SCTR BIOTECHNOLOGY INTEREST GROUPRegulatory Series

Talk 1 of 2

1

February 9, 2011

2

Regulatory Knowledge & Support Services

3

Regulatory Knowledge & Support Aims

• Guidance• Mentoring• Education• Resources• Tools

Support an increase of regulatory

knowledge base &

comprehension of research regulatory

requirements.

Research mission of MUSC to

advance Clinical & Translational

research

4

Regulatory Consultation ServicesGuidance, mentoring and education & resources for

Institutional Regulatory

Submissions

• IRB/IACUC/IBC Pre-Review Submissions

• Researcher’s Response to Review Comments

• User support for eIRB

Federal Regulatory Requirements

• IND/IDE application

• Federal Wide Assurances

• ClinicalTrials.gov process

• Certificates of Confidentiality

Regulatory Compliance &

Quality

• Global considerations

• Consenting Documents Review

• Study Initiation Review

• Documentation & Organization

5

Regulatory Consultation Service Requests

6

Regulatory Resources & Tools

7

MA

P-R

MU

SC’s

App

rova

l Pl

an f

or R

esea

rch Regulatory Resources & Tools

Checklist to help determine research regulatory approvals required

8

Regulatory Resources & ToolsOnline resource guides & links to assist in navigating & conducting research

Res

earc

h To

olki

t

9

Contact Regulatory Knowledge & Supportand SUCCESS services

Phone: 843-792-8300Internet: http://sctr.musc.edu

E-mail: success@musc.edu

Kathryn Magruder, PhD, MPH, RKS Program DirectorSusan Sonne, PharmD, RKS Program Associate Director

Royce Sampson, MSN, RN, CCRA, SUCCESS Center DirectorStephanie Gentilin, MA, CCRA, SUCCESS Center Associate Director

Brigette White, MA, CCRP, SUCCESS Center Regulatory Coordinator

10

Regulatory Considerations -Industry and Academic Drug and

Device Development

Bruce Burnett, PhD, RACDirector, Regulatory Affairs

Duke Translational Medicine Institute

Who We Are

12

Regulatory MetricsCurrent Investigator Metrics• Total INDs: 101• Sponsor-Investigators Holding INDs: 53

• Total IDEs: 2 (2 more in development)• Sponsor-Investigators Holding IDEs: 2

Number of IND/IDE-related Submissions*• 2008 - 10• 2009 - 23• 2010 - 45*Does not include work associated with determining if a study is IND/IDE exempt

Marketing Application• Cord Blood BLA submission (target March/April 2011)

13

Our Services

Regulatory Training and Education Regulatory Consultation Regulatory Submission and Maintenance Support of GMP Activities Support of GLP Activities

One Resource:

Detailed Webinars on IND (drug) and IDE regulations, processes and submissions:

https://www.dtmi.duke.edu/for-researchers/regulatory-support/ind-ide-training-webinars

14

Overview

Drug and Biologic Development Centers Definitions IND requirements and Types of INDs Considerations

GLP and GMP

Good Clinical Practice and Clinical Trials Device Development Classification and Approval Paths

15

NCTR CBER: Center for Biologics Evaluation

and Research;Biologics

CDRH: Center for Devices and

Radiological Health; Devices

CFSAN CVM

Food and Drug Administration

CDER: Center for Drug Evaluation

and Research; Drugs

ORA

-Food safety/Supplements -Veterinary Meds.

Divisions Relevant to talk:

17

A drug is defined as:(A)articles recognized in the official USP, HPUS or NF or any supplement, thereof

(B)articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, (C)articles (other than food) intended to affect the structure or any function of the body of man or other function of the body of man or other animals…..

In Brief: Any product that is to be used in treating or curing a disease

Food and Drug Administration

CDER Small molecule drugs Prescription drugs – branded and generic Therapeutic biologics Over the counter drugs Non-medicine products including antiperspirants,

fluoride toothpaste, dandruff shampoos and sunscreens are all considered “drugs”

19

A Biologic is defined as:Any virus, therapeutic serum, toxic,

antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or its derivatives, applicable to the prevention treatment or cure of diseases or injuries of man.

Food and Drug Administration

CBER Blood-derived products Vaccines Allergenics Tissues Cellular and gene therapies Protein therapeutics transferred to CDER in 2003

21

Summary of Drug/Biologic Development Process:

•Screening

•Pre-Clinical Testing

•IND Application

•Phase I Clinical Trials

•Phase II Clinical Trials

•Phase III Clinical Trials

•New Drug Application (NDA) / Biologics License Application (BLA)

•Phase IV and Beyond

$74 mil $286 mil $516 mil

New Chemical Entity (NCE):

22

Drug Development Phases

(BLA forBiologic)

Interacting With FDA

BasicResearch

PrototypeDesign or Discovery

FDA Filing/Approval &

LaunchPreparation

PreclinicalDevelopment

Clinical Development

Phase 1 Phase 2 Phase 3

Sponsor – FDA Interactions

During Development

Pre-IND MeetingPre-IND Meeting Safety Update

End of Phase

2a Meeting

End of Phase

2a Meeting Initial IND

Submissions

Initial IND

SubmissionsEnd of Phase 2

MeetingEnd of Phase 2

Meeting

Market Application Submission

Market Application Submission

Pre-BLA or NDA Meeting

Pre-BLA or NDA Meeting

Ongoing Submission

Ongoing Submission

IND Review Phase Application Review Phase

When Interacting With FDA Things to keep in mind about FDA Time and costs are not relevant With the PDUFA timelines (2-4 week pre-meeting

briefing packet, 30-75 day pre-review periods, 10 months for NDA/BLA, 6 mos. priority review, etc.) reviewers are very busy – so provide clear scientific rationale for any position

FDA driven by science and data FDA sees many related drug development

programs besides the one under review

25

•Investigational New Drug is a new drug or biologic drug used in a clinical investigation

-Can be use of an approved drug in new indication-Can be a novel combination of drugs

•IND Application is a request for authorization to administer an investigational drug or biologic to humans or a marketed drug in a new indication and/or patient population

Definitions:

Two Main Types of INDs Commercial Ultimate goal is to obtain marketing approval Typically 5+ volumes for a Phase 1 IND

Sponsor-Investigator (Investigator-Initiated) Primarily research driven IND can be a single volume Preclinical and CMC often cross-referenced Letters of Authorization for investigational drug Reference to label for a marketed drug

Notes Regarding INDs INDs are specific for the drug and the

indication A drug tested in a new indication would require a

new IND Changing the route of administration (IV vs IM/SC

vs oral) would necessitate a new IND

Other Types of INDs

Emergency use Exploratory Treatment Single Patient Compassionate Use

Definitions Sponsor is an individual, company, or academic

institution that takes responsibility for and initiates a clinical investigation of a drug or device

Investigator is an individual under whose immediate direction a drug or device is administered, dispensed or used

Sponsor-Investigator is an individual who both initiates and conducts an investigation, and under whose immediate direction a drug is administered or dispensed

Sponsor Responsibilities (312.50-59)

Selects qualified investigators Ensures IRB review and approval of study Ensures study is conducted according to the

protocol Ensure proper monitoring Maintains IND Informs FDA of significant new AEs Maintains proper records

Investigator Responsibilities (21 CFR 312.60-68)

Personally supervises the investigation Ensures study is conducted according to the

investigational plan and regulations Protects the rights and safety of study subjects,

and obtain their informed consent Maintains adequate and accurate case histories

that record all observations Ensures IRB review and approval of study Reports AEs to sponsor

1. Form 1571 (cover sheet)2. Table of Contents3. Introductory Statement4. General Investigation Plan5. Investigators Brochure6. Protocols7. Chemistry, Manufacturing and Control Data (CMC)8. Pharmacology and Toxicology Data9. Previous Human Experience10.Additional Information

IND Format and Content

33

When is an IND Needed:•When Human subjects will receive an unapproved drug•Typically when human subjects will receive an approved drug for an unapproved use; consider indication, dose, population, etc.

-Some studies with approved drugs may be granted an IND waiver (exempt); must meet 5 criteria

Five criteria for IND waiver with approved drugs: Reference: 21 CFR 312.2. The investigation: (1) Is not designed to support approval of a new indication or a

change in label

(2) Is not intended to support a significant change in the advertising for the product

(3) Does not involve a route of administration, dosage level or patient population that significantly increases the risks with the drug

(4) Is in compliance with the IRB and informed consent regulations

(5) Is in compliance with regulations regarding promotion and charging for investigational drug

35

How to decide? Resources:-DHHS Office for Human Research Protections (OHRP)

-FDA Guidance: www.fda.gov/cber/gdlns/indcancer.pdf (Similar logic applies for non-cancer studies)

-SUCCESS center and useful tools:

Examples of Tools:SCTR MAP-R: https://sctrweb2.musc.edu/maprORRP: http://www.hhs.gov/ohrp/policy/checklists/decisioncharts.html

Note: Even if exempt from IND requirements, studies still subject to other FDA regulations including 21 CFR part 50 (human subjects protections), part 54 (conflict of interest requirements), and part 56 (IRB requirements).

36

Good Laboratory Practice(Part 58. Title 21. Code of Federal Regulations)

•Drug development requires extensive pre-clinical testing conducted under GLP Guidelines and regulations. Requires specialty labs; typically not investigator’s labs.

•GLP deals with the organization, process and conditions under which laboratory studies are planned, performed, monitored, recorded and reported.

•GLP practices are intended to promote the quality and validity of test data.

•Objectives are centered around quality of data but also traceability and integrity of data.

•DOCUMENT, DOCUMENT, repeat.

37

IND Package and Human Dosing Equivalents:-In general, in the US, allowed one day of dosing in man for every day of pre-clinical tox. dosing in animals

-Chronic tox. dosing required in 2 species (1 lg. non-rodent) to cover proposed exposure levels in humans.

IND Package Includes:• Carcinogenicity studies •Mutagenicity studies •Teratogenicity studies •Embryotoxic studies •Drug Absorption/Distribution/Metabolism studies •Pharmacokinetic/ Pharmacodynamic studies •Chronic/Long-term safety studies

38

Current Good Manufacturing Practices (cGMP):•cGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities.

•Adherence to the cGMP assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations.

•Includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories.

•Enforced and regulated by FDA; documentation, documentation….

Full cGMP is not required for Phase 1 clinical material

FDA views cGMP compliance as a continuum throughout drug development

Guidance for CGMP for Phase 1 Investigational Drugs (2008) gives insight to the quality systems that must be in place for Phase 1

Notes on cGMP

Material used in animal toxicity studies does not have to be the clinical material

FDA expects tox material to be ‘representative’ of the clinical material IND would describe the differences between

the two batches The drug used in tox studies is often pilot lot

material

Notes on cGMP, cont.

41

IND Submitted (phew….)•FDA to respond within 30 days•Sponsor received letter with IND number

•Name of ‘project manager’ (address this person in future correspondence)•Save this letter!

•If no issues, identified by day 30, the IND is considered to be in effect (“approved”)

•FDA does not routinely send approval letter that IND is in effect•This 30th day after receipt is your ‘effective date’

42

Issues with IND?•FDA’s primary objective in all reviews is to ensure the safety and rights of subjects•If issues cannot be resolved within this 30 day period, the FDA places the study (or IND) on “clinical hold”•Commitments in writing will often preclude a clinical hold (this would be submitted as an amendment to the IND)•When hold is lifted – verify the ‘effective date’

In Addition to Law (CFR),Trials Conducted According to Good Clinical Practice (GCP) ICH E6 http://www.ich.org/LOB/media/MEDIA482.pdf

What is GCP? A standard for designing, conducting, recording and

reporting trials that involve the participation of human subjects

Provides public assurance that the rights, safety and well-being of trial subjects are protected and the clinical trial data are credible

Medical Devices

44

Drug Versus Device Development

Drug Development

Patent Approva

l

Patent Approva

l

INDIND FDA

FDA

Review

Review Patent

Patent

Expira

tion

Expira

tion

(17 yr

s)

(17 yr

s)

66--10 yrs10 yrs 88--10 yrs10 yrs

Discovery

Discovery

33--6 yrs6 yrs

Chemical Chemical SynthSynthPharmacologyPharmacologyToxicologyToxicology

Clinical Trials:Clinical Trials:Phase IPhase IPhase IIPhase IIPhase IIIPhase III

Phase IVPhase IVstudiesstudiesMarketingMarketing

Clinical

Clinical

PrePre--clinical

clinical

ND

A 1.

5 yr

s

Source: Parexel’s Pharmaceutical R&D Statistical Sourcebook 2001

Source: AdvaMed, The Lewin Group

Design

Pre-clin

ical

Clinical

12 12 -- 2424mosmos

3 3 -- 99mosmos

6 6 -- 36 36 mosmos

FDA

Market R

eleaseFe

asib

ility

stu

dy

Postmarket studiesPostmarket studiesPM

A -1

4 m

os

IDE

Bench Bench Testing &GLP Testing &GLP

StudiesStudies

HumanHumanStudiesStudiesDevice

Development

46

Food and Drug Administration CDRH Medical devices Radiation-emitting products (medical and non-

medical) Lasers Ultrasound equipment Microwave ovens Color televisions

Imaging devices (imaging agents reviewed by CDER)

48

49

(e.g., dental floss, medical scissors)

(e.g., MRI, clinical thermometer)

(e.g., heart valve, coated stents, defibrillators)

50

51

52

*30 day review period for IDE with SR Device

Device Clinical Studies Content of IDE application Described in 812.20 Name and address of sponsor Report of prior investigations Investigational plan Manufacturing information Investigator agreement (equivalent to 1572)

54

Follow-up Questions?

Speaker:Bruce Burnett, PhD, RACDirector, Regulatory Affairs at Duke Translational Medicine InstituteE-mail: bruce.burnett@duke.edu; (919) 668-7178

MUSC SCTR SUCCESS Center:

Phone: 843-792-8300

Internet: http://sctr.musc.edu

E-mail: success@musc.edu