1. Drug Development Marilyn Lockyer, RN, BSc, CCRP Senior Clinical Research Coordinator King Faisal Heart Institute Marilyn Lockyer, RN, BSc, CCRP Senior Clinical Research Coordinator King Faisal Heart Institute

2. What is a drug? Any chemical compound Anything which produces a change in the body Defined by characteristics: use or potential use in diagnosis, prevention or treatment of disease selective in its actions Any chemical compound Anything which produces a change in the body Defined by characteristics: use or potential use in diagnosis, prevention or treatment of disease selective in its actions

3. Why are new drugs/devices needed? Unmet medical need: treat old and new diseases that have no or ineffective treatments Desire for drugs with less side effects that present treatments (e.g. drugs used in oncology, steroids) Less expensive treatments than presently used ones Decrease costs to individual/country Sustain industrial activity: pharmaceutical industry employs thousands and makes a massive contribution to overseas earnings Unmet medical need: treat old and new diseases that have no or ineffective treatments Desire for drugs with less side effects that present treatments (e.g. drugs used in oncology, steroids) Less expensive treatments than presently used ones Decrease costs to individual/country Sustain industrial activity: pharmaceutical industry employs thousands and makes a massive contribution to overseas earnings

4. How are potential new drugs identified? Alteration of a Known Compound to act on a selected target Computer aided molecular design Plant extracts Screening large collections of chemical compounds and natural compounds for desired activity Alteration of a Known Compound to act on a selected target Computer aided molecular design Plant extracts Screening large collections of chemical compounds and natural compounds for desired activity

5. Drug discovery and development During the 1800s drugs were natural sources; therefore there were limited possibilities; prepared by individuals; small scale; not purified; limited administration; no controls; no idea of mechanism of action. In the 1990s types of drugs expanded to include synthetic sources, resulting in unlimited possibilities; prepared by companies; massive scale; highly purified, standardized and tested; world-wide administration; tight legislative control; mechanism of action partly understood. During the 1800s drugs were natural sources; therefore there were limited possibilities; prepared by individuals; small scale; not purified; limited administration; no controls; no idea of mechanism of action. In the 1990s types of drugs expanded to include synthetic sources, resulting in unlimited possibilities; prepared by companies; massive scale; highly purified, standardized and tested; world-wide administration; tight legislative control; mechanism of action partly understood.

6. Sources of drugs Animalinsulin (pig, cow) Plantdigitalis (digitalis purpurea - foxglove) morphine (papaver somniferum) Inorganic arsenic, mercury, lithium, platinum Synthetic chemical (propranolol) Animalinsulin (pig, cow) Plantdigitalis (digitalis purpurea - foxglove) morphine (papaver somniferum) Inorganic arsenic, mercury, lithium, platinum Synthetic chemical (propranolol)

7. Drug development process marketing regulatory process discovery; refinement; chemical & biological characterization safety & toxicity in animals; formulation development volunteer studies; patient studies post marketing Discovery = find new active structure & develop/refine it = convert it to a useful drug

8. The Regulatory process Differs from country to country (Medicine Control Agency (MCA) in UK, European Medicine Evaluation Agency (EMEA) a central body in Europe, or the Food and Drugs Administration [FDA] in USA) Demands safety and quality of product Grants clinical trials certificate if volunteer and animal data acceptable Approves protocols and examines data Differs from country to country (Medicine Control Agency (MCA) in UK, European Medicine Evaluation Agency (EMEA) a central body in Europe, or the Food and Drugs Administration [FDA] in USA) Demands safety and quality of product Grants clinical trials certificate if volunteer and animal data acceptable Approves protocols and examines data

9. Pre-clinical testing in animals Done in at least two species of animals One rodent & one non-rodent species Potential safety & toxic effects measured Mutagenicity / Genotoxicity, Teratogenicity Carcinogenicty LD 50 (Lethal Dose) determined The dose which kills 50% of animals tested Done in at least two species of animals One rodent & one non-rodent species Potential safety & toxic effects measured Mutagenicity / Genotoxicity, Teratogenicity Carcinogenicty LD 50 (Lethal Dose) determined The dose which kills 50% of animals tested

10. Animal testing (cont.) ADME (Absorption, Distribution, Metabolism and Excretion) Absorption includes route of administration, dosage form, effects of food, % of absorption, and effect of the first pass through the liver. Distribution includes peak and trough tissue concentrations and accumulation in serum, CSF, urine and bile. Metabolism refers to organs and percentages of toxicity and teratogenicity of metabolites. Excretion pertains to quantities and routes. ADME (Absorption, Distribution, Metabolism and Excretion) Absorption includes route of administration, dosage form, effects of food, % of absorption, and effect of the first pass through the liver. Distribution includes peak and trough tissue concentrations and accumulation in serum, CSF, urine and bile. Metabolism refers to organs and percentages of toxicity and teratogenicity of metabolites. Excretion pertains to quantities and routes.

11. Pre-clinical testing By the end of pre-clinical testing many drugs that seemed promising are abandoned. Research on a compound may be stopped due to problems with poor absorption, toxicity or simply because it doesn’t work. By the end of pre-clinical testing many drugs that seemed promising are abandoned. Research on a compound may be stopped due to problems with poor absorption, toxicity or simply because it doesn’t work.

12. Pre-clinical testing Lasts 3 to 5 years Only 1 out of 1000 compounds that enter pre- clinical testing continue to human testing. Before testing in humans can begin a licence will be required from the regulating authorities; each country will have its own body such as: FDA (USA) MCA (UK) EMEA (EU) Lasts 3 to 5 years Only 1 out of 1000 compounds that enter pre- clinical testing continue to human testing. Before testing in humans can begin a licence will be required from the regulating authorities; each country will have its own body such as: FDA (USA) MCA (UK) EMEA (EU)

13. Pre-clinical testing The regulating bodies (e.g. FDA) will have a team of scientists and doctors who will review all the pre-clinical data Drug companies will need to address these agencies’ guidelines and deliver the kind of results that they require if they want to gain the go ahead for testing in humans The regulating bodies (e.g. FDA) will have a team of scientists and doctors who will review all the pre-clinical data Drug companies will need to address these agencies’ guidelines and deliver the kind of results that they require if they want to gain the go ahead for testing in humans

14. Pre-clinical testing A licence for testing in humans should be granted, only when the regulators are entirely satisfied that the drug has not shown any potential adverse effects in pre-clinical testing. In the USA, after pre-clinical testing the pharmaceutical company applies to the FDA for an Investigational New Drug (IND) application. A licence for testing in humans should be granted, only when the regulators are entirely satisfied that the drug has not shown any potential adverse effects in pre-clinical testing. In the USA, after pre-clinical testing the pharmaceutical company applies to the FDA for an Investigational New Drug (IND) application.

15. “Pre-clinical” to “clinical” trials First consideration is the protection of the rights, safety and well-being of the study subject

16. Clinical trials Drug action depends on: Medical condition being treated Pharmacodynamics Pharmacokinetics and dose regimen Drug interactions Receptor sensitivity of patient Mood/personality of patient & doctor Patients expectations and past experience Social environment of patient Clinical state of patient Drug action depends on: Medical condition being treated Pharmacodynamics Pharmacokinetics and dose regimen Drug interactions Receptor sensitivity of patient Mood/personality of patient & doctor Patients expectations and past experience Social environment of patient Clinical state of patient Clinical trials account for or control these variables and examine the effect of the drug being tested.

17. Clinical trials Phase I (usually healthy volunteers) Phase II (patients or person with the condition) Phase III (large scale multi-centre) Phase IV (post marketing) Phase I (usually healthy volunteers) Phase II (patients or person with the condition) Phase III (large scale multi-centre) Phase IV (post marketing)

18. New Drug Application (NDA) USA Filed with the FDA after Phase I thru Phase III trials are completed Contains all scientific information the company has gathered May run thousands of pages or more in length Average FDA review time is 29.9 months Filed with the FDA after Phase I thru Phase III trials are completed Contains all scientific information the company has gathered May run thousands of pages or more in length Average FDA review time is 29.9 months

19. Cost of Developing New Drugs

20. Top 14 pharmaceutical companies spent over almost $29 billion (65% of their total research and development expenditure of $44.5 billion) but obtained FDA approval for only 26% of their new compounds. (2005) On average, it costs a company $359 million to develop one new medicine from the laboratory to the pharmacist's shelf (according to figures filed by the pharmaceutical companies to the US Internal Revenue Service) On average, it takes 12 -13 years for drug discovery to drug aproval. Only one in 1,000 compounds that enter pre-clinical testing make it to human testing. Top 14 pharmaceutical companies spent over almost $29 billion (65% of their total research and development expenditure of $44.5 billion) but obtained FDA approval for only 26% of their new compounds. (2005) On average, it costs a company $359 million to develop one new medicine from the laboratory to the pharmacist's shelf (according to figures filed by the pharmaceutical companies to the US Internal Revenue Service) On average, it takes 12 -13 years for drug discovery to drug aproval. Only one in 1,000 compounds that enter pre-clinical testing make it to human testing.

21. Unit sales Time serious side effects adverse reactions serious side effects adverse reactions wonder drug no side effects wonder drug no side effects not always effective not always effective appreciate where best used and risks appreciate where best used and risks balanced view of advantages & problems balanced view of advantages & problems Drug Sales Curve

22. New Devices New devices are divided into class: (USA) Class 1: Minimal potential for harm. May not be life- sustaining or life-supporting or play a substantial role in preventing impairment of health (eg hospital bed) Class 2: More direct impact on patient care (eg IV infusion pump) Class 3: Usually devices that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury (eg pacemaker, ventilators, perfusion pumps) In Canada devices are divided into 4 classes. New devices are divided into class: (USA) Class 1: Minimal potential for harm. May not be life- sustaining or life-supporting or play a substantial role in preventing impairment of health (eg hospital bed) Class 2: More direct impact on patient care (eg IV infusion pump) Class 3: Usually devices that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury (eg pacemaker, ventilators, perfusion pumps) In Canada devices are divided into 4 classes.

23. Phases of Clinical Research: Drugs Versus Devices Drugs generally have 4 phases in clinical research (I, II, III, IV) Devices generally have 2 clinical phases:  feasibility study (pilot) – small number of patients to confirm device design, operating specifications, and initial safety.  pivotal studies – larger number of patients; refines any issues identified in pilot study; safety and effectiveness confirmed. Drugs generally have 4 phases in clinical research (I, II, III, IV) Devices generally have 2 clinical phases:  feasibility study (pilot) – small number of patients to confirm device design, operating specifications, and initial safety.  pivotal studies – larger number of patients; refines any issues identified in pilot study; safety and effectiveness confirmed.

24. Conclusion Developing new drugs and devices: is a long and costly process, requires extensive testing before being tested in human subjects, must pass through phases of testing in sequence (eg 1 and 2 before 3, or pilot before feasibility) Requires the experience, knowledge, and cooperation of healthcare providers to be safely tested in patients. Developing new drugs and devices: is a long and costly process, requires extensive testing before being tested in human subjects, must pass through phases of testing in sequence (eg 1 and 2 before 3, or pilot before feasibility) Requires the experience, knowledge, and cooperation of healthcare providers to be safely tested in patients.