s ome observations on the design of early stage clinical trials in the pharmaceutical industry

SOME OBSERVATIONS ON THE

DESIGN OF EARLY STAGE CLINICAL TRIALS IN THE

PHARMACEUTICAL INDUSTRY

Hans HockeyBiometrics Matters Limited (BML)

13 Nevada RoadHamilton 3216New Zealand

[email protected], Kobe, Japan, August 2012

EMR-IBS, Tel Aviv, 23 April 2013 1

mailto:[email protected]

Structure of talk

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Structure of talk• There is no structure!

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Five Case Studies1) Two doses plus placebo2) “Factorial” dose escalation and food effect3) 3-treatment, 3-period cross-over design4) Escalating dose study with placebo substitution

plus 5) Augmented placebo insertion and food effect

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Take-home points1. Use contrasts that are orthogonal, and are models, not

tests2. Design programs to include more combined studies,

including factorial and similar designs3. Don’t worry about ‘imbalance’ 4. Practical matters can matter more than statistical issues5. In cross-over designs, never ever fit Sequence6. Use mixed, not fixed, models for maximum information

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Take-home point 11. Use contrasts that are orthogonal, and are models, not

tests. 2. Design programs to include more combined studies,


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Treatment5 mg 10 mg Placebo

Case Study 1

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TreatmentContrast 5 mg 10 mg Placebo10 v placebo 0 1 -15 v placebo 1 0 -1

Case Study 1

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Dose (mg)Contrast 0 5 10Linear -1 0 1Quadratic -1 2 -1

Case Study 1

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1 1 2Dose (mg)

Contrast 0 5 10Linear -1 0 1Quadratic -1 2 -1

2 2 2

Case Study 1

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Dose (mg)Contrast 0 5 10Linear -1 0 1Quadratic -1 2 -1

A modeller, not a tester,would prefer even more dose levels

Case Study 1

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Take-home point 21. Use contrasts that are orthogonal, and are models, not tests2. Design programs to include more combined studies,


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A typical Phase 1 drug development program list of

studies

Over 50 studies, many are escalating doses or 2x2 crossover designs

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29 studies with drug plasma concentrations and liver function tests (LFTs)

202 Safety, toleration and PK of single dose escalating oral solution study 203 Compare PK of oral solution and capsule formulation in fasted state 204 Safety, Toleration and PK of single escalating capsule dose study 205 Safety, Toleration and PK of oral SD followed by 10 day oral MD 206 Safety, Toleration and PK of single IV escalating dose 207 Safety, Toleration and PK of single IV escalating dose 208 Compare PK of 200mg capsule dose in fed and fasted states 209 Safety, Toleration and PK of single IV dose followed by 10 day multiple IV 210 PK, Safety and Toleration after oral admin & effect of XYZ on Prednisolone 213 Safety, Toleration and PK of single IV escalating dose 214 Safety, Toleration and PK of single IV dose followed by 10 day multiple IV 217 Compare PK of 200mg oral solution dose in fed and fasted states 222 Compare PK of multiple oral solution dose in fed and fasted states 224 Compare multiple dose bioequivalence of commercial tablet v research capsule 228 Effect of Rifamycins on the PK of XYZ study 229 Cimetidine/ranitidine interaction on PK of XYZ study 230 Multiple dose IV-oral switch over 231 XYZ Visual Electrophysiological Study 232 Pivotal BE study 233 Effect of Phenytoin on XYZ Study 237 Renal Impairment Study 238 Hepatic Insufficiency Study 240 Protease Inhibitor Study 243 Azithromycin Interaction Study 245 Capsule vs tablet bioequivalence study 247 Omeprazole Interaction Study 248 BE Oral Suspension versus new Commercial Tablet Study 250 Young/Elderly Male/Female Study 1005 BE Clinical Tablet v Commercial Tablet/Food Interaction Study

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26 studies excluded - no LFTs or no XYZ drug alone 001 Tacrolimus Study 201 SD 216 Compare Safety, Toleration and PK of 200mg dose given IV and orally 220 Absorption, Metabolism and Excretion of single oral and single IV dose 225 Toleration, safety of ABC versus placebo 226 Toleration, Safety & PK of IV XYZ with ABC 227 Safety, Toleration & PK of IV XYZ with ABC. 234 Warfarin Interaction study 235 Cyclosporin Interaction Study 236 Digoxin interaction 239 Repeat Warfarin Study 241 XYZ on Phenytoin Study 242 Genotype/phenotype 244 XYZ on Indinovir Study 249 IV Paediatric SD Study 1007 IV Paediatric MD Study 1009 Tacrolimus Interaction Study 1012 Hepatic Impairment Study 1013 Omeprazole Study 1016 Summary (renal impairment) Study JP-501 Oral SD Study JP-502 Intravenous SD Study JP-503 Oral MD Study JP-504 IV MD Study JP-505 Oral SD Genotype Study JP-506 IV SD Genotype

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Combining studiesRonald Fisher argued in 1926 that "complex" designs (such as factorial designs) were more efficient than studying one factor at a time.Fisher wrote,"No aphorism is more frequently repeated in connection with field trials, than that we must ask Nature few questions, or, ideally, one question, at a time. The writer is convinced that this view is wholly mistaken."Nature, he suggests, will best respond to "a logical and carefully thought out questionnaire".

A factorial design allows the effect of several factors and even interactions between them to be determined with the same number of trials as are necessary to determine any one of the effects by itself with the same degree of accuracy. (Wikipedia) 18

Protocols with drug plasma concentrations and liver function tests (LFTs)


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Case Study 2

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Combining studies (part 1)

•Three doses by two food regimes. Use all 6 combinations? Both food regimes at all 3 doses

A Phase 1 PK studyDesign 1

Cohorts SubjectsPeriod

1 2 3 4

1

1-4 150 fasted

150 fed

5-8 150 fed 150 fasted

2

9-12 300 fasted

300 fed

13-16 300 fed 300 fasted

3

17-20 600 fasted

600 fed

21-24 600 fed 600 fasted

Fed v fasted always a 2x2 crossoverToo long! (7-day washout three times)

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1 2 3 4

1

1-4 150 fasted

150 fed

5-8 150 fed 150 fasted

2

9-12 300 fasted

300 fed

13-16 300 fed 300 fasted

3

17-20 600 fasted

600 fed

21-24 600 fed 600 fasted

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1 2 3 4

11-4 150

fasted5-8

2

9-12 300 fasted

300 fed

13-16 300 fed 300 fasted

317-20 600

fasted21-24

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1 2 3 4

1 1-12150 fasted

213-18

300 fasted

300 fed

19-24300 fed 300

fasted

1 1-12600 fasted

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A Phase 1 PK study – Design 3

4, not 6, treatments (6 not 12 cells)Only one washout period

Safe escalationWhat assumptions? Two analyses? NO!

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Combining studies (part 2)

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Case Study 3

Capsule v tablet&

Fed v fast for capsules

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Bioequivalence

Food

effe

ct

A B

C



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31

Formulation effect (1 v 2)

Food

effe

ct (A

v B

)

A1 A2

B2B1

NOT a Case Study

Not seen by me anyhow

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extraction

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Take-home point 3• Use contrasts that are orthogonal, and are models, not tests• Design programs to include more combined studies,

including factorial and similar designs• Not every PK crossover subject needs a placebo • Practical matters can matter more than statistical issues• In cross-over designs, never ever fit Sequence• Use mixed, not fixed, models for maximum information

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Design: This is a single-blind, placebo-controlled, randomised, “cross-over”, single-dose escalation study in which the toleration, safety and pharmacokinetics of XYZ-123,456 will be investigated.

Both ‘cross-over’ and escalation? Two groups or cohorts, 8 each 35

Case Study 4

Subjects Week 1 Week 3 Week 5 Week 7

1&2 Placebo 1 5 20

3&4 1 Placebo 5 20

5&6 1 5 Placebo 20

7&8 1 5 20 Placebo

Group A doses (mg) over time

8 subjects per dose, 8 per Placebo(Same pattern for Group B doses, but 2.5, 10 & 40 mg)

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Subjects Week 1 Week 3 Week 5 Week 7

1&2 Placebo 1 5 20

3&4 1 Placebo 5 20

5&6 1 5 Placebo 20

7&8 1 5 20 Placebo

Placebo insertion design8 subjects per dose, 8 per Placebo(Same pattern for Group B doses, but 2.5, 10 & 40 mg)

Placebo insertion

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Subjects Week 1 Week 3 Week 5

1&2 Placebo 5 20

3&4 1 Placebo 20

5&6 1 5 Placebo

Placebo substitution

4 subjects per dose, all 6 per Placebo(Placebo is of least interest for PK, but needed for safety comparisons)

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1&2 Placebo 5 20

3&4 1 Placebo 20

5&6 1 5 Placebo

7&8 1 5 20

Why notPlacebo substitution plus!

6 subjects per dose, all 6 per Placebo(Placebo is of least interest for PK, but needed for safety comparisons)

6 per treatment!39


1&2 Placebo 5 20

3&4 1 Placebo 20

5&6 1 5 Placebo

7&8 1 5 20

“¾ placebo substitution”

Embrace imbalance!

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Subjects Week 1 Week 3 Week 5 ABCD drop

BIBD

1&2 0 5 20 B ACD

3&4 1 0 20 C BAD

5&6 1 5 0 D BCA

7&8 1 5 20 A BCD

¾ placebo substitution

Embrace imbalance!(but it isn’t unbalanced! – it’s a BIBD)

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Case Study 5

Still don’t worry about imbalance (it also is a BIBD, but plus extra replications of non-placebo sequences)

Do worry about practical issues

(in this case, not sure if 10, 11 or 12 pre-screened subjects will turn up on Day 1, and less on Day 2)

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Subject Day Dose per dayor First Second First Second

Sequence AM PM AM PM1 E0 E2 A4 A8 2 12

2 A0 A2 E4 E8 2 12

3 E2 E0 A4 A8 2 12

4 A2 A0 E4 E8 2 12

5 E2 E4 A0 A8 6 8

6 A2 A4 E0 E8 6 8

7 E2 E4 A8 A0 6 8

8 A2 A4 E8 E0 6 8

9 E2 E4 A8 A8 6 16

10 A2 A4 E8 E8 6 16

11 E2 E4 A8 A8 6 16

12 A2 A4 E8 E8 6 16

Augmented insertion design for 12 subjects over 4 sessions in 2 days

Ex = Food (fEd) with x capsules Ax = Fasted (fAst) with x capsules

(from final protocol) 44

Practical Design Issues•The design includes placebo insertion such that placebo occurs twice in each of 4 sessions, with double blinding. Each subject has exposure to each active dose, with subjects 9-12 receiving the maximum of two 8-capsule sessions in the one day, after having been exposed to 4 capsules the previous test day. Total exposure ranges from 2 to 16 capsules per day per subject.

•The design is robust to not having all planned 12 subjects available as there is double replication of the sequences 9 and 10 (sequences 11 and 12). Random allocation of sequences to subjects will be arranged such that if there is a shortfall of 1 or 2 subjects then sequence 12 and then 11 will not be allocated. If there is a further shortfall (very unlikely) then all missing Day 1 subjects will be replaced.

•All sequences/subjects include the highest dose on Day 2, so given that 10 to 12 subjects completed Day 1, there is no imperative to replace subjects if up to 2 do not attend Day 2. If the Day 2 discontinuation rate is higher though, then consideration will again be given to subject replacement.

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Advantages of cross-oversUsing within subject variation gives increased precision and power

Lower costs (usually extra subjects more expensive than extra periods)

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Advantages of cross-oversUsing within subject variation gives increased precision and power

Lower costs

Sequence, carryover and treatment.period are all aliased

Disadvantage of 2x2 cross-overs

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2x2 cross-over ANOVA table (12 subjects)d.f.

Subjects Sequence 1 Between subject error 10Total 11Periods within subjects Treatment 1 Period 1Within subject error 10Total 12TOTAL 23

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Subjects Carryover 1 Between subject error 10Total 11Periods within subjects Treatment 1 Period 1Within subject error 10Total 12TOTAL 23

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Subjects Treatment.Period 1 Between subject error 10Total 11Periods within subjects Treatment 1 Period 1Within subject error 10Total 12TOTAL 23

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Subjects Sequence 1 Between subject error 9Total 10Periods within subjects Treatment 1 Period 1Within subject error 10Total 12TOTAL 23

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Subjects Sequence 1 Between subject error 9Total 10Periods within subjects Treatment 1 Sequence.Treatment 1Within subject error 10Total 12TOTAL 23

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My personal preference!d.f.

Subjects Treatment.Period 1 Between subject error 10Total 11Periods within subjects Treatment 1 Period 1Within subject error 10Total 12TOTAL 23

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ReferencesAny of the classic design texts of the 1950s, such as:

• Cochran and Cox (1950)• Kempthorne (1952)• Cox (1958)• Quenouille (1958)• and even Fisher (1935) and Yates (1937)!

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References (cont’d)

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s ome observations on the design of early stage clinical trials in the pharmaceutical industry

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