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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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Presentation Transcript
slide1

BrAPP - Module 6

Non-Clinical Safety Testing:

Its Place in Drug Development

slide2

The Opening Questions....

What do we do?

What can happen?

How successful are we?

Are we supporting ‘medicine’ & our organisations?

slide3

PHARMACOLOGY

TOXICOLOGY

(Related or Unrelated)

Non-Clinical Development - The Questions

DOES IT WORK

?

IS IT SAFE

Defining the margin between desirable and undesirable

slide4

Separation of Pharmacodynamic and Toxicologic effects

The toxicologic effects seen may be related or unrelated

to pharmacology

slide5

Reproduction

Chronic Effects

Acute Responses

Development

“. . . . Aspects of a Safety Assessment. . . . “

ONE DOSE

LIFETIME USE

Genetic damage

Carcinogenicity

characterisation of toxic effects
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
slide7

NON-CLINICAL SAFETY ASSESSMENT

DETERMINING THE RISK

Putting adverse effects into clinical perspective - Some considerations

  • Relevance
  • Seriousness
  • Margin
  • Marker
  • Reversibility
slide8

NON-CLINICAL SAFETY ASSESSMENT

Supporting Clinical Development:

Provide reassurance & build confidence to proceed

‘Post marketing’

Regulatory Approval

Healthy volunteers

Volunteer Patients

Workplace & Environment

slide9

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

slide10

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

slide11

That covers what we do. What about...

What can happen?

How successful are we?

Are we supporting ‘medicine’ & our organisations?

slide12

Working with the Portfolio

Drug Development to a New Medicine

slide13

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.
slide14

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.

slide15

Over $5billion/annum!!

What was this medicine?

slide16

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)

slide17

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

slide18

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.

slide19

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.

slide20

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

slide21

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).

slide22

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.

slide23

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

slide24

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
slide26

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)]

slide27

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

slide28

79% predicted

63% predicted

64% predicted

Success of animal studies in predicting human toxicities emerging during clinical trials

ILSI survey - 2001

slide29

94% detection within 4-Weeks

Duration of animal studies to predict human toxicities

First time to detection in rodent or non-rodent (n=151)

slide30

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)

slide32

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
slide33

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