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 IRBs 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 Pharmaceuticals Large, often multi-national firms Extensive clinical trial experience Devices Entrepreneurial firms common Device “developer” often involved Many have minimal clinical trial experience Sponsor-investigators common

Studies Devices Pharmaceuticals Nonclinical Nonclinical Clinical 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 www.fda.gov/cdrh/oivd/ 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 4% 13% 31% CFSAN had only GLP inspections in 2005 n = 964 52%

GCP/BIMO Inspections by Type FY 2006 9% 13% n = 964 78%

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 4% 51% 44% n = 595

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 4% 47% 49% n = 68

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 14% 52% 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