1. No category

Pre-clinical – unwrapped for a
Clinical audience
Gareth Thomas
Philip Jarvis
Mike Aylott
PSI Conference 2014
www.huntingdon.com
Agenda
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Aim of Session
Toxicology SIG History
Pre-clinical vs Clinical: Are we significantly different?
Influence of Toxicology studies on Clinical
How can Toxicology learn from Clinical?
www.huntingdon.com
Aim of Session
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To raise awareness of Pre-clinical Statisticians
and our role in Pharmaceutical Development
www.huntingdon.com
ToxSIG History
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Founded in September 2006
Ran our first workshop in September 2007
Held a total of five 2-day workshops
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Run every 18 months, last one being March 2013
Around 40 affiliates on our mailing list
www.huntingdon.com
Statisticians
Pre-clinical vs Clinical:
Are we significantly different?
Gareth Thomas
Global Head of Statistics and Data Management
Huntingdon Life Sciences
www.huntingdon.com
Differences
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Demonstrate our impact to business
- to retain headcount
Greater liaison with scientists
Lower profile contribution to projects
- less sense of belonging
More variety
Rapid turnover of studies
- rapid turnover of stats analyses!
New topics/challenges often
www.huntingdon.com
Day-to-Day
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Immediacy of work
Less regulation
Less idea of future workload
– not sure what is around the corner
Smaller studies, quicker turnaround
More ad hoc (less defined duties and processes
than clinical) and more freedom
www.huntingdon.com
Challenges
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Supporting many different studies
Diverse range of scientific knowledge required
Various levels of statistics buy in
Multiple Statisticians working on one study
Quick turnarounds
Wide variety of data-types, study designs,
areas of work
Demonstrating our impact/contribution to business
Finding and retaining resource
www.huntingdon.com
Advantages
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Huge variety of new challenges to be tackled
Easy to make a difference
See results quickly
Interactions with scientists and new scientific areas
New things frequently come up
Freedom to operate
www.huntingdon.com
Disadvantages
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Distant from good news (drugs to market)
No clear career path
More vulnerable if budgets cut (than clinical)!
Lack of knowledge about what we do and
the value we add
Too few of us
Lack of recognition from regulatory authorities as an
area where trained statisticians mandated
www.huntingdon.com
A life in the day of ...
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Morning
0615 – Get up, shower, get dressed
0645 – Feed cats, make lunch, enjoy Crunchy nut cornflakes and cuppa tea
0715 – Leave for work
0730 – Arrive at work
0735 – Cuppa tea and check emails
0745 – Sign and issue urgent US study stats report
0800 – S and K arrive – catch up with any questions they have
0815 – Continue checking Safety Pharm Telemetry Study
0852 – Meet all team for huddle
0930 – Meeting with HR about recruitment
1000 – Check Repro Tox Litter Stats for Study A
1100 – Finished checking, time for tea. Make tea for team! Hopefully chocolate treat to enjoy!
1115 – Senior Management meeting to discuss workload, prioritises and scheduling
www.huntingdon.com
A life in the day of ...
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Afternoon!
1215 – Eat sandwich quickly at desk
1230 – Analysis of bracketing assay data for CMC area
1330 – Answer email query from SD about ANCOVA
1400 – Analyse Genetic Tox Micronucleus study data
1500 – Wonder how it is 1500 already – time for another cuppa?!!
1505 – Analyse ADA cutpoint data
1600 – Update meeting on SEND
1700 – Go to the gym (or for a run)
1800 – Home, shower etc
1830 – Time for dinner 
1900 – Finish checking any other emails
2000 – Cuppa tea and Star Trek!
www.huntingdon.com
Contract Research Snapshot
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Jobs – 110 booked in January
Time spent on them
0.25 hrs Protocol Amendment Review
 >40 hrs Telemetry Study
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Turnaround – Same day to 18 days
Analyses per study – 70 x 1, 17 x 2, 2 x 3
Data analysed –
Activity, AUC, Bracketing Assay, Cytokines…
…Respiration, Telemetry, Xenopus & Zooplankton

www.huntingdon.com
Survey results
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In which area of pharmaceutical drug development do you work?
11%
19%
63%
7%
www.huntingdon.com
Survey results - continued
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Have you ever collaborated with statistician colleagues in the “other” area?
37%
63%
www.huntingdon.com
Survey results - continued
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Does the work of your colleagues from the “other” area influence activities
in your area?
45%
55%
www.huntingdon.com
Impact
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ICH S6 Addendum – includes recommendations on
both study design and sample size requirements for
use in the Developmental Toxicology Assessment of
Biologics
OECD Comet Assay Guidelines reference (Bright et
al, Recommendations on the statistical analysis of
the Comet assay)
www.huntingdon.com
Impact
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Many papers published by ToxSIG members
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Jarvis P, Srivastav S, Vogelwedde E, Stewart J, Mitchard T and Weinbauer G. The Cynomolgus
Monkey as a Model for Developmental Toxicity Studies: Variability of Pregnancy Losses, Statistical
power Estimates, and Group Size Considerations. Birth Defects Research (Part B), 2010: 89; 175187.
Aylott M, Bate S, Collins S, Jarvis P and Saul J. Review of the statistical analysis of the dog telemetry
study. Pharmaceutical Statistics, 2011; 10, 239-249.
Weinbauer G , Jarvis P, Srivastav S, Mitchard T ,Vogelwedde E, Stewart J. Objective group size
determination for developmental toxicity studies in a nonhuman primate model (Macaca fascicularis).
Future Trends in Primate Toxicology and Biotechnology. Waxmann Publishing Company, Munster,
2011; 81-93.
Jenkins M, Flynn A, Smart T, Harbron C, Sabin T, Ratnayake J, Delmar P, Herath A, Jarvis P and
Matcham J. A Statistician’s perspective on biomarkers in drug development. Pharmaceutical
Statistics, 2011; 10: 494-507.
Bright J, Aylott M, Bate S, Geys H, Jarvis P, Saul J, Vonk R. Recommendations on the statistical
analysis of the Comet assay. Pharmaceutical Statistics, 2011; 10: 485-493.
Jarvis P, Saul J, Aylott M, Bate S, Geys H. An assessment of the statistical methods used to analyse
toxicology studies. Pharmaceutical Statistics, 2011; 10: 477-484.
Mitchard T, Jarvis P and Stewart J. Assessment of the Male Rodent Fertility in General Toxicology Six
Month Studies. Birth Defects Research Part B: Developmental and Reproductive Toxicology, 2012 95:
410-420.
www.huntingdon.com
Significantly different?

Do you like chocolate?
No
10%
Yes
90%
Clinical
Pre-clinical
Yes, 79
No, 0
No, 10
Yes, 11
www.huntingdon.com
Influence of Toxicology studies on Clinical
Philip Jarvis
12th May 2014
FJ Spence
February 18th, 2014
“ All substances are poisons; there are none which is not a
poison. The dose differentiates a poison from a remedy”
Paracelsus, 1531
How do we know that a drug is safe?
All pharmacologically active substances have the
potential to cause harm.
Medicines are taken by patients with an expectation of
benefit and usually some awareness that side-effects
may occur.
Some patients will experience harmful side-effects,
sometimes leading to death or permanent disability.
24| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
The concept of safety (risk versus benefit)
 Safety is relative absence of harm or a low level of risk that, in
context, can be considered acceptable.
 Toxicology assessment forms a key part of the risk/benefit
evaluation
• Need to identify the hazard, to be able to assess the risk
• What is the potential benefit to humans versus the potential risk?
i.e. efficacy versus toxicity
 Need to consider:• Therapy area and patient population – e.g. a toxicity risk which is
unacceptable for an asthma therapy may be acceptable for cancer
patients
• The competition - what is already on the market what are its liabilities?
 The risk/benefit assessment is unique for each compound and
evolves with the accumulation of further preclinical and clinical
data
25| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Outline
1. Toxicology studies run prior to and in parallel with clinical
development
2. Study design options are restricted by “Current” toxicology
package
• clinical trial duration, study inclusion criteria e.g. extending the clinical
trial population into women of child bearing potential, children, etc.
3. Small molecules and biologics are different
• duration of clinical effects, tox data required
4. The human relevance of a tox package finding may not be
understood
5. Pre-clinical/Non-clinical data will appear on the drug label
26| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Outline
1. Toxicology studies run prior to and in parallel with clinical
development
2. Study design options are restricted by “Current” toxicology
package
• clinical trial duration, study inclusion criteria e.g. extending the clinical
trial population into women of child bearing potential, children, etc.
3. Small molecules and biologics are different
• duration of clinical effects, tox data required
4. The human relevance of a tox package finding may not be
understood
5. Pre-clinical/Non-clinical data will appear on the drug label
27| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Healthy
Animals
[Homogenous
with respect to
age, size, weight]
Randomise
Toxicology Basic Design
Control (vehicle dosed)
Low dose
Intermediate dose
High dose
Dosing period
All doses have to be tolerated
Animals necropsied
i.e. majority of animals display no overt
signs of toxicity.
[All major organs
Analysed macro
and microscopically]
28| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
1. Toxicology studies run prior to and in parallel
with clinical development
sPoC
Pre-clinical
 Safe to
take cmpd /
biological
entity into
humans?
PoC
Early Clinical
Submission
Late Clinical
 Safe to dose women of
child-bearing potential?
 Safe to dose children?
 Safe to dose women
who are pregnant?
 Safe to dose for
extended duration?
29| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Post
marketing
 Safe for use
in the general
patient
population?
 Safe when
used “offlabel”?
1. Toxicology studies run prior to and in parallel
with clinical development
PoC
sPoC
Pre-clinical
Early Clinical
 Geneotox
• Cells / rodents
 Safety
Pharmacology
• CVS, CNS, resp, GI
[cells, rodents, nonrodent]
 General Tox
• 1 month study
[rodent & nonrodent]
Submission
Late Clinical
 Development and Repro
Tox?
 General Tox [3, 6, 9 &12
month studies – 2
species]?
 Carcinogenicity Studies
and/or transgenic mice
 Mode of action (tox)
investigative studies
30| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Post
marketing
• Surveillance
 Word of caution
• Think carefully before
proposing a clinical
Post marketing study
as a means to
evaluate the relevance
of a toxicity study
finding to humans.
• These studies are
long, difficult to
manage and you will
be held to your
commitment.
Ref: Jarvis et al (2011)
Outline
1. Toxicology studies run prior to and in parallel with clinical
development
2. Study design options are restricted by “Current” toxicology
package
• clinical trial duration, study inclusion criteria e.g. extending the clinical
trial population into women of child bearing potential, children, etc.
3. Small molecules and biologics are different
• duration of clinical effects, tox data required
4. The human relevance of a tox package finding may not be
understood
5. Pre-clinical/Non-clinical data will appear on the drug label
31| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
2. Study design options are restricted by “Current”
toxicology package – Study duration
 Duration of clinical studies limited by “Tox coverage”
• Duration measured by chronological time and animal lifespan
covered
ICH Topic M 3 (R2)
Knowledge check. Will a typical pre-clinical package of
toxicity studies support a one-year first in human clinical study?
32| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Correlation of body weight with different phases of
postnatal days
Int J Prev Med. Jun 2013; 4(6): 624–630.
 Rats live for 2 to 3.5 years and are sexually mature after
approximately 6 weeks
33| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
2. Study design options are restricted by “Current”
toxicology package – Women of child bearing potential
 Women of child-bearing potential (WOCBP) up to a
maximum of 150 women can be included in early clinical
trials, provided
• Confirmed to be not pregnant at the start of the study
• Pregnancy risk is controlled throughout study
• Duration of treatment no more than 3 months
 For studies of longer duration or in larger studies, the
definitive reproductive toxicity studies package is required
34| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
2. Study design options are restricted by “Current”
toxicology package – Pediatric indications
 Generally, data from adult human volunteers and the
supporting nonclinical data (in two species) will be available
prior to pediatric clinical trials even when the product is not
intended for development in adults.
 Section 12 of ICH M3(R2), Clinical Trials in Pediatric
Populations, generally provides recommendations for the
situation in which adult clinical trials precede pediatric trials
and indicates that
• juvenile animal toxicity studies are not considered important to support
short term PK trials in pediatric populations.
• However, if data from adult humans are not available and the drug will
be developed only for pediatric subjects, then this is a case where
juvenile animal studies in two species would be appropriate to support
pediatric PK trials.
35| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Outline
1. Toxicology studies run prior to and in parallel with clinical
development
2. Study design options are restricted by “Current” toxicology
package
• clinical trial duration, study inclusion criteria e.g. extending the clinical
trial population into women of child bearing potential, children, etc.
3. Small molecules and biologics are different
• duration of clinical effects, tox data required
4. The human relevance of a tox package finding may not be
understood
5. Pre-clinical/Non-clinical data will appear on the drug label
36| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
3. Small molecules and biologics are different
37| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Small molecule
Linear PK often (but not always) reasonable
Linear PK
PD tracks PK
J Am Coll Cardiol. 2003;41(4):557-564. doi:10.1016/S0735-1097(02)02868-1
38| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Large molecule
1 mg/kg
0.1 mg/kg
Time (days)
Higher
dose
Extended
period of
Receptor
Occupancy
Extended
duration of
clinical
effect
Receptor Occupancy (%)
10 mg/kg
10 mg/kg
1 mg/kg
0.1 mg/kg
Time (days)
Clinical effect
Change from BL
Concentration
Non-Linear PK, duration of receptor occupancy and clinical effect linked
39| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Time (days)
The TeGenero Incident
March 13, 2006 UK
 TGN1412-a Superagonist
 Anti-CD28 Antibody
40| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
TeGenero Incident - 1/2
Facts
 TGN1412 - Humanized IgG4 mAb derived from precursor mouse mAb 5.11A1
 Superagonist - Binds to CD28 and activates Tc without need for TCR preactivation,
resulting in polyclonal Tc expansion/activation and IL2 production.
 Treatment for B cell CLL (chronic lymphocytic leukemia) in which T cells
are deficient, and for AIDs in which Treg cell expansion might be
beneficial
 March 13, 2006, the first dose administered was 0.1 mg/kg
 Rapid onset of severe life-threatening AEs in all 6 HVs
• Rapid T cell activation, systemic inflammatory response, proinflammatory cytokine
release, depletion of circulating Tc ... nausea, diarrhea, vasodilatation, hypotension
• Intensive CU, intensive cardiopulmonary support (incl. dialysis),
high-dose methylprednisolone, and an aIL2R antagonist Ab
 It was concluded that TGN1412 had caused a ‘‘cytokine storm’’
followed by modest Tc proliferation 2 weeks later
 All six volunteers survived. One Pt has since had all of his toes and the tips of several
fingers amputated
41| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
TeGenero Incident - 2/2
Investigation of the incident and review of the science behind
 Expert Group on Phase One Clinical Trials appointed by the Medicines and Healthcare
Products Regulatory Agency. Leadership of Professor Gordon Duff. ‘Duff report’ 2006
• Royal Statistical Society in 2007 ; Early Stage Clinical Trial task Force in 2007
 MHRA initially concluded that ‘an unpredicted biological action of the mAb in
humans was the most likely cause of the adverse reactions’
 ‘The preclinical development studies performed with TGN1412 did not predict a safe
dose for use in humans, even though current regulatory requirements were met’
 Well ... really un-avoidable ? Probably not !
 Jan. 2007 - Committee for Medicinal Products for Human Use (CHMP) of the European
Medicines Agency (EMEA) announced that a guideline would be created
 ‘Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials
with Investigational Medicinal Products’ was final July 19, 2007
 Application to both biologics and NCEs
42| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Receptor Occupancy and Dose Escalation in First in
Human studies
RO
100
90
128 µg/kg; 93% RO
80
64 µg/kg; 86% RO
RO [%]
70
32 µg/kg; 75% RO
60
FIH dose >60 times
higher than 1.5 µg/kg,
calculated to lead to
10% RO
RO
16 µg/kg; 58% RO
50
40
8 µg/kg; 40% RO
FIH dose
administered
(100 µg/kg*)
30
4 µg/kg; 24% RO
20
2 µg/kg; 13% RO
1 µg/kg; 7% RO
10
*Leading to > 90% RO.
0
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
TGN1412 single dose (i.v.) [µg/kg]
Split dose approach may be an option for mAbs with very steep
dose/response curves expected in humans:
» Initially, 10% of the intended dose is administered, followed by
» A few hours later further 40%
» A few hours later remaining 50%
43| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Beyond the ‘Safety Factor Approach’ for Defining the
1st Dose in Human
Toxicological effect
Target-related PD effect
100%
100%
Toxicology
Most-sensitive
animal species
Anticipated
Human
Toxicology
Anticipated
Human PD
No observable
adverse
effects
Animal
PD
Minimal
PD Effect
MABEL
1st dose in human
Human NOAEL
(HED)
MABEL: Minimum Anticipated Biological Effect Level
Animal
NOAEL
Dose or Exposure
NOAEL: No Observable Adverse Effect Level
44| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
The Journal of Immunology, 2007, 179: 3325–3331.
45| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Outline
1. Toxicology studies run prior to and in parallel with clinical
development
2. Study design options are restricted by “Current” toxicology
package
• clinical trial duration, study inclusion criteria e.g. extending the clinical
trial population into women of child bearing potential, children, etc.
3. Small molecules and biologics are different
• duration of clinical effects, tox data required
4. The human relevance of a tox package finding may not be
understood
5. Pre-clinical/Non-clinical data will appear on the drug label
46| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
4. The human relevance of a tox package finding
may not be understood
 The assessment of safety is not trivial
• Safe for use in the general patient population?
• Safe when used “off-label”?
 Needs to be tailored to mechanism/mode of action for a
given therapeutic indication
 For end-points that are understood, “normal” can be
defined and departures from “normal” can be identified.
 However, not everything can be predicted.
• Hyper-sensitivity / Idiosyncratic drug reactions
47| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Safety record of phase 1 trials
However, some healthy subjects have died.
 A man died of cardiac arrest after taking an IMP in a trial
in Ireland in 1984. When he was screened for the trial, he
did not declare that he had recently been given a depot
injection of an anti-psychotic medicine (Darragh A et al.
Sudden death of a volunteer. Lancet 1985; 1: 93-94).
 A woman died after receiving a high dose of lidocaine - a
widely used local anaesthetic - to prevent discomfort from
endoscopy in a trial in the USA in 1996 (Trigg et al. Death
of a healthy volunteer. Int J Pharm Med 1998; 12: 151153).
 Another woman with mild asthma died of lung damage
after inhaling hexamethonium in a trial in the USA in 2001
(Steinbrook R. Protecting research subjects. NEJM 2002;
346: 716-720).
48| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Outline
1. Toxicology studies run prior to and in parallel with clinical
development
2. Study design options are restricted by “Current” toxicology
package
• clinical trial duration, study inclusion criteria e.g. extending the clinical
trial population into women of child bearing potential, children, etc.
3. Small molecules and biologics are different
• duration of clinical effects, tox data required
4. The human relevance of a tox package finding may not be
understood
5. Pre-clinical/Non-clinical data will appear on the drug label
49| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
5. Pre-clinical/Non-clinical data will appear on the
drug label e.g. rHu-Growth Hormone
 In the late 1980s soon after the approval of rHu-growth hormone there were
some concerns about de novo leukemia in paediatric patients without risk
factors
Watanabe et al (letter) 1988, Lancet 331:1159-1160
 After more than 20 years, leukemia has not been confirmed, but other signals,
including risk of second malignancies in patients previously treated with
irradiation, have been detected or confirmed through the National Cooperative
Growth Study (NCGS) which monitored the safety and efficacy of rHu-GH in
54,996 children
Bell et al, 2010, J Clin Endocrinol Metab 95(1):167-177
 Carcinogenicity studies conducted in rats and mice with recombinant rat and
mouse growth hormones – no effect on incidence of tumours at high doses
selected to provide systemic exposure of GH up to approx 10-fold over basal
levels and administered daily SC for 2 years
Farris et al, 2007, Toxicol. Sci. 97:548-561
50| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Rat carcinogenicity studies for rHu Parathyroid
hormone (1-34) and rHu PTH (1-84)
 rHu PTH (1-34) (teriparatide) –FORTEO/FORSTEO approved in US & EU
 rHu PTH (1-84) – Preotact is approved in EU
 Both produce osteosarcoma in carcinogenicity studies in Fischer rats (not
tested in other rat strains or in mice)
• The clinical relevance of these findings to patients will not be known with certainty until
extensive clinical experience has accrued
• Risk believed to be low & benefit of treatment considered to outweigh risk
 But USPI carries black box warning
51| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Example: Lorcaserin
Mammary tumours in female rats
Lorcaserin dose (mg/kg/day)
Vehicle
10
30
100
Plasma exposure margin
Number of Animals
Adenocarcinoma
Fibroadenoma
65
26
24
7
65
21
54*
24
65
24
55*
82
75
51*
51*
* p<0.01
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303198.pdf (Table 9)
52| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Example: Lorcaserin
Tumours in male rats
* p<0.05; ** p<0.01
Plasma exposure margin
Lorcaserin dose (mg/kg/day)
Vehicle
10
30
100
Skin: Subcutis; benign fibroma
65
3
7
65
7
24
65
11**
82
75
17**
Nerve Sheath: Scwannoma; all
0
0
2
9**
0
0
1
0
4
2
6**
2
0
1
0
0
4
4
5*
8**
Number of Animals
sites
Mammary gl, benign fibroadenoma
Mammary gl, adenocarcinoma
Skin; squamous cell carcinoma
Brain; Astrocytoma
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303198.pdf (Table 3c)
53| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Examples: US label lorcaserin, 2013
http://www.belviq.com/pdf/Belviq_Prescribing_information.pdf
54| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
55| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Outline
1. Toxicology studies run prior to and in parallel with clinical
development
2. Study design options are restricted by “Current” toxicology
package
• clinical trial duration, study inclusion criteria e.g. extending the clinical
trial population into women of child bearing potential, children, etc.
3. Small molecules and biologics are different
• duration of clinical effects, tox data required
4. The human relevance of a tox package finding may not be
understood
5. Pre-clinical/Non-clinical data will appear on the drug label
56| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
“Knowledge is experience. The universities do not
teach all things, so a doctor must seek out old
wives, gypsies, sorcerers, wandering tribes, old
robbers and such outlaws and take lessons from
them”.
Paracelsus 1493-1541
 Old wives, gypsies, .........
• Richard Knight
• Simon Chivers
• Pascal Espie
• Patrick Y. Mueller
• Per Sjoeberg
57| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
Any Questions
58| PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12th May 2014 |
How can Toxicology Learn
from Clinical?
Mike Aylott
12th May 2014
Contents
1. A Dose Response approach
2. Moving away from p-values
3. Using Bayesian statistics
1) Dose Response
•
Traditionally in Toxicology studies three or more dose levels are
identified, and all are compared directly to the control
•
But the current thinking in Clinical is to look at the Dose
Response curve, to gain a better understanding of the
therapeutic window
•
In January the EMA issued a recommendation on model-based
design and analysis of Phase II dose-finding studies
•
If we could model toxicity against dose, would this put
us at an advantage?
Traditional Approach
No information on the
toxicity of the
compound, other than
at these three dose
levels
Dose Response Approach
A far greater idea of the
relationship between
the dose and the
response
Benefits of the Dose Response Approach
•
•
•
•
•
•
•
A better understanding of the entire dose range
Essential when running adaptive designs
More knowledge of the variability of the response
The NOAEL may not exist with only three dose levels
No great increase in overall data
No loss in power by having smaller group sizes
You can predict certain doses, e.g. TD90.
Barriers to the Dose Response Approach
•
Toxicologists would need a change of mindset!
o
•
•
•
They like to know which dose levels are safe and which are not
High toxicity levels could be unethical
Having more dose levels might cause:o
housing difficulties
o
difficulties in preparing the test article
Less information at any given dose
o
rare findings could be missed (as fewer animals would be used at each dose
level)
o
•
Comparisons against background levels may be harder
Could not be applied to all study designs
o
Would be easier to apply to Early Tox studies
o
Carcinogenicity study designs must be acceptable to the regulators!
2) Moving away from p-values
•
•
Toxicologists love p-values, and tend to only look at significant stars
We are trying to move away from p-values, towards confidence
intervals, as this gives us:-
•
o
an indication of the magnitude of change
o
the direction of change
o
the precision of the study
o
statistical significance (yes or no)
The distinction between statistical significance and biological
relevance
•
We are winning the battle!
3) Using Bayesian Statistics
•
In most Genetic Tox assays, the Treated groups are compared to the
concurrent control first…
Control Treated
•
Historical
Control
•
… and then compared to the
Historical control
If the Treated group falls within
the Historical control bounds,
then it is assumed that there is
no biological relevance
As we have prior belief of how the control values are distributed,
this is an area that should use Bayesian Methodology!
This also has the potential to reduce sample sizes.
MPE Vehicle 24hr Counts (2000&4000
combined, average /2000)
Study A
3.29
1.69
Summary
What I would like to see in Toxicology in 10 years’ time:-
•
A Dose Response approach applied in Toxicology, particularly
early Toxicology studies
•
•
Confidence intervals routinely used instead of p-values
Bayesian statistics used in Genetic Toxicology, or any assays with
large historical datasets.
Questions / Discussion
Conclusions



Pre-clinical and clinical role responsibilities
(should) overlap
We are working on the same compounds/projects
We can learn from each other
www.huntingdon.com
Any final questions?
www.huntingdon.com