regulated studies at utmb - purdue university eitzen utmb.pdfsupport applications for research or...

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Regulated Studies at UTMB

1st Annual Summit of Academic Excellence in Quality Assurance & Regulatory Science

18‐19 May 2017

Melissa Eitzen, MT (ASCP), MS, RQAP‐GLPDirector, Regulatory Operations

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Institutional Office of Regulated Nonclinical Studies

Schedule

UTMB

The Animal Rule

Office of Regulated Nonclinical Studies (ORNcS)

The Case for Quality Systems

Gaps, Challenges, and Misconceptions

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Schedule & Objectives

UTMB

The Animal Rule

Describe the application of the FDA GLP regulations to Animal Rule studies



Examine sponsor requirements for Quality Systems


Identify at least one challenge when conducting regulated studies in an academic setting

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The University of Texas Medical Branch (UTMB)

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The University of Texas System

• 8 Academic Institutions• 6 Health Institutions

Galveston, TX

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UTMB

Opened in 1891

> 3200 students

~ 13,000 employees

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UTMB Schools

Medicine

Nursing

Health Professions

Graduate Biomedical Sciences

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UTMB Centers and Institutes

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Galveston National Laboratory

47,826 ft2 laboratory space (4,443 m2)

12,222 ft2 BSL‐4 space (1,135 m2)

$174 million

Move‐in date: October, 2008

Pathogens: Anthrax, avian influenza, bubonic plague, hemorrhagic fevers (such as Ebola), Zika virus, typhus, West Nile virus, drug‐resistant tuberculosis, etc.

UTMB/NIAID

“GLP capability”

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Why GLP?


Schedule

UTMB

The Animal Rule




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Animal Rule

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May 31, 2002

FDA amended its new drug and biological product regulations (21 CFR Parts 314 & 601) to “allow appropriate studies in animals in certain cases to provide substantial evidence of the effectiveness…This rule will apply when adequate and well‐controlled clinical studies in humans cannot be ethically conducted and field efficacy studies are not feasible.”


ResearchNon-ClinicalSafety

ClinicalPhase1

ClinicalPhase2

ClinicalPhase3

Approval

Studies conducted in compliance withGood Laboratory Practice regulations (GLP)

ClinicalPhase4

Not regulated by FDA

Well planned,documentedstudies.

Non-Clinical Proof-of-Concept

Animal Rule

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Animal Rule studies (GLP to the extentPracticable)

Safety studies in humans

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Mechanism of toxicity is well understood

Endpoints in the animal trials are clearly related to benefit in humans

Efficacy is demonstrated in a species expected to react similarly to humans

Data allow selection of an effective human dose [SAME]

Animal Rule—Demonstrating Efficacy

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SUPPLEMENTARY INFORMATIONIntroduction:

“All studies subject to this rule must be conducted in accordance with preexisting requirements under the good laboratory practices (21 CFR part 58) regulations and the Animal Welfare Act (7 U.S.C. 2131 et. seq.).”

Animal Rule

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21 CFR 58, Sec. 58.1 Scope. (a) This part prescribes good laboratory practices for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the Food and Drug Administration…Compliance with this part is intended to assure the quality and integrity of the safety data filed pursuant to sections…

Scope of GLP Regulations

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Definition

Nonclinical laboratory study

In vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety …

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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM399217.pdf

Guidance

“FDA…recommends the use of the GLP regulations, to the extent practicable, to ensure the quality and integrity of the data from these studies.”

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Applicability of the Animal Rule determined by FDA

May be justifiable limitations to apply GLP

Frequent Sponsor communication with FDA

Sponsors seek concurrence from FDA for data quality and integrity plan

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Guidance for Industry

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Quality includes, but is not limited to, whether the study was conducted in accordance with the protocol, standard operating procedures, and applicable standards of research.

Integrity includes, but is not limited to, the assurance that the raw data and documentation are consistent with reported results.

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Guidance for Industry


FDA has the authority to inspect these studies prior to taking an action

Inspectional observations will be shared with the inspected entity and evaluated by the review division determine the impact of the observations on the acceptability of the data to support drug approval

FDA will verify that study personnel followed the agreed‐upon data Quality and Integrity Plan

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Guidance for Industry—Inspections

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Inspections verify the quality and integrity of the:

Raw data Supporting documentation FacilitiesEquipmentResults submitted to

FDA in the final report

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Guidance for Industry—Inspections


Animal Model Qualification

“…FDA recommends the use of the GLP regulations, to the extent practicable, for the model‐defining natural history studies submitted to support the qualification of an animal model…Qualification is a regulatory conclusion, and thus, these studies should be conducted in a manner that ensures data quality and integrity.”

Guidance for Industry—Study Conduct

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Rule

Draft Concept Paper

Pyridostigmine bromide approved

Draft Guidance

Cyanokit approved

2002

Draft Guidance

20122009200820062003 2014 2013

Raxibacumab approved

Botulism Antitoxin approved

Levofloxacin approved (for

plague)

FDA Education Grant

2015

FinalGuidance

Avelox approved

Neupogenapproved

Anthrasil approved

BioThraxapproved

Neulastaapproved

Ciprofloxacin (for plague) approved

2016

Anthimapproved

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Product Approval Under the Animal Rule



http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMRegulatoryScience/ucm391604.htm

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Institutional Office of Regulated Nonclinical Studies 25



Product Labeling ‐ BAT

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http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM345147.pdf

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NPRM GLP

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Schedule

UTMB

The Animal Rule




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ORNcS Development

Institutional Office of Regulates Nonclinical Studies

2004 = QA

2006 = GLP Program Office (Grants Management)

2011 = Recruited Director of Regulatory and Scientific Affairs

2012 = Established Institutional Office with Study Director(s) and Technical staff

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ORNcS Organizational Chart

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QAU

ArchivistEDMS & IT Compliance

StudyDirectors

Technical / QC

Equipment

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ORNcS Pre & Post Award (Pre‐study)

Pre

Scope of Work (RFP, contracts, etc.)

Regulatory Requirements Inspection requirements Proposal submissions Budget

Post

Quality Agreement / Plan Protocol review Data audits In‐life inspections (monitoring) QA inspection logs QA reports

Education Education

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UTMB Survey Results—2005

Survey distributed to attendees of (first) GLP training class:

68.1% Had never been taught QC/QA as part of a course or degree program (73.4% response rate)

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Education—Classes

Laboratory Safety & Good Laboratory PracticesCTPS 6108Course Length: 8 hoursCredit Hours: 1

Good Documentation Practices Course Length: 1 hour

Writing Effective Standard Operating Procedures Course Length: 1 hour

CTPS 6107: Animal Research Topics and IACUC Protocol Basics

CTPS 6121: Effective Laboratory & Resource Management

BBSC 6219: Vaccine Development Pathway

GRAD 544: Ethical Conduct of Research

Pilot Program / Rigor and Responsibility in Research

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UTMB Partnership with FDA

Data Quality and Integrity

in BSL‐4 laboratories

Collaborative education

grant

2012 – 2017

5 day course

Mock BSL‐4 lab activity

On‐line GLP course

Continuing Education Units

https://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMiProfessionalDevelopmentActivities/ucm400029.htm

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Schedule

UTMB

The Animal Rule




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Enhancing Reproducibility

Documenting first discovery

Transferring discovery protocol

Developing regulatory protocol

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Research

Non‐Clinical Safety

Non‐clinicalProof ofConcept

ClinicalPhasesI ‐III

ApprovalClinicalPhaseIV

communication


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SBIR, STTR

https://www.sbir.gov/about


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“Track performance of animal studies and the performance of bacterial strains and controls as an ongoing QA/QC of reagents and strains.”

─NIH RFP, 2010

“The United States Government seeks laboratories that can provide microbiological support…pathogen(s)…including quality‐controlled master and working banks; SOPs for production & characterization of challenge material under standardized media and growth conditions, and master and working banks for cell lines where applicable…”

─ BARDA RFI, 2010


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“Documented experience/familiarity with performing validated ELISA assays…”

─NIH/NIAID RFP, 2011 (Technical Evalua on Factors)

“Some of the studies under this award will require GLP. Describe your present or planned GLP capabilities or any other standards of laboratory practices, meant to substitute for GLP for execution of animal model studies.”

─BARDA RFP, 2011 (Scope of Work)


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“The study will be non‐GLP but must be performed in accordance with an approved quality plan…The Offeror must have a validated or qualified quantitative virology assay to conduct sample analysis…”

─BARDA RTOR 2015


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Institutional Office of Regulated Nonclinical Studies 41

Gaps Challenges Misconceptions

Regulatory knowledge Shared equipment Quality is an “add on”

Regulatory vernacular Regulated study timelines “GLP Compliant Facility”

Training documentation System sustainability Short timeline to GLP

Equipment records Appropriate budgeting (cost) Reproducibility = publication

Good documentation practices

Academic Infrastructure(management)

Audit reports do not require a response

Standardized procedures Culture

Sponsor audits

FOIA

Gaps, Challenges & Misconceptions

Melissa’s List


Contact Information

Melissa M. Eitzen, MT (ASCP), MS, RQAP‐GLP

Director, Regulatory Operations


University of Texas Medical Branch at Galveston

Phone (409)266‐9422

Email: [email protected]

Web: www.utmb.edu/orncs

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Reference Links

The Animal Rule: http://www.gpo.gov/fdsys/pkg/FR‐2002‐05‐31/pdf/02‐13583.pdf

Guidance Document:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM399217.pdf

Products Approved under the Animal Rule:

http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMRegulatoryScience/ucm391604.htm

Botulism Antitoxin Label:

http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM345147.pdf

GLP Regulations:

http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/default.htm

FDA Notice for Proposed Rule Making (NPRM) – GLP

https://www.federalregister.gov/documents/2016/08/24/2016‐19875/good‐laboratory‐practice‐for‐nonclinical‐laboratory‐studies

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regulated studies at utmb - purdue university eitzen utmb.pdfsupport applications for research or...

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