# Presentation: 314937

## FDA Regulation of Pharmaceuticals and Devices

- Jean Toth-Allen, Ph.D.
- Good Clinical Practice Program
- Office of Science and Health Coordination
- Office of the Commissioner

## Overview

- FDA regulations versus 45 CFR Part 46
- Pharmaceuticals and devices
- What they have in common
- How they differ
- Bioresearch Monitoring (BIMO)
- Resources
- Acronyms

## FDA versus 45 CFR Part 46 -1

- FDA regulations found in Title 21, _Code of Federal Regulations_ – 21 CFR
- Regulate **products**
- Coverage includes – but not limited to:
- Nonclinical studies
- Clinical studies
- Human Subject Protection
- Institutional Review Boards (IRBs)
- Manufacturing
- Labeling
- Post-market adverse event reporting

## FDA versus 45 CFR Part 46 -2

- FDA regulations “speak” to:
- Manufacturers
- Importers/exporters
**Study sponsors**
**Nonclinical laboratory personnel**
**Clinical investigators**
**IRBs**
- Medical product users – hospitals, clinics, nursing homes, individual practitioners

## FDA versus 45 CFR Part 46 -3

- 45 CFR Part 46 - regulates studies with **human subjects** that are **federally funded** – biomedical, sociological, behavioral, educational
- Subpart A = Common Rule – general human subject protections
- Remaining subparts cover research protections in studies with vulnerable populations (pregnant women, fetuses, neonates, prisoners, children)
- “Speaks” to institutions and their **IRB**s
- Crosses government agencies – enforcement led by the Office of Human Research Protections (OHRP)

## FDA versus 45 CFR Part 46 -4

- Human subject protections of Common Rule covered by FDA regulations in
- 21 CFR Part 50 – Protection of Human Subjects
- 21 CFR Part 56 – Institutional Review Boards
- 45 CFR 46, Subpart D comparable to 21 CFR 50, Subpart D – research with children
- Preambles to FDA regulations identify the need for special protections for other vulnerable populations but FDA regulations do not separately address

## FDA versus 45 CFR Part 46 -5

- Both may apply to a given research study
- If there are regulatory differences, the more stringent requirements usually apply (e.g., FDA regulations allow for very few exceptions from informed consent)

## Pharmaceuticals versus devices

- Pharmaceuticals (drugs and biologics) are covered by different FDA regulations from those covering devices, though some regulations are shared
- Many differences result from differences among the products themselves

## SHARED REGULATIONS

- Part 50 – Protection of Human Subjects
- Part 56 – Institutional Review Boards
- Part 54 – Financial Disclosure by Clinical Investigators
- Part 58 – Good Laboratory Practices for Nonclinical Laboratory Studies
- Part 11 – Electronic Records; Electronic Signatures

## COMPLIANCE PROGRAMS

- Programs are Agency-wide (available at http://www.fda.gov/oc/gcp/compliance.html)
- Contain instructions to FDA field personnel for inspecting regulated entities
- Center-specific differences are included where applicable

## DIFFERENCES

- Nature of product, firms, and studies
- Statutory distinctions
- Regulatory distinctions

## Nature of product

**Pharmaceuticals (drugs & biologics)**
- Molecular entities
- Limited shelf life
- Long market life
- Potential for interactions with other drugs
- Wrong drug/dose issues

**Devices**
- Complex components
- Many = durable equipment
- Short product cycles – “tweaking” of design
- Device malfunctions
- User errors

## Nature of firms

**Devices**
- Entrepreneurial firms common
- Device “developer” often involved
- Many have minimal clinical trial experience
- Sponsor-investigators common

**Pharmaceuticals**
- Large, often multi-national firms
- Extensive clinical trial experience

## Studies

**Devices**
- Nonclinical
- biocompatibility
- nonclinical studies may suffice
- Clinical
- subject populations usually 100s
- pilot study possible + pivotal
- blinding less common
- “controls” vary
- CI training often critical (Human Factor concerns)

**Pharmaceuticals**
- Nonclinical
- toxicology
- Clinical
- subject populations commonly 1000s
- phases
- routinely blinded
- placebo = common control

## Statutory Distinctions

- Devices lack market exclusivity provisions
- Waxman-Hatch – pediatric studies and extension of patent (drugs)
- Orphan drug tax exemptions (drugs/biologics)
- FDAMA (1997) – included a “least burdensome” provision for devices

## Regulations

- Pharmaceuticals
- 21 CFR Part 312 – IND
- Part 314 – NDA
- Part 600 – general biologics provisions
- Part 601 – BLA

- Devices
- 21 CFR Part 812 – IDE
- Part 809 - IVDs
- Part 814 – PMA
- Part 807, Subpart E – 510(k)

## Clinical Investigators -1

- Common responsibilities across products:
- Personally conduct or supervise the study
- Ensure site study team is properly trained
- Follow FDA regulations regarding HSP, including obtaining and maintaining IRB approval and obtaining subject informed consent
- Follow the approved investigational plan/protocol

## Clinical Investigators -2

- CI responsibilities (cont.):
- Maintain adequate, complete, and accurate study records
- Submit all required reports (e.g., IND safety reports, study progress reports)
- Maintain control of the investigational product

## Sponsors -1

- Common responsibilities across products:
- Obtain FDA approval, where necessary, before study initiation
- Manufacture and label investigational products appropriately
- Initiate, withhold, or discontinue clinical trials as required
- Refrain from commercialization of investigational products
- Maintain control of the investigational product

## Sponsors -2

- Sponsor responsibilities (cont):
- Select qualified investigators and disseminate appropriate information to them
- Select qualified monitors and ensure the study is adequately monitored
- Evaluate and report adverse experiences
- Maintain adequate records
- Submit progress and final reports

## Regulatory distinctions -1

- Pharmaceuticals
- Adequate, well-controlled trials
- CROs – 312.52 = transfer of regulatory obligations
- Form FDA 1572
- FDA agreement not usually required before enacting studies changes
- AE reports ***during study*** may use Form 3500A (Med Watch) – 312.32(c)(B)

- Devices
- Valid scientific evidence
- CROs – regulations silent save for definition of monitor [812.3(j)]
- Investigator agreement [812.43(c)]
- Significant study changes require IDE supplement approval
- AE reports ***during study*** **not** to go to MedWatch (i.e., not use MDR)

## Regulatory distinctions -2

- Pharmaceuticals
- Manufacturing – cGMPs – Parts 210 & 211 + Part 606 for blood & blood products
- MedWatch reports for ***approved*** pharmaceuticals are voluntary

- Devices
- Manufacturing – Part 820 (QSR)
- MDRs for ***approved ***devices are mandatory – Part 803

## Additional Device Distinctions -1

**Classes of Devices** – risk-based determination
- 21 CFR 860 – classification procedures
- 21 CFR 862 through 892 – specific device classifications by product type

## Additional Device Distinctions -2

**Cleared devices** – 510(k)
- 21 CFR 807, subpart E – Premarket Notification Procedures
- “substantially equivalent”
**Approved devices**
- 21 CFR Part 814
- PMA, PDP, HDE
- Safety and effectiveness – PMA & PDP
- Safety – HDE

## Additional Device Distinctions -3

- Significant risk/non-significant risk studies
- Exempt studies/in vitro diagnostics (IVDs)
- Protocol changes and 5-day notices

## Significant Risk (SR)

**Regulatory definition** (21 CFR 812.3(m)) – device that presents potential for serious risk to health, safety, or welfare of a subject, particularly if it
-  Is intended as an implant
-  Is purported or represented for use in supporting or  sustaining life
-  Is for a use of substantial importance in   diagnosing, curing, mitigating, or treating disease, or  otherwise preventing impairment of human health

## Non-Significant Risk (NSR)

- Decision based on use of device in study
- Sponsor makes initial assessment
- IRB makes determination
- FDA can disagree
- If NSR study, no IDE application to FDA
- Informed consent required
- Abbreviated requirements apply (21 CFR 812.2(b))
- Considered to have an IDE

## Exempt device studies

- 21 CFR 812.2 (c)
- Studies with cleared devices, used as specified in clearance
- By policy, extended to approved devices, with same conditions
- Diagnostic devices that meet requirements specified – basically IVDs, as references labeling conditions of 809.10

## In Vitro Diagnostics (IVDs)

- SR/NSR/exempt studies
- Exempt if:
-  labeled according to 21 CFR 809.10
-  noninvasive
-  noninvasive sampling or no significant risk
-  does not introduce energy into a subject
-  not used as the diagnostic for     determination of treatment

## Significant Risk IVD Studies

-  If study involves invasive sampling that presents  a significant risk
-  If results from use of an investigational IVD will   determine treatment, could inaccurate results:
- 	be life-threatening
- 	result in permanent functional impairment
- 	result in permanent structural damage
- 	necessitate medical or surgical intervention    to prevent impairment or damage

## IVD Studies & HSP Issues

- Studies on specimens – included in device definition of a subject (812.3(p))
- Expedited review by IRB possible
- Confusion with 45 CFR Part 46
- Privacy & confidentiality
- FDA data audits

## Additional IVD issues -1

- Drug-diagnostic co-development concept paper – April 2005 – http://www.fda.gov/cder/genomics/pharmacoconceptfn.pdf
- Guidance on use of left-over specimens that are not individually identifiable – April 2006 – http://www.fda.gov/cdrh/oivd/guidance/1588.html

## Additional IVD issues -2

- Interim final rule regarding exception from informed consent (bioterrorism, emerging diseases) – September 2006 http://www.fda.gov/OHRMS/DOCKETS/98fr/E6-8790.pdf
- Draft guidance on Analyte Specific Reagents (ASRs) – September 2006 http://www.fda.gov/cdrh/oivd/guidance/1590.pdf

## Additional IVD issues -3

- Draft guidance on Multivariate Index Assays (MIA) – September 2006 http://www.fda.gov/cdrh/oivd/guidance/1610.html
- Public meeting held February 8, 2007

## WEB PAGE

**Office of In Vitro Diagnostic Device Evaluation and Safety** **(OIVD)**
- www.fda.gov/cdrh/oivd/

## IDE Protocol Changes -1

- IDE Supplement required if* *changes significantly affect:
-  validity of data
-  scientific soundness of study
-  rights, safety, or welfare of subjects

## IDE Protocol Changes -2

**Examples when supplement required:**** **
** **indication change
-  different type of study control
-  alternative primary endpoint
-  reduction in study population size
-  change in method of evaluation
-  early termination of the study

## IDE Protocol Changes -3

**5-day notice**** **
- 1998 amendment to Part 812- if changes do not meet requirements for an IDE supplement
**Examples:**
** **additional measurements
-  more targeted subject criteria
-  more frequent follow-ups
-  change in secondary endpoints

## IDE Protocol Changes -4

**GUIDANCE DOCUMENT – issued by Office of Device Evaluation (ODE)**
**Changes or Modifications During the Conduct of a Clinical Investigation - **issued May 29, 2001
**www.fda.gov/cdrh/ode/guidance/1337.html**
**www.fda.gov/cdrh/ode/guidance/1337.pdf**

## BIMO Program

- Comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated research

## BIMO Program Objectives

- To ensure
- the integrity of data supporting submissions to the Agency
- the rights, safety, and welfare of study subjects

## Bioresearch Monitoring (BIMO) -1

- Specific group in each Center to oversee BIMO program
- Bioresearch Monitoring Branch/Division of Inspections and Surveillance/Office of Compliance – CBER
- Division of Scientific Investigations (DSI)/Office of Compliance - CDER
- Division of Bioresearch Monitoring (DBM)/Office of Compliance – CDRH

## Bioresearch Monitoring (BIMO) -2

- Present BIMO contacts
- CBER
- Pat Holobaugh
- Branch Phone # - (301) 827-6220
- CDER
- Gary Della’Zanna
- Division Phone # - (240) 276-8817
- CDRH
- Michael Marcarelli
- Division Phone # - (240) 276-0125

## Bioresearch Monitoring (BIMO) -3

- Headquarters BIMO staff:
- Interact with Center reviewers
- Issue inspection assignments
- Interact with ORA BIMO investigators
- Review and classify EIRs
- Issue post-inspectional correspondence
- Take part in regulatory actions (AIP, DQ)
- Provide staff for ORA BIMO investigator training
- Provide speakers for outreach activities

## Inspection assignments

- Assigned by HQ BIMO staff
- Majority issued on receipt of an application or submission
- When for marketing, supporting study usually completed
- “for cause” –  usually when suspicion of integrity or human subject protection (HSP) issue – often for on-going studies

## BIMO Compliance Programs

- Good Laboratory Practice – CP 7348.808
- Institutional Review Board – CP 7348.809
- Sponsor, Contract Research Organizations (CROs), Monitors – CP 7348.810
- Clinical Investigator – CP 7348.811
- In Vivo Bioequivalence – CP 7348.001
- http://www.fda.gov/oc/gcp/compliance.html

## Inspectional follow-up

- Final inspection classification made by HQ
- Post-inspectional correspondence issued to inspected party
- Administration/regulatory options vary by party inspected
- Recommendations may also be sent to those reviewing a research or marketing application/submission

## GCP/BIMO Inspections Completed FY 2006

_**Center**_**	**_**CI**_**	**_**IRB**_**	**_**Spon/Mon**_**	****	**_**Total**_
**CBER**		108	    8 		  5	             121
**CDER**		401 	  66       	32  	             499
**CDRH**		203	  48		51       	  302
**CFSAN**	    0	    0	             0                        0
- CVM	  	  41       n/a		  1		    42
**All Centers**	 753	 122	          	89  	             964

## GCP/BIMO Inspections by CenterFY 2006

- n = 964

- 31%

- 52%

- 13%

- 4%

**Notes:**
CFSAN had only GLP inspections in 2005

## GCP/BIMO Inspections by Type FY 2006

- n = 964

- 13%

- 78%

- 9%

## Clinical Investigators 

- Compliance inspection program covers study specific inspections and audits of CIs (physicians, veterinarians, others) conducting clinical trials on human and veterinary products
- Usually preannounced
- Inspection includes an interview with the clinical investigator and pertinent study staff + an in-depth study/data audit – to validate study findings and verify compliance with regulations

## BIMO CI Inspections – FY 2006All Centers – completed & classified	

- n = 595

- 4%

- 51%

- 44%

## Most Common CI Deficiencies

- Failure to follow the investigational plan
- Protocol deviations
- Inadequate recordkeeping
- Inadequate accountability for the investigational product
- Inadequate subject protection – including informed consent issues

## Administrative/regulatory options

- Untitled or Warning letter
- Initiation of disqualification procedures
- Sharing information with Office of Criminal Investigations (OCI) for pursuit of prosecution
- Recommendation for rejection of site/study data

## Institutional Review Boards (IRBs)

- Board, committee, or other group formally designated by an institution to
- review
- approve the initiation of
- conduct periodic review of
- research involving human subjects
- Primary purpose of review = ensure protection of rights, safety, and welfare of the human subjects

## Applicable regulations

- 21 CFR Part 50 – Protection of Human Subjects – contains informed consent requirements
- 21 CFR Part 56 – Institutional Review Boards – includes specifics of IRB’s make-up and duties

## IRB Inspections

- Compliance program provides for regularly scheduled inspections to verify compliance with regulations
- Objective is protection of human subjects rather than data validation
- Inspections
- usually preannounced
- consist of
- interviews with responsible IRB staff
- in-depth review of SOPs, files, and records
- review of active studies to assess IRB operations

## IRB Inspections – FY 2006All Centers – completed & classified

- 47%

- n = 68

- 4%

- 49%

## Most common IRB deficiencies

- Inadequate initial and/or continuing review
- Inadequate SOPs
- Inadequate membership rosters
- Inadequate meeting minutes
**Specific to devices** – lack of or incorrect SR/NSR determination

## Administrative/regulatory options

- Untitled or Warning letter
- Restriction of functions
- prohibiting increase of subject population in on-going FDA-regulated studies
- prohibiting review of new FDA-regulated studies
- Initiation of disqualification procedures

## Sponsors/CROs/Monitors

- Compliance program
- covers parties responsible for initiating and overseeing research and for submitting research results to FDA
- lists sponsor responsibilities
- Inspections
- usually preannounced
- consist of interviews and audits of study records
- objective is to both evaluate compliance with regulations and validate data
- commonly assigned for NDAs for new molecular entities (NMEs) and for PMAs

## Sponsor-Monitor InspectionsFY 2006 - All Centers – completed & classified

- 52%

- 14%

- 34%

- n = 64

## Most common S/M deficiencies

- Inadequate monitoring
- Failure to bring investigators into compliance
- Inadequate accountability for the investigational product

## Administrative/regulatory options

- Untitled or Warning letter
- Invocation of the Application Integrity Policy (AIP)
- Refusal to accept site or study data
- Denial of NDA/BLA/PMA
- Sharing information with Office of Criminal Investigations (OCI) for pursuit of prosecution

## Bioequivalence (BEQ) studies

- Primarily support
- Abbreviated drug applications (ANDA) for generic drugs
- Applications for new form or formulation of marketed drugs
- Compliance program
- Provides for inspection of both clinical facilities and analytical laboratories involved with BEQ studies
- Focuses on inspecting
- New facilities
- Previously violative sites
- Suspicious data
- Non-conventional studies
- Studies pivotal to NDA decision-making

## BEQ inspections

- Conducted by an inspection team, including a laboratory chemist and an ORA field investigator
- May involve multiple facilities
- Include
- physical inspection and technical evaluation of laboratory facilities and methods
- audits of analytical and clinical data

## Resources - 1

- GCP website – http://www.fda.gov/oc/gcp/
- Links include
- pertinent regulations and guidance
- FDA contacts
- related sites with HSP/GCP information
- Recent documents of interest relate to
- Data monitoring committees
- Use of a centralized IRB
- AE reporting
- CI supervisory responsibilities
- Computerized systems in clinical trials

## Resources - 2

- GCP queries e-mail account (about 1,200 queries answered per year) – gcp.questions@fda.hhs.gov
- Previous answers captured – http://www.fda.gov/oc/gcp/redactedEmails/default.htm
- Listserve – via GCP website – notice of updates on FDA’s GCP/HSP activities
- Site maintained by Good Clinical Practice Program (GCPP)

## Acronyms -1

- 510(k) – premarket notification
- AE – adverse event (or effect)
- AIP – Application Integrity Policy
- BEQ – bioequivalence
- BIMO – Bioresearch Monitoring
- BLA – biologics license application
- CBER – Center for Biologics Evaluation and Research
- CDER – Center for Drug Evaluation and Research

## Acronyms -2

- CDRH – Center for Devices and Radiological Health
- CFR – Code of Federal Regulations
- CI – clinical investigator
- cGMPs – current good manufacturing practices
- CRO – contract research organization
- DBM – Division of Bioresearch Monitoring
- DSI – Division of Scientific Investigations
- DQ – disqualification

## Acronyms -3

- EIR – establishment inspection report
- FDAMA – Food and Drug Administration Modernization Act (1997)
- GCP – Good Clinical Practice
- GCPP – Good Clinical Practice Program
- HDE – humanitarian device exemption
- HSP – human subject protection
- HQ – headquarters
- IDE – investigational device exemption
- IND – investigational new drug

## Acronyms -4

- IRB – institutional review board
- IVD – in vitro diagnostic
- MDR – medical device report
- NAI – no action indicated
- NDA – new drug application
- NME – new molecular entity
- NSR – non-significant risk
- OAI – official action indicated
- OHRP – Office of Human Research Protections

## Acronyms -5

- OIVD – Office of In Vitro Diagnostic Device Evaluation and Safety
- ORA – Office of Regulatory Affairs
- PDP – product development protocol
- PMA – premarket approval
- QSR – quality system regulation
- SOPs – standard operating procedures
- SR – significant risk
- VAI – voluntary action indicated