CLINICAL TRIAL AGREEMENTSTrey Fraune, JDOffice of Industry Contracting720 Martin Luther King Jr. Blvd Suite 100, CB # 1651 919-843-2891Trey_Fraune@unc.edu

Learning Objectives

• Overview of agreement negotiation at

UNC

• Submitting a CTA for review

• Importance of the CTA to UNC and

Investigator

• Critical CTA provisions

Research Contracts at UNC: Office Responsibilities

OCED OIC OSR

• MTAs (unfunded) • Licensing agreements

not linked to sponsored projects

• CDAs• DUAs• Clinical Trial

Agreements • MTAs (funded) • Contracts with

“industry” SRA, Services, Testing, Start up, core/recharge

• Contracts and grants with federal, state, foreign government

• Non-profit grants/contracts

• Proposals

Submitting a CTA into CRMS

Submitting a CTA into CRMS

Submitting a CTA for Review

CTA Submit to OIC via CRMS

Contract and Budget

Negotiation

Fully-executed contract

Protocol, ICF, Investigator’s

brochure Submit to IRB

via IRBIS Stipulations

and Contingencies

IRB approval

Billing Coverage Analysis

Submit to OCT via CRMS

Integrated Billing/Budget Calendar build

Clinical Trial Start Up Process: Submission of CTA though Account

Assignment

OICNegotiates and

Executes the CTA

OCTBCA, GCP, COI, Internal Budget

OSRIssues Project IDs (account numbers)

Agreement Status • No assignment to CM until your submission is complete

• CTA, ICF, and draft budget• external contact• Lead PI designated, and PI Certification

• Agreements are assigned to CM on a rotating basis, notification email • Try to be specific in listing department personnel (Regulatory, Budget,

Coordinator)

Negotiation Detail

Parties to the Contract

Sponsor

CRO

UNC • Investigator is not a

party, signs as “read and understood”

• No need for PI to sign CDA, but be aware of obligations

• CRO as a party = expect delays

CTAs: Important Terms and Provisions

For UNC • Liability (Indemnification) • Subject Injury • Publication • CRO involvement• Subject Privacy (HIPAA) • Subject Safety Reporting

(AAHRPP) • Intellectual Property • Governing Law (Enforcement) • Term and Termination • Avoiding “Incentive” language

For the department• Budget and Payment Schedule • Billing and Invoicing

Requirements • Publication • Data Capture requirements

(CRFs) • Record Retention • Adverse Events Reporting • Audits, monitoring • Return/Destruction of Study

Materials • Equipment • Enrollment

Note: Depending on whether the protocol is Sponsor- vs. Investigator-initiated will impact terms and conditions

Confidential Information

• The cost to develop new pharmaceutical drug now exceeds 2.5 billion.

• Sponsor is motivated to protect their rights in their product: Confidential Information and Intellectual property.

• Typically 5-7 years confidential treatment.

Cost to Develop New Pharmaceutical Drug Now Exceeds $2.5B, Rick Mullen, Scientific American, Nov 24, 2014

Publication

BMJ 2016;352:i637

• Publication required by BOG policy, tax exempt status, export control law (FRE) • PI develops expertise and reputation in their field • Registration requirements (ICMJE ) • Delay Period: for Sponsor review, multi-center publication

Ownership and Intellectual Property

• Ownership of Study Data/Results Data is primary “product”

• Intellectual Property may include: Patents Copyright TrademarkTrade secret

• Sponsor will typically own IP, data/resultsPlease alert OIC if additional funding for your study is coming from other sources (e.g., Federal, Industry, Foundation) because the other funders may have study-related IP rights!

Study Data and Study Records• Data Capture: CRFs/eCRFs• Mandatory progress reports to Sponsor • Record Retention: Time • Record Storage: Secure, on/off site • Record Destruction: Notification, transfer to Sponsor • Plan for storage, and ask for funding!

Equipment and Study Materials • “Materials” (Drug/Device) and Equipment: storage,

maintenance, accounting• Repair and replacement of loaned/leased equipment• Insuring equipment: risk management insurance policies

available • Return of equipment, department retention

Sponsor Access to UNC

•Monitoring/Auditing access for Sponsor/CRO

•Sponsor presence at regulatory audits

•Privacy Concerns (Epic SOP*)•Availability of study records, facilities, and personnel

PRIVACY and HIPAA • Even if research is intended to

be de-identified, Sponsor/CRO may have access to individually identifiable information about subjects

• UNC has a regulatory responsibility to ensure that sponsors maintain confidentiality

• Contract may specify language to be included in the ICF/IRB application

Source: Loma Linda Investigator's guide to HIPAA: http://researchaffairs.llu.edu/sites/researchaffairs.llu.edu/files/docs/hipaa-flowchart.pdf

Indemnification• Indemnification is a contractual promise

to compensate the other party for loss• Shifts risk to party best suited to control it• Related to subject injury provisions, but

not the same!

Narrow Intermediate Broad

Sponsor indemnifies UNC for subject injury

Sponsor indemnifies UNC for subject injuries, Sponsor breach of agreement and law, Sponsor use of data and results

Sponsor indemnifies UNC forperformance of the Protocol

Subject Injury Language

UNC preferred language diagnosis and treatment

injuries and illnessesdrug/device and protocolprocedures

PI’s determination

subject has right to seek treatment from any health care provider

• Sponsors not required by law to pay

• Probably the most contentious part of the negotiation

• ICF should be consistent with CTA

Sponsor preferred language payment only after insurance denial, or billingdifferentlyno payment for subjectfailure to follow instructionslimits in time/value: SOL or dollar cap

payment solely for emergency, “out of pocket” expenses

Reasonable exceptions: UNC’s negligence, UNC’s failure to follow protocol, Subject’s underlying disease

ICF and CTA Consistency

• Internal and external IRB, processes differ slightly.

• Your CM should alert you to any edits to the ICF injury section.

• If you don’t hear from your CM–reach out!

Dept. submits ICF to OIC

CM reviews ICF, sends

to Dept.

Dept. submits ICF to Sponsor

Sponsor accepts or

revises

Dept. alerts CM

CM sends email

confirming ICF

CM review limited to “What will happen if you are injured” section of the ICF.

Let CM know if the Sponsor makes further edits to ICF injury language.

For External IRBs: confirmation email should be attached within IRBIS.

If using external IRB, notify UNC IRB (“Permission to Register” letter).

What if a subject gets hurt?

Provide Care

• Provide or arrange appropriate treatment• Coordinate with any other health care provider as applicable.

Subject Injury Determination

• PI determines if injury is related to the study• Perform adverse event reporting as required by protocol or contract • Alert Sponsor • Contact health care system- Stop Bill!

Bill Appropriately

• Read your contract/ICF: If sponsor has a responsibility to pay, cannot bill insurance, medicare

• Coordinate with Andrea Eiring at OCT to determine which costs are injury costs • Investigate if costs have been accrued elsewhere

Budget and Payment Terms: Negotiation Tips

CM cannot negotiate the budget BUT will provide assistance upon request

Issue Sponsor Proposed Language: Request this instead:

Frequency of Payment

Sponsor will pay quarterly Sponsor will pay monthly

Contingencies Sponsor will pay if Institution performs the Protocol correctly. .

Sponsor will not pay for visits in which a protocol violation occurred. . .

Hold Backs Sponsor will pay 80% of the invoiced amounts. . .

Sponsor will pay 90% of the invoiced amounts. . .

Forfeiture Sponsor will pay for invoices submitted within 60 days of study close out.

Institution will submit invoices to Sponsor within 90 days of study closeout.

Incentive Language

Sponsor will provide $500 additional dollars for each subject enrolled before July 1st.

Sponsor will provide an additional $1000 to support enhanced coordinator enrollment efforts prior to July 1st.

Investigator-Initiated Protocols

CTA: Industry Initiated IIT: Investigator Initiated

Protocol written by company

Protocol developed by Investigator

Company is the Sponsor UNC is the Sponsor*

UNC seeks broad indemnification

Company will offer limited indemnification

UNC requires broad subject injury

Often no subject injury

UNC may be one of many sites

UNC may have sub-sites to manage

Company has broad rights to study data, results, IP

UNC will own study data, results, and limit Company's IP rights appropriately

Company must register study, perform monitoring

UNC may be responsible for registration, monitoring

Publication often delayed, limited

Often no delay for publication

Company may seek a CDA before sharing protocol with UNC

Consider a CDA before sharing your protocol

• Sponsorship carries important regulatory requirements!

• Expect different timelines for CTAs vs. IITs.

• Let your CM know if you will have sub-sites

• Understand your regulatory requirements!

BEFORE SIGNING THE AGREEMENTREAD THE CONTRACT

Questions and FAQs

• Does UNC have a template? • Why is my CM asking me so many questions? • Can we start the study before the contract is signed?

• My sponsor cancelled the study. Can we reimbursed for start-up costs?

• Where is my account number? • How long will my CTA take to be signed?

TRIAL REGISTRATION & RESULTS REPORTING AT CLINICALTRIALS.GOV:FDA, ICMJE, NIH, AND CMS

Monica Coudurier Office of Clinical Trialsm_coudurier@unc.edu(919) 843-2333

What is ClinicalTrials.gov?• Web-based registry maintained by National Library of

Medicine (NLM) providing regularly updated information for federally and privately supported clinical trials

• Mandated by 1997 FDA Modernization Act (FDAMA)• First version publicly available February 29, 2000• Expanded by FDA Amendments Act 2007 (FDAAA)

• Requires certification Form FDA 3674• Final Rule:

Effective Date Compliance Date

January 18, 2017 April 18, 2017

Types of Information Seen in CT.gov• Some information provided in ClinicalTrials.gov records

includes the following:• Disease or condition and experimental treatments

studied• Title, description, and design of study• Requirements for participation• Location(s) where the study is available• Overall study status• Recruitment contact information• Links to relevant information at other health Web sites,

such MedlinePlus and PubMed

What Trials Must be Registered?There are 4 independent bodies requiring trial registry:

• ICMJE (International Committee of Medical Journal Editors)

• FDA - FDAAA Section 801/Code of Federal Regulations

• NIH (National Institutes of Health)• CMS (Centers for Medicare & Medicaid Services)

The International Committee of Medical Journal Editors (ICMJE) PolicyPer the ICMJE, any trial meeting their definition of “clinical trial”must be registered prior to enrollment of the 1st subject to be considered for publication: “any research project that prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the cause-and-effect relationship between a health-related intervention and a health outcome.”

• Health-related intervention includes any intervention used to modify a biomedical or health-related outcome (e.g., drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes).

• Health outcome includes any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events.

ICMJE Policy

?? Purely observational studies (those in which the assignment of the medical intervention is not at the

discretion of the investigator or the study protocol) will not require registration??

FDAAA Section 801Pertains to trials using an FDA-regulated intervention--irrespective of approval status– and meeting the regulatory definition of an Applicable Clinical Trial (ACT).

• ACTs generally include:

• Trials of Drugs and Biologics: Controlled, clinical investigations, (other than Phase 1 investigations), of a product subject to FDA regulation (If efficacy is an endpoint of Phase I study, it must be registered).

• Trials of Devices: Controlled trial with health outcomes, other than small feasibility studies, and pediatric post market surveillance.

National Institutes of Health (NIH)• NIH requires Registration and Results reporting of all

trials funded either in whole or in part that meet their definition of a clinical trial.• Includes Phase 1 studies• Independent of FDAAA requirements• Applies to Extramural and Intramural award programs• Funding applications submitted on or after 01/18/2017

requesting support for trials initiated after 01/18/2017 (not applicable to ongoing clinical trials in non-competing awards)

Clinical trials using NIH-supported infrastructure, not receiving NIH funds for conduct not subject to policy

NIH Policy:Clinical Trial Definition

• “Clinical trial” means “a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.”

• NIH “clinical trial” definition is broader than the term Applicable Clinical Trial (ACT) defined by FDAAA

The study is a clinical trial

The study

is not

a

clinical trial

NIH Clinical Trial Decision Tree

Centers for Medicare and Medicaid Services (CMS)

• January 1, 2014 - CMS began requiring the NCT (National Clinical Trial) number on all clinical trial-associated claims submitted to Medicare.

• available only from ClinicalTrials.gov• must be entered into CRMS• claims submitted without NCT rejected

NCT number

Trial Registration Deadlines

• ICMJE – Study must be registered prior to enrollment of first subject.

Publication eligibilityt

• FDAAA– ACTs must be registered no later than 21 days after enrollment of the first subject.

Required by US Public Law and must be done to avoid $$ penalties

• NIH – not later than 21 calendar days after the enrollment of the first participant

Required by US Public Law and must be done to avoid $$ penalties

• CMS– Prior to claims submissionClaims submission (to avoid rejection)t

Trial Registration Overview

Who is Responsible for Registering Trials? Reporting results?

Clinicaltrials.gov registration is the responsibility of the trial Sponsor:

• UNC Investigator initiates and sponsors trial – PI registersTrial in which PI obtains industry fundsNIH or other grant funded trial (external or internal grants)UNC PI holds an IND or IDE

• Industry sponsored + initiated trial – Industry sponsor registers

Getting StartedCT.gov User Account Set-Up

• If UNC PI responsible for registry, CT.gov user account set-up and record assistance available through:

• Each person requiring record access must have their own user account

Non-Oncology Oncology

Monica Coudurier Marie Malikowski

m_coudurier@unc.edu marie_malikowski@med.unc.edu

(919) 843-2333 (919) 966-4432

http://research.unc.edu/clinical-trials/clinical-trials-gov/

Which Studies Require Results Entry?

• FDAAA 801: trials meeting the definition of “Applicable Clinical Trial” or ACT (regardless of whether the study has an IND or IDE)

• NIH (Final Rule effective January 18, 2017)All Federally funded studies meeting “clinical trial” definition

ICMJE and CMS do not require results reporting

Deadline for Posting ResultsClinicalTrials.gov results reporting should be final within 1 year of ‘Actual’ Primary Completion date.• Primary Completion Date: date that the last participant

was examined or received intervention for final collection of primary outcome-related data

• ClinicalTrials.gov minimally takes 30 days to review records with results

• Multiple reviews are typical

START EARLY!! ACTsNIH

Complementary Initiatives

• Must submit full protocol and statistical analysis plan along with results submission. Informed consent not req’d

• ACT definition expanded to include unapproved products

• All single & multi-arm/group studies with prespecified outcome measures considered “controlled.”

• NIH will post records within specified time despite QC review status (disclaimer citing concern may be posted)

• Reporting frequencies changed

Record Upkeep: Following Registration• Ensure the information is complete, accurate,

and updated annually (minimum), or as changes occur. • Record Verification date field must be updated each time

• More frequent updates required for certain data elements:• 30 day Reporting Frequency:

• Overall Recruitment Status• Primary Completion Date• Study Completion Date• Protocol amendments resulting in subject

updates following IRB approval

Quality Control Corrections• Within ‘X’ days of electronic notification (i.e., email), all

apparent errors, deficiencies, and/or inconsistencies identified during quality control review must be addressed and record re-released to ClinicalTrials.gov

Record Type Completed not later than:

Protocol registration records 15 calendar days

Results information 25 calendar days

New Rule--Useful Links

• Federal Register Notice: HHS Final Rulehttps://s3.amazonaws.com/public-inspection.federalregister.gov/2016-22129.pdf

• Federal Register Notice: NIH Policyhttps://s3.amazonaws.com/public-inspection.federalregister.gov/2016-22379.pdf

• Summary of Changes: HHS Final Rule and NIH Policyhttps://www.nih.gov/news-events/summary-hhs-nih-initiatives-enhance-availability-clinical-trial-information

Monetary Penalties What are the penalties for failing to comply with registration and/or results reporting requirements for an “Applicable Clinical Trial” or NIH-funded study?

• Penalties for responsible parties failing to register or providing false or misleading information in connection with applicable clinical trials may include civil monetary penalties (up to $10,000/day)

• Federally-funded trials, the withholding or recovery of grant funds.

Trial Registry & Results Reporting Cost Recovery

• Award grantees are permitted to charge the salaries of administrative and clerical staff as a direct cost [Ref. below]. Such staff could assist investigators in meeting their responsibilities under the policy.

• In addition, administrative costs can be covered through indirect cost recovery.

45 CFR 75.413(c) and Chapter 8.1.1.6, Direct Charging Salaries of Administrative and Clerical Staff. NIH Grants Policy Statement.

http://grants.nih.gov/grants/policy/nihgps/HTML5/section_8/8.1_changes_in_project_and_budget.htm

Questions

INVESTIGATIONAL DRUG SERVICE (IDS)Sue Pope, PharmacistManager, UNC IDS

Investigator Responsibility for Drug Product

• The ICH E6 GCP guidelines outline the requirements of investigators (Section 4.6): The investigator is responsible for product accountability at the study site …...

• Investigators can delegate the duties involved in product accountability to qualified personnel, such as the pharmacist or study coordinator.

• At UNC, the IDS Pharmacist is delegated this responsibility• However, ultimate responsibility for investigational product(s)

accountability at the trial site(s) rests with the investigator.

IDS Operational Overview • IDS staff

– 3 Pharmacist and 4 Technician FTEs• Studies managed

– Over 330 total studies managed annually• IDS hours of operation

– 0730 to 1600 Monday through Friday – IDS closed on major hospital and university holidays

• Locations– 3rd floor Memorial Hospital - Prepares medications for

protocols that contain IV products– Ground floor Neurosciences Hospital- Prepares

medications for protocols that only contain oral, non-chemotherapy medications

– 3rd floor North Carolina Cancer Hospital

IDS StaffLEADERSHIP• Sue Pope,Rph

Manager, IDSEmail: suw.pope@unchealth.unc.eduPager: 216-2540Office: 984-974-0040

• Lindsey Amerine, PharmD, MSAssistant Director, Oncology, IDSPager: 919-216-6597

PHARMACISTS• Linda Manor, RPh -

linda.manor@unchealth.unc.edu• William Zhao, PharmD, PhD

yun.zhao@unchealth.unc.edu• Ashley Khan, PharmD.(per diem)

ashley.khan@unchealth.unc.edu• Lynda Haberer, Rph, PhD (per diem)• Lynda.haberer@unchealth.unc.edu• Marie Bullis, PharmD• Marie.bullis@unchealth.unc.edu

IN AN EMERGENCY:• Outside of normal business

hours – IDS maintains an on-call pager

• In an emergency, an IDS clinical pharmacist can be reached by dialing 919-216-9727. They will provide assistance with:

• Individual drug or research questions

• The breaking of a treatment blind

• Provide support for inpatient or IV room staff who may be unfamiliar with a particular research protocol

Investigational Drug Service

Memorial Hospital, 3rd Floor• 984-974-6359 (fax for orders)• Prepares medications for protocols that

contain IV products

Neurosciences Hospital, Ground Floor• 984-974-3471 (fax for orders)• Prepares medications for protocols that only

contain oral, non-chemotherapy medications

Do I need to use IDS for my research protocol?• For research protocols within the Hospital system, the

clinical and distributional services of IDS are required• IDS Pharmacy required to be involved with all

investigational studies that use an agent/drug – Joint Commission Medication Management standards

• An agent/drug (including supplements) will be considered investigational, if following two criteria met:1. Administration of agent is part of protocol which requires IRB

approval2. A subject is required to sign an Informed Consent Form before

receiving the agent• Study locations other than main Hospital (e.g. Southern

Village, Carrboro Dialysis, UNC School of Dentistry, EPA, etc)

How and when do I initiate a request for IDS services?• Request for IDS services should be initiated simultaneously with Contract negotiation (OCT) and request for IRB approval

• IDS needs notification 6 to 8 weeks prior to 1st

study subject enrollment• Use Clinical Research Management System (CRMS) to submit protocol materials to IDS

• Or, email a completed IDS Request for Services (RFS) form, an Intensity Worksheet, and copy of protocol to the IDS manager.

What do the services of the IDS cost?• Complexity of protocol determines extent of IDS services used and cost.

• Protocol Intensity Worksheet uses a fee for service pricing structure to determine budget for study. –Score the protocol with a point based system to

determine the level of service–4 levels of service - the level determines the start up

and monthly fee. –One time start up fee, non-refundable, charged as soon

as notebook is ready for dispensing.• Once drug is received and on shelf in IDS, begin billing monthly fee.

• IDS ceases to bill when the drug has been removed from the pharmacy and a final pharmacy close out visit has been conducted.

• Need protocol intensity worksheet before IDS can process memo for IRB.

New IDS Billing Procedures • Billing will now use the Vestigo Software system• Billing will be monthly• Bills will come from Support@McCreadiegroup • Bills will be sent via email to the PI or any contact that is

given to the IDS manager• Payments will be remitted to General Accounting• If your study is open any portion of the month you will be

billed for that month.• Notify study closings by the 25th of the month to avoid

further billing.

What types of products can be compounded by IDS?

• IDS can participate in treatment and placebo blinding for solid oral dosage forms

• More complex compounding (liquid formulations, suppositories, troches, patches, etc) are outsourced to a local compounding pharmacy–Compounding fees of the local pharmacy apply in addition to standard IDS fees

How are research protocols handled outside of normal business hours?

• Approximately 95% of research protocols are handled during normal business hours (M-F, 0730 to 1600)

• However, if a research protocol will require after hour dispensation, an assigned pharmacist can coordinate this with Hospital inpatient Pharmacy or IV room

• IDS pharmacist will coordinate delivery and storage of materials to the IV room/Inpatient Pharmacy as well as provide necessary in-services to the staff

Scheduling a Monitoring Visit

• In an effort to accommodate all sponsors, monitoring visits and site initiation visits must be coordinated in advance. Contact your assigned pharmacist or call IDS• Call 984-974-0469 or 984-974-3777 to schedule a

monitoring visit• 2 monitoring visits allowed per day per IDS work

area• Scheduled typically a month or more in advance• “Remote” monitoring visits are typically not

supported by IDS

How are Investigational Medications Dispensed? IDS can begin preparing an investigational medication foryour patient ONLY when:

1. Completed protocol orders are faxed to 3W IDS or NS IDS Pharmacy

2. Orders must be signed by provider listed on 1572 and IRB application (original signature, not a copy)

3. Coordinator must give IDS verbal confirmation that patient is available for treatment (if pertinent to protocol)

4. Coordinators must present an original signed prescription order when picking up an investigational medication in the IDS pharmacy.

Paper vs. Epic Orders• All CTM that is dispensed on an outpatient basis will be

paper orders i.e. CTM is going home with subject• CTM that is administered in the clinic or in CTRC by clinic

nurses will be on EPIC so it can be recorded on the MAR• All infusions are entered on EPIC and should have a build

in the pump library under Study (name of drug)• Epic builds with start with the word STUDY and then the

name of the protocol for ease of finding the build. • Epic orders should not be entered in advance of subject’s

treatment day unless CTM can be prepared ahead.

To whom and where can Clinical Trial Materials (CTM) be sent?

• After contacting IDS (984-974-0469) to make them aware of the incoming shipment as well as total volume of expected shipment, CTMs can be directed to the following address:

Investigational Drug Services3rd Floor, Room N3122

101 Manning DriveChapel Hill, NC 27514Phone: 984-974-0469Fax: 984-974-6359

UNC INVESTIGATIONAL DEVICE POLICYAmanda Wood, B.S., CCRP, RACIND / IDE Program Coordinator, TraCS Regulatory Service

amanda_wood@med.unc.edu919-843-9445

What Is A Medical Device?An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which:

• Is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or

• Intended to affect the structure or any function of the body, and

• Does not achieve its primary intended purposes through chemical action within or on the body and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

Section 201(h) of the FD&C Act

What Is A Medical Device?An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which:

• Is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or

• Intended to affect the structure or any function of the body, and

• Does not achieve its primary intended purposes through chemical action within or on the body and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

Section 201(h) of the FD&C Act

What Is A Medical Device?An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which:

• Is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or

• Intended to affect the structure or any function of the body, and

• Does not achieve its primary intended purposes through chemical action within or on the body and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

Section 201(h) of the FD&C Act

What Is A Medical Device?An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which:

• Is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or

• Intended to affect the structure or any function of the body, and

• Does not achieve its primary intended purposes through chemical action within or on the body and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

Section 201(h) of the FD&C Act

What Is A Medical Device?

What Else can be classified as a Device?Devices don’t need to be applied to or implanted in someone to be considered a device.

Novel blood tests, diagnostic algorithms, and software can all be classified as a device if they meet the federal definition: “Is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease”

Section 201(h) of the FD&C Act

FDA’s new focus on APPS“Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease”

FDA’s new focus on APPS“Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease”

reSET® : a prescription digital therapeutic to be used in conjunction with standard outpatient treatment for substance use disorder (SUD)

FDA’s new focus on APPS“Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease”

UNC Device Policy Overview

UNC Device Policy OverviewThe University of North Carolina Health Care System must ensure compliance with regard to utilization of investigational devices.

There is a policy that governs investigational devices: https://research.unc.edu/human-research-ethics/resources/ccm3_034228/

• Administrative Procedures• Device Receipt• Device Storage• Device Use/Dispensing• Device Return

Administrative ProceduresPrior to use of an investigational device, the following has to occur:

• IRB approval

• Final sponsor budget- will sponsor provide device free of cost or must UNC Hospitals purchase? (contact Hospital Purchasing)

• Contract must be fully executed (UNC Office of Clinical Trials)

• Must enter trial in CRMS and complete Billing Coverage Analysis(to obtain codes and charges from Integrated Billing Office)

• Notify UNC HCS Reimbursement of pending trial. They will coordinate with Medicare Fiscal Intermediary.

• If the study is Investigator-Initiated, additional steps must be taken. (Federal submission and approval, PI oversight, etc.)

Receipt, Storage• Device Receipt-

• What Does Protocol say?• Request Sponsor to notify of shipment• Comply with Sponsor documentation requirements

• Device Storage-• Secure and segregated. • Clearly identified as investigational

Investigator-Initiated studies carry additional responsibilities pertaining to recordkeeping, etc.

NC TraCS IDE and IND AssistanceIt is crucial if your PI is running an Investigator-Initiated Device Study (or drug study!) that they understand the federal requirements involved with holding an IND/IDE. This includes annual reporting, amendment and new protocol submissions, and SAE reporting.

NC Tracs can assist with:• Determining if an IND or IDE is necessary, or if exemption is possible.• Preparing IND & IDE submissions to the FDA• Communicating with the FDA to ensure a smoothly executed clinical

investigation

• ReGARDD.org : A shared CTSA website that is comprised of helpful tools, templates, decision trees, and educational resources to support academic investigators’ regulatory needs. Hosted and maintained by ReGARDD affiliates at UNC, Duke, Wake Forest, and RTI.

RECRUITMENT SERVICESCarol Breland, MPH, RRT, AE-CResearch Recruitment DirectorNC TraCS

NC TraCS Recruitment ServicesAccelerate Subject Recruitment across UNC!

Community promotion of UNC research studies via interneto Provide a free engaging education website geared to the general

public to list studies https://jointheconquest.org/index.php/en/.• A simple research volunteer registration process• A easy to read studies listing geared to the general public• An online location for volunteers and UNC researchers to interface• Promoted via social media tools- Facebook, Twitter, etc.• Link on Epic patient portal My UNC Chart

Assist researchers with consultations and recruitment toolso Recruitment plan consultationso Tool kit for recruitment campaignso Researcher networkingo E-recruitment methodologieso Best practices workshops and presentations

https://tracs.unc.edu/index.php/services/recruitment-services

Is this your study recruitment plan?

Barriers to Study Recruitment Success• A recent poll was conducted by Zogby Analytics for Research America • One question asked was “Fewer than 10% of Americans participate in

clinical trials. Why don’t people take part in research studies?”• Answers:

• Not aware/lack of information = 53%• Lack of trust = 53%• Too risky = 51%• Adverse health outcomes = 44%• Little or no monetary compensation = 35%• Privacy Issues = 27%• Too much time = 27%• Not sure = 11%

Recruitment Plan Considerations

Recruitment Tactics

Internal Resources External Outreach

Recruitment Strategies

Population Identification Population Availability

Protocol Feasibility

Facilitators BarriersVS

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Basic Recruitment Planning StepsA recruitment plan should be developed as soon development begins on the protocol or as soon as you receive it, whether investigator-initiated, industry-sponsored, NIH or other sponsor.

1. Start with a protocol review with a focus on recruitment

– inclusion/exclusion criteria, study procedures and timelines

2. Develop a subject profile; identify participation barriers and benefits

3. Use i2b2 to estimate available population cohort counts

4. List your recruitment strategies – identify your population and goals

5. For each strategy, list your tactics – where, when, how you will contact

potentialsMore

Basic Recruitment Planning Steps

6. Create a promotional campaign timeline for your tactics

7. Evaluate your plan for risks and develop contingencies

8. Develop a practical budget and estimate resource needs

9. Start slow, make adjustments and then increase your

speed

10. Review your plan at least monthly or more often as

needed

Remember! All recruitment promotional materials require IRB approval!

Basic Recruitment Strategies

Identify your target population

Define your goals and timelines

Consider benefits and barriers

Engage with the community stakeholders

Recruitment TacticsBefore you develop your promotional campaign materials, ask yourself:What message do you want to convey to potential volunteers about the study?

To promote your study, remember that each study requires a customized approach!

• Send an email, letter, postcard or call patients from approved registries or chart review

• Create posters, pamphlets, mailings (flyers, letters, post cards)

• Request a consult from the Carolina Data Warehouse for potentials from the EMR

• Develop a friendly and informative phone screen/script

• Build a study-specific website using Wordpress or consider StudyPages/other vendor

• Create a social networking outreach campaign- Facebook, Twitter, Instagram

• Attend Community events (fairs, flea markets, senior center health events)

• Develop a UNC mass email

• Consider mass media advertising - TV, radio, print

• List on ResearchMatch.org

• List on JointheConquest.org

Recruitment Tactics - continued

Tactics that don’t require IRB approval:

• Develop a system for identification of potential subjects in your clinic

• Attend conferences • Conduct informational lunch ‘n learns on the condition

you are studying• Arrange for presentations at departmental meetings

Note! “Dear Doctor” Letters and Finder’s FeesDear Doctor Letters • Snail mail, fax or email to local providers to ask for their assistance with

recruitment. These types of communications are not seen by patients but inform providers about your study.

• Although FDA regulations are less stringent, our UNC IRB requires approval for doctor to doctor letters.

Learn more about FDA guidance on recruiting study subjects at:http://www.fda.gov/RegulatoryInformation/Guidances/ucm126428.htm

Finder’s Fees: • UNC IRB SOP 26.2 - “…prohibited are finder’s or referral fees to

colleagues who may identify or refer eligible subjects to a research study (e.g., a general practitioner sending patients to a specialist conducting a study.)

What’s New at Recruitment Services?Updates to Join the Conquest:• New video featuring Dr. Carrie Anders - Oncology• Using IRBIS to submit (use Section B.1.1)• In development – researcher dashboard

Other Services:• Referrals for recruiting participants from the entities• Referrals for coordinator assistance• Trial Innovation Network webinars

In development: • Recruitment literature search engine• Participant recruitment training academy• Enhanced consultation model

Where Can I Learn More About Recruitment Services?

• Visit NC TraCS Recruitment Services Website

http://tracs.unc.edu/index.php/plan-research/research-recruitment

• Access the Recruitment Boot Camp Slides: https://tracs.unc.edu/index.php/services/recruitment-services/webinars-training

• Contact Carol Breland at carol_breland@med.unc.edu919 966-6274

• Call or email NC TraCS at nctracs@unc.edu• 919 966-6022

RECRUITMENT THROUGH THE CDW-H: REQUIREMENTS AND CONSIDERATIONSCarol Breland, MPH, RRT, AE-CResearch Recruitment DirectorNC TraCS

Carolina Data Warehouse (CDW-H)• What is the Carolina Data Warehouse for Health?

• The CDW is a central data repository containing clinical, research and administrative data sourced from the UNC Health Care system.

• UNC Healthcare now includes Rex, Chatham, Pardee, etc. so with Epic introduced at these outlying hospitals, patient data flows into CDW

• What is included in the CDW:• All legacy Webcis data and now all Epic data• Includes medical, financial and other hospital data • For new hospitals now in UNC Healthcare (i.e., Rex

Hospital), this means their patient data is also in the CDW, if they are using Epic.

CDW and Participant Recruitment• The CDW serves as a gatekeeper for EMR data on

patients that can be used for recruitment purposes• If recruiting using the CDW, recognize that patient

information provided could be for patients at many locations

• You may want to narrow recruitment search to those in specific zip codes to avoid getting patients outside main UNC campus area (if so desired)

• If you want to recruit from our entity hospitals there are other gatekeepers who need to be aware of your recruitment plans and approach – contact Diane Powers at ORSC@unchealth.unc.edu for more information.

Recruitment Etiquette• Old-fashioned courtesy is paramount!• Review carefully the list of potential participants provided

by CDW-H and exclude any that are not eligible• Engage any known providers in recruitment early in the

process- (Do you have patients that meet these criteria?) • Request a PCP contact from participants and send a letter

or email to alert them of trial participation • Affiliate hospitals and clinics new to the UNC research

mission require additional time to absorb recruitment methods developed for main campus- be patient!

• Promote trial opportunities as a benefit of being part of the UNCHCS provider network.

Indicating Use of CDW in IRB Application

• A.9 Identifiers: Mark all identifiers you will receive from CDW (names, telephone #s, dates or date of birth, zip code, email, medical record number). Must match CDW request form.

• B.1 Methods of Recruiting: Indicate use of a telephone script or recruitment letter to reach out to potential participants. IRB will require you submit the documents for approval.

• B.2.1 Request a Limited Waiver of HIPAA to identify potentially qualified subjects in order to contact them to elicit their interest in study.

• B.3.4 Where are you studying subjects: Indicate Healthcare setting and check places that apply (UNC medical center, Rex Hospital, Chatham Hospital, etc.) and specify where in the facility subjects will be studied (e.g., CTRC, ACC, Peds Clinic).

• C.1 Data Sources: Indicate use of UNC Health Care System Medical records, then check electronic medical records using CDW-H.

Suggested Language- Recruitment Letters Dear XXX:• We are contacting you because you were seen by UNC Health Care

or one of our affiliate hospitals or clinics in the past year… or • Your records in the UNC Health Care System indicate you may be

eligible to participate in our research study entitled “Xxxxxxxxxx”. We are contacting people who have either an xxxx (lab value) or xxxx(specific inclusion criteria) ……or

• You were seen by UNC Health Care in the past year. We are contacting people who are in the xx to xx age range who have been seen by the UNC Health Care System in the past year in order to tell them about a research program that we are doing… or

• Based on your medical history, you may be eligible to participate in this study.

Suggested Language- Phone Scripts • Telephone scripts should begin with something

similar to the recruitment letters:• Hello, my name is __________. I am a (student/faculty

member/staff member) from the University of North Carolina at Chapel Hill. Am I speaking with ___________________ (patient’s name)? [Verify before proceeding].

• I’m calling to tell you about a research study at UNC. The study is (“study title”). This study will test xxxxx in xxxxxpatients. Your records in the UNC Health Care System indicate you may be eligible to participate in our research study OR based on your medical history, you may be eligible to participate in our study

Telephone Q & AIf participant asks “How did you get my name and contact information?”

• Answer: When you check in for care at UNC Health Care, you are given a copy of the Notice of Privacy Practices and asked to sign that you received it. This document describes that, because UNC is a teaching and research institution, your information may be shared with UNC researchers for research purposes provided they first get approval from a research ethics review board called the IRB.

• Additional information, if needed. We received IRB approval to access a limited set of information from your medical records. Specifically, we obtained your xxxx (list variables). This information helped us to know that you might be eligible for our research study.

• If participant states, “but I am not a UNC Health Care patient, I go to Rex (or other) Hospital.• Answer: UNC Health Care System now includes several affiliate hospitals and

clinics, including Rex (or name of other UNC hospital affiliate). So, even though you receive your care at Rex (or other name), your records are part of the UNC Health Care System.

• If participant asks “How did you get my name/contact information?”• Answer: We received approval to access medical records of patients in the

UNC Health Care System who meet our research study criteria. Based on your medical history, you appear eligible to participate in this study.

Suggested Language- Email• Recruitment emails should begin with one of the following:• Dear XXX: • We are contacting you because you were seen by UNC Health Care

or one of our affiliate hospitals or clinics in the past year.• Your records in the UNC Health Care System indicate you may be

eligible to participate in our research study. • You were seen by UNC Health Care in the past year. We are

contacting people who are in the xx to xx age range who have been seen by the UNC Health Care System in the past year in order to tell them about a research program that we are doing.

• Based on your medical history, you may be eligible to participate in a study conducted by UNC researchers.

Note! Extra guidance when sending emails for recruitment using CDW data

• Because email messaging may not be secure or an unintended person may receive a message or open an email message (spouse if joint email or boss if work email address), it is not acceptable to include sensitive information such as a medical condition, lab result, specific clinic or study title in an email message.

• As such, researchers should only include general statements like those listed in their email recruitment message. If one is able to infer from the information in the email the person’s health condition, the PI may consider only including the recipient’s first name.

What not to say…• One should NEVER say “We are contacting you because you signed up

with the Carolina Data Warehouse for Health” as this is incorrect.

• Subjects do NOT sign up for the Carolina Data Warehouse for Health. The names of potential research participants are in the CDW by virtue of them having been seen by the UNC Health Care System (includes affiliate Hospitals and Clinics) in the last few years.

• Recruitment letters / emails/telephone scripts should NOT make a reference or describe that patient data or records were provided by the Carolina Data Warehouse for Health. The language used should only reference or describe records coming from the UNC Health Care system.

• Note that UNC Health Care System now includes the UNC Hospitals in Chapel Hill, and multiple affiliate Hospitals and Clinics (Rex, Chatham, Nash, High Point, Pardee, Johnston, Caldwell, Wayne, Lenoir). The data pulled via the CDW could include patients from any of these locations if those hospitals have implemented the Epic Electronic Medical Record.

Contact for more information• Carol Breland, MPH, RRT, Research Recruitment

Director, NC TraCS carol_breland@med.unc.edu

• Marie Rape, RN, BSN, Associate Director of Regulatory, NC TraCS marie_rape@med.unc.edu

• Cat Collins, IRB Analyst (catcollins@.unc.edu)