Slide 1:New drug development


Slide 2:A process which applies to drugs, products and protocols to be used on human subjects. New Drug development is divided into 4 phases 1.Drug discovery 2.Pre clinical development 3.Clinical trial 4.Post approval


Goals and objectives :Goals and objectives Clinical pharmacology and pharmacometrics Safety Activity Effectiveness Differentiation Successful FDA submission Market expansion and post marketing surveillance


Is this a costly affair :Is this a costly affair Very much so …. 99% failures 500 million $ 15 long years May fail at any stage ?????


Drug discovery process :Drug discovery process Screening consists of testing many compounds in assays relevant to the disease in question……HIT If the compound or its structural derivatives continue to show promise after further biological and chemical characters….LEAD


Slide 7:Two basic strategy are applied 1. Compound centered 2. Target centered Compound centered approach Natural products: isolated from plants, animals and microorganisms. ex. Morphine, Quinine, Atropine Adrenaline, Thyroxine Penicillin


Natural ligands :Natural ligands Examples: Dopamine- Parkinson- L-dopa Insulin – diabetes – exogenous insulin


Slide 9:Target centered approach Use biochemical or molecular target Adv : pharmacological activity system assay


Structure based approach :Structure based approach Use 3-D structure of the target obtained through x-ray crystallography or NMR. Adv : -potency -limited number of drugs Disadv : -synthesis


Slide 11:Chemical synthesis: Based on SAR - ex. Histamine blockers Based on enantiomers - ex. dopa Rational approach: ex. Proton Pump Inhibitors. Molecular modelling: ex. COX 2 inhibitors Combinatorial chemistry: Biotechnology: ex. Growth factors, cytokines.


Lead optimization :Lead optimization Is the stage where physical, chemical, biological and pharmacological properties are characterized and refined with the ultimate goal of selecting a single molecule to enter into clinical testing and formal drug development.


Reasons :Reasons Failure to demonstrate Efficacy Low bioavailability Extensive metabolism Low solubility Toxic effects Cost effectiveness in synthesis


Drug discovery :Drug discovery Identifies interesting drug compounds, drug targets and delivery mechanisms with the potential for development into products. Characterize compounds and their targets Are “proof of concept” in nature Provide fundamental information on target biological system Identify lead compounds for further development


Pre clinical drug development :Pre clinical drug development Space the gap between drug discovery and clinical trials. Provide data on the safety and efficacy of the product Includes In vitro study, drug manufacturing, formulation and packaging, In vivo studies


In vitro study :In vitro study Intact cell lines assess drug effects on cells with specific DNA mutation Cell free system assay of enzyme activity, receptor binding, protein interaction with signal transduction


Drug manufacturing and formulation :Drug manufacturing and formulation Conducted under current good manufacturing practices (CGMP) guidelines IN-VIVO STUDIES PK study – ADME study PD study Therapeutic index Toxicological study


Toxicological study :Toxicological study Objectives : Acute study Method Aim : to provide safety/therapeutic index Observation


Sub acute study :Sub acute study aim : To identify the target organ To determine the clinical parameters To estimate the safety margin Method: Evaluation: Chronic study Similar to sub acute study except for the duration


Special study :Special study Effect on reproductive system and Teratogenicity Mutagenicity- ame’s test Carcinogenicity


Clinical drug evaluationAuthorization :Clinical drug evaluationAuthorization Investigational new drug (IND) submission -the rationale for the drug and patient group to be treated -all pre clinical safety and efficacy data -detailed plan for clinical development -CIB( clinical investigators brochure) Submitted to FDA for review and permission to proceed.


Ethics :Ethics Declaration of Helsinki-1964 The clinical trial must minimize the risk for participants Provision for care of the patients Terminate the trial when the risk becomes incompatible with the goals of the trial Adverse events to be reported immediately to an ethical committee


Ethics Committees :Ethics Committees The ethics committee reviews a protocol before the study is allowed to start. Their job is to ensure that the risks of being in the study are not greater than the potential benefit.


IRB( Institutional Review Board) IEC (Independent Ethical Committee) :IRB( Institutional Review Board) IEC (Independent Ethical Committee) To ensure the rights and welfare of the participants FDA regulations mandates to review the clinical trial protocols for ethical and legal issues Also has the authority to approve, modify or disapprove it


Informed Consent :Clinical Trials & Research 25 Informed Consent Participation in clinical trials is always voluntary. No, thank you, I’d rather not participate. Yes, I would like to participate.


Informed Consent :Clinical Trials & Research 26 Informed Consent Purpose Medicine to be studied Procedures and schedule Risks Potential benefits Alternatives to participation Confidentiality


What is a Clinical Trial? :Clinical Trials & Research 27 What is a Clinical Trial? Identify a health question. Develop a plan. Enroll volunteers and follow the plan. Study the information collected. Share the results with others. Improve treatment.


Historical MinuteFirst “Clinical Trials” :Historical MinuteFirst “Clinical Trials” Clinical trials have a long history – even if not acknowledged as Clinical trials Formal record of clinical trials dates back to the time of the “Trialists”: Dr. Van Helmont’s proposal for a therapeutic trial of bloodletting for fevers [1628] Dr. Lind’s, a ship surgeon, trial of oranges & limes for scurvy [1747] NY/VI AETC


COMPONENTS OF A CLINICAL TRIAL :Review of scientific background Written hypothesis/hypotheses to be tested Study design -type -study population -statistical analysis -enrollment of subjects -intervention -follow up of subjects Organization COMPONENTS OF A CLINICAL TRIAL PROTOCOL


Phases of Clinical Trials :Clinical Trials & Research 31 Phases of Clinical Trials


Phase 0 :Phase 0 Recent designation FDA-2006 guidelines First in humans 100th of the pharmacological dose Early PK and PD data Minimal pre clinical study Adv : unreliable in vitro and animal study Disadv : safety/efficacy


Phase 1 :Phase 1 Participants Dose Determines safety of the drug Involve dose ranging studies to determine toxicity and major adverse effects May provide early evidence of efficacy End point- toxicity


Phase 2 :Phase 2 Evaluate efficacy and therapeutic benefit Involve 80-100 Patients Identify common short term side effects Establish dosing regimen and dose optimization Validate the design of phase 3 Duration : 1-2year


Phase 2A :Phase 2A Pilot study Dose defining and dose form Safety and efficacy PK/PD data Risk – benefit ratio


Phase 2B :Phase 2B Controlled pivotal study Placebo Double blind Safety and efficacy


Phase 3 :Phase 3 Large multi-center Randomized study Involve 1000-3000 patient volunteers Placebo controlled blind studies to clearly demonstrate efficacy, safety and therapeutic benefit Package insertion and labeling Adverse drug reactions Duration: 2-3 years


Phase 1V (Postmarketing surveillance) :No fixed time and population The purpose is usually to support the marketing campaign Rare ADR’s Drug interaction New clinical indication (Phase 5) Phase 1V (Postmarketing surveillance)


Slide 39:Is it safe? Does it work? Does it work in double blind trials?


The Impact of Clinical Trials-Successful :The Impact of Clinical Trials-Successful Some clinical trials have been critical to patient health & provision of health care For instance: Protocol 076: ? HIV perinatal transmission 1st trial of AZT Various cancer treatments Development of other HIV related medications like PIs NY/VI AETC


The Impact of Clinical Trials-Unsuccessful :The Impact of Clinical Trials-Unsuccessful Medications did not work as in pre clinical study Loss of Follow-Up Harmful substance Unethical & poorly conducted study (Ex: Gene Replacement Study) NY/VI AETC


APPROVAL :APPROVAL Once all clinical data has been submitted, reviewed and approval is granted to license in market Post marketing surveillance Approval takes 6 months to 2 years


Slide 43:Thank you