FDA Regulation of Pharmaceuticals and Devices. Department of Health and Human Services Food and Drug...

FDA Regulation of FDA Regulation of Pharmaceuticals and Pharmaceuticals and

DevicesDevices

Department of Health and Human Services

Food and Drug AdministrationOffice of the Commissioner

Center for Devices and Radiological Health

(CDRH)

Center for Drug EvaluationAnd Research

(CDER)

Center for Biologics Evaluation and Research

(CBER)

Center for VeterinaryMedicine

Center for Food SafetyAnd Applied Nutrition

National Center for Toxicological Research

FDA Organizational Chart

CDRH Mission: Ensure medical devices are CDRH Mission: Ensure medical devices are safe and effective via premarket and safe and effective via premarket and postmarket evaluationpostmarket evaluation

• guide manufacturers in product development• evaluate data submitted on device design,

performance, and clinical use• authorize marketing of devices found safe and

effective• ensure that claims are supported by valid scientific

evidence• focus special emphasis on medical breakthrough

devices (expedited review)

Total Product Life CycleTotal Product Life Cycle

Brachytherapy

Coated Stents

CoatedStents


Q ualitySystem s

A dverseE ven t R eportin g

E ngineerin g

Toxicology

B iocom patibil i ty

S tatisticsR ev iew Scien ces

Stu dy D esign

Foren sicE n gineerin g E p idem iology R eu se Steri l i ty

E n v iron m en t

E M CSh ock V ibration

Post-M ark etingSurvei l lance

E nd ofL ife

M ode ofA ction

D esign

C l in icalSciences

R iskA n alysis

H azardA n alysis


The Pipeline

FDAFDA• 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

FDAFDA

• FDA regulations “speak” to: – Importers/exporters– Study sponsors– Nonclinical laboratory personnel– Clinical investigators– IRBs – Medical product users – hospitals, clinics,

nursing homes, individual practitioners

Pharmaceuticals versus devicesPharmaceuticals 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

Nature of productNature of product

Pharmaceuticals Pharmaceuticals (drugs & biologics)(drugs & biologics)

• Molecular entities• Limited shelf life• Long market life• Potential for

interactions with other drugs

• Wrong drug/dose issues

DevicesDevices• Complex components• Many = durable

equipment• Short product cycles

– “tweaking” of design• Device malfunctions• User errors

Nature of firmsNature of firms

DevicesDevices• Entrepreneurial firms

common• Device “developer”

often involved• Many have minimal

clinical trial experience

• Sponsor-investigators common

PharmaceuticalsPharmaceuticals• Large, often multi-

national firms• Extensive clinical trial

experience

StudiesStudies

DevicesDevices• 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)

PharmaceuticalsPharmaceuticals• Nonclinical

– toxicology

• Clinical – subject populations

commonly 1000s– phases– routinely blinded– placebo = common control

RegulationsRegulations

PharmaceuticalsPharmaceuticals• 21 CFR Part 312 –

IND• Part 314 – NDA• Part 600 – general

biologics provisions• Part 601 – BLA

DevicesDevices• 21 CFR Part 812 –

IDE• Part 809 - IVDs• Part 814 – PMA• Part 807, Subpart E –

510(k)

Clinical Investigators -1Clinical 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 -2Clinical 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 -1Sponsors -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 -2Sponsors -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 -1Regulatory distinctions -1PharmaceuticalsPharmaceuticals• 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)

DevicesDevices• 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 notnot to go to MedWatch (i.e., not use MDR)

Regulatory distinctions -2Regulatory distinctions -2

PharmaceuticalsPharmaceuticals• Manufacturing –

cGMPs – Parts 210 & 211 + Part 606 for blood & blood products

• MedWatch reports for approved pharmaceuticals are voluntary

DevicesDevices• Manufacturing – Part

820 (QSR)• MDRs for approved

devices are mandatory – Part 803

Additional Device Distinctions -1Additional 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


• 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


• Significant risk/non-significant risk studies

• Exempt studies/in vitro diagnostics (IVDs)

• Protocol changes and 5-day notices

Significant Risk (SR)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)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

In Vitro Diagnostics (IVDs)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 StudiesSignificant 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

Clinical Investigators 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

Most Common CI DeficienciesMost 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 Administrative/regulatory optionsoptions

• 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 Institutional Review Boards (IRBs)(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 regulationsApplicable 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 InspectionsIRB 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

Most common IRB deficienciesMost 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



• 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/MonitorsSponsors/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

Most common S/M deficienciesMost common S/M deficiencies

• Inadequate monitoring

• Failure to bring investigators into compliance

• Inadequate accountability for the investigational product



• 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) studiesBioequivalence (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

Resources - 1Resources - 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 - 2Resources - 2

• GCP queries e-mail account (about 1,200 queries answered per year) – [email protected]

• 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 -1Acronyms -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 -2Acronyms -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 -3Acronyms -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 -4Acronyms -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 -5Acronyms -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

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