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An Update on Efforts to Modernize FDA’s Clinical Trials and BIMO Programs Janet Donnelly, RAC, CIP Policy Analyst, FDA's Office of Good Clinical Practice Human Subject Protection: SPEAKER Changes Thursday, October 6, 2016

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An Update on Efforts to

Modernize FDA’s Clinical

Trials and BIMO Programs

Janet Donnelly, RAC, CIP Policy Analyst, FDA's Office of Good Clinical Practice

Human Subject Protection: SPEAKER Changes Thursday, October 6, 2016

JANET DONNELLY, RAC, CIP, is a Health Scientist, Policy Analyst in FDA’s

Office of Good Clinical Practice. The Office of Good Clinical Practice is

the focal point within FDA for Good Clinical Practice (GCP) and Human

Subject Protection (HSP) issues arising in human studies regulated by

FDA. Within the GCP office, Janet assists in the development and

revision of regulations, policy, and guidance, and serves as a resource to

a variety of internal and external stakeholders on GCP and HSP issues.

Janet brings over twenty years of experience to FDA in regulatory affairs

and regulatory compliance in the sponsor, CRO and independent IRB settings. Prior to joining FDA in 2008,

Janet served as Director of Compliance for an independent IRB providing regulatory consultation to the IRB

and external clients.

Human Subject Protection: SPEAKER Changes Thursday, October 6, 2016

An Update on Efforts to Modernize

FDA’s Clinical Trials

and BIMO Programs

Janet Donnelly RAC, CIP

Policy Analyst

FDA Office of Good Clinical Practice

October 6, 2016

1

Overview

1. General Overview of FDA’s HSP/BIMO Program

2. Challenges in Clinical Trials

3. Initiatives & Accomplishments to Address Challenges

4. The Changing Landscape

5. Emerging HSP/BIMO Program Activities

2

HSP/BIMO Program

• Comprehensive oversight program includes guidance

and policy development, inspections, data audits,

internal/external outreach and communication

• Inspection programs include CI, IRBs, Sponsors, CROs,

Monitors, BE testing facilities, Nonclinical labs (under

GLP)

• HSP/BIMO crosses multiple Centers, Office of

Regulatory Affairs and the Commissioner’s Office

3

HSP/BIMO Program

FDA HSP/BIMO Program goals:

1. Protect the rights, safety, and welfare of subjects

involved in FDA-regulated research

2. Determine the accuracy and reliability of clinical trial

data submitted to FDA in support of research or

marketing applications

3. Assess compliance with FDA's regulations

governing the conduct of clinical trials, including

those for informed consent and ethical review4

HSP/BIMO Program

• Center HSP/BIMO Program Responsibilities (partial list)

– Select sites for inspection (for-cause/routine/risk-based)

– Issues assignments and serves as SME, as needed

– Analyzes inspection results, communicates with the field, and

determines final classification

– Develops and issues final determination letter

– Assess CAPA and follows up, as needed

– Collaborates with Review Divisions

– Initiate Disqualifications/Debarments

– Develops Center-specific GCP policies

– Participates in training/outreach

– Queries

5

HSP/BIMO Program

• ORA HSP/BIMO Program Responsibilities (partial list)

– Prioritizes, assigns field inspector, and conducts inspections

– Determines “observations”

– Writes establishment inspection reports (EIRs)

– Makes recommendation for initial classification/regulatory

actions

– Clears inspection reports prior to sending to Centers

– Participates in training and outreach

– Queries

6

Office of Good Clinical Practice

• OGCP Responsibilities

– Advise Commissioner/FDA Senior Leadership

– FDA lead for GCP/HSP BIMO policy

– Facilitate policy harmonization across Centers and with Federal

partners (e.g., OHRP, VA)

– Assist with providing responses to press inquiries, congressional

inquiries, GAO and OIG inquiries/visits

– Provide internal and external outreach

• Training and education (e.g. SoCRA, PRIM&R, ACRP)

• Respond to stakeholder questions via

[email protected] (≈1,300-1,500/year)

7

Office of Good Clinical Practice

• OGCP Responsibilities

– Represent FDA on Secretary’s Advisory Committee on Human

Research Protections (SACHRP)

– Coordinate FDA activities related to ClinicalTrials.gov including

compliance/enforcement

– Provide bioethics consultations to the Centers

– Support activities related to IRB disqualifications and CI

disqualifications/debarments

– Support Office of International Programs GCP harmonization

activities

8

OGCP Governance Responsibilities• HSP/BIMO Council

– Chaired by Director of OGCP

– Guiding body and decision-making group for FDA GCP

policy/regulation development

– Comprised of senior scientists and managers from all Centers

• 50.24 Consultative Board

– Chaired by OGCP

– Guiding body to the Centers on issues related

to emergency research being conducted under

exception to informed consent (21 CFR 50.24)

9

Clinical Trial Challenges

• Research paradigm constantly changing; many

regulations >40 years old

– HSP/BIMO core principles remain the same but need to adapt to

keep pace

• More Recent Trends

– Genomics, novel therapies, combination products

– Big data and privacy concerns

– Demands for transparency and return of results

– Use of Centralized IRB review process

10

Clinical Trial Challenges

• Less Recent Trends but Still Relevant

– Public mistrust in research enterprise

– Growing concerns about privacy

– Growing number of trials involving vulnerable populations

– Many studies conducted outside the US

– Complex Informed Consent documents

– Ever changing pool of investigators

– System over-burdened with process and under-resourced

– Public demanding access to investigational products

– Push for harmonization (e.g., OHRP and FDA)

11

Oversight Entities

– Office of Inspector General (OIG)

• Mission: to protect the integrity of Department of Health and

Human Services programs as well as the health and welfare

of program beneficiaries

– Government Accountability Office (GAO)

• Mission: to support Congress in meeting its constitutional

responsibilities and to help improve the performance and

ensure accountability of the federal government for the

benefit of the American people

12

Oversight Entities

OIG Investigations

• FDA Oversight of Clinical Investigators

• FDA Oversight of Clinical Trials

• FDA Oversight of CI Financial Disclosures

GAO Reports

• Disqualification and Debarment Process

13

Recent Accomplishments(Regulations)

• 2016: ClinicalTrials.gov ISSUED BY HHS

– Requirements for registration and submission of summary study results

from applicable clinical trials to CT.gov

– FDA has enforcement responsibilities

• 2013: Additional Safeguards for Children in Clinical Investigations

– 21 CFR 50, Subpart D

– Aligns FDA regulations with Common Rule (45 CFR part 46)

• 2013: Acceptance of Data From Clinical Studies of Medical Devices

(PROPOSED RULE)

– Covers all device applications

– Defines criteria for FDA acceptance of data from studies conducted in

the US or OUS based on conformity with GCP or as otherwise indicated

(e.g., ISO, ICH, etc.) to assure HSP and data validity14

Recent Accomplishments(Regulations)

• 2012: Disqualification of a Clinical Investigator

– 21 CFR 312.70

– Expands the scope of CI disqualification

• 2011: ICDs for “applicable clinical trials”

– 21 CFR 50.25(c)

– Mandatory verbatim statement:

“A description of this clinical trial will be available on

http://www.ClinicalTrials.gov as required by U.S. law. This Web

site will not include information that can identify you. At most,

the Web site will include a summary of the results. You can

search this Web site at any time.”15

Recent Accomplishments(Regulations)

• 2010: IND Safety Reporting Requirements

– 21 CFR 312.32

– Revises definitions used for safety reporting and clarified what

needs to be submitted

• 2010: Reporting Information Regarding Falsification of

Data (PROPOSED RULE)

– Requires sponsors promptly report any information indicating

that a person has, or may have, engaged in the falsification of

data

– Includes falsification in the course of proposing, designing,

performing, recording, supervising, and reviewing or reporting

results

– Covers all parties involved with clinical investigations 16

Recent Accomplishments(Regulations)

• 2009: Expanded Access to Investigational Drugs for

Treatment Use

– 21 CFR 312 subpart I

– Improves access to investigational drugs for serious or life

threatening conditions

• 2009: Charging for Investigational Drugs Under IND

– 21 CFR 312.8

– Clarifies what costs can be recovered

• 2009: IRB Registration

– 21 CFR 56.106

– Requires IRB registration (leveraged for site selection)17

Recent Accomplishments(Guidance)

• 2016: Expanded Access to Investigational Drugs for

Treatment Use - Q&As

• 2016: Charging for Investigational Drugs Under an IND -

Q&As

• 2016: Individual Patient Expanded Access Applications:

Form FDA 3926

• 2014: Considerations When Transferring Clinical

Investigation Oversight to Another IRB

• 2013: Electronic Source Data in Clinical Investigations

18

Recent Accomplishments(Guidance)

• 2013: Investigational New Drug Applications (INDs) -

Determining Whether Human Research Studies Can be

Conducted Without an IND

• 2013: IRB Responsibilities for Reviewing the

Qualifications of Investigators, Adequacy of Research

Sites, and the Determination of Whether an IND/IDE is

Needed

• 2013: IDEs for Early Feasibility Medical Device Clinical

Studies Including Certain First in Human Studies

• 2013: Oversight of Clinical Investigations – A Risk-Based

Approach to Monitoring 19

Recent Accomplishments(Guidance)

• 2013: Financial Disclosure by Clinical Investigators

• 2013: Humanitarian Use Device (HUD) Designations

• 2012: Safety Reporting Requirements for INDs and

BA/BE Studies

• 2012: Safety Reporting Requirements for INDs and

BA/BE Studies – Small Entity Compliance Guide

• 2012: FDA Acceptance of Foreign Clinical Studies Not

Conducted Under an IND; Frequently Asked Questions

20

Recent Accomplishments(Guidance)

• 2012: IRB Continuing Review After Clinical Investigation

Approval

• 2012: Questions and Answers on Informed Consent

Elements, 21 CFR 50.25(c)

• 2011: Exception from Informed Consent Requirements

for Emergency Research - 50.24 Studies

• 2010: Radioactive Drug Research Committee – Human

Research Without an IND

• 2010: Frequently Asked Questions – Statement of

Investigator (Form FDA 1572)21

Recent Accomplishments(Draft Guidance)

• 2016: IRB Written Procedures

• 2015: Minutes of IRB Meetings

• 2015: Acceptance of Medical Device Clinical Data from

Studies Conducted Outside the United States (OUS)

• 2015: Use of Electronic Informed Consent in Clinical

Investigations

• 2014: Informed Consent Information Sheet

• 2014: Humanitarian Device Exemption (HDE): Q&As

• 2011: Guidance on Exculpatory Language in Informed

Consent22

Recent Accomplishments(Inspection/Oversight Program)

• Updated Compliance Program Guidance Manuals

(CPGMs)

– 2012: Radioactive Drug Research Committee CPGM

– 2011: Sponsor, CRO, Monitor CPGM

– 2011: IRB CPGM

– 2008: Clinical Investigator CPGM

(All available to the public)

Updates include new or added emphasis on things such as financial

disclosure, disqualification rules, improved communication, IRB

registration, new required element for ICD for CT.gov, expanded

access, part 11, documents related to studies conducted outside the

US (312.120), AE reporting, Subpart D 23

Recent Accomplishments(Inspection/Oversight Program Trends)

• Early Intervention Activities

– Consider more real-time inspections (i.e., study ongoing)

– Goal: to promptly correct any identified problems while the

research is ongoing rather than after-the-fact

• Minimize risks to subjects

• Preserve the integrity of the clinical trial

• “Risk-based” Site Selection for Inspection (CI, IRB)

– e.g., studies involving vulnerable subjects; no inspection history;

high risk studies (50.24); novel products; past findings

24

Recent Accomplishments(Inspection/Oversight Program)

• Revamped CI Disqualification Process

– Revised procedures

Clarified responsibilities for all parties, identified target timeframes

from the end of the inspection to the issuance of a NIDPOE (Notice

of Initiation of Disqualification Procedures and the Opportunity to

Explain)

– Revised the FDA Information Sheets guidance on the inspection

of a CI and the CI disqualification process

– Improved transparency by posting all pending and completed

disqualification actions

• Developed IRB Disqualification Process

– Can be IRB, Parent Institution, or Component of Parent

Institution25

Recent Activities(Collaboration/Harmonization)

• FDA-OHRP Harmonization – ongoing

– Goal: to reduce burdens to the extent possible

• Examples:

– IRB Registration requirements

– Guidance: IRB Written Procedures, IRB Minutes, IRB

Continuing Review, Retention of Data When Subjects Withdraw

– Participation on SACHRP as ex-officio member

– Outreach

– Occasionally limited by statute

26

Recent Activities(Collaboration/Harmonization)

• Clinical Trials Transformation Initiative (CTTI)

– Public-private partnership (established by FDA and Duke)

– Membership includes wide variety of stakeholders (e.g., patient

and consumer reps, CIs, industry, regulators, academia, etc.)

– Goal: to identify and promote practices that will increase the

quality and efficiency of clinical trials

– Vision: A high quality clinical trial system that is patient-centric,

efficient, and produces timely access to evidence-based

prevention and treatment options

27

Recent Activities(Collaboration/Harmonization)

• Examples of CTTI Recommendations

– Electronic Portals for Expedited Safety Reporting

– Informed Consent

– Engagement of Patient Groups

– Quality by Design

– GCP Training for Investigators

– Improving Reporting of Unexpected SAE to IND Investigators

– IND Safety Assessment and Communication

– Use of Central IRBs for Multi-center Clinical Trials

– Best Practices for the Use of DMCs

– Efficient and Effective Clinical Trial Recruitment Planning

– Streamlining Antibacterial Drug Development28

see CTTI website for details

Recent Activities(Collaboration/Harmonization)

• Examples of CTTI Projects

– Central IRBs

– Data Monitoring Committees

– GCP Training

– Registry Trials

– Recruitment

– Using mobile technology to facilitate Clinical Trials

– Large Simple Trials

– Guidance for pregnancy testing in clinical trials

– Opioid Project

see CTTI website for details

29

Recent Activities(International)

• FDA-EMA GCP Initiative

– Included joint and observational inspections

– Goal: Facilitate sharing of inspectional information and best practices

• Expanded International Capacity

– FDA has offices in China, India, Europe, and Central and South

America

• International Harmonization

– Advice/comments provided on multiple international GCP/HSP

guidelines and documents (e.g., ICH E-6 update, WMA Declaration of

Helsinki update, CIOMS Guidelines)

• Outreach Activities

– Participation on OHRP International Work Group

– Information sharing on evolving GCP issues around the world 30

Recent Activities(Transparency)

• Considered in all aspects of FDA GCP activities

• Sometimes limited by statute/regulations (e.g., FOIA rules, trade

secrets)

• Examples of GCP-related data posted on FDA website:

– Warning letters

– Notice of Initiation of Disqualification Proceedings and Opportunity to

Explain (NIDPOE)

– Notice of Opportunity for Hearing (NOOH)

– Disqualification determinations

– Debarment actions

– Archive of OGCP Mailbox Queries

31

The Changing Landscape• Scientific Innovation

– Increasing breadth and complexity of the products that FDA

regulates

– Evolving technologies

• Unique Trial Designs

– Adaptive Trials

– Basket Trials

– Cluster Randomized Trials

• Big Data

– Privacy

– Re-identification

– Consent 32

The Changing Landscape

• Proposed Legislation

– Modernize clinical trials in an effort to accelerate discovery,

development and delivery of new treatments

– Incorporating the patient experience

• Post-Approval Data/Trials

– Real World Evidence

– Pragmatic trials

– Registries

• Changes to Common Rule

– Publication of the Final Rule

– FDA rulemaking

33

BIMO Program Alignment Group (PAG)

• Multiyear project: launched

2013

• Goal: to develop commodity-

based and vertically-integrated

regulatory programs (BIMO

considered a distinct program)

withWell-defined leads

Coherent policy and strategy

development

Well-designed and coordinated

implementation

Streamlined management structure

Specialized Inspectorate

New Skills & Disciplines

Increased Technical

Knowledge

Targeted Hiring

Impact on HSP/BIMO Program

• How does it differ from the current approach?

• Define specialization in the BIMO Program

– BIMO as a discipline including all commodities

35

Approach to Implementation

• BIMO formed a Leads group representing all FDA

organizations with stake in BIMO Program

• Subgroups for major areas in FY 2015 Action Plan

• Specialization, Training and Development and Program

Processes

36

Approach to Implementation

• Defined specialization in BIMO Program

• Began work on comprehensive training and development

plan (curriculum based)

• Identified processes for harmonization & best practices

• FY 2016 continued the work required to transition to a

stand-alone BIMO Program

• Working on transition period from current state to future

state under program alignment

37

Transition• Moving from a largely geographically-based field

organization to a commodity/program based organization

• Vertically integrate operations throughout the programs;

Centers and ORA

• A major reorganization effort required, no changes to be

made until approved by DHHS and Union negotiation

requirements are met

– Structures

– Processes

– Communications

– Remote management

– Program management across traditional district boundaries 38

Impact for Stakeholders• Communications with Center representatives will remain

same

• ORA BIMO Investigators will have access to a

comprehensive training and development program

focused on BIMO

• Increased consistency and efficiency

• Increased communications between ORA and Center

BIMO staff, including field

• Program success metrics being designed to determine

improvements in educational outreach and improved

efficiencies in review process and other areas 39

Why is Modernization Important?

• Enhance public confidence in the clinical trial process

• Evolving product development processes

• Improve the efficiency of bringing new products to US

consumers without diminishing HSP or the validity of

clinical trial data

40

Resources• FDA’s GCP Website

– http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/OfficeofScienceandHealthCoordination/ucm2018191.htm

• OGCP Staff Contacts– http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/uc

m134476.htm

• FDA’s GCP Questions Mailbox– [email protected]

• OGCP Mailbox Archives (previously answered queries)– http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/R

epliestoInquiriestoFDAonGoodClinicalPractice/default.htm

• FDA GCP/HSP E-mail Updates – sign up to receive– http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/de

fault.htm

• Check out “In the News” for the latest updates – http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/de

fault.htm 41

Resources• BIMO Metrics

– http://www.fda.gov/scienceresearch/specialtopics/runningclinicaltrials/ucm261409.htm

• Periodic HSP/BIMO Modernization Initiative Updates – http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/u

cm228722.htm

• BIMO Compliance Program Guidance Manuals (CPGMs)

– http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/ucm255614.htm

• CTTI

– https://www.ctti-clinicaltrials.org/

• FDA Program Alignment

– http://www.fda.gov/aboutfda/centersoffices/ucm392733.htm

42