator’s brochureE6B: Addendum: Essential Documents
35ICH: Efficacy Groups (GCP) (4) E8: General guidelines for clinical trialsE9: Biostatistical issues in planning, analysis, and interpretation of clinical trials to support efficacy and safetyE10: Choice of control groups in clinical trials