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Non-Clinical Safety Testing: Its Place in Drug Development

BrAPP - Module 6. Non-Clinical Safety Testing: Its Place in Drug Development. The Opening Questions. What do we do?. What can happen?. How successful are we?. Are we supporting ‘medicine’ & our organisations?. PHARMACOLOGY. TOXICOLOGY. (Related or Unrelated).

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Non-Clinical Safety Testing: Its Place in Drug Development

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  1. BrAPP - Module 6 Non-Clinical Safety Testing: Its Place in Drug Development

  2. The Opening Questions.... What do we do? What can happen? How successful are we? Are we supporting ‘medicine’ & our organisations?

  3. PHARMACOLOGY TOXICOLOGY (Related or Unrelated) Non-Clinical Development - The Questions DOES IT WORK ? IS IT SAFE Defining the margin between desirable and undesirable

  4. Separation of Pharmacodynamic and Toxicologic effects The toxicologic effects seen may be related or unrelated to pharmacology

  5. Reproduction Chronic Effects Acute Responses Development “. . . . Aspects of a Safety Assessment. . . . “ ONE DOSE LIFETIME USE Genetic damage Carcinogenicity

  6. CHARACTERISATION OF TOXIC EFFECTS THE STUDIES Safety pharmacology Genetic toxicity Single/repeat dose toxicity Fertility & early embryonic development Embryo-fetal development Pre- & post-natal development Carcinogenicity Local tolerance, immunotox., phototox, environmental, health & safety THE ENDPOINTS • Undesirable pharmacodynamic effects on specific physiological systems • Gene mutation and chromosome damage • Max tolerated dose/Target organ toxicity/local tolerance/Drug exposure • Effects on fertility, embryo-fetal development, parturition, and post-natal development • Carcinogenicity • Special studies

  7. NON-CLINICAL SAFETY ASSESSMENT DETERMINING THE RISK Putting adverse effects into clinical perspective - Some considerations • Relevance • Seriousness • Margin • Marker • Reversibility

  8. NON-CLINICAL SAFETY ASSESSMENT Supporting Clinical Development: Provide reassurance & build confidence to proceed ‘Post marketing’ Regulatory Approval Healthy volunteers Volunteer Patients Workplace & Environment

  9. Development Phases and Non-clinical Safety Support?A typical medicine development timetable Candidate Selection to 1st human dose Move on to Patient studies (Phase 2a) Confidence to start Phase 3 (Phase 2b?) File & Launch Lifecycle Management PHASE 3

  10. Timing of core Non-clinical Safety Studies Preliminary screening activities (eg) Genetic tox screens QT-prolongation liabilities (hERG etc.) P450 interaction Initial rodent safety and PK Identify optimum non-rodent model Selection of Drug Candidate Preparing for First Human Dose (Phase 1) ICH-M3 “Package” Genetic tox (2x in vitro tests) Safety Pharmacology (CV/Respiratory/Behavioural) Dose range, PK – (rodent and non-rodent) 14-28 Day Repeat dose toxicology (rodent/non-rodent) • ICH-M3 - Continuation • Genetic tox (In vivo test) • >28 Day Repeat dose toxicology (rodent/non-rodent) • Often 3 Months • Followed by 6-Month rat, 9 Month non-rodent • Reproductive Toxicology • Embryofetal development (rat/rabbit) Repeat dose volunteer studies and Later clinical Phases ICH-M3 - Completion Carcinogenicity (rat & mouse; 3 years) Reproductive Tox (rat Fertility & Pre/post-natal) Additional ‘special’ studies Marketing

  11. That covers what we do. What about... What can happen? How successful are we? Are we supporting ‘medicine’ & our organisations?

  12. Working with the Portfolio Drug Development to a New Medicine

  13. What might confront the toxicology and clinical team? • CNS Toxicity? • Dog: Brain haemorrhage at 120 mg/kg • Dog: Brain haemorrhage and optic nerve vacuolation at doses up to 280 mg/kg • Dog: A single tonic convulsions (in 2 male dogs) - 10 mg/kg and 120 mg/kg • The 120 mg/kg resulted in a exposure approximately 16 times the human level. • No CNS lesions have been observed in mice or rats after chronic treatment for up to 2 years. The doses were at least 6 times the human AUC (0-24). • Other related agents? • CNS vascular lesions, characterized by perivascular haemorrhages, oedema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. • A chemically similar drug in this class has produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibres) in clinically normal dogs at high doses.

  14. What might confront the toxicology and clinical team? Endocrine Disruption? These agents …………might theoretically blunt adrenal or gonadal steroid production. Clinical studies have shown that xxxxxxxxxx does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of xxxxxxxxx drugs on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Carcinogenesis? In a 2-year carcinogenicity study in rats ………. 2 rare tumors were found in muscle in high-dose females (rhabdomyosarcoma and a fibrosarcoma). This was at dose giving approximately 16 times human plasma drug exposure.A 2-year carcinogenicity study in mice: significant increase in hepaticadenomas and carcinomas. These findings occurred at plasma AUC values of approximately 6 times the mean human exposure.

  15. Over $5billion/annum!! What was this medicine?

  16. Increased liver weights • hepatocellular hypertrophy • hepatic enzyme induction & and SER proliferation • Changes reflect physiologic adaptation not hepatotoxicity • Nothing notable in PK or metabolism studies • No histopathological changes in liver SER = Smooth Endoplasmic reticulum Drug # 1 Toxicology Study Observations (rat, cynomolgus monkey up to 12 months)

  17. Hepatic monitoring from the clinical trials of Drug #1 ALT (xULN) % affected 3x 1.9 5x 1.7 8x 0.9 30x 0.2 n 2510 Does not look too serious? ALT = alanine aminotransferase

  18. Compare these observations with normal variation and diabetic patients Normal Variation: Sporadic increases in hepatic enzyme ‘markers’ do occur in normal human volunteer populations From: Neil Kaplowitz MD, University of Southern California, http://www.fda.gov/cder/livertox/stateArt.htm#Clinical Picture Type II Diabetics (NIDDM) Some clinical and epidemiological studies suggest that diabetes and liver disease occur more often together than would be expected by chance. Everhart, J.E. Digestive Diseases and Diabetes. In Diabetes in America (2nd ed.). NIH Publications. Chapter 21, pp 457-79.

  19. Hepatic monitoring from the clinical trials of Drug #1 Does not look too serious…. However, some cases of hepatic transplant and fatal hepatitis emerge post-marketing.

  20. ALT (xULN) % affected 3x 1.9 5x 1.7 8x 0.9 30x 0.2 n 2510 From: Neil Kaplowitz MD, University of Southern California, http://www.fda.gov/cder/livertox/stateArt.htm#Clinical Picture

  21. 1. Hepatocellular injury, generally shown by more frequent 3-fold or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control agent or placebo. 2. Among subjects showing such AT elevations, often with ATs much greater than 3xULN, some subjects also show elevation of serum TBL to >2xULN, without initial findings of cholestasis (serum alkaline phosphatase (ALP) activity >2xULN).

  22. The Troglitazone Experience Death Jaundice ALT 10x 1/200 1/2000 1/20000 1/10 will progress to 1/10 will progress to Incidence values from FDA, Actos, Advisory Committee (23 Apr 00) transcript The “Hy Zimmerman Rule” of Hepatotoxicity For patients who have a 10x increase in ALT, 1/10 will develop jaundice. Of those with jaundice 1/10 will either die or require liver transplant.

  23. Hepatic monitoring from the clinical trials of Drug #1 Troglitazone Rosiglitazone ALT (xULN) % affected 3x 1.9 5x 1.7 8x 0.9 30x 0.2 n 2510 % affected 0.25 0.23 0.05 0 4421 “Does not look too serious?” Further analysis suggests a problem & action is taken. Same drug class, same indication. Concerns for Troglitazone reinforced? (Pioglitazone data supports the conclusion) Troglitazone withdrawn from use

  24. Could we have done better predicting this event? • Animal studies • No signal (mouse, rat, monkey, very slight in dog) • No issue with companies or Agencies at review • Even retrospective review failed to identify hepatic lesions • Clinical Studies • Low level of signal - Clear in the data • Acknowledged in submissions and during reviews • True idiosyncratic effect • No clear mechanism even today!! • A worst case scenario for Patients, Medical Professionals, Agencies and Corporations

  25. Neil Kaplowitz MD, University of Southern California

  26. How are we doing………….? Concordance of Toxicity of Pharmaceutical in Humans and in Animals International Life Sciences Institute Workshop - April 1999 (ILSI) [Regulatory Toxicology and Pharmacology 32:56-67 (2000)]

  27. Concordance of Toxicity of Pharmaceutical in Humans and in Animals International Life Sciences Institute Workshop - April 1999 (ILSI) ex. Regulatory Toxicology and Pharmacology 32:56-67 (2000) • 12 Companies • 150 Compounds • 221 Human Toxicities (HT) • 47 Multiple Human Toxicities True positive concordance 71% for rodents & non-rodents 63% for non-rodents alone 43% for rodents alone Concordance Best Haematologic, Gastrointestinal, Cardiovascular HTs Least Cutaneous HT’s

  28. 79% predicted 63% predicted 64% predicted Success of animal studies in predicting human toxicities emerging during clinical trials ILSI survey - 2001

  29. 94% detection within 4-Weeks Duration of animal studies to predict human toxicities First time to detection in rodent or non-rodent (n=151)

  30. Analysis of Causes of Development Failure Kennedy, T. 1997, DDT 2:436-444 (Similar info in: Prentis, 1988, Br J Clin Pharm, 25:387-396) (* = 7% if exclude anti-infectives)

  31. “Cases where even the best clinical and non-clinical data fail to provide support”

  32. Need thorough awareness of the epidemiological criteria to establish causation. Overwhelming scientific evidence, in the animal and clinical studies, that Debendox was not teratogenic ……….. claims in the media, public opinion and fear of litigation intervened. 1983: Merril Dow ceased production and sale of the drug Possibly the most studied and safest treatment available? http://www.reprotox.org/samples/1035.html The Debendox (Bendectin/Diclectin) Saga. • Combination of doxylamine (a sedative-antihistamine), pyridoxine (vitamin B6) • and dicyclomine (antispasmodic) • Treatment of nausea and vomiting in pregnancy • Oral clefts in infants of treated mothers

  33. The Opening Questions.... What can happen? • Almost anything. This is an experiment!! How successful are we? • Reasonably - but great need to improve • (greater predictivity and earlier detection) Are we supporting ‘medicine’ & our organisations? • Yes, but we all need more! • Technologies promise a lot. Delivery? • ‘Regulatory Studies’ (properly) remain the big hurdles

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