Prof. Dr. Basavaraj K. Nanjwade Clinical Studies and Trials on Traditional Medicine and Natural Products Prof. Dr. Basavaraj K. Nanjwade Department of Pharmaceutics Rani Chennamma College of Pharmacy, Belagavi-590010, Karnataka, INDIA. E-mail: nanjwadebk@gmail.com 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand The Ultimate Goal 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

Discovery, Design and Development 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Medicines research 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

Clinical Pharmacokinetics Clinical pharmacokinetics is the process of applying pharmacokinetic principles to determine the dosage regimens of specific drug products for specific patients to maximize pharmacotherapeutic effects and minimize toxic effects. TDM stands for therapeutic drug mointoring 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

Clinical Pharmacokinetics Application of these principles requires an understanding of the absorption, distribution, metabolism, and excretion characteristics of specific drug products in specific diseases and patient populations 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Pharmacokinetics 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Clinical Studies Treatment studies 1. Randomized controlled trial Blind trial Non-blind trial 2. Adaptive clinical trial 3. Nonrandomized trial (quasi-experiment) Interrupted time series design (measures on a sample or a series of samples from the same population are obtained several times before and after a manipulated event or a naturally occurring event) - considered a type of quasi-experiment 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Clinical Studies Observational studies 1. Cohort study Prospective cohort Retrospective cohort Time series study 2. Case-control study Nested case-control study 3. Cross-sectional study Community survey (a type of cross-sectional study) 4. Ecological study 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

Clinical Drug Development Bioavailability Bioequivalence Cross-over designs Comparison Dose-ranging Special populations (renal, hepatics, elderly) Drug-drug interactions Drug interaction Drug metabolism Safety and efficacy Patient selections 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

Steps in Pharmaceutical Products 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Phase I Clinical Trial (INITIAL SAFETY TESTING IN A SMALL GROUP OF HEALTHY VOLUNTEERS ) In Phase I trials the candidate drug is tested in people for the first time. These studies are usually conducted with a small number of healthy volunteers, generally 100 or less. The main goal of a Phase I trial is to assess the safety of the medicine when used in humans. Researchers look at the pharmacokinetics of a drug: How is it absorbed? How is it metabolized and eliminated from the body? They also study the drug’s pharmacodynamics: Does it cause side effects? These closely monitored trials are designed to help researchers determine what the safe dosing range is and if the candidate medicine should move on to the next stage of development. 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Phase I Patients: 20 to 100 healthy volunteers or people with the disease/condition. Length of Study: Several months Purpose: Safety and dosage   Percentage of Drugs that Move to the next Phase 70% 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Study Types Included Safety & Tolerability studies (Single/ multiple dose in patients or healthy volunteers) Oncology studies in patients with tolerability / MTD as primary endpoint (efficacy might be a secondary endpoint) Drug-Drug interaction & Food Effect PK in renal or hepatic impaired patients 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Phase II Clinical Trial (ASSESS SAFETY AND EFFICACY IN A SMALL GROUP OF PATIENTS) In Phase II trials researchers evaluate the candidate drug’s effectiveness in 100 to 500 patient volunteers with the disease or condition under study. Researchers also analyze optimal dose strength and schedules for using the drug and examine the possible short-term side effects (adverse events) and risks associated with the drug. If the drug continues to show promise, they prepare for the much larger Phase III trials. 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Phase II Phase IIA: Exploratory (non-pivotal) study that has clinical efficacy, Pharmacodynamics or biological activity as primary endpoint, conducted in patients or healthy volunteers. Phase IIB: Definite dose range finding study in patients with efficacy as primary endpoint. 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Phase II Patients: Up to several hundred people with the disease/condition. Length of Study: Several months to 2 years Purpose: Efficacy and side effects   Percentage of Drugs that Move to the Next Phase 33% 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Study Type Included Proof of concept, efficacy, or mechanism Mechanistic studies Dose range exploration Pilot studies Definite dose finding studies Extension studies of Phase IIB studies 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Phase III Clinical Trial (DEMONSTRATE SAFETY AND EFFICACY IN A LARGE GROUP OF PATIENTS) Phase III trials generate statistically significant data about the safety, efficacy and the overall benefit-risk relationship of the investigational medicine. Phase III trials may enroll 1,000 to 5,000 patients or more across numerous clinical trials sites around the world. This phase of research is essential in determining whether the drug is safe and effective. It also provides the basis for labeling instructions to help ensure proper use of the drug (e.g., information on potential interactions with other medicines, specific dosing instructions, etc.) 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Phase III Patients: 100 to 5000 volunteers who have the disease or condition Length of Study: 1 to 4 years Purpose: Efficacy and monitoring of adverse reactions Percentage of Drugs that Move to the Next Phase 25-30% 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Phase III Phase IIIA: A Pivotal study that is a trial designed & executed to get statistically significant evidence of efficacy and safety as required NDA/ sNDA approval. It also provides the basis for labeling instructions to help ensure proper use of the drug (e.g., information on potential interactions with other medicines, specific dosing instructions, etc.) Phase IIIB: A study started prior to approval and whose primary intention is support of publications rather than registration or label changes. The results are not intended to be included in the submission dossier. 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Study Time Included Pivotal studies (vs placebo/comparator) Long term safety studies for registration Local registration studies Post marketing study commitments Phase IIIA extension studies Studies intended to support publication, claims or to prepare launch, which start before approval but are not intended for Regulatory submissions 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Phase IV Phase IV: A study started after approval with primary intention to support publications rather than registration or label changes. The results are not intended to be included in a submission dossier. 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

Phase IV Clinical Trial Patients: Several thousand volunteers who have the disease/condition Purpose: Safety and efficacy 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Patient care Knowledge of drug therapy the disease laboratory and diagnostic skills Communication skills monitoring Patient assessment Physical Drug Information Skills Therapeutic planning nondrug therapy 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

20th World Congress on Clinical Nutrition, Bangakok, Thailand Reference Namrata Bahadur, Overview of Drug Development, Head of Clinical Development & Medical Affairs Emerging Growth Markets, 17th - 21st March, Bangkok. http://www.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf http://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm http://www.camargopharma.com/clinical-studies phases-i-iv.aspx http://www.cailsilorin.com/safety-and-efficacy/ http://www.yourgenome.org/facts/how-are-drugs-designed-and-developed. http://cenblog.org/the-haystack/2012/02/drug_design/ Anurag S Rathore & Helen Winkle Quality by design for biopharmaceuticals. Nature Biotechnology 27, 26 - 34 (2009), doi:10.1038/nbt0109-26. 15/12/2016 20th World Congress on Clinical Nutrition, Bangakok, Thailand

E-mail: nanjwadebk@gmail.com THANK YOU E-mail: nanjwadebk@gmail.com 15/12/2016 14/12/206 20th World Congress on Clinical Nutrition, Bangakok, Thailand