NEW DRUGDEVELOPMENT PRESENTED BY- DR. RAJESH. A. KAMTANE, 2nd YEAR PG DEPARTMENT OF PHARMACOLOGY,
From the synthesis /identification of the molecule to itsmarketing, a new drug takes at least 10 years and costs500-1000 million US$. New drug development is done as per the guidelineslaid down by Schedule Y of Drugs and Cosmetics Act(10th amendment)2001, which were amended later in2005.
STAGES IN NEW DRUG DEVELOPMENT1.Synthesis / isolation of compound : (1-2 years)2. Preclinical studies : (2-4 years)3. Scrutiny and grant of permission for clinical trials : (3-6 months)4. Pharmaceutical formulation, standardization of chemical /biological / immuno-assay of the compound : (0.5-1 year)5. Clinical studies : phase 1, 2, 3 and long term animal toxicitytesting : (3-10 years)6. Review and grant of marketing permission : (0.5-2 years)7. Post marketing surveillance : (phase 4 studies)
Does it work in doubleIs it safe? Does it work? blind trials?
Drug development process can be divided into 3 mainphases-1. Drug discovery phase- during which candidate molecules are chosen on the basis of their pharmacological properties.2. Preclinical phase- during which wide range of animal studies are performed.3. Clinical trial phase- during which the lead compound is evaluated for safety and efficacy in human volunteers and patients.
Drug Discovery PhaseMost new drugs are discovered and identified throughone of the following approaches-1.Random Screening- It is a sort of blind hitting procedure where newchemical entities (natural or synthetic) are subjected toseries of pharmacological screening procedures toexplore different types of biological activity. Such tests include studies on animal behaviour, animalmodels of the human diseases and on isolated tissues.
Although these approaches are time consuming,expensive and inefficient in providing fruitful results,sometimes these are valuable, since many drugs likemorphine, atropine, digitalis, quinidine werediscovered in this way. Cyclosporine, an immunosuppressant drug was alsodiscovered during routine screening of fungal products.
2. Serendipity (happy observation, by chance)•Sometimes a new use is discovered for an old drug orits side effect finds a new therapeutic application.Examples-1. Penicillin was discovered in this way, which started the beginning of antibiotic therapy.2. Lignocaine (local anaesthetic) and phenytoin (antiepileptic) were later used as antiarrhythmics .3. Methotrexate, an anticancer drug, is also used for psoriasis.4. Cyclophosphamide and azathioprine (both cytotoxic drugs) are also used to prevent tissue rejection in kidney transplant.
3. Rational drug designing-•Two basic strategies are used in rational drugdesigning---compound-centered approach and target-centered approach.•Promising agents, through compound-centeredapproach, could be obtained from natural products.E.g. penicillin from penicillium notatum, paclitaxel(anticancer drug) derived from Pacific yew tree,cyclosporine (immunosuppressive drug) obtained fromfungus.
•The main disadvantage in obtaining lead products fromnatural source is that these are often complex moleculeswhich are difficult to be synthesized. It is ultimatelydifficult to synthesize their modified analogues also.Hence lead optimization becomes difficult.•Compound centered drug designing can be followedfor synthetic products also.•Drugs can be developed from pharmacological dataobtained from structure activity relationship of anestablished drug.E.g.--- many beta blocking drugs available today are based on propranolol structure, --- many ‘triptans’ are based on structure of sumatriptan.
Target-centered approach---•Biochemical or molecular targets are used to search forpromising compounds.•Example—it was known that inhibition of angiotensin-converting enzyme (ACE) blocks conversion ofangiotensin 1 to angiotensin 2 and hence lowers theblood pressure. Hence it made sense to look for ACEinhibitors (ramipril, lisinopril, etc) or for angiotensin 2receptor antagonists (losartan, candesartan, telmisartan)as useful antihypertensives.•With this approach, there is high possibility ofgetting useful promising agents for leadoptimisation.
4. Designing of a prodrug or an activemetabolite as a drug-•Prodrug- e.g. levodopa used in treatment ofparkinsonism.•Active metabolite-e.g---Paracetamol, an active metabolite of phenacetin, was introduced as a safe analgesic this way. ---Similarly, active metabolite of procainamide, N- acetyl procainamide, is an effective antiarrhythmic drug which does not cause lupus-like syndrome that occurs with procainamide.
•After the synthesis or isolation of compound, their purityis ascertained by physico-chemical and analyticalstudies.•Next comes the stage of LEAD OPTIMISATION wherethe aim is to identify one or two drug candidates suitablefor further investigation.
•Three to five years may be spent to come to this stage.•The promising LEAD COMPOUND is then subjected topreclinical evaluation.•The clinical trials follow only when the results ofpreclinical evaluations are encouraging.
PRECLINICAL EVALUATION PHASE (ANIMAL STUDIES)•After synthesizing / identifying a prospective compound,it is tested on animals to expose the wholepharmacological profile.•Experiments are generally performed on a rodent (rat,rabbit, mouse, guinea pig, hamster) and then on alarger animal (cat, donkey, monkey).•As the evaluation progresses, unfavorable compoundsget rejected at each step, so that only a few out ofthousands reach the stage when administration tohumans is considered.
Objectives of animal studies are to evaluate---1.Activity2.Toxicity3.Selectivity and Specificity4.Mechanism of action5.Drug metabolism
•The following types of studies are performed---1.Pharmacodynamic Studies---•Here actions relevant to the proposed therapeutic use(and other effects) are studied on animals.•For e.g., antihypertensive activity of the lead compoundon dogs, cats or rats to find out blood pressure changesand other cardiac effects like ECG changes, etc.
2. Tests on isolated organs, bacterial cultures,etc--- performed to detect specific activity, such as antihistaminic, antisecretory, antibacterial, etc.3. Tests on animal models of human diseases---such as spontaneously (genetically) hypertensive rats, alloxan induced diabetes in rat or dog, etc.4. General observational test---The drug is injected in tripling doses to small groups of mice which are observed for overt effects. Preliminary clues are drawn from the profile of effects observed.
5. Confirmatory tests and analogous activities--- Compounds found active are taken up for detailed study. Other related activities. e.g antipyretic and anti- inflammatory activity in an analgesic are tested.6. Mechanism of action---attempts are made to find outthe mechanism of action,e.g. whether an antihypertensive is an alpha blocker orbeta blocker, etc.
7. Systemic pharmacology---irrespective of the primaryaction of drug, its effects on major organ systems suchas CNS, CVS, RS, GIT are worked out.8. Quantitative tests---the dose-response relationship,maximal effect and comparative efficacy with existingdrug is ascertained.
9. Toxicological studies---•Aim – to determine safety of the compound in at least 2animal species, mostly mouse/rat and dog by oral andparenteral route.•Types of toxicity studies are-(1) Acute toxicity- Aim is to find out the acutedose that is lethal to 50% ofthe animals (LD 50).Organ toxicity is examined byhistopathology on all animals.
2. Subacute toxicity-Aim is to identify the target organs susceptible to drugtoxicity.The animals are maintained at the maximum tolerateddoses for a period of 1-3 months so as to allowdevelopment of pathological changes.Finally, animals are killed and subjected tohistopathological examination.
3. Chronic toxicity-Such studies are important if the drug is intended forchronic use in human beings.The duration of study may range from one to twoyears.These studies may also run simultaneously withclinical trials, to cut short the time factor.
10. Pharmacokinetic studies-Done after toxicological studies.Information is obtained for its pharmacokineticparameters (ADME, Vd, BA, t1/2)11. Special long term toxicity-these tests are generallyperformed only on drugs which cross phase 1 clinicaltrials.12. Reproduction and teratogenecity-effects onspermatogenesis, ovulation, fertility and developingfoetus are studied.
13. Mutagenecity-ability of the drug to induce geneticdamage is assessed in bacteria (Ames test), mammaliancell cultures and in intact rodents.14. Carcinogenecity-drug is given for long term, eventhe whole life of the animal and they are watched fordevelopment of tumours.Standardizied procedures under ‘Good LaboratoryPractices’ (GLP) are laid down for conduct of animalexperiments, especially toxicity studies.
Assessment of Safety Index-Therapeutic indexMaximum Tolerated Dose (MTD),No Observable Adverse Effects Level (NOAEL),No Observable Effects Level (NOEL) andHuman Equivalent Dose (HED) are determined inspecies similar to humans (like monkeys), finally tocalculate First in Human Dose (FIH) which will be latterused in phase 1 clinical trials.FIH is 1/5 or 1/10th of HED.
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)• To ensure the rights and welfare of the participants.• FDA regulations mandates to review the clinical trial protocols for ethical and legal issues.
IRBThe investigator must furnish the IRB with the following documents for review and approval:• Trial Protocol• Written Informed Consent Forms• Written Information for Subjects (Advertisements)• Information about compensation to patients• Investigator Brochure• Available (or additional) Safety Information• Investigator’s CV• All amendments to study protocol 34
IRBThe IRB’s possible responses:• approval or favorable opinion• modifications required for approval• disapproval or negative opinion• withdrawal or suspension of an earlier approval No subjects should be enrolled until the IRB has issued an approval (21 CFR 56.109) 35
Informed Consent• Eight basic elements of informed consent (21 CFR 50.25) 1. Trial involves research, purpose of the research 2. A description of any reasonably foreseeable risks or discomforts 3. A description of any benefits to the subject which may reasonable be expected from the research 4. A disclosure of appropriate alternative procedures or treatment that may be available to the subject
Informed Consent 5. A statement describing the extent to which confidentiality of records identifying the subject will be maintained. 6. An explanation as to whether any compensation and whether any medical treatments are available if injury occurs. 7. An explanation of whom to contact for answers to questions about the research and research subjects’ rights . 8. A statement that participation is voluntary 37
Informed Consent• Participation in clinical trials is always voluntary. No, thank you, I’d Yes, I would rather not participate. like to participate.Clinical Trials & Research 38
Informed Consent• Purpose • Risks• Medicine to be • Potential benefits studied • Alternatives to• Procedures and participation schedule • Confidentiality Clinical Trials & Research 39
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.Clinical Trials & Research 40
Objectives of a clinical trial are to establish---1.Safety2.Efficacy3.Therapeutic conformation in a large population.4.Drug metabolism in humans.5.Unpredicted adverse reactions and new therapeutic applications during wide use in the community.
CLINICAL TRIALS-•When a compound deserving trial in man is identifiedby animal studies, the regulatory authorities areapproached who on satisfaction issue an‘investigational new drug’ (IND) license.•The drug is formulated into asuitable dosage form and clinicaltrials are conducted in a phasedmanner.
•Standards for design, ethics, conduct, monitoring,auditing, recording and analyzing data and reporting ofclinical trials have been laid down in the form of ‘GoodClinical Practice’ (GCP) guidelines by an InternationalConference on Harmonization (ICH) and Declaration ofHelsinki. NAZI HUMAN EXPERIMENTS
Declaration of Helsinki-19641.The clinical trial must minimize the risk for participants.2.Provision for care of the patients.3.Terminate the trial when the risk becomes incompatible with the goals of the trial.4.Adverse events to be reported immediately to an ethical committee
Phases of Clinical Trials Phase I: Safety (15–30 people) A A A A A A A A Phase II: Safety and Effectiveness (Fewer than 100 people) A A A A Phase III: Effectiveness compared to standard of care; Safety (More than 100 to a few thousand) A A A A A A A A A A A A A A A A A A A A A A A AClinical Trials & Research 46
Phase 0 Clinical trialsKnown asHuman Micro dosing. To confirm whetherthe drug behaves inhuman subject as wasexpected from pre clinicalstudies.
Phase 0 Clinical trials Single sub therapeutic doses of the study drug is given to a small number of subjects ( 10 to 15 ). Purpose is to gather preliminary data on best PK and PD parameters in humans to take forward for further development. It gives no data on Safety or Efficacy.
The clinical studies are conventionally divided into 4phases-Phase 1: Human pharmacology and Safety.The objectives of this phase are---1. To check for safety and tolerability .2. To determine the pharmacokinetics of the drug in humans.
3.To determine a safe clinical dosage range in humans. The common rule is to begin with 1/5th or 1/10th of the maximum tolerated dose (mg/kg) in animals and calculating it for an average human body weight of 70 kg. The drug is then given in small increments till the therapeutically effective dose is attained by clinical observation.
Phase 1 trial is carried out by qualified clinicalpharmacologists/ trained physicians in a setting whereall emergency/ resuscitative facilities are available.
Subjects (mostly healthy volunteers, sometimespatients) are exposed to the drug one by one (total20-40 subjects) , starting with lowest estimated doseand increasing stepwise to achieve the effective dose.No blinding is done: the study is open label. i.e.both, the investigator and the subjects know what isbeing given.
Phase 2: Therapeutic exploration and dose ranging-•In this phase, the drug is studied for the first time inpatients with target disease, to determine itsefficacy.•The main purpose is to decide an end point.e.g.•pain relief is the end point for testing an analgesic.•reduction in tumour size for anticancer drugs.
•The study is generally carried out at 2-4 centers.•Phase 2 can be single or double blind study.
•Such studies are mainly conducted in two ways-a. Parallel design--- One group receives the new drug under trial while other group receives control (established drug) or placebo. Then results in one group are compared with those in other group.
b. Crossover design--- Here the new drug is alternated with control (established drug or placebo) in the same patient. In this method, patient acts as his own control. This reduces the chances of erroneous results due to individual variation amongst the patients.
Phase 3: Therapeutic Conformation/ Comparison-•Generally these are randomized, double blindcomparative, controlled clinical trials.•Conducted on a larger patient population (500-3000) byseveral physicians at many centers.•Here new drug is compared with previously establisheddrug or placebo, under standardized conditions.
•Safety, tolerability, and possible drug interactions areassessed on a wider scale.•Indications are finalized and guidelines fortherapeutic use are formulated.•A ‘new drug application’ (NDA) is submitted to thelicensing authority, who if convinced gives marketingpermission, with ‘New Drug Status’
Phase 4Drug is placed in the market and patients aremonitored for side effects.
Phase 4: Postmarketing surveillance-•In phase 4, data on safety, efficacy and tolerability iscollected from practicing physicians.•Uncommon/ idiosyncratic adverse effects andunsuspected drug interactions are detected at this stage.•Additional indications may emerge from surveillancedata.•The phase 4 has no fixed duration as it is thesurveillance phase.
•During the ‘New Drug Status’, the manufacturer isexpected to report any new information about the drugconcerning its safety.•Such Periodic Safety Update Report (PSUR) is to besubmitted every six months for first 2 years and thenannually for the next 2 years.•The drug may remain in ‘New Drug Status’ for severalyears until the Drug Control authorities are confidentabout its release to unrestricted marketing.
•Further therapeutic trials involving special groups likechildren, elderly, pregnant, lactating women, patientswith renal/ hepatic diseases, etc (which are generallyexcluded during clinical trials) may be undertaken at thisstage.
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