conducting investigator-initiated research in a community

Conducting Investigator-Initiated

Research in a Community

Health System

Presented by: Bruce Steinert, PhD, CCRA

Date: June 3, 2014

Goals

At the conclusion of today’s session, you should be

able to:

• Explain the ethical basis and regulations

governing clinical research

• Explain the fundamentals and nuances of

investigator-initiated research

• Explain general funding opportunities for

investigator-initiated research

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Drug Development Process

• 10-15 years concept to market

• Average cost $802 million in 2000

– Forbes estimated $3-11 billion in 2012

– 1 day delay to market costs $600,000 to $8 million

• For each drug approved by FDA1

– 5,000 chemical entities screened

– 250 enter pre-clinical testing

– 5 enter clinical testing; 1 licensed for market

• Market exclusivity and follow-on time2

– Exclusivity - 10.2 yrs (‘70s) to 2.5 yrs (‘00-’03)

– Follow On – 16.1 yrs (’60s) to 1.1 yrs (‘00-’03)

• Only 2 of 10 drugs recoup development costs

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Drug Development in 2013

• More than 900 drugs in development

• Cancers, infectious and autoimmune diseases top

the list

• 27 new drugs approved.

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Ethical and Regulatory Basis for

Clinical Research

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Research is Evolution not Revolution

• Research method is a recent development

• Oversight of research is even more recent

• Compliance:

– Driven by regulations

– What you must or must not do

• Ethics:

– What you should or should not do even if not expressly

required or prohibited

– Some choices driven by regulation or guidance

– Institutional ethics ‘Culture’

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Example: Vulnerable Subjects

• Defined by regulation

– Pregnant Women and

fetuses

– Prisoners

– Children

• By institutional choice – Economically

disadvantaged

– Educationally disadvantaged

– Employees

– Physically disabled

– Life threatening or debilitating condition

– Mentally disabled

– Non-English speaking

– Nursing home residents

– Ethnic minorities

– Refugees

– Military personnel

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Early Regulations

• Regulation of and consistency of products – Consistent chemistry; prohibited misbranding

– Biologics and Control Act of 1902

– Pure Food and Drug Act of 1906 (FDA created)

• Federal Food, Drug and Cosmetic Act of 1938 (The Act) – Elixir of Sulfanilamide incident; safety testing required

– Definitions • Drug – test article that exerts its effect by altering

metabolism or becomes effective when metabolized

• Device - test article that exerts its effect by non-metabolic means

• Biological - virus, therapeutic serum, toxin, antitoxin, or analogous product

• Combination device – device with a drug or biological component (e.g., delivery system – EpiPen®)

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Problems Regulating Only Chemistry

• Research processes not regulated – Walter Reed – Yellow Fever

– Nuremberg War Crimes

– Unit 731

– Willowbrook State School

– Public Health Service Syphilis Study at Tuskegee

• Study participants not protected – Gaps in regulations

– Lack of oversight

– No guidance for ‘proper’ research

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Post-World War II

• Nuremberg Tribunal (1947) – First recognition of rights of research subjects

– Nuremberg Code

• Consent and ability to withdraw consent without penalty

• Qualified investigators

• Scientific basis for experiments

• Risks should not exceed benefits

• No a priori death or disablement

• Declaration of Helsinki (1964-2004) – World Medical Association

– Independent review (pre-IRB)

– Written consent with option for “surrogate consent”

– Required compliance for studies not under FDA oversight

– Regulatory requirement removed in 2008

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Safety Testing Is Not Enough

• Kefauver-Harris Amendment of 1962 – Thalidomide incident

– Efficacy testing required (defined ‘prescription drugs’)

– Qualified investigators

• Device regulations – No pre-market approval process for devices

– FDA given no authority to regulate devices

– FDA policed Federal Trade Commission or Postal Fraud rules

• FDA had to bring charges that a device was faulty

• Removal from market required court action

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Post-World War II

• National Research Act (1974)

– Established the National Commission for the Protection

of Human Subjects of Biomedical and Behavioral

Research

– Tasked to establish guidelines for human research

– Belmont Committee convened

• Medical Device Amendments of 1976 – Driven by injuries by Dalkon Shield, pacemaker failures

and other device related hazards

– FDA granted authority to establish approval criteria

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MDA Terminology

• Risk Classification System – Class I – General controls

– Class II – General controls and special controls

– Class III – General Controls and Pre-market Approval

• Pre-amendment devices

– Marketed before 28 May 1976

• Post-amendment devices

• 510k devices

• Predicate devices

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Significant Risk Device

• Definitions – Experimental or investigational device

– Implant – risk to health, safety, welfare

– Used to support or sustain life

– Substantial importance in diagnosing, curing, mitigating, or treating disease

– Other potential for serious risk to health, safety, welfare

• Sponsor initially evaluates risk – Required to obtain Investigational Device Exemption

– IRB re-evaluates risk during review • In addition to evaluating protocol, consent, etc.

• Decision and vote recorded in IRB minutes

• Results reported in approval letter

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Humanitarian Use Device (HUD)

• HUD is an FDA-approved device

– Device counterpart to orphan drugs

• <4,000 cases/year; no other approved therapy

• Receives a Humanitarian Device Exemption (HDE)

• Safety demonstrated, but efficacy testing not required

– IRB authorizes use at site (initial and continuing rev.)

– Adverse reporting to IRB, FDA, manufacturer

• Use of HUD according to ‘label’ is not research

– Manufacturer may add a research component

• IRB requirement limits market

• Intention to collect additional data for future licensing

– Treat like any other device study

• IDE and informed consent form required

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Post-World War II

• Report of the Belmont Committee (1979)

• Three foundational principles

– Respect for Persons

» Autonomy of subjects

» Diminished autonomy requires safeguards

– Beneficence

» “Do no harm”

» Maximize benefits and minimize risks

– Justice

» Fairness of Distribution

» Benefactor assumes the risk

• Principles not yet regulations

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Post-World War II

• Belmont Report codified – 45 CFR Part 46 (Part A;1981)

– 15 Agencies adopt 45 CFR 46 for protecting human research subjects (1991)

» Referred to as the “Common Rule”

» CIA, Social Security Admin., Homeland Security adopted

– Applies to research conducted or supported by federal government

– Subparts B-D added later

• FDA published similar regulations in Title 21 – Good Clinical Practice (Parts 50, 54 and 56)

– Review of research in Parts 312, 600, 812 and 860

– Applies to research of regulated products

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Regulations Not Static

• Changes in 2013

• FDA regulations (§§50 and 56) aligned with 45

CFR 46 subpart D

– “Guardian” modified to match 45 CFR 46.402(e)

– Definition of permission modified

• Emancipated or mature minors not “children”

• New §50.51(a) requires IRBs to assess risk to

children in research not involving greater than

minimal risk

• Modified §50.55(e) clarifies exception for

emergency research in §50.24 applies to research

in children (including consent provisions)

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Post-World War II

• Council for International Organizations of Medical Sciences (CIOMS; 1991)

– Guidelines for international research

» By advanced countries in developing countries

» Address cultural differences

– Not a common requirement in North America, Europe or Japan

• International Conference on Harmonisation of Technical Requirements for the Licensing of Pharmaceuticals (ICH; 1991)

– Participants

• United States, Japan, EU

• Numerous observer nations

• Representatives from government and industry

– Simplify and standardize approval requirements

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International Conference on

Harmonisation

• 4 sections – Efficacy (16 subparts)

• E2 – Adverse Event Reporting

• E6 – Good Clinical Practice

• E7-E11 – Clinical Trials

– Safety

– Quality

– Multidisciplinary

• Take home message – Guidelines – not regulatory in US

– FDA has approved ICH E6 (GCP); will enforce if asked

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Standardization of Devices

• Global Harmonisation Task Force

– Began 1992 to “encourage convergence in regulatory

practices … of medical devices”

– Device counterpart to ICH guidelines

• The International Medical Device Regulators

Forum (IMDRF)

– Began February 2011 on foundation of GHTF

(http://www.imdrf.org/)

– Has not attained same impact as ICH

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http://www.imdrf.org/

What is ‘Research’?

• [HHS] Systematic investigation: – Produce generalizable knowledge, through:

• Direct interactions or interventions with living subjects

• Indirect activities such as the analysis of specimens or data from subjects

• [FDA] Any experiment that:

– Involves a test article and

– One or more human subjects and

– Either:

» “Meet the requirements for prior submission to the FDA or”

» “Intended to be later submitted to, or held for inspection as

part of an application for a research or marketing permit.” 21CFR56.102

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What is ‘Research’?

• [ICH] Any investigation of an investigational

product (active ingredient or placebo)

– In human subjects

– To discover or verify the effects, and/or

– To identify any adverse reactions, and/or

– To study absorption, distribution, metabolism, and

excretion to determine its safety and/or efficacy.

– Not dependent on funding source or future licensing

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Health Insurance Portability and

Accountability Act (HIPAA)

• More control by patient over information – Protected Health Information (PHI)

– Limits the use and disclosure of health records

– Covers all medical records

– Other identifiable health information

• Covered Entities (CE)

– Health plans

– Health care providers

– Health care clearinghouses

• Business Associates (via BAA)

– Perform a covered function on behalf of a CE

– Research collaborators and sponsors not BAs

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Privacy Changes - American Recovery

and Reinvestment Act of 2009

• Business Associates now have same duties and

penalties as covered entities

– Subtitle D, section 13400

– Definition unchanged – still not research

• New definition – Personal Health Record

– “Identifiable health information that can be drawn from

multiple sources” [section 13407(f)(2)]

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Health Insurance Portability and

Accountability Act (HIPAA)

• Covered Functions

– Treatment

– Payment for treatment

– Healthcare operations

• Use and disclosure for covered functions requires

patient notification of CE’s privacy policy

• Research is not a covered function

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Using PHI for Research

• Access to information

– Written Authorization by subject

– Waiver of Authorization (IRB/PB)

– Alteration of Authorization (IRB/PB)

– De-identified information

• Removal of 18 specified elements

• Statistical certification

– Limited Data Set (via Data Use Agreement)

– Use Preparatory to Research

• Privacy rule protects identifiable information

– Tissue not protected

– Associated PHI is protected

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Review of PHI Preparatory

to Research

• Review PHI as necessary to prepare a research

protocol or for similar purposes

– No PHI may be removed from the CE

– PHI must be necessary for the research purposes

• Use of PHI to screen potential study subjects is

permitted as ‘preparatory to research’

• Covered Entity may contact subjects

– Prior or existing ‘covered function’ relationship

– Authorization required for continued use of PHI

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Questions?

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Budgets (“No Margin, No Mission”)

• Critical process for a successful program

• Heavily regulated with nasty consequences

• Regulations

– Anti-Kickback Statutes

– Stark Rules (prohibits self-referrals) – 3 flavors

– False Claims Act

– Fraud Enforcement and Recovery Act (FERA)

– Anti-Markup Rule

– Wire and Mail Fraud Regulations

– Unrelated Business Tax Regulations

• Tax exempt organizations

• Income from non-exempt activities

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Sponsor’s Budget

• Sponsors know your market

• Subscription resources

– National clinical trial databases

– Example – Medidata Solutions Worldwide

» Medidata Grants Manager™

» Medidata CRO Contractor™

– Internal databases

» Budgets, timelines, enrollment history

» Regional differences

• Best Practice Tip

– Maintain your own metrics

– Self and sponsor

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Site’s Budget

• Develop independent from Sponsor’s budget

– Zero-Base Budgeting

– Consider the big picture when budgeting

– Look for potential ‘hidden’ costs

• Time and effort ‘leakage’

• Enrollment timing

• High cost staff for low revenue tasks

• Budget components

– Start-up Charges (not ‘costs’)

– Per Subject Charges

– Contingent Charges

– Close-out Charges

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Site’s Budget - Start-Up Charges

• Covers work done up to enrollment of first subject – One-time charge

– Non-Cancelable/Non-Refundable

– Good faith effort

• Includes: – Protocol review (PI, coordinator, Pharmacy, Lab, etc.)

– Department review and set-up fees

• Pharmacy, Laboratory, Radiology

– Advertising for subjects

– IRB review fee

– Facility and Administration Rate applied

• Embedded or additional?

• Presentation depends on sponsor

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Site’s Budget - Per Subject Charges

• Every study different

– Protocol driven

– Make flow chart if not provided

– Don’t rely on sponsor’s flow chart

– Read the description

– Separate procedure costs from recording costs

• Electronic data capture

• Could be significant additional labor involved

• Know which tests sponsor will cover

– Research – study budget

– Usual Care – subject or insurance

– Be aware of usual care covered by sponsor

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Site’s Budget - Contingent Costs

• Only invoiced if occur

• Examples

– Pharmacy record maintenance

– Annual IRB review

– Protocol amendments

– Consent form changes or translations

– Unscheduled visits

– Screen Failure charges

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Site’s Budget – Close-Out Charges

• Reports to IRB

• Closeout monitor visit

• Test article disposal (return, destruction, waste)

• Record storage – Archive storage charges

» Volume, time and movement

» Can be difficult to estimate

– Could be a long time

» Longevity of media is important, too

» Clay tablets, paper, magnetic tape, CD-R, CD-RW

– Special considerations

» Computer (electronic record) – onsite vs online

» Recordings, tapes, video

» Readers and players

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Questions?

Click to add section subtitle

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Stages of Drug Development

• FDA definitions(21CFR312.21)

– Similar for NIH, different names for ICH

• Phase I – 1st time in humans – 20-100 healthy (normal) subjects, < 1 year

– Safety and pharmacology testing (ADMET)

– Escalating dosage

• Phase II – Early studies in intended population – 100 - 1,000 subjects with intended condition, 1-2 years

– Mostly safety, some efficacy

• Phase III – Safety, efficacy, cost benefits – 200 - thousands of subjects

– 2-4 years

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Stages of Clinical Research

• Phase IIIb – Post NDA submission

– Sponsor collects additional S&E data

• Phase IV – Post marketing (21CFR312.85)

– Large numbers of subjects

– General treatment population

– Safety – rare adverse events

– Potential COI issue - OIG guidelines

• ICH Terminology

– Human Pharmacology (Phase I)

– Therapeutic Exploratory (Phase II)

– Therapeutic Confirmatory (Phase III)

– Therapeutic Use (Phase IV)

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Ethics Review

• Institutional Review Board

– Different names in other jurisdictions

– Sole responsibility to protect human subjects

• Different types

– Local

– Central (Commercial)

– Central (non-Commercial)

• Can use any combination depending on local

policy

– Supplement local expertise

• Recombinant DNA

• Pediatrics (e.g., ‘407’ review)

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Ethics Review

• Full Board - convened meeting

• Continuing Review – Full Board – same requirements as initial review

– Some exceptions

– Adverse events, unforeseen problems, deviations

• ‘Limited’ Reviews – Exempt research

– Expedited review

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Expedited vs. Exempt

• Categories of review not requiring convened meeting – Have same legal effect as full board review

– IRB must be informed of decisions at a convened meeting and may request full board review

– Projects may not be ‘disapproved’ by expedited review process

• Limited to categories defined by regulation – Expedited - 45 CFR 46.110 and 21 CFR 56.110

– Exempt – 45 CFR 46.101(b)

• IRB should decide if a study qualifies – Investigators should not make the decision

– Apparent conflict of interest for PI

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Expedited Review

• General project requirements – Involves no more than minimal risk

• What is minimal risk?

– Involves only procedures in specific categories

– Some categories limited by age of participants

– May not be used where identification of the subjects and/or their responses could place subjects at risk of criminal or civil liability or other harms

• Standard requirements for informed consent apply including waiver, alteration, or exception

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Expedited Review Categories 1 and 2

• Clinical studies of drugs and medical devices only when: – IND or IDE is not required; or

– Medical device is used in accordance with its approved labeling

• Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture provided: – Not to exceed 550 ml in an 8 week period and not more

often than 2x/week from health, non-pregnant adult

– Not exceed the lesser of 50 ml or 3 ml per kg in an 8

week period and not more often than 2x/week (adults or

children)

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Expedited Review Categories 3 - 6

• Prospective collection of biological specimens for research purposes by noninvasive means

• Collection of data through noninvasive procedures routine in clinical practice (no anesthesia or sedation; x-rays or microwaves)

• Research involving materials (data, documents, records, or specimens) collected solely for non-research purposes (e.g., treatment or diagnosis)

• Collection of data from voice, video, digital, or image recordings made for research purposes

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Expedited Review Categories 7 - 8

• Research on individual or group characteristics or behavior (excluding exempt research)

• Continuing review of research previously approved

by a convened IRB, where:

– study is permanently closed to new enrollment; AND all

subjects have completed all research-related

interventions; AND the research remains active only for

long-term follow-up of subjects; or

– no subjects have been enrolled and no additional risks

have been identified; or

– where the remaining research activities are limited to

data analysis

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Expedited Review Category 9

• Continuing review of research

– Not conducted under an IND or IDE

– Categories two (2) through eight (8) do not apply but;

• IRB has determined and documented at a convened

meeting that the research involves no greater than minimal

risk; and

• no additional risks have been identified.

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Exempt Research Categories 1 and 2

(Common Rule)

• Research in educational settings, involving normal

educational practices

• Research involving educational tests, surveys,

interviews or observation of public behavior,

unless:

– information obtained is recorded such that human

subjects can be identified, directly or through

identifiers linked to the subjects; and

– any disclosure of the human subjects' responses outside

the research could reasonably place the subjects at risk

of criminal or civil liability or be damaging to the subjects'

financial standing, employability, or reputation.

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(Common Rule) • Research involving the use of educational tests,

surveys, interviews, or observation of public behavior not otherwise exempt (category 2), if: – subjects are elected or appointed public officials or

candidates for public office; or

– federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter

• Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens – if these sources are publicly available or

– if the information is recorded by the investigator such that subjects cannot be identified, directly or through identifiers linked to the subjects

– Note: existing means that data exist at time exemption is granted

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(Common Rule) • Research and demonstration projects

– Conducted by or subject to the approval of department or agency heads, and which study:

• Public benefit or service programs

• Procedures for obtaining benefits or services

• Possible changes in or alternatives to programs or procedures; or

• Possible changes in methods or levels of payment for benefits or services under those programs

• Taste and food quality evaluation and consumer acceptance studies – If wholesome foods without additives are consumed, or

– If food is consumed that contains food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the FDA or approved by the EPA or the Food Safety and Inspection Service of the USDA.

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Exempt Research Categories FDA

• Research started before July 27, 1981

– Did not require FDA approval before that date, or

– Was subject to IRB review prior to that date and remains

subject to IRB review;

• Emergency use of a test article, provided use is

reported to the IRB within 5 working days;

• Same taste and food quality evaluation as

Common Rule category (6).

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Exempt Research Caveats

• Exemption requires compliance with pertinent

federal laws or regulations providing additional

protections for human subjects

• Exemption does not affect any applicable state or

local laws or regulations which provide additional

protections for human subjects

• Exemption does not affect any foreign laws or

regulations which may otherwise be applicable

and which provide additional protections to human

subjects of research

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Standard Operating Procedures (SOPs)

• Standardize local methods and procedures – ‘How To’ coverage

– ‘Where does it say that?’

– ‘Buy-In’ from other departments

– Special situations

• Regulations provide no guidance

• How much is enough? – Regulatory minimum?

– Higher standard to address known issues?

– Institution should decide

• Enhance compliance without excessive burden – Regulators want to see them

– Deviation from SOP same as deviation from regulation

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Responsibilities

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Sponsor’s Responsibilities

• Overall responsibility for the research – 21 CFR 312 & 812

– ICH E6 section 5

• Obtaining IND or IDE ‘approval’ – Investigational New Drug (Form 1571; drug, biological)

– Investigational Plan (device)

– Select investigators and monitors

» Investigators, Monitors

» Qualified by training and experience

» Evaluate and mitigate financial conflicts of interest

» Contract Research Organization, if applicable

• Inform FDA, investigators of new developments – Adverse events

– New risks involving the test article

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• Ensure IRB approval attained by sites

– Protocol, ICF, Investigator’s Brochure,

– Patient instructions, advertising, recruitment materials

• Obtain signed FDA Form 1572 (drug, biological) or

Investigator’s Agreement (device)

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• Create Data Safety Monitoring Board (if applic.) – Monitors rights and welfare of subjects

• Independent of study staff

• Sees unblinded data, interim analysis

– Oversight depends on protocol

• Risks to subjects

• Complexity of study

– Not an IRB substitute

– Federally supported studies

• Required for all Phase III clinical trials

• Phase I and II trials

» Multiple sites, blinded, high risk

» Involve a vulnerable population

– Industry studies – if requested by FDA

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ClinicalTrials.gov

• Register the study on ClinicalTrials.gov website

– Required by FDA Amendments Act (PL 110-85, sect. 801)

– Sponsor should register (unless delegated to PI)

• "Applicable clinical trials”

– Interventional studies (one or more arms) of FDA-

regulated drugs, biological products, or devices that meet

one of the following conditions:

• The trial has one or more sites in the United States

• The trial is conducted under an FDA-approved IND or IDE

• The trial involves a drug, biologic, or device that is

manufactured in the United States or its territories and is

exported for research

– Humanitarian Use Devices

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ClinicalTrials.gov

• Responsible party must also update records

• Certification of Compliance (Form FDA 3674)

required for any license applications to FDA

• Penalty for not registering a study

– $10,000 initial fine

– Additional $10,000 per day fine if not corrected within 30

days

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ClinicalTrials.gov - Exclusions

• Do not register

– Phase 1 drug trials including studies in which

investigational drugs are used as research tools to

explore biological phenomena or disease processes

– Small clinical trials to determine the feasibility of a device

or a clinical trial to test prototype devices where the

primary outcome measure relates to feasibility and not to

health outcomes

– Trials that do not include drugs, biologics, or devices

(such as behavioral interventions)

– Non-interventional (observational) clinical research, such

as cohort or case-control studies

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Physician Payment Sunshine Act

(Open Payments)

• Open Payments improves transparency of financial relationships of manufacturers, physicians, and teaching hospitals.

• The following information is reported annually to CMS:

– Applicable manufacturers of covered drugs, devices, biologicals, and medical supplies to report payments or other transfers of value they make to physicians and teaching hospitals to CMS.

– Applicable manufacturers and applicable group purchasing organizations (GPOs) to report to CMS certain ownership or investment interests held by physicians or their immediate family members.

– Applicable GPOs to report to CMS payments or other transfers of value made to physician owners or investors if they held ownership or an investment interest at any point during the reporting year.

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(Open Payments)

– Consulting Fee

– Compensation for services other than consulting, including serving as faculty or as a speaker at a venue other than a continuing education program

– Honoraria

– Gift

– Entertainment

– Food and Beverage

– Travel and Lodging

– Education

– Charitable Contribution

– Royalty or License

– Current or prospective ownership or investment interest

– Compensation for serving as faculty or as a speaker for a non-accredited and noncertified continuing education program

– Compensation for serving as faculty or as a speaker for an accredited or certified continuing education program

– Grant, or

– Space rental or facility fees (teaching hospital only)

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(Open Payments)

• Patient drug samples are not included in the reporting

• Physicians or representatives can review reports prior to publications and dispute inaccurate reports (registration begins 1 June 2014)

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Investigator’s Responsibilities

• Responsible for everything – May delegate authority (not responsibility) for tasks

– Delegate must be qualified by training and experience

• Familiarity with protocol, Investigator Brochure

• Know and follow GCPs, SOPs

• Obtain IRB approvals, renewals, make reports

• Conduct study, oversee sub-Is and staff

• Maintain records of disposition of test article

• Maintain records (case history) for each subject

• PI Qualifications – Qualified by training and experience

– FDA’s “Investigator Study”

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Qualifications

• What is Qualified? – Ability to direct or contribute to a clinical investigation

• Sufficiently experienced to handle any problem

– Clinical experience

– Regulatory experience

– Not taught in medical school, rarely in residency

• How to get qualified – Research cannot be a ‘hobby’

– Can’t learn research or clinical trials only from a book

– “I, Pencil”

– Training courses for structured education

– Research fellowship

– Find an experienced mentor

• Experienced in the type of research you will do

• Bench or translational research, clinical trial, outcomes

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Qualifications

• How to get qualified (cont.) – Join professional research associations

• Association of Clinical Research Professionals

– Academy of Physicians in Clinical Research

• Society of Clinical Research Associates

• Society of Research Administrators International

• National Council of University Administrators

– Get certified

• Not required by sponsors

• Affirms dedication to quality

– Clinical Physician Investigator (ACRP)

– Certified Clinical Research Coordinator (ARCP)

– Certified Clinical Research Associate (ACRP)

– Certified Clinical Research Professional (SoCRA)

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Form FDA 1572

• Site overview – PI Experience (CV or other statement)

– Study site(s), IRB of record, clinical laboratory(ies)

– Sub-investigators and other key personnel

– Protocol (Title and Number)

– Signature of PI (Form 1572) and handwritten date

• Note: All investigators sign an Investigator’s Agreement (device)

• No felt tip pens!

– Required when new investigator added to study

• Does not expire – Update other changes in study records

– Industry sponsors typically require an updated form

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Form FDA 1572

• Who is a Sub-Investigator? (Box 6) – Regulations

• ‘‘Subinvestigator’’ - any other member of the team

• Research Fellows and Residents

– Guidance

• Any part of the investigative team who

– Assists the investigator, and;

– Makes a direct and significant contribution to the data;

– Directly performing a procedure required by protocol and collection of data

• Record CVs, licenses, COI disclosures for all sub-Is

• Who is not a Sub-Investigator? – Hospital staff, nurses, residents providing ancillary care

– On-call physicians providing temporary care (e.g., AE)

– Temporary substitute for any research staff (ICH E3 §6)

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Form FDA 1572 – Box 9 Commitments

• Conduct the study(ies) in accordance with current protocol(s); except when necessary to protect the safety, rights, or welfare of subjects.

• Personally conduct or supervise investigation(s)

• Inform any patients or controls that the drugs investigational, and follow IRB and consent rules

• Report to the sponsor adverse experiences. Understand the Investigator’s Brochure

• Ensure that all associates, colleagues, and employees assisting in the study(ies) are informed about their obligations

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Form FDA 1572 – Box 9 Commitments

• Maintain adequate and accurate records.

• Ensure research reviewed by an IRB that complies with 21 CFR Part 56. Report to the IRB all changes in the research and unanticipated problems involving risks to subjects. Make no changes in the research without IRB approval, except to protect subjects.

• Comply with all other requirements regarding the obligations of clinical investigators

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Investigator’s Responsibilities

• Federal studies

– Submit annual progress reports

– Submit final reports

» Technical (PI)

» Financial (Institution)

• Institutional Reports

– Reports to IRB, Administration, Finance, etc

– Oversee collaborators, staff and expenses

– ‘Other duties as assigned’

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Record Retention

• Study records must be made available for audit – Originals, certified copies

– Readable format

• Archiving study records – For HHS - 3 years following submission of final reports

– For FDA - 2 years following:

» Date the New Drug Application (NDA) is approved, or

» Date FDA notified that NDA is withdrawn

» Investigator may not know these dates

» Applies to study data and financial disclosure records

• IRB Records - 3 years after a study completed at institution (HHS and FDA)

• Potential conflict - how to handle?

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Investigator-Initiated Research

• Investigators conducting own research takes on the role of the Investigator and the Sponsor – Called ‘Sponsor-Investigators’

– Fulfills the regulatory responsibilities of both roles

• ‘New’ responsibilities above those of an Investigator – Obtain IND or IDE as required

– Arrange for study monitoring

– Form the DSMB, if required

– Oversight of sub-investigators and collaborators

– Assure off-site collaborators have obtained IRB approval

– Keeping sub-investigators and collaborators informed

– Budget management

– Test article accountability

– Reports to FDA, IRB, ClinicalTrials.gov and/or funding agency

• Adverse events, unexpected events, deviations

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Investigator-Initiated Research

• IND/IDE application – Letter of cross-reference (letter of authorization)

– Allows FDA to review a manufacturer’s prior IND or IDE for your application

• Chemistry

• Manufacturing

• Quality Controls

• Environmental Impact

• Monitoring details (part of IND/IDE application) – Name and title of party responsible for monitoring

– Institutional solution

• Monitoring by another department

– Not ideal, depends on risk to subjects, can be affected by conflicts of interest or commitment

• Contracted monitoring services

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Simplifying the Process

• Data Safety Monitoring Board – Determine early in the project if one is required

– Begin contacting potential members

• Documentation of qualifications

• Declaration of any conflicts (financial, commitment, etc)

• Establish the meeting schedule and review criteria

– Establish criteria to revise or stop the study

• Informing other study members – Newsletter

– Meetings (can be online or conference call format)

– Website

• Manage financial conflicts of interest – Can be an uncomfortable conversation with coworkers

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Conflicts of Interest (Federal)

• 42 CFR Part 50 Subpart F – $5,000 equity interest, annual salary, royalties, etc

– Includes self, spouse, dependent children

– Phase I of the SBIR and STTR awards excluded

• Financial COI training required

– Initial and biennial renewal

– Document in study records

• Institution responsible for managing conflicts

• Public disclosure when applicable

• Responsibility for duration of project

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Conflicts of Interest (FDA)

• 21 CFR Part 54 – $50,000 equity interest

• Proprietary interest (patent, licensing, etc)

• Includes self, spouse, dependent children

– $25,000 “Significant payments of other sorts” (SPOOS)

• Payments to investigator or institution

• Grant for ongoing studies

• Residual equipment

• Consulting retainers or honoraria

• Travel expenses even if investigator receives no direct payment

• Report at study initiation, end, and 1 year later – 1-year follow-up report is common audit finding

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Conflicts of Interest (FDA)

• Investigator reports conflicts to sponsor

• Sponsor certifies to FDA

– Form 3454 - Certification: Financial Interest and

Arrangements of Clinical Investigators

– Form 3455 - Disclosure: Financial Interest and

Arrangements of Clinical Investigators

• Sponsor responsible for managing conflicts • Or Sponsor-Investigator

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Challenges of Hospital-based Research

• Focus of hospital is patient care not research

• Time – Clinical load usually takes priority

– Oversight and research administration tasks

– Block time for research

– Incorporate research into practice

• Specimen management – Collection by ‘lab’ or research staff

– Processing and shipping

• Facilities – Imaging, Pharmacy

– Space for monitors, auditors

– Record storage (Onsite and Archived)

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Meeting the Challenges

• Corporate culture for research – Visible support by leadership

– Economies of scale

– Critical mass

• Staffing

• Study selection – Feasibility

– Impact on patient care

– Impact on bottom line

• Outreach – Visibility to stakeholders, peer groups and community

– Research events

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Building Your Program

• How to get new industry studies? – Prior experience with sponsor (Catch 22)

– Sponsor and CRO databases

– Recruiting services

– Referral by colleague

– Local site networks

– Publications and trade journals

• FDANews

• BioSpace

– Requests for Applications (RFAs)

– Attendance at professional conferences

• What are colleagues doing?

• Meet with potential sponsors

– Call study monitors

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Building Your Program

• How do you support your own program? – Federal funding

• NIH, DoD, PCORI

• Responses to RFAs

– Disease specific societies and foundations

– Intramural funding

• Department funding

• Development office

– Publications and trade journals

• FDANews

• BioSpace

– Attendance at professional conferences

• Collaborations with colleagues

• Meet with industry reps – new therapeutic uses

– Be aware of intellectual property policies

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Assess for Feasibility

• Scientific merit and interest

• Qualified PI, Sub-Is, Coordinators

• Any conflicting studies?

• Study complexity – Do visits and procedures differ from usual care

• Frequency or intensity

– Long follow-up period

– Pharmacokinetics/Pharmacodynamics

– Tissue banking

• Patient population – Enthusiasm for study

– Effort to participate

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• Staffing – Research staff

– Clinical staff (after-hours procedures?)

• Budget – Sponsor likely derived from national database

– Unlikely to lose a study by negotiating the budget

– Do a zero-based budget, then look at sponsor’s offer

– Consider hidden and hard to track costs

• Delays, equipment unavailability, weather

• Staff time off

• Facilities – Timed imaging can be a problem

– Subjects need a place to wait for observation or complete questionnaires?

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• Ancillary department buy-in – Laboratory, Pharmacy, Radiology, Cardiology, Neurology,

Psychiatry, Finance

• Past history with sponsor – Short negotiation

– Payments on time

– Frequent changes or amendments

• Not all studies worth doing – Sponsor’s prefer you decline a study you can’t do well

rather than underperform

– Bad study is an expense

– Good study is an investment

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Conclusions

• Challenging, rewarding addition to clinical practice – Improved patient care

– Impact on the bottom line

– Career advancement

• Requires specialized knowledge and experience – Regulations, regulations and more regulations

– Local laws, policies, procedures

• Very difficult to do without skilled help

• No short-cuts

• Planning is key to success – All the pieces arranged before starting – feasibility

– Buy-in from leadership, departments, stakeholders

– Revisit the plan throughout the study

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conducting investigator-initiated research in a community

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