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From the test tube to the market
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This presentation is a lecture delivered to Post Graduate students of Microbiology. it describes the various steps in drug development. it takes the student through stages in R&D of a drug,......

This presentation is a lecture delivered to Post Graduate students of Microbiology. it describes the various steps in drug development. it takes the student through stages in R&D of a drug, preclinical testing, clinical trials and so on.

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  • For example if a person drinks too much alcohol on a regular basis then their health may suffer as a result. The alcohol does not have a long biological half life but it is supplied on a regular basis to the body of the person For example if a person were to ingest radium much of it would be absorbed into the bones where it would exert a harmful effect on a person's health. The radium might cause a disturbance in the blood cell-forming part of the bone (bone marrow)
  • Reproductive Toxicity Reproductive toxicity testing is intended to determine the effects of substances on gonadal function, conception, birth, and the growth and development of the offspring. The oral route is preferred. Developmental toxicity testing detects the potential for substances to produce embryotoxicity and birth defects Dermal Toxicity Dermal toxicity tests determine the potential for an agent to cause irritation and inflammation of the skin. This may be the result of direct damage to the skin cells by a substance. It may also be an indirect response due to sensitization from prior exposure. Ocular Toxicity Ocular toxicity is determined by applying a test substance for one second to the eyes of 6 test animals, usually rabbits. The eyes are then carefully examined for 72-hours, using a magnifying instrument to detect minor effects. The ocular reaction may occur on the cornea, conjunctiva, or iris. It may be simple irritation that is reversible and quickly disappears or the irritation may be severe and produce corrosion, an irreversible condition. The eye irritation test is commonly known as the "Draize Test." This test has been targeted by animal welfare groups as an inhumane procedure due to pain that may be induced in the eye. The test allows the use of an eye anesthetic in the event pain is evident. The Draize Test is a reliable predictor of human eye response. However, research to develop alternative testing procedures that do not use live animals is underway. While some cell and tissue assays are promising, they have not as yet proved as reliable as the animal test. Genetic Toxicity Genetic toxicity is determined using a wide range of test species including whole animals and plants (e.g., rodents, insects, and corn), microorganisms, and mammalian cells. A large variety of tests have been developed to measure gene mutations, chromosome changes, and DNA activity. The most common gene mutation tests involve:
  • A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials . Types of observational studies in epidemiology such as the cohort study and the case-control study provide less compelling evidence than the randomized controlled trial. In observational studies , the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. A randomized controlled trial is the study design that can provide the most compelling evidence that the study treatment causes the expected effect on human health. Currently, some Phase II and most Phase III drug trials are designed as randomized, double blind , and placebo -controlled. Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo. Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment is being given to any given subject. This 'blinding' is to prevent biases, since if a physician knew which patient was getting the study treatment and which patient was getting the placebo, he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it. In addition, a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. A form of double-blind study called a "double-dummy" design allows additional insurance against bias or placebo effect. In this kind of study, all patients are given both placebo and active doses in alternating periods of time during the study. Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment. Of note, during the last ten years or so it has become a common practice to conduct "active comparator" studies (also known as "active control" trials). In other words, when a treatment exists that is clearly better than doing nothing for the subject ( i.e. giving them the placebo), the alternate treatment would be a standard-of-care therapy. The study would compare the 'test' treatment to standard-of-care therapy. Although the term "clinical trials" is most commonly associated with the large, randomized studies typical of Phase III, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. In the field of rare diseases sometimes the number of patients might be the limiting factor for a clinical trial. Other clinical trials require large numbers of participants (who may be followed over long periods of time), and the trial sponsor is a private company, a government health agency, or an academic research body such as a university.
  • Phase I trials are the first stage of testing in human subjects. Normally, a small (20-100) group of healthy volunteers will be selected. This phase includes trials designed to assess the safety ( pharmacovigilance ), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. The subject who receives the drug is usually observed until several half-lives of the drug have passed. Phase I trials also normally include dose-ranging , also called dose escalation, studies so that the appropriate dose for therapeutic use can be found. The tested range of doses will usually be a fraction of the dose that causes harm in animal testing . Phase I trials most often include healthy volunteers. However, there are some circumstances when real patients are used, such as patients who have terminal cancer or HIV and lack other treatment options. Volunteers are paid an inconvenience fee for their time spent in the volunteer centre. Pay ranges from a small amount of money for a short period of residence, to a larger amount of up to approx $6000 depending on length of participation. There are different kinds of Phase I trials: SAD Single Ascending Dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the Maximum tolerated dose (MTD). MAD Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level. Food effect A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study , with volunteers being given two identical doses of the drug on different occasions; one while fasted, and one after being fed.
  • Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorised as "Phase IIIB studies."[19][20] While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as FDA (USA), or the EMEA (European Union), for example. Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities[3] in different countries. They will review the submission, and, it is hoped, give the sponsor approval to market the drug. Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines, but in case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.[21]


  • 1. From the test tube… intothe marketDr. Anita JoshiGarware College, Pune – lecture forPost graduate students02/04/10
  • 2. 05/29/13 Dr. Anita Joshi 2New drug/ biologicCandidate drug5 batchesPre-clinical testing IND Clinical trials NDADCGICandidate biologicIBSC RCGM Pre-clinical testing Clinical trialsDCGIMANUFACTURING ANDMARKETINGLICENSEDCGIIn vitrocharacterisation
  • 3. 05/29/13 Dr. Anita Joshi 3Pre-clinical testing Done after In-vitro testing – characterization ofthe molecule and safety perspectives – “risk” Objective: preliminary efficacy, toxicity andmechanism of action and pharmacokinetics of thedrug under investigation In-vivo testing- rodent / non-rodent because adrug may affect different species in differentways Done in GLP environments only, Schedule Y A drug that successfully completes this phaseonly has a 20% chance to make it to market
  • 4. 05/29/13 Dr. Anita Joshi 4Toxicological testing The study of the adverse effects ofchemical, physical or biological agents onliving organisms and the ecosystem Advantages- chemical exposure can be precisely controlled environmental conditions can be well-controlled virtually any type of toxic effect can beevaluated the mechanism by which toxicity occurs can bestudied
  • 5. 05/29/13 Dr. Anita Joshi 5In vivo testing How much of the drug is absorbed into theblood? How is the drug broken down in the body? What is the toxicity of the drug and itsbreakdown products? How quickly does the body excrete the drugand its breakdown products? Safe route for administration, safe dosage,safe schedule
  • 6. 05/29/13 Dr. Anita Joshi 6In vivo testing critical parameters Choice of animal – mice, rats, guinea pigs,rabbits etc (Sprague Dawley rats, Wistar rats,Swiss albino mice, New Zealand white rabbits,monkeys, dogs) Age of the animals Gender Dosage and route Duration
  • 7. 05/29/13 Dr. Anita Joshi 7Efficacy In case of a vaccine, the efficacy would bedefined by the potency of a vaccine Immunogenecity studies – antibodiesgenerated in response to vaccine Challenge tests Safety tests
  • 8. 05/29/13 Dr. Anita Joshi 8Different types of toxicity tests Most commonly used tests are Acute Toxicity Subacute toxicity Subchronic Toxicity Chronic Toxicity
  • 9. 05/29/13 Dr. Anita Joshi 9Acute Toxicity Adverse effects of a substance after asingle dose or brief exposure Observation period- 14 days 3 doses recommended- dose responsecurve Small grp of animals- 5 of each sex / dose Exposures: fractionated dose or singledose over 24hrs for oral and 4 hrs forinhalation studies LD50 calculated
  • 10. 05/29/13 Dr. Anita Joshi 10Sub acute and sub chronic(repeated dose) Repeated exposure for several weeks or several months Two distinct situations need to be considered: Prolonged exposure to a substance Prolonged internal exposure because a substanceremains in the body for a long time 3 dose levels + control group; 2 different animal sps 10 of each sex per dose level Observation 30 days for sub acute Observation 90 days for sub chronic Observed each day for signs of toxicity: weight change,appetite, signs of disease or abnormal behavior. Evaluation of effects and histopathology is conducted on allanimals. This is outlined in ISO 10993-11.
  • 11. 05/29/13 Dr. Anita Joshi 11Chronic toxicity Determines toxicity from exposure for asubstantial portion of a subjects life Extend over a longer period of time andinvolve larger groups of animals. Two sps of animals 20 animals of each sex / dose level 3 dose levels 12-24 months
  • 12. 05/29/13 Dr. Anita Joshi 12Other toxicity tests Reproductive toxicity – reproductive organs,conception, birth Developmental toxicity - embryotoxicity Dermal toxicity Occular toxicity – Draize test Genotoxicity – Ames test, cell line based tests Neurotoxicity Carcinogenecity In vitro testing
  • 13. 05/29/13 Dr. Anita Joshi 13Good Laboratory Practices GLP - (guidelines are like GMP) forlaboratory and pre-clinical (i.e., animal)studies Defined in 21 CFR 58. All about control and documentation/implementation for the lab
  • 14. 05/29/13 Dr. Anita Joshi 14GLP Requirement for a Study Director Requirement for a Quality Assurance unit Responsible for maintaining a Master Schedule Sheet ofall studies conducted Responsible for inspecting the study during its conduct Determine no deviations Review final report for accuracy Maintain records Facilities designed to Permit segregation necessary to ensure study integrityincluding: Areas for preparation of test and control articles Routine and specialized analytical procedures Separation of animal species and their propermaintenance Animals in different studies Quarantine of new animals
  • 15. 05/29/13 Dr. Anita Joshi 15GLP Equipment must be inspected, cleaned, and maintained,including calibration Reagents appropriately labeled Test and control articles characterized for identity, strength(potency), purity, and composition Manufacturing of test article documented Stability determined before or during study according towritten SOPs SOPs for routine procedures (listed examples in 21 CFR58.81) Study protocol detailing specific study Results recorded and raw data documented Records (including raw data) maintained for specified timeperiods Final report written documenting procedures, results,statistical analyses
  • 16. 05/29/13 Dr. Anita Joshi 16Pharmacokinetics Pharmacokinetics describes how thebody affects a specific drug afteradministration. Pharmacokinetic properties of drugs maybe affected by elements such as the site ofadministration and the concentration inwhich the drug is administered. These may affect the absorption rate.
  • 17. 05/29/13 Dr. Anita Joshi 17Pharmacokinetics ADME measures the extent and rate ofAbsorption, Distribution, Metabolism andExcretion. recent understanding about the drug-bodyinteractions brought about the inclusion of newterm Liberation. Now LADME. Liberation- release of drug from the formulation. Absorption -a substance entering the body. Distribution - dispersion or dissemination ofsubstances throughout the fluids and tissues ofthe body. Metabolism- irreversible transformation of parentcompounds into daughter metabolites. Excretion- elimination of the substances from thebody. In rare cases, some drugs irreversiblyaccumulate in a tissue in the body.
  • 18. 05/29/13 Dr. Anita Joshi 18Pharmacodynamics Study of the physiological effects of drugs on thebody or on microorganisms or parasites within oron the body Mechanisms of drug action and the relationshipbetween drug concentration and effect There are 5 main drug actions: depressing stimulating cytotoxicity irritation replacing substances
  • 19. 05/29/13 Dr. Anita Joshi 19Desired activity The desired activity of a drug is mainly due toone of the following: Cellular membrane disruption Chemical reaction Interaction with enzyme proteins Interaction with structural proteins Interaction with carrier proteins Interaction with ion channels Ligand binding to receptors: Hormone receptors Neuromodulator receptors Neurotransmitter receptors
  • 20. 05/29/13 Dr. Anita Joshi 20Undesirable effects of drugs Increased probability of cell mutation(carcinogenic activity) A multitude of simultaneous assortedactions which may be deleterious Interaction (additive, multiplicative, ormetabolic) Induced physiological damage, orabnormal chronic conditions
  • 21. 05/29/13 Dr. Anita Joshi 21Clinical trials Once the pre clinical trials are complete the datais submitted to DCGI for approvals for a clinicaltrial. Research study to answer specific questionsabout vaccines or new therapies or new ways ofusing known treatments. Safety and efficacy of drugs in humans GCP – ensure safety of subjects, protection ofhuman rights, reliability of results andmaintenance of scientific quality
  • 22. 05/29/13 Dr. Anita Joshi 22The roadmap of a trial In accordance with the GCPs ICH guidelines, Schedule Y,Helsinki Declaration Sponsor approaches CRO Feasibility check Investigators appointed Protocol is designed Ethics Committee approvals Recruiting the volunteers – eligibility criteria set Informed Consent forms Starting the trials Audits by sponsor Completion of trials Submission of data
  • 23. 05/29/13 Dr. Anita Joshi 23Experimental design of a trial Randomized Blind- The subjects involved in the studydo not know which study treatment theyreceive. Double-blind- the researchers also do notknow which treatment is being given toany given subject to prevent biases Placebo-controlled: The use of a placebo(fake treatment) allows the researchers toisolate the effect of the study treatment.
  • 24. 05/29/13 Dr. Anita Joshi 24Phase 1 trials First stage of testing in humans Done in a small group of healthyvolunteers (20 -100) Objective: to assess the safety,tolerability, pharmacodynamics,pharmacokinetics of a drug Single ascending dose studies Multiple ascending dose studies
  • 25. 05/29/13 Dr. Anita Joshi 25Phase II trials Typically done on larger groups – 100-300 Patients are enrolled for this phase Phase II studies are sometimes divided intoPhase IIA and Phase IIB. Phase IIA is specifically designed to assess dosingrequirements (how much drug should be given). Phase IIB is specifically designed to study efficacy (howwell the drug works at the prescribed dose(s)). When the development process for a new drugfails, this usually occurs during Phase II trialswhen the drug is discovered not to work asplanned, or to have toxic effects.
  • 26. 05/29/13 Dr. Anita Joshi 26Phase III trials Much larger group 300-3000 Multi centric trials Gold standard gather additional information abouteffectiveness and safety evaluate overall benefit-risk relationship ofthe drug provide the basis for the precautionaryinformation that accompanies the drug
  • 27. 05/29/13 Dr. Anita Joshi 27The CTDDrug has proved satisfactory after Phase III trials•Trial results are usually combined into a large document containing•a comprehensive description of the methods•results of human and animal studies•manufacturing procedures•formulation details•shelf life.Regulatory Authorities for review- DCGIMost drugs undergoing Phase III clinical trials can be marketedunder FDA norms with proper recommendations and guidelinesIf any adverse effects are reportedthe drugs need to be recalled immediately
  • 28. 05/29/13 Dr. Anita Joshi 28Phase IV- Post Marketing Surveillance Trial Safety surveillance (pharmacovigilance) Ongoing technical support of a drug after it receives permission tobe sold. Required by regulatory authorities May be undertaken for finding a new market for the drug Study interactions with other drugs, or on certain new populationgroups such as pregnant women Rare or long-term adverse effects over a much larger patientpopulation and longer time period than was possible during thePhase I-III clinical trials. Harmful effects if discovered - drug being no longer sold, orrestricted to certain uses Recent examples involve cerivastatin (brand names Baycol andLipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
  • 29. 05/29/13 Dr. Anita Joshi 29Performance of vaccine Hemagglutinin inhibition assay (alaboratory test used to measure theamount of antibody present in a sample bydetermining if the antibody inhibitsinfluenza virus from attaching to red bloodcells) Microneutralization assay (a techniqueused to determine if the level of antibodyin the sample inhibits the virus frominfecting cells grown in the laboratory)
  • 30. 05/29/13 Dr. Anita Joshi 30Pipeline of drug developmentAstraZeneca (AZN) , Bristol-Myers Squibb Company (BMY) , Eli Lilly andCompany (LLY) , GlaxoSmithKline (GSK) , Merck (MRK) , Pfizer (PFE) ,Sanofi-Aventis
  • 31. 05/29/13 Dr. Anita Joshi 31General trendsTIME REJECTIONPRECLINICAL 2-5 YRS 2.5PHASE I 1-2 YRS 1.5 90%PHASE II 2-3 YRS 2 50%PHASE III 2-5 YRS 4 20%REGULATORY 1-2 YRS 2 10%ESTIMATED 12TIMEEST. COSTS 5-8 MILLION USD