Can the ‘thorough QT study’ be replaced?

Borje Darpo MD PhDAssociated Professor of Cardiology,

Global Medical DirectoriCardiac Technologies

November 2013

• No one is truly satisfied with the blanket requirement for a TQT study for each and all drugs in development;

• There is an increased focus on methodologies to replace the TQT study:

Staggered approach seems likely; alternative approaches may become acceptable initially for some compounds.

• Sponsors will, for good reasons, resist changing the design of the FTIM study dramatically, but:

will be willing to explore novel methodologies within the ‘standard design’.

may consider adapted designs for specific projects, for which an early read of ECG effects may be vital for project viability.

Assumptions

• Modern techniques for ECG recordings and interval measurements enable better precision in the assessment of drug-induced changes of ECG parameters.

• Exposure response analysis using concentration-effect models has greater power to detect or exclude small ECG changes as compared to the E14 time-matched analysis.

• Provided the same confidence in the data can be achieved, it may be a more efficient use of human resources to perform QT assessment as part of a standard clinical pharmacology study, as compared to conducting a designated through QT study.

Background

• Both FDA and EMA seem to have an interest in moving away from the blanket request to perform TQT studies for all projects:

The Pharmacometrics group at the FDA, has published extensively on the use of concentration effect modeling (CEM) for QT assessment;

Both Hao Zhou and Joanne Zhang (IRT) have suggested CEM criteria to waive the TQT study;

CSRC had a Think tank meeting in February 2012 on ‘Enhanced confidence in Early QT assessment’ with extensive participation form FDA (Drs. Stockbridge, Temple, Throckmorton, Garnett, Zhang), EMA (Dr. Prasad) and the E14 Implementation group (FDA, EMA, PhRMA, EFPIA and Health Canada represented);

CSRC will soon publish a White paper on ‘How to replace the TQT study’ with E14 representatives from FDA, EMA, EFPIA and PhRMA participating.

The IQ-CSRC group will study 5 marketed drugs with a positive TQT study, selected by the FDA, in a ‘SAD’-like study to evaluate the concordance between Early QT assessment and the TQT study

Changing Regulatory Landscape

1. Q&A document completed2. Based on ‘recent initiatives’, the E 14

Implementation group has recommended that the group is transferred into a ‘Discussion group’ to follow the development in the area the next coming years.

Brief ICH E14 Update

1. The view of the regulators: Reassurance that a new approach can identify QT

prolonging drugs at the same level of confidence:• Very low incidence of false negatives

It seems that FDA is debating internally whether ‘excluding an effect > 10 ms’ is too conservative

Regulators are less concerned over ‘false positives’2. The view of the sponsor:

In addition to the above, Assurance that the frequency of false positives is

sufficiently low Cost-effectiveness

What Will it Take to Replace the TQT study?

1. Acceptance of analytical approaches other than the E14 time-matched analysis, allowing data to be used more effectively (= concentration effect modeling)

2. Improved precision of QT measurement technologies;

3. Potentially: Demonstration of assay sensitivity, i.e. that the study can detect a small QTc prolongation (or just change?), without the use of moxifloxacin as a positive control, alternatively some level of quality control of ECG data

What Will it Take to Enhance our Confidence in Early QT Assessment?

1. Use more data, not less:a) Analysis based on concentration effect modeling

results in greater power to exclude small effects the more data are used;

b) To some extent, the power to exclude a small effect with the time matched analysis gets lower the more data (at least # of time points) are used.

2. Use more precise methodologies for QT measurement:a) The precision of measurement substantially affects

the power to exclude a small effect.

Key Factors – In My Opinion

• Clinical QT assessment in early studies should be incorporated into the standard design:• There are many other, important objectives of these studies• Many projects are terminated for other reasons• Cost must be weighed against performing TQT studies in ‘surviving’

projects only.

• Within this scope, early QT assessment provides an opportunity for ‘high confidence’ estimation of the effect:• Unparalleled, high plasma levels;• Large potential to improve precision of QT measurement• Consensus on demonstration of assay sensitivity is needed.

QT Assessment in Early Clinical Studies- Starting Points

Background:◦ Safety pharmacology:

hERG effects - concentration-dependent inhibition with high IC50 (43 M)

No effect on heart rate or blood pressure.

Current Study:◦ Primary objectives safety and tolerability◦ Secondary CV safety objective – characterize QT effects as precisely as

possible in a small N study. Conventional SAD/MAD study with enhanced ECG monitoring:

◦ N=8 subjects (6+2) per dose cohort, parallel design◦ Predose (SD) and Day-1 (MD) baseline recording ◦ On-drug 24 hr recording; 10 ECGs extracted at prespecified timepoints◦ High Precision QTc analysis

Cost of enhanced ECG monitoring ~10% of the total study budget.

Case Study:Phase I SAD/MAD Study of a Novel CNS Drug

Results: SAD PART

QTc effect of 12 ms could be excluded across doses

Concentration effect modeling of SAD/MAD data

0 2000 4000 6000 8000 10000

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-50

51

0

Concentration (ng/mL)

Q

TC

F (

ms

)Median concentration quantiles

Mean (90% CI) predicted QTcF prolongation

Linear model Intercept: 2.78 ms (-0.16 to 5.71)with intercept Slope: -0.00011 ms per ng/mL (-0.00087 to 0.00066)

3-dose study with supra-therapeutic dose Once-daily drug with non-linear PK and with auto-

induction of CYPs leading to ↓↓ plasma levels with MD◦ Challenge to achieve high plasma levels◦ 3 doses of supra-therapeutic dose q12 hours

Achieved plasma levels 2 x as high as in MD over 14 days with same high dose

18 healthy subjects in 2-period XO with placebo One (high) active dose level vs. placebo High precision QT measurement technique

◦ Achieved precision: SD of ∆QTcF: 6.6 ms

Case Study - Adapted Design

Darpo B et al. Assessment of the cardiac safety and pharmacokinetics of a short course, twice daily dose of orally-administered mifepristone in healthy male subjects. Cardiol J 2013; 20: 152

Adapted Design Phase 1 Study for Definitive QT Assessment

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DD

QTcF (msec)

Time (hours)

DD QTcF

ST dose DRUG: Day 1 ST dose DRUG: Day 2

Achieved precision: SD of ∆QTcF: 6.6 ms

Darpo B et al. Assessment of the cardiac safety and pharmacokinetics of a short course, twice daily dose of orally-administered mifepristone in healthy male subjects. Cardiol J 2013; 20: 152

Adapted Design - Concentration Effect Modeling

Linear model with mean intercept fixed to 0 (with variability)Slope: -0.0010 (-0.0014;-0.0005)

Darpo B et al. Assessment of the cardiac safety and pharmacokinetics of a short course, twice daily dose of orally-administered mifepristone in healthy male subjects. Cardiol J 2013; 20: 152

Results

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5

10

15

20

25

QTcF

Dose X Dose 3X Dose 5X

Time

QT

cF (

mse

c)Dose Dose

Achieved precision: SD of ∆QTcF:7 ms on active; 8 ms on placebo

Concentration Effect Modeling

Linear model Intercept: 3.9 ms (90% CI: 1.0 to 6.8 ms)with intercept: Slope 0.016 ms per ng/mL (0.011 to 0.021 ms)

Improving Precision of ECG Measurements

Increasing the Power of SAD-MAD QT Studies

Conventional Semi-Automated ECG Analysis Method

Holter Flashcards

Surveyor DVDs

Extract ECGs

Average of 9 QT-RR values/

timepoint

Over-read ECGs Calculate QTc

Se

mi-

Au

tom

ate

d P

roc

es

s

Incoming Data

3 beats per ECG

3 ECGs

Timepoint 1…n

• Typically, visual assessment

High Precision QT Analysis MethodiC

ard

iac

HP

QT

Pro

ce

ss

up to 10 ECGs

Full Manual Review of 3 ECGs

Manual Adjudication of Beats from 10 ECGs

• Adjudicate QT interval in all “low confidence” beats using pass-fail approach

• No mixing of computerized and manual measurements improves precision

QTc Measurement at timepoint is derived from

100-120 QT-RR values

Holter Flashcards

Surveyor DVDs

TQT Plus ECG Extraction

• Identify periods of minimal QT-RR variability/ noise within timepoints

Holter data on flashcards

ECGsextracted

TQT Plus ECG Extraction Criteria:

• Protocol timepoints

• Steady-state repolarization periods identified in Holter data

• High quality signal (low noise) evaluated within identified periods

TQT Plus ECG Extraction Criteria:

• Protocol timepoints

• Steady-state repolarization periods identified in Holter data

• High quality signal (low noise) evaluated within identified periods

Timepoint 0

Timepoint 1

Timepoint n

…

ECGsover-read

iCardiac Technologies, Inc. and University of Rochester 10

QTQT-- RR adaptationRR adaptationCOMPAS methodCOMPAS method

Rapid changes

Slow changes Time adaptation to slow changes

Time adaptation to rapid changes

Sustained and non-sustained rapid changes on Holter ECGs (repolarization reserve)

Repolarizationsteady-state

identifiedHolter data on flashcards

ECGsextracted

TQT Plus ECG Extraction Criteria:

• Protocol timepoints

• Steady-state repolarization periods identified in Holter data

• High quality signal (low noise) evaluated within identified periods

TQT Plus ECG Extraction Criteria:

• Protocol timepoints

• Steady-state repolarization periods identified in Holter data

• High quality signal (low noise) evaluated within identified periods

Timepoint 0

Timepoint 1

Timepoint n

…

ECGsover-read

iCardiac Technologies, Inc. and University of Rochester 10

QTQT-- RR adaptationRR adaptationCOMPAS methodCOMPAS method

Rapid changes

Slow changes Time adaptation to slow changes

Time adaptation to rapid changes

Sustained and non-sustained rapid changes on Holter ECGs (repolarization reserve)

Repolarizationsteady-state

identified

• QC and confidence rank all beats, flag “low confidence” beats

• Auto measurements of QT interval only in “high confidence” beats

• Manual read of 3 ECGs to assess T-wave morphology, confirm QT, PR, QRS by Cardiologist

Extract ECGs Over-read ECGsIncoming Data

Calculate QTc

Industry-Average Precision vs. High Precision QT

Study N Design

SD of ∆QTc,

ms

Method

Morganroth, 2010

47 P 18.4 SA

Moore, 2010 41 XO 12 Manual

DeKam, 2010 82 XO 8.9 Manual

March, 2009 51 P 14 SA

Poordad, 2009

60 XO 10.2 SA

Vande, 2009 73 XO 8.9 Manual

Tyl,  2009 62 XO 13.1 Fully automated

62 XO 10.1 SA1

62 XO 9.4 SA2

Average for SA/Manual

~10-11

Notes:• P: Parallel; XO: crossover; SD of ∆QTc: standard deviation of ∆ QTc for moxifloxacin arm• Eclysis is a “high precision” analysis method proprietary to AstraZeneca• For TQT studies – precision from moxi arm, other studies – precision from drug arm(s)

Study N Design

SD of ∆QTc, ms

Pfizer and Roche TQTs, Darpo, 2010

35 XO 6

50 XO 6

Lenvatinib TQT, 2010

50 XO 5.7

Unpublished Study 1 (SAD-MAD), no moxi

8 P 5-6

Pridopidine MAD Study (no moxi)

55 P 8

Albiglutide TQT Study

85 P 6

Lomitapide TQT 54 XO 6.5

Unpublished Study 5 (MAD)

18 XO 6.6

Dalen, 2010 (Eclysis*)

35 XO 6.3

Average for High Precision

~6-7

Industry-Average Precision, Semi-Automated or Manual Studies with High Precision QT

Why is QT Measurement Precision Important?

Study 1 (n=47 men)

Mo

xif

lox

ac

inS

tud

y D

rug

Study 2 (n=50 both genders)

SD of ∆QTc ~18 msec SD of ∆QTc = 5.7 msec

From: Morganroth J et al. CPT March 10, 2010; doi:10.1038/clpt.2009.265Study conducted by COResearch.

From: Shumaker R et al. LENVATINIB (E7080) DOES NOT PROLONG THE QTc INTERVAL – RESULTS FROM A THOROUGH QT STUDY IN HEALTHY VOLUNTEERS. Poster presented at the AARC-NCI-EORTC 2011, San Francisco, CA, USA, November 12–16, 2011.

Another example….

March et al. Assessment of the cardiac safety of fampridine-SR sustained-release tablets in athorough QT/QTc evaluation at therapeutic and supratherapeutic doses in healthy individuals.Expert Opinion Invest Drugs 2009; 18: 1807-15

Result of a TQT study (2)

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F (m

sec)

Time (hours)

QTcF

75 mg Lomitapide adjusted for Placebo

200 mg Lomitapide adjusted for Placebo

75 mg Lomitapide + Ketoconazole adjusted for Ketoconazole alone

Ketoconazole adjusted for Placebo

Moxifloxacin adjusted for Placebo

54 healthy volunteers, 5-way SD, XO studyPrecision: Mean SD of ∆QTcF 6 to 7 ms

Darpo et al. ANE 2013; Doi: 10.1111/anec.12103 [doi]

Precision => Power, False-Positives and/or Sample Size

Sample size estimates (one tail t-test) for crossover or approx. size for parallel studies*

*(1) Type I error: α = 0.05 (2) True mean difference: Δ = 3 ms (3) The upper limit of the upper 2-sided 90% confidence interval (CI) will fall below 10 ms for up to 12 timepoints (4) Independent assumption across all time points

High Precision QT

High Precision QT

Conventional semi-Auto/Manual QT Analysis

Conventional semi-Auto/Manual QT Analysis

Important Determinants to Enhance Precision of the QT Measurement

1. How subjects/patients are handled, i.e. experimental conditions Environment, activity, mental stress, etc.

2. Extraction of optimal ECG recordings from nominal (prespecified) timepoints

3. Measurement of high quality beats only4. No mixing between manually adjusted and

computer made measurement5. Amount of data

Power of Concentration Effect Modeling vs. E14 Time-Matched Analysis

CEM provides sufficient power to exclude an effect > 10 ms with 9 subjects, assuming High Precision ECG analysis

Underlying Effect

Analysis type N=12 N=9 N=6

3 ms E14 time-matched 0.63 0.42 0.20

CEM 1 0.96 0.89 0.70

CEM 2 0.93 0.88 0.78None TM 0.78 0.58 0.31

CEM 1 1.00 0.97 0.88

CEM 2 0.99 0.97 0.89

Values in bold = more than 85% power to exclude an effect

Does the Precision of the QTc Measurement Matter?

Assumed underlying effect

SD of QTcF Number needed

3 ms 6 ms 93 ms 10 ms 21

Sample size to provide 90% power to exclude a QTc effect > 10 ms using CEM

Parallel designed study

IQ-CSRC Prospective Study

Borje Darpo MD PhD

History of the Project

CSRC Think Tank Meeting (Feb 2012)– https://www.cardiac-safety.org/think-tanks/november-2011/

thinktank-meeting-on-qt-assessment-in-early-clinical-development

FDA-IQ Clinical Pharmacology Leadership Meetings– May 2012. FDA’s retrospective analysis was presented and

prospective study was discussed as a path forward.– Sep 2012. Study design concepts and analyses were discussed.

FDA agreed to select drugs to be tested.

CSRC-IQ Clinical Pharmacology Collaboration (Dec 2012)

Borje Darpo MD PhD

CSRC-IQ Core Working Group

IQ Consortium Clinical Pharmacology Leadership Group• Nenad Sarapa (Bayer)• Venkat Jarugula (Novartis)• Jim Keirns (Astellas)• Charles Benson (Lilly)• Danise Subramaniam

(Lilly)Project Management

CSRC• Christine Garnett (Certara)• Borje Darpo (iCardiac)• Catherine Ortemann-Renon

(Sanofi)• Corina Dota (AstraZeneca)

OQT Working Group (SAP)• Steve Riley (Pfizer)• Georg Ferber (Consultant)

FDA• Kevin Krudys• Lars Johannesen

Borje Darpo MD PhD

Current project status

• FDA has identified 5 ‘TQT-study positive’ compounds that will be studied

• In addition, 1 negative (levocetirizine) has been added• Agreed criteria for a negative result in Early QT assessment

in future studies: Based on exposure response analysis The upper bound of the 90% CI for the predicted

QTc effect < 10 ms at clinically relevant high concentrations ‘Relevant high concentrations’ will be defined based on the

exposure (and its variability) in the targeted patient population

Borje Darpo MD PhD

List of drugs endorsed by FDADrug and DoseAll Oral

Sponsor Results from TQT or QT study

Ondansetron(ZOFRAN)56 mg oral

GSK Mean ∆∆QTc 19.5 (UCL: 21.8) ms and 5.6 (UCL: 7.4) ms after 15 minute intravenous infusions of 32 mg and 8 mg ZOFRAN, respectively.

Dofetilide(TIKOSYN )0.125 mg oral

Pfizer Based on ER of ∆QTc: 15-25 ms per ng/mL and expected Cpl of 0.5 ng/mL: around 10 ms 

Quinine 648 mg oral(QUALAQUIN)

AR Scientific **not TQT study, not placebo-controlled**The mean ± SD maximum ∆QTc around the quinine Tmax was 12 ± 18 ms for 648 mg dose.

Dolasetron (ANZEMET)100 mg oral

Sanofi 14.1 (UCL: 16.1) ms for 100 mg administered intravenously

Moxifloxacin (Avelox)400 mg

Bayer 8 to 14 ms

Borje Darpo MD PhD

Update as of December 1, 2013

• The protocol synopsis is final: A negative drug (levocetirizine) has been added = total of 6

drugs to be studied 2nd, higher dose has been added on Day 2 to provide similarity

with SAD design and to increase precision of slope ER estimate Sample size of 20 to generate at least 9 subjects on each drug

and 6 subjects on placebo Both gender; standard FiM approach The power of the study to exclude a QTc effect > 10 ms will be

comparable to SAD studies using a range of escalating doses 2 separate cohorts; 3 treatment periods for each. Continuous ECG recordings with serial ECG extraction Digital tracings to be stored in a 3rd party database for research

access iCardiac Technologies will sponsor the study, which will be

conducted at the Covance Evansville facility

Borje Darpo MD PhD

Update as of December 1, 2013Primary Objective:• To study the effect of 6 marketed drugs on the QTc interval using

concentration effect modeling.Secondary Objectives:• To evaluate the safety of the two single doses of 6 marketed drugs in

healthy subjects.• To evaluate the effect of the two single doses of 6 marketed drugs on heart

rate, QTc, PR and QRS intervals using a descriptive statistical analysis by time point by dose.

• To evaluate the pharmacokinetics of the 6 marketed drugs in healthy subjects

Primary endpoint:• Change-from-baseline QTcF (∆QTcF)Secondary endpoints:• ∆∆QTcF by time point• Categorical analysis of the QTc outliers• Effects on heart rate, PR and QRS intervals.

Borje Darpo MD PhD

Update as of December 1, 2013

Criteria for QT assessment

Positive QT assessment (for the positive drugs):• The upper bound of the 2-sided 90% confidence interval (CI) of the

projected placebo-corrected ∆QTcF is above 10 ms at the observed peak plasma level of the drug.

In addition, the following criterion will be applied to ensure that the study has sufficiently low variability to allow confidence in the data:

• The confidence interval for the slope of placebo-corrected ∆QTcF with respect to concentration is completely above zero.

Negative QT assessment (for the negative drug):• The upper bound of the confidence interval of the predicted placebo-

corrected ∆QTcF at the geometric mean Cmax of the drug. is below 10 ms.

Borje Darpo MD PhD

Update as of December 1, 2013Action point Time-line Comments

Protocol synopsis incl. the statistical part

Completed • Study should achieve same power to exclude small effects as standard SAD, without necessarily being identical

• Criteria for CEM selection

3rd FTF meeting with FDA Completed • Agreement of design and endorsement of concept

Funding and site selection Completed • iCardiac Technologies will provide the funds and assume sponsorship role

• Covance Evansville, US will conduct the study

Study conduct Q1/2014 • On track, probably latter part

Analysis, storage of digital file for research access

Q2-3/2014 • Results will be shared with FDA and disseminated publicly during H2/2014

• Governance procedure for ECG database access needs to be established

• Principle will be freely accessible under conditions to share results

Borje Darpo MD PhD

Summary

• The objective of the IQ-CSRC prospective clinical study is to evaluate whether ‘Early QT assessment’ incorporated into standard clinical pharmacology studies can provide QT data with the same confidence as the TQT study

• If successful, ‘Early QT assessment’ may serve as an alternative to the TQT study

• Five marketed ‘QT positive’ drugs + 1 ‘QT negative’ drug will be evaluated in a ‘SAD-like’ trial

• To achieve sufficient power with a substantially smaller sample size, the primary analysis will be based on exposure response analysis; not the E4 time-matched analysis

• The area should be followed closely, as there are other on-going efforts to replace the TQT studies, including non-clinical initiatives (see e.g.: http://www.hesiglobal.org/files/public/Committees/CV/Proarrythmia%20workshop/CSRC_HESI_FDA%20logistics.pdf)