DRUG DEVELOPMENT and discovery and preclinical trails

Drug development , uses and it's applications, pre clinical trails

1. DRUG DEVELOPMENT Dr.K.CHAITANYA Postgraduate Department of Pharmacology

2. NEW DRUG DEVELOPMENT Drug discovery phase Preclinical studies Clinical trials Pharmacodynamic studies Pharmacokinetic studies Systemic toxicity studies Local toxicity studies

3. New Drug Development At least 10 years 500 – 1000 million dollars Complex Tedious Competitive Costly Risky

4. Synthesis/ isolation of the compound 1- 2 years Preclinical studies: screening, 2- 4 years evaluation, pharmacokinetic and short-term toxicity testing in Animals Scrutiny and grant of permission for 3- 6 months clinical trials Pharmaceutical formulation, 0- 5 months standardization of chemical/ biological/immuno-assay of the compound Clinical studies: phase I, phase 11, 3- 10 years phase Ill trials; long-term animal toxicity testing Review and grant of marketing 0.5- 2 years permission Post marketing surveillance Phase IV studies STAGES IN NEW DRUG DEVELOPMENT

5. DRUG DISCOVERY/ INVENTION: Exploration of natural sources: Plants are the oldest source of medicines. Clues about these have been obtained from traditional systems of medicine prevalent in various parts of the world. Eg: Opium (morphine), Ephedra (ephedrine), belladonna (atropine), Quinghaosu (artemisinin) Cinchona (quinine), curare (tubocurarine)

6. A nimal pa rts have been used as cures since early times, it was physiological experiments performed in the19th and early 20 th century that led to introduction of some animal products into medicine E .g: A drenaline, thyroxine, insulin, liver extract, antisera, etc. N atural medicinal substances - Few minerals (iron/calcium salts, etc.) The discovery of penicillin (1941) opened the flood-gates of a vast source-microorganisms-of a new kind of drugs (antibiotics). The use of microbes for production of vaccines is older than their use to produce antibiotics.

7. Random or targeted chemical synthesis: Synthetic chemistry made its debut in the 19th century and is now the largest source of medicines. Barbiturates, chlorpromazine have been produced serendipitously by this approach, it has very low probability of hitting at the right activity in the right compound: rarely employed now. L ead optimization : A more practical approach is to synthesize chemical congeners of natural products/synthetic compounds with known pharmacological activity in the hope of producing more selective / superior drugs.

8. Many families of clinically useful drugs have been fathered by a 'lead compound'. Often only “me too” drugs are produced. but sometimes breakthroughs are achieved . E.g. Thiazide diuretics from acetazolamide, T ricyclic antidepressants from phenothiazines Application of this structure- activity relationship information has proven useful on many occasions, E g. Selective agonists (salbutamol) and beta blockers (propranolol) have been produced by modifying the structure of isoprenaline, H2 blockers by modifying the side chain of histamine, ethinyl-estradiol by introducing a substitution that resists metabolic degradation, misoprostol (more stable) by esterifying PGE1

9. A lead compound capable of interacting with the target is searched by applying diverse approaches The affinity and selectivity of the lead compound for the target is determined. It is then chemically modified to optimize these parameters as well as pharmacokinetic, pharmaceutical, toxicological and other characteristics.

10. Single enantiomers: Many drugs are chiral c ompounds. Because pharmacological activity depends on three dimensional interaction of drug molecules with their target biomolecules, the enantiomers ( R and S forms or d and I isomers) of chiral drugs differ in biological activity metabolic degradation etc. Single enantiomer drug could be superior to its racemate, because the additional enantiomer may not only be a 'silent passenger ' but contribute to side effects, toxicity (dextro-dopa is more toxic than levo-dopa), Load on metabolism or even antagonize the active enantiomer.

11. Regulatory authorities in many countries, led by US-FDA, have mandated separate investigation of the enantiomers in case the new drug is a chiral molecule. Approval is withheld unless the pure enantiomers are shown to be no better than the racemate.

12. Rational approach: D epends on sound physiological, biochemical, pathological knowledge and identification of specific target for drug action. N ew classes of drugs generally follow the identification of a novel target for drug action Eg: H+K+ ATPase for gastric acid suppression or glycoprotein lla/lllb receptor for platelet function inhibition. The drug is aimed at mitigating the derangement caused by the disease, E .g . L evodopa was tried in parkinsonism based on the finding that the condition resulted from deficiency of dopamine in the striatum.

13. The purine, pyrimidine, folate antimetabolites were introduced in cancer chemotherapy after elucidation of key role of these metabolites in cell proliferation. Because virus directed reverse transcriptase is unique to retroviruses, its inhibitors have been developed as anti-HIV drugs.

14. Molecular modelling/ Docking: Suitable computer programmes are being used to optimise the three-dim e nsional structure of the candidate drug to fit the identified target site(s) and/or have optimum pharmacokinetics. The designing of selective COX-2 inhibitors was prompted by the comparative configuration of COX- I and COX-2 isoenzyme molecules.

15. Combinatorial chemistry: Chemical groups arc combined in a random manner to yield innumerable compounds and subjected to high throughput screen on cells, genetically engineered microbes. receptors, enzymes, etc. in robotically controlled automated assay systems. Computerized analysi s is used to identify the so called “hits” These compounds are then subjected to conventional tests. This new approach has vast potentials, but failure rates are high.

16. Biotechnology: Several drugs are now being produced by recombinant DNA technology. e.g. human growth hormone , human insul i n, interferon, etc. New molecule, especially antibiotics, regulatory peptides, growth factors, cytokines, etc. produced by biotechnological methods can be eva l uated as putative drugs. Some monoclonal and chimeral antibodies have been introduced as drugs.

17. Other experimental approaches A ntisense oligonucleotides Gene therapy.

18. PRE CLINICAL PHASE Aim of this phase is to satisfy all the requirements that are needed before a compound is considered fit to be tested for first time in humans. Done according to the standards laid down in “ GOOD LABORATOTY PRACTICE”(GLP),especially toxicity testing Takes 1.5 to 2 yrs for completion.

19. Experiments are generally performed on a rodent (mouse, rat, guinea pig, hamster, rabbit) and then on a larger animal (cat, dog, monkey) Preclinical evaluation As the evaluation progresses unfavorable compounds get rejected at each step, so that only a few out of thousands reach the stage when administration to man is considered.

20. The following types of tests are performed : 1. Screening tests: S imple Rapidly performed test I ndicate presence or absence of a particular pharmacodynamic activity e.g. A analgesic or hypoglycaemic activity. 2. Tests on isolated organs, bacterial cultures, etc. P reliminary test T o detect specific activity eg : antihistaminic. antisecretory, vasodilator, antibacterial, etc.

21. 3. Tests on animal models of human disease: K indled seizures in rats, Spontaneously (genetically) hypertensive rats, Experimental tuberculosis in mouse, A lloxan induced diabetes in rat or dog, etc. 4 . Confirmatory tests and analogous activities: Compounds found active are taken up for detailed study by more elaborate tests which confirm and characterize the activity. e.g. anti pyretic and anti-inflammatory activity in an analgesic are tested

22. 5. Systemic pharmacology: Irrespective of the primary action of the drug, its effects on major organ systems such as Nervous, Cardiovascular, Respiratory, Renal, GIT are w orked out. Mechanism of action including additional mechanisms. e.g. alpha adrenerg i c blockade. calcium channel blockade, nitro-va s odilatation, etc. in beta adrenergic blocker antihypertensive are elucidated.

23. 6. Quantitative tests: Do se-response relationship maximal effect and comparative potency/efficacy with existing drugs is ascertained. 7. Pharmacokinetics: A bsorption, Volume of distribution. M etabolism, Excretion pattern of tissue distribution plasma half-life of the drug are quantified.

24. 8. Toxicity tests: The aim is to determine safety of the compound in at least two animal species. one rodent and one nonrodent. e.g. mouse/rat and dog by oral and parenteral routes. Acute toxicity: Single escalating closes are given to small groups of animals that are observed for oven effects and mortality for 1- 3 days. The dose which kills 50% animals (LD50 ) is calculated. Organ toxicity is examined by histopathology on all animals.

25. Subacute toxicity: Repeated doses are given for 2-12 w eeks depending on the duration of intended treatment in man. Doses are selected on the basis of ED50 and LD50 Animals are examined for o ver effects, food intake, body weight, haematology. etc. and organ toxicity. Chronic toxicity: The drug is given for 6- 12 months and effects are studied as in subacute toxicity. This is generally undertaken concurrently with early clinical trials.

26. Reproduction and t eratogenicity: Effects on spermatogenesis, ovulation, fertility and developing foetus are studied . Mutagenicity: Ability of the drug to induce genetic damage is assessed in bacteria (Ames test), mammalian cell cultures and in intact rodents. Carcinogenicity: Drug is given for long-term , even the whole life of the animal and they are watched for development of tumours.

27. CLINICAL TRIALS A prospective, ethically designed investigation in human subjects to objectively discover / verify / compare the results of two or more therapeutic measures or drugs.

28. TYPES OF CLINICAL TRIALS The US national institutes of health (NIH) organizes clinial trials into five different types: Treatment trials- These trials are conducted to test drugs, treatments, new approaches to surgery and novel methods. Prevention trials- Purpose of these trials is to study medicines, vitamins, minerals or exercises that may lower the risk of developing certain diseases. Diagnostic trials- Conducted to find better tests or procedures for diagnosing a particular disease or condition.

29. Screening trials- are conducting for screening a disease through methods like MRI, Mammography or blood tests. Quality of life trials- these trials study the benefits of treatments or lifestyle changes that may improve the quality of life.

30. A clinical trial can begin only when all preclinical studies have been completed and an approval has been received from the drug regulation authority(DRA). In US the DRA is food and drug administration (FDA). In India the DRA is central drugs standard control and organization (CDSCO). Prior to the conduct of a clinical trial an investigational new drug (IND) application must be filled with DRA.

31. Investigational New Drug Application Submitted to DCGI to initiate clinical trial Submitted after a successful preclinical drug development

32. Investigational New Drug Application Animal Pharmacology and Toxicology Studies Manufacturing Information Clinical Protocols and Investigator Information “Investigational New Drug ”license

33. Standards for the design, ethics, conduct, monitoring, auditing, recording and analyzing data and reporting of clinical trials have been laid down in the form of 'Good Clinical Practice ' (GCP) guidelines by an International Conference on Harmonization (ICH). N ational agencies in most countries, including ICMR in India, have also framed ethical guidelines for clinical trials. Adherence lo these provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected as enunciated in the Helsinki Declaration of the World Medical Association. The requirements and regulations for the conduct of clinical trials on a new drug in India have been laid down in the schedule Y of the Drugs and Cosmetics Rules.

34. Phases of Clinical studies 4

35. Phases of Clinical studies PHASE II Microdosing PHASE 0 PHASE I PHASE III PHASE IV

36. IND

37. Phase 0 : Micro dosing study Phase 0 is recent designation for Exploratory and first in Human dose Trials (in accordance with US FDA Guidance) Known as Human Micro dosing Designed to speed up the development of promising drugs To confirm whether the drug behaves in human subject as was expected from pre clinical Studies

38. Administration of single sub therapeutic doses of the study drug to a small number of subjects ( 10 to 15 ) Purpose is to gather preliminary data on the Pharmacokinetics and Pharmacodynamics It gives no data on Safety or Efficacy It is done to rank drug candidates in order to decide which has the best Pk parameters in humans to take forward for further development

39. Phase I : Human pharmacology and safety Involves about 20 to 80 normal healthy volunteers aged 18 to 45 years. May also be conducted in severely ill patients ( eg : cancer patients). Single or multiple doses- single ascending dose or multiple ascending dose studies Dose range and route of administration established. Pharmacokinetic data.

40. Maximum tolerated dose. Start with low dose The common rule is to be begin with 1/5 th or 1/10 th of maximum tolerated dose in animals and averaging it for human body weight. The drug is given in small increments till the therapeutically effective dose is attained. Patient monitored for adverse drug reactions These trials are usually performed by clinical pharmacologists in a research center. These trails are non blind or open label.

41. Phase II : Therapeutic exploration and dose ranging The drug is tested for the first time in patients with target disease Involve supervised administration of the drug to about 100 to 400 patients for Rx or prophylaxis against the disorder for which the drug is intended Usually randomized study comparing new drug with proto-type drug for the intended disorder. Provide first opportunity to observe the effect of long-term administration of the drug to humans. Ideally participants should have no health problems other than the intended disorder.

42. Purpose To determine an optimal dose – response range for the new drug To verify its efficacy for the intended disorders Participants also monitored for adverse effects Population is large; hence greater chances of detecting additional adverse effects Phase crucial Data used to determine whether to proceed with extensive studies in large populations

43. Phase II clinical trials are carried out by physicians trained as clinical pharmacologists. Single blind or double blind These trials are usually done at special centers. Phase II trials have highest rate of drug failures

44. Phase III : Therapeutic confirmation/ comparison Phase III trial is most rigorous and extensive type of scientific clinical investigation of a new treatment. To compare efficacy of the new treatment with the standard regimen Randomized Control, double blind 250 to 1000 patients with disease It may take 5 years

45. To determine additional safety data To determine additional indications To minimize errors in information gathered from Phase I & phase II trials To determine therapeutic benefits At the end of phase III trial, the sponsor can file for ‘New drug application’ to the licensing authority If convinced, they give marketing permission

46. Phase IV : Postmarketing surveillance/data gathering studies Post licensing phase – field trials, no fixed duration, may take several years Safety of the drug is monitored in a large number of patients Periodic safety update report (PSURS) every 6months for first 2 yrs then annually for next 2 yrs Rare side effects, unknown drug interactions, or previously unknown therapeutic use may be detected

47. Therapeutic trials involving special groups – like children, elderly, pregnant/ lactating women, patients with renal or hepatic impairment may be undertaken Modified release dosage forms, additional routes of drug administration, fixed dose combinations can be explored May remain in ‘New drug status’ for many years before its release for unrestricted marketing

48. Pre DRA phases Target identification Target validation Lead discovery Lead optimization Preclinical studies Clinical trial: phase 0 Phase 0 results: help identify most promising candidate IND application for promising candidate Clinical trials: phases I-III New drug application (NDA) Phase IV post marketing surveillance DRA phases Exploratory IND application DRA submission DRA approval DRA submission DRA approval DRA submission DRA approval STEPS OF DRUG DISCOVERY AND DEVELOPMENT

49. CLINICAL TRIALS -PHASES PHASE PURPOSE SUBJECTS SAMPLE TIME DURATION I SAFETY, ADME, BIOACTIVTY, DRUG-DRUG INTERACTION HEALTHY VOLUNTEERSOR ILL PATIENTS 20-80 6-12 MONTHS II SHORT TERM SIDE EFFECTS & EFFICANCY SUBJECTS WITH INDICATIONS ` SEVERAL HUNDREDS 1-2 YEARS III SAFETY & EFFICENCY BASIS FOR LABELING NEW FORMULATIONS SUBJECTS WITH INDICATIONS HUNDREDS-THOUSANDS 2-3 YEARS IV NEW INDICATIONS, SURVEILLANCE SUBJECTS WITH INDICATIONS HUNDREDS-THOUSANDS 1-6 YEARS

50. GOOD CLINICAL PRACTICE (GCP) “An international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve participation of human subjects” Quality Data + Ethics = GCP

51. Purpose: To avoid research misconduct and fraud as this a growing public and professional concern nowadays. To provide public assurance that the rights, safety, and well-being of trial subjects are protected and are consistent with the principles that have their origin in the Declaration of Helsinki . To assure that the clinical trial data are credible. To provide a unified standard for different countries to facilitate the mutual acceptance of clinical data by the regulatory authorities.

52. Sources and development of the GCP guidelines

53. Principles of GCP- ICH : Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCPA and the applicable regulatory requirements. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/ independent ethics committee (IEC) approval/favorable opinion.

54. THE PLAYERS: Under the GCP guidelines Institutional Review Board/ Ethics committee, the investigators and the sponsors have a series of clearly defined roles.

55. INSTITUTIONAL REVIEW BOARD (IRB)/ ETHICS COMMITTEE : 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 Responsibilities Review research to ensure that potential benefits outweigh risks 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.

56. 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

57. Investigator: Qualified by education, training, experience to assume responsibility for the proper conduct of the trial, and should meet all the qualifications specified by the applicable regulatory requirements. Permit monitoring and auditing by sponsor, and inspection by the appropriate regulatory authorities. Conduct the trial in compliance with the protocol agreed to by the sponsor and, approved by the regulatory authorities. Adverse drug reactions must be managed appropriately followed by reporting to the regulatory authority, IRB/IEC, and sponsor. Comply with the sponsors for timely completion of the project and recording of all clinical and nonclinical data.

58. SPONSOR: Quality management Quality assurance and quality control Trial design Trial management, data handling, recordkeeping Trial monitoring Investigator selection Manufacturing, packaging, labelling, coding, supplying Adverse drug reaction reporting Trial audit

59. MONITOR: Verifying resources, staff and facilities, including laboratories and equipment, are adequate to safety and properly conduct the trial. Verifying the investigational product. Verifying that written informed consent was obtained before each subjects participation in the trial. Verifying enrollment and recruitment of subjects. Verifying that source data/documents and other trial records are accurate, complete, up to date and maintained.