The R&D process Clinical development

1. The R&D processClinical development Andy Gray Consultant pharmacist

2. Demonstration of: • Efficacy • Does the drug work? • Safety • Is the drug safe to use, in the context of the condition being treated? • Quality • Is the drug always going to work as predicted, in that it will be delivered as promised in a suitable, consistent dosage form? 3 basic objectives

3. http://www.treat-nmd.eu/userfiles/file/TACT_flowchart.pdf

4. Pre-clinical development

5. Objectives • To sufficiently describe the reaction of various animals to the drug, so as to identify major areas of concern • ICH headings • Carcinogenicity • Genotoxicity • Toxicokinetics and pharmacokinetics • Toxicity • Pharmacology • Immunotoxicology • The challenge – early identification of failure Pre-clinical development

6. Deciding which pre-clinical investigations are really needed and which may be superfluous • ICH M3(R2): Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals • Local variants? • Ability of local regulatory authorities to authorise deviations from global “norms” • Capacity to undertake pre-clinical studies to GLP standards Challenges for south-driven innovation

7. PART 4 PRE-CLINICAL STUDIES a) Pre-clinical Expert Report b) The following are results obtained and conclusions drawn from tests performed pre-clinically to demonstrate all aspects of the toxicity of the medicine and to prove the safety of its use, with special reference to - (i) acute toxicity; (ii) subacute toxicity studies; (iii) chronic toxicity studies; (iv) reproduction toxicity and teratogenicity studies; (v) carcinogenicity studies; (vi) mutagenicity studies; or (vii) other tests to substantiate the safety of the medicine; and (viii) pharmacokinetic studies. c) The methods and experimental results of, and the conclusions drawn from tests performed pre-clinically with reference to the efficacy of the medicine, with special emphasis on the relationship between the tests performed and the purpose for which the medicine is, or will be used or for which it will be propagated, and further, with regard to the dosage and method of administration of the medicine, are as follows: In cases concerning well-known active pharmaceutical ingredients, the Council may grant exemption from the submission of some or all of the above information. SA MRF1 directive

8. Clinical development

9. PART 5 CLINICAL STUDIES a) Clinical Expert Report  b) The clinical trials performed on human volunteers and patients with regard to the safety of the medicine, with special reference to the particular dosage, routes of administration and the side effects observed, are as follows:  c) The particulars of clinical trials conducted to establish the efficacy of the medicine are as follows:  d) Experimental details and results of the studies performed to establish the correlation between the applicable blood and other suitable physiological levels, and the pharmacological action claimed for the medicine, are as follows:  e) Periodic Safety Update Report for medicines for human use SA MRF1 directive

10. Examples of EMA guidelines • Pharmacokinetic Studies in man • Reporting the Results of Population Pharmacokinetic Analyses • Investigation of drug interactions • Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Hepatic Function • Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Renal Function Human pharmacology and PK issues

11. Interactions with medicines not commonly used • Methadone • When to investigate special populations • Adolescents • Post-menopausal women • Pregnant and lactating women • Emphasis on specific safety issues • QT prolongation • Capacity issues – as before Challenges for south-driven innovation

12. INNOVATIVE DRUG DEVELOPMENT APPROACHES FINAL REPORT FROM THE EMEA/CHMP-THINK-TANK GROUP ON INNOVATIVE DRUG DEVELOPMENT EMEA/127318/2007 • Communication issues • Guidelines • Biomarkers • Statistical methods and clinical trial designs • Faster access – conditional authorization Clinical trials

13. Ability to access scientific advice/protocol assistance from appropriate regulators • “Rolling review” process • A clear development pathway for follow-on products: • Paediatric dosage forms • New applications for drugs used already • Fixed dose combinations Challenges for south-driven innovation

14. Article 58 application to EMA • Additional safety studies • young women aged 16‐17 years, women with hepatitis B infection and women with impaired kidney function; safety in pregnancy • Confirmatory efficacy studies • including younger women (aged 16‐30 years); and adding prevention of HSV‐2 as a primary endpoint • Effectiveness and safety trial of simplified dosing and HIV testing schedules • Effectiveness study • Treatment outcome and resistance study • in those who seroconverted on gel Next steps with 1% tenofovir gelhttp://www.who.int/reproductivehealth/topics/rtis/WHO_UNAIDS_Next_steps_tenofovir_gel_Ex_report.pdf

15. “During the meeting, the FDA stated their preference for two well-controlled studies to verify the safety and efficacy of 1% tenofovir gel prior to submission of a New Drug Application (NDA). The FDA furthermore stated that the NIH-sponsored Phase IIB study, MTN-003, known as VOICE (Vaginal and Oral Interventions to Control the Epidemic), represents a second adequate and well-controlled study that would, if successful, serve as the second pivotal trial together with CAPRISA 004 to support the submission of an NDA for 1% tenofovir gel.” “The agency agreed that the current preclinical program for 1% tenofovir gel is sufficient to support a future NDA. However, they stated that additional safety data on adolescents would be needed and that information on in vivo drug interaction studies with commonly used vaginal products should be obtained. Also, the FDA will ultimately need data on post menopausal women. It was also agreed that a future meeting with the FDA would be held to address any outstanding discussions associated with product quality, including chemistry, manufacturing and controls (CMC).” FDA pathway (Oct 2010)

16. Clinical development requirements stipulated by medicines regulatory authorities are necessarily stringent Finding an appropriate balance between access and safety is not simple “Southern” regulators may not always be in a position to offer advice, decide whether to deviate from international “norms” (such as ICH), or conduct “rolling reviews” The capacity to conduct pre-clinical and early phase clinical studies in the “South” may be limited Summary