Pharmacokinetics Data Evaluation for Safety Monitoring in Early Stage Clinical Studies

Luana Pesco Koplowitz, MD, PhD, FCP, FFPM

President and Chief Medical & Scientific Officer

DUCK FLATS Pharma, LLCElbridge, New York, USA

Adjunct Assistant Professor of Medicine

University of Delaware School of Medicine, Wilmington, Delaware, USAUniversity of Miami School of Medicine, Miami, Florida, USA

Department of Clinical Pharmacology

Member of FDA Cardiac Safety Research Consortium

OVERVIEW

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This presentation will focus on the following:

Role of Data Monitoring Committees (DMCs)

Pharmacokinetic and Safety Data in Translational Medicine

Early Stage Clinical Trial Design

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Concept first introduced by National Institute of Health in 1967 due to recognition that: Interim monitoring of accumulating study data vital to ensuring

safety of participants Independent, objective review may not be possible for individuals

closely tied to trial design and/or conduct

FDA issued guidance in 2006

Was primarily used in large, randomized, multi-center trials sponsored by federal agencies

Only recently has oversight been incorporated into trials sponsored by the pharmaceutical industry

DATA MONITORING COMMITTEES: HISTORY

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Some government agencies that sponsor clinical research have required the use of DMCs in certain clinical trials.

Current FDA regulations impose no requirements for the use of DMCs in trials unless there are exceptions from informed consent requirements for emergency research per 21 CFR 50.24(a)(7)(iv).

In those instances, DMCs exercise oversight of the clinical investigation.

DMC: NECESSITY AND PRACTICALITY

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Determining the Need for a DMC

Practicality of DMC review

Enhancement of trial subject and patient safety

Assurance of scientific validity

Trial Design - Traditional Studies versus Adaptive Studies

The FDA defines an adaptive design clinical study as:“A study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study.”1

DMC: NECESSITY AND PRACTICALITY

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The following should be considered 2:

Trial Length/PhaseFor short-term trials, DMC have the opportunity for meaningful impact. In the past, DMCs were not usually warranted in early studies such as Phase 1 or early Phase 2 studies, however this has changed in recent years.

Expected Trial Outcome(s)Usually considers safety but efficacy may also be assessed

Safety ConcernsWhen trials pose an elevated safety risk, DMC oversight valuable regardless of trial length, phase, or outcome.

DMC: NECESSITY AND PRACTICALITY

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Study endpoint(s) that might ethically require termination of the study before its planned completion

For trials designed to evaluate the effect of a drug on disease: Related mortality or major morbidity, endpoint information usually collected, tracked, and monitored by a DMC

A priori reasons for a particular safety concern

For Example: If the procedure for administering the treatment is particularly invasive

DMC: STUDY SAFETY CONSIDERATIONS

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Prior information suggesting the possibility of serious toxicity with the study treatment

Potentially fragile populations or populations at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser endpoint

DMC: STUDY SAFETY CONSIDERATIONS

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The DMC advises the Sponsor regarding the continuing safety of trial participants and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial.

The trial Sponsor makes several decisions regarding use, types of membership, and operations of a DMC.

Can be critical to the success of the trial in meeting regulatory requirements.

The composition and operation of a DMC must be described in the study protocol.

DMC: ROLE AND RESPONSIBILITIES

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The exact role, scope of authority and membership of a DMC should be defined in a DMC charter.

The DMC should understand and agree on the statistical approach chosen.3

The DMC should consider how the trial design will impact their role and responsibilities.

Adaptive Design clinical trials create a larger role for DMCs over traditional clinical trials.

DMC: ROLE AND RESPONSIBILITIES

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Interim Monitoring

Monitoring for Effectiveness

Monitoring for Safety

Monitoring for Exposure/Response

Monitoring Study Conduct

Other Responsibilities

Making Recommendations

Maintaining Meeting Records

Ensuring confidentiality of unblinded interim comparative data

DMC: ROLE AND RESPONSIBILITIES

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All clinical trials conducted under an IND are subject to regulatory safety reporting requirements.

In the United States, these requirements include prompt reporting to FDA of certain serious and unexpected adverse events (AEs). This includes any recommendations by a DMC that are related to serious AEs in clinical trials of new drugs.

On September 29, 2010, the FDA issued its final rule amending the IND safety reporting requirements under 21 CFR Part 312. In addition, this rule also includes safety reporting requirements under 21 CFR 320.31(d) for bioavailability or bioequivalence studies that are exempt from the IND requirements.4

DMC: REGULATORY REQUIREMENTS

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The IND safety reporting requirements provide that in certain situations, (to determine whether a single AE is a serious, unexpected, suspected adverse reaction), the Sponsor or Investigator may need to break the blind for a study subject.5,6

A DMC could be used to analyze and evaluate unblended AEs to determine whether the events should be reported as serious, unexpected, suspected adverse reactions.

In addition, study endpoints should be reported as directed by the protocol and not as IND safety reports. Endpoints should be reviewed by a DMC throughout the study.

The European Commission and China FDA have their own requirements and guidelines for reporting adverse events in clinical trials.

DMC: REGULATORY REQUIREMENTS

USE OF DMCS

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Considerations and disciplines used to assess study results:

Preclinical Study Results

Toxicity, drug-drug interaction(s), First-In-Human dose determination, safety parameters for clinical monitoring

Phase 1/Phase 2 Study Data

Dose escalation and selection, PK/ADME studies, proof-of principle/proof-of-concept studies

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TRANSLATIONAL MEDICINE: PRECLINICAL

Components

Bioanalytical Methods

Non-Clinical Pharmacology

Toxicology

Safety Pharmacology

Drug-Drug Interactions

PK/ADME/Transporter Studies

Estimation of FIH Dose

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PRECLINICAL SAFETY EVALUATION

Potential target organs for toxicity7

Assess dose-response relationship(s)

Assess reversibility of observed toxicity

Determine mode of action of observed toxicity

Assess potential species specificity

Initial safe starting dose and subsequent escalation schemes in humans Determine the No Observable Adverse Effect Level (NOAEL)/Minimal

Anticipated Biological Effect Level (MABEL)

Apply safety margins and interspecies extrapolations

Safety parameters for clinical monitoring

All studies that support assessment of safety are required to be GLP.

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PRECLINICAL SAFETY PHARMACOLOGY

Studies should be conducted to assess the effects on the cardiovascular, central nervous, and respiratory systems at minimum.

Hepatic safety testing should be included.

In Vitro and In Vivo

If needed, additional follow-up testing can be conducted during later clinical development.

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PRECLINICAL TOXICOLOGY

Toxicity testing on various biological systems reveals the species-, organ- and dose- specific toxic effects of an investigational product.

Testing should be conducted with the following in mind:

Two Species Required (one rodent and one non-rodent)

Minimum: Single DoseDuration of repeated dose toxicity studies are usually related to the duration, therapeutic indication, and scope of the proposed clinical trial

Program Dependent on Clinical Program

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DRUG METABOLITES – REQUIRED STUDIES

Drug Metabolites in Safety Testing (MIST)

In general, the following should be considered for safety assessment:8

Metabolites identified only in human plasma

Metabolites present at disproportionately higher levels in humans than in any of the animal test species

Human metabolites that can raise a safety concern are those formed at greater than 10 percent of parent drug systemic exposure at steady state.

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DRUG METABOLITES – REQUIRED STUDIES

MIST (continued)

General Toxicity

Genotoxicity

Embryo-Fetal Development Toxicity

Required if drug will be used in women of child-bearing potential

Carcinogenicity

Needed if drug will be administered continuously for ≥6 months or if used for the treatment of chronic or recurrent conditions

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DRUG METABOLITES – REQUIRED STUDIES

MIST (continued)

Exclusions Not required for cancer drugs (ICH S9 guideline)

Exceptions may also be made for other serious, life-threatening diseases on a case-by-case basis

Timing Safety studies should be completed prior to initiation of large-scale

clinical trials

Requires early identification of disproportionate metabolites to avoid delays in development

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Appropriateness of study endpoint(s)

Identification of safety concerns

Potential for DDIs (patient studies), Immunogenic/Inflammatory responses

Classification of drug product and route of administration

Impacts study design

Stopping criteria

Inclusion/exclusion criteria

Frequency of sampling (eg, blood collection for PK data)

CLINICAL TRIALS: DESIGN CONSIDERATIONS

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Healthy volunteers versus patients

Dependent on therapeutic area

Individual Variations

Appropriate number of volunteers/patients

Special Populations

Elderly

Children

Women of child-bearing potential

Hepatic or renal disorders

Genetic polymorphisms (eg, Sickle Cell, Rh Factor, CYP450 2D6)

CLINICAL TRIALS: DESIGN CONSIDERATIONS

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Single Dose/Multiple Dose

Safety/tolerability, identify maximum tolerated dose (MTD)

General PK characteristics, variability, linearity/ proportionality

Steady-state parameters (accumulation, time-dependency)

Preliminary exploration of drug elimination

• Urine PK

• Metabolite identification

DOSE ESCALATION STUDIES

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In order to understand the full clearance mechanisms of the drug and its metabolites in humans:

Primary mechanism(s) of elimination and excretion from body

Proportion of parent drug converted to metabolite(s)

PHARMACOKINETIC/ADME STUDIES

Required Clinical PK Data PK/Toxicokinetic Endpoints

Absorption

Distribution

Metabolism

Excretion

Cmax

Area Under the Curve

Volume of Distribution

tmax

Bioavailability

Clearance

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PROOF OF PRINCIPLE/PROOF OF CONCEPT

POP/POC Studies:

Assesses the safety of drug in healthy volunteers/target population

Explore the relationship between dose(s) and desired activity

Link between Phase 1 and dose ranging (Phase 2) studies and determination of dose and patient population for Phase 3 studies

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Dose-Ranging

Estimate the dose-response relationship for efficacy and safety

Should cover no-effect, low, medium, and high doses

Dose-Finding Studies

Confirm efficacy and safety of 1 (or more) doses

Data analysis tends to be of hypothesis testing of each dose vs. control

DOSE SELECTION STUDIES

CONCLUSION

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Design and implication of early clinical trials determine the need for a DMC.

It is the role and responsibility of a DMC to review data and make recommendations to the clinical trial Sponsor regarding conduct of the trial.

Study population, drug classification/route of administration, and potential drug-drug interactions all impact the trial design.

Examination of pharmacokinetic and safety data ensures subject/patient safety.

THANK YOU!

谢谢

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DUCK FLATS Pharma, LLC

Elbridge, New York

USA

REFERENCES

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1. FDA Adaptive Design Clinical Trials for Drugs and Biologics. February 2010 (Draft). Available from:

http://www.fda.gov/downloads/Drugs/Guidances/ucm201790.pdf

2. FDA. Guidance for Clinical Trial Sponsors, Establishment and Operation of Clinical Trial Data Monitoring Committees. March 2006. Available

from: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf

3. Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al. Issues in data monitoring and interim analysis of trials.

Health Technol Assess. 2005 Mar;9(7):1-238, iii-iv. Accessed 11 Aug 2014. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15763038.

4. FDA CDER/CBER Safety Reporting Requirements for INDs and BA/BE Studies December 2012 . Available from:

http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf

5. Wain A. Data Monitoring Committees’ Role in Patient Safety in Clinical Trials. 22 Jun 2011. Accessed 23 Sep 2014. Available from:

http://www.ppdi.com/Expert-Community/Patient-Safety/Data-Monitoring-Committees-Role-in-Patient-Safety-in-Clinical-Trials.aspx

6. Sherman RB, Woodcock, J, Norden J, Grandinetti C, Temple RJ. New FDA Regulation to Improve Safety Reporting in Clinical Trials. N Engl J

Med 365;1 July 7, 2011. Accessed 11 Aug 2014. Available from: nejm.org.

7. Piper, E. First-Time-In-Human Studies of Biopharmaceuticals. 2014 ACSO Clinical Presentation. 11 Jun 2014. Accessed 28 Aug 2014.

8. FDA. Safety Testing of Drug Metabolites. February 2008. Available from: http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0065-

GDL.pdf