www.huntingdon.com


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


www.huntingdon.com





Run every 18 months, last one being March 2013

www.huntingdon.com

Global Head of Statistics and Data Management
www.huntingdon.com







www.huntingdon.com






www.huntingdon.com


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


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


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















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














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




0.25 hrs Protocol Amendment Review


>40 hrs Telemetry Study

70 x 1, 17 x 2, 2 x 3


A ctivity, AUC, Bracketing Assay, Cytokines…
…Respiration, Telemetry, Xenopus & Z ooplankton www.huntingdon.com


In which area of pharmaceutical drug development do you work?
11%
19%
63%
7% www.huntingdon.com


Have you ever collaborated with statistician colleagues in the “other” area?
37%
63% www.huntingdon.com


Does the work of your colleagues from the “other” area influence activities in your area?
45%
55% www.huntingdon.com


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


Many papers published by ToxSIG members

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 ; 175-
187.






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


No
10%
Clinical
Yes; 79
No; 10
Yes
90%
No, 0
Pre-clinical
Yes, 11 www.huntingdon.com

Influence of Toxicology studies on Clinical
Philip Jarvis
12 th May 2014
FJ Spence
February 18 th , 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| 12 th 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| 12 th 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| 12 th 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| 12 th May 2014 |

Toxicology Basic Design
Healthy
Animals
[Homogenous with respect to age, size, weight]
Control (vehicle dosed)
Low dose
Intermediate dose
High dose
Dosing period
i.e. majority of animals display no overt signs of toxicity.
Animals necropsied
[All major organs
Analysed macro and microscopically]
28 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th May 2014 |

1. Toxicology studies run prior to and in parallel with clinical development sPoC
Pre-clinical
PoC
Early Clinical
Submission
Late Clinical
Post marketing

Safe to take cmpd / biological entity into humans?

Safe to dose women of child-bearing potential?

Safe to dose children?

Safe for use in the general patient population?

Safe to dose women who are pregnant?

Safe when used “offlabel”?

Safe to dose for extended duration?
29 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th May 2014 |

1. Toxicology studies run prior to and in parallel with clinical development sPoC
Pre-clinical
PoC
Early Clinical
Submission
Late Clinical
Post marketing

Geneotox
• Cells / rodents

Development and Repro
Tox?
•
Surveillance

Safety
Pharmacology
•
CVS, CNS, resp, GI
[cells, rodents, nonrodent]

General Tox
•
1 month study
[rodent & nonrodent]

General Tox [3, 6, 9 &12 month studies – 2 species]?

Carcinogenicity Studies and/or transgenic mice

Mode of action (tox) investigative studies

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.
30 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th May 2014 |
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| 12 th 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| 12 th 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| 12 th 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| 12 th 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| 12 th 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| 12 th May 2014 |

3. Small molecules and biologics are different
37 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th 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| 12 th May 2014 |

Large molecule
Non-Linear PK, duration of receptor occupancy and clinical effect linked
10 mg/kg
10 mg/kg
1 mg/kg
1 mg/kg
0.1 mg/kg
0.1 mg/kg
Time (days)
Time (days)
Higher dose
Extended period of
Receptor
Occupancy
Extended duration of clinical effect
39 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th 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| 12 th 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| 12 th 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 M edicines and H ealthcare
Products R egulatory A gency. 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 C ommittee for M edicinal P roducts for H uman Use (CHMP) of the E uropean
M edicines A gency (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| 12 th May 2014 |

Receptor Occupancy and Dose Escalation in First in
Human studies
100
90
80
70
60
50
40
30
20
10
0
0
32 µg/kg; 75% RO
64 µg/kg; 86% RO
16 µg/kg; 58% RO
4 µg/kg; 24% RO
2 µg/kg; 13% RO
1 µg/kg; 7% RO
10
8 µg/kg; 40% RO
20 30 40 50 60
RO
70
FIH dose administered
(100 µg/kg*)
80 90 100 110
TGN1412 single dose (i.v.) [µg/kg]
128 µg/kg; 93% RO
RO
120 130 140
*Leading to > 90% RO.
FIH dose >60 times higher than 1.5 µg/kg, calculated to lead to
10% RO
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| 12 th May 2014 |

Beyond the ‘Safety Factor Approach’ for Defining the
1 st Dose in Human
Toxicological effect
Target-related PD effect
100% 100%
Anticipated
Human
Toxicology
Toxicology
Most-sensitive animal species
Anticipated
Human PD
Animal
PD
No observable adverse effects
Minimal
PD Effect
MABEL
1 st dose in human
Human NOAEL
(HED)
Animal
NOAEL
Dose or Exposure
MABEL: Minimum Anticipated Biological Effect Level NOAEL: No Observable Adverse Effect Level
44 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th May 2014 |

The Journal of Immunology, 2007, 179: 3325 –3331 .
45 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th 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| 12 th 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 endpoints 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| 12 th May 2014 |


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: 151-
153).

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| 12 th 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| 12 th 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| 12 th 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| 12 th May 2014 |

Example: Lorcaserin
Mammary tumours in female rats
Plasma exposure margin
Number of Animals
Adenocarcinoma
Fibroadenoma
Lorcaserin dose (mg/kg/day)
Vehicle 10 30 100
-
65
7
65
24
65
82
75
26
24
21
54*
24
55*
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| 12 th May 2014 |

Example: Lorcaserin
Tumours in male rats
* p<0.05; ** p<0.01
Plasma exposure margin
Number of Animals
Skin: Subcutis; benign fibroma
Lorcaserin dose (mg/kg/day)
Vehicle 10 30 100
-
65
7
65
24
65
82
75
3
0
7
0
11**
2
17**
9** Nerve Sheath: Scwannoma; all sites
Mammary gl, benign fibroadenoma
Mammary gl, adenocarcinoma
Skin; squamous cell carcinoma
Brain; Astrocytoma
0
1
0
0
1
0
0
0
4
2
4
4
6**
2
5*
8** http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303198.pdf
(Table 3c)
53 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th 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| 12 th May 2014 |

55 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th 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| 12 th 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 ” .

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| 12 th May 2014 |
Paracelsus 1493-1541

Any Questions
58 | PSI Conference 2014 - Influence of toxicology on Clinical | Philip Jarvis| 12 th May 2014 |

Mike Aylott
12 th 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.

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.




www.huntingdon.com

www.huntingdon.com