DRUG DEVELOPEMENT 2 Summary Acronyms used in preclinical development Life cycle of medicine Clinical trials for Beginners The Funnel Road map Example of drug development: Chemical level Pharmaceutical level Preclinical pharmacology Preclinical Toxicology Preclinical ADME 3 Preclinical development acronyms (1) ADME Absorption, distribution, metabolism, and excretion API Active pharmaceutical ingredient: any component intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease. CFR Code of Federal Regulations CGMP, GMP (Current) good manufacturing practice CMC Chemistry manufacturing and controls CoA Certificate of analysis CRO Contract research organization CTM Clinical trial material Cmax Maximum plasma concentration 4 Preclinical development acronyms (2) DP Drug product: finished dosage form (for example, tablet, capsule, solution) that contains an active drug ingredient, generally in association with inactive ingredients DS Drug substance: any substance that is represented for use in a drug and that, when used in manufacturing, processing, or packaging of a drug, becomes an active ingredient or a finished drug form FDA US Food and Drug Administration FIH First in human FRS Foreign related substances GLP Good laboratory practice HPLC High performance liquid chromatography ICH International Conference on Harmonization IND Investigational New Drug application MTD Maximum tolerated dose NCE New chemical entity 5 Preclinical development acronyms (3) NDA New drug application NCI National Cancer Institute NIA National Institute on Aging NOAEL No observed adverse effect level PIB Powder in bottle PK Pharmacokinetics RAID Rapid Access to Intervention Development (preclinical program) SBIR Small Business Innovative Research (grant) STTR Small Business Technology Transfer (grant) TI Therapeutic Index TK Toxicokinetic Tmax Time of maximum plasma concentration after dose administration TTP Target product profile 6 Drug development for beginners 7 8 9 The Funnel Translating a Discovery into a Product 10 Typical problems 11 'begin with the end in mind This adage is particularly appropriate for preclinical development, as the resulting IND must support the planned clinical trial design. For example, a clinical trial involving daily chronic administration requires repeat-dose toxicity studies in preclinical animal models. 12 Road map The drug development process is typically divided into three major steps: Discovery, Preclinical development, and Clinical trial. Preclinical development Research and Development Product development Preclinical studies Toxicology studies (PK, ADME) GLP toxicology studies IND package 13 Ethical Principles in Preclinical Study 14 Requirement to publish Experiments should be conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and should have the approval of the Ethics Committee for Animal Experiments. 15 Ethics for experimental studies AMERICAN UNIVERSITY OF Public and private research in France BEIRUT: INSTITUTIONAL has established ethics committees ANIMAL CARE AND USE that analyze experimental protocols COMMITTEE submitted to them. REQUEST FORM FOR RESEARCH The committees may ask researchers PROTOCOL APPROVAL to develop protocols to reduce or Search for Alternatives: eliminate, if possible, any animal FRAME Guide to Searching suffering. for Alternatives to the Use of Laboratory Animals This is an additional guarantee for the civil society about the scientific justification of experiences and animal welfare Search for alternatives is encouraged! 16 Binding study Cell test Animal models Toxicology study Preclinical evaluation Investigational New Drug application summarizes the results of the above activities for submission to the US FDA 17 IND Table of Contents 1. Form FDA 1571 [21 CFR 312.23(a)(1)] 2. Table of contents [21 CFR 312.23(a)(2)] 3. Introductory statement [21 CFR 312.23(a)(3)] 4. General investigational plan [21 CFR 312.23(a)(3)] 5. Investigator's brochure [21 CFR 312.23(a)(5)] 6. Protocol(s) [21 CFR 312.23(a)(6)] a. Study protocols [21 CFR 312.23(a)(6)] b. Investigator data [21 CFR 312.23(a)(6)(iii)(b)]a c. Institutional review board data [21 CFR 312.23(a)(6)(iii)(b)]a 7. Chemistry, manufacturing, and control data[21 CFR 312.23(a)(7)] 8. Pharmacology and toxicology data [21 CFR 312.23(a)(8)] 9. Previous human experience [21 CFR 312.23(a)(8)] 10. Additional information [21 CFR 312.23(a)(10)] 18 Discoveries during last years Anti-TNF in auto-immune disease (PR) AIDS: 5 mechanism of action Cardiology : prevention – NOAC (Dabigatran/Rivaroxaban/Apixaban) Anti-Alzheimer: Bapineuzumab New anticancer drugs: Tinibs 19 2003 Blockbusters at the Drugstore (US/Worldwide; out of ~$500b) Lipitor (Pfizer) cholesterol $6.8/10.3 billion (66%) Zocor (Merck) cholesterol $4.4/6.1 billion (72%) Zyprexa (Eli Lilly) antipsychotic $3.2/4.8 billion (72%) Norvasc (Pfizer) blood pressure $2.2/4.5 billion (40%) Procrit (J&J) anemia $3.3/4.0 billion (83%) Prevacid (TAP) ulcers $4.0/4.0 billion (100%) Nexium (AstraZeneca) ulcers $3.1/3.8 billion (82%) Plavix (BMS-Sanofi) blood thinner $2.2/3.7 billion (59%) Seretide (GSK) asthma $2.3/3.7 billion (62%) Zoloft (Pfizer) depression $2.9/3.4 billion (85%) Epogen (Amgen) anemia $3.1/? billion (?%) Celebrex (Pfizer) arthritis $2.6/? billion (?%) Source: IMS Health, March 2004 20 Me too drugs: antidepressants 1986 Fluvoxamine (Luvox; Solvay) SSRI 1987 Fluoxetine (Prozac; Lilly) SSRI 1992 Sertraline* (Zoloft; Pfizer) SSRI/NRI 1993 Venlafaxine (Effexor; Wyeth) SSRI/NRI 1996 Buproprion (Wellbutrin; Wyeth) SNRI/DRI 2002 Escitalopram (Lexapro; Forrest) SSRI 2004 Duloxetine (Cymbalta; Lilly) SSRI/NRI 21 “Big Pharma” Drug Discovery in the 21st Century The pharmaceutical industry is short of new drugs. In the 2nd part of the 20th century, about 50-60 new drugs (NCEs) were approved by the FDA every year. In contrast, in 2002, a historical low of 18 NCEs were approved (in 2001, 24 NCEs, in 2000, 27 NCEs, in 2003, 21 NCEs). Conversely, research costs for a new drug are estimated to be in the $1-1.5 Bi. range. 22 Clinical Trial: Phase I In Phase 1, we seek to understand what the organism does to the new molecule, which is also known as 1. pharmacokinetics: Healthy volunteers, Bioavailability and the best route of administration. 2. Research for the right dose. 3. In fact, the primary objective is to ascertain safety. Thirty percent of synthesized molecules is lost in Phase 1. 23 Clinical Trial: Phase II It is called the therapeutic exploratory phase. In Phase 2, we seek to establish the efficacy of a drug (in subjects) with a specific illness. We also compare how the illness responds to established standard drugs or to a placebo. Phase 2 studies also allow us to determine the level of short-term safety and range of appropriate dosage. Test in a relatively small population of about 300 to 500 patients. That is where the wisdom of clinical researchers is found. 24 Clinical Trial: Phase III This phase is also known as the therapeutic confirmatory phase. It consists of large-scale studies designed to find the efficacy and safety of the new drug relative to already accepted drugs. Thousands of subjects are involved at this point, including people from different populations. These studies are usually controlled with a placebo or with drugs that are universally accepted for treating that specific condition. Phase 3 studies allow us to build a good profile of how the drug behaves when it is used in large populations. 25 Clinical Trial: Phase IV The drug is submitted to health authorities and if it is approved, the phase 4 begins. It consists of studies that differentiate the investigational drug from other drugs in its class; studies that compare the drug’s efficacy and demonstrate the drug’s benefits in terms of pharmaco-economics. Phase 4 is never-ending. 26 27 Remarks Transition from discovery to preclinical development is a continuum, and results of preliminary pharmacology and toxicology testing often contribute to lead drug candidate selection. Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Investigational New Drug application 28 Preclinical drug development stages. Following identification of a drug target and candidate compounds, several early activities, such as pharmacology, in vivo efficacy, and experimental toxicology, can contribute to the selection of a lead candidate for preclinical development. These preclinical activities provide the basis for an Investigational New Drug (IND) application to the FDA for permission to initiate clinical testing in humans. ADME, absorption, distribution, metabolism, and excretion; API, active pharmaceutical ingredient; PK, pharmacokinetics; Prep, preparation; Tox, toxicity. 29 Lead product Once a lead candidate is identified, a typical preclinical development program consists of six major efforts: Manufacture of drug substance (DS)/active pharmaceutical ingredient (API); Pre-formulation and formulation (dosage design); Analytical and bio-analytical methods development and validation; Metabolism and pharmacokinetics; Toxicology, both safety and genetic toxicology and possibly safety pharmacology; And good manufacturing practice (GMP) manufacture and documentation of drug product for use in clinical trials. 30 Time is money 31 Dépenses en R&D 32 DRUG DISCOVERY 33 Medicinal Chemistry The science that deals with the discovery or design of new therapeutic agents and their development into useful medicines. It involves: Synthesis Structure-Activity Relationships (SAR) Receptor interactions 34 2003 Blockbusters at the Drugstore HO O O (US/Worldwide; out of ~$500b) CH3 O N N O H N OH H OH N O N H H O Zyprexa CH3 OH N H C Lipitor H S CH3 3 F Zocor O H N OH 2 S O O N Ph H HO (H2C)4 N N S N O CF3 HN O CF3 HO N CH3 (CH2)6 OH Prevacid Seretide CO2H H C 3 Celebrex H N NH O 2 NHCH3 HCl N MeO C CO Et 2 2 Cl CO2Me MeO Cl S N 2+ )2 Mg N Zoloft N O S - HSO4 Nexium Norvasc Cl Plavix Cl 35 Why Is It So Difficult to Make Drugs? 40 Estimates of the number of possible drug molecules average 10 .