Coordinators

As conducting clinical trials is a high priority at most major institutions, we, the clinical research staff (nurses, study coordinators and research study assistants) play an important and supportive role in clinical trial activities. We provide administrative assistance to investigators, are responsible for submission of regulatory documents to the Institutional Review Committees, handling and sometimes distributing investigational drugs and data collection/entry. However, the most important responsibility we all have, is to ensure that our study participants receive high quality, scrupulously monitored care while protecting their rights and improving their well being.

With all of the above in mind, I hope you will find the resources and tools on this website useful and will help you to enhance your commitment to clinical research, so it can be said “A Trial Well Done”!

Thank you!

Karen Williams, PSG Executive Member (Coordinator representative)

PSG Research Coordinator Resource Listing

We realize how hard the job of a coordinator is, and we would like to help make your lives just a little bit easier. We have pooled a premier group of PSG coordinators together to help answer any and all of your questions. You can review the list below along with their featured areas of expertise and contact information.

Karen Williams, BA, CCRP
Northwestern University, Dept. of Neurology
710 N. Lake Shore Drive, 11th Fl
Chicago, IL 60611
(312) 503-5645 (office)
(312) 503-0787 (fax)
k-willliams8@northwestern.edu
• Training/on-boarding new research staff
• Monitoring preparation
• Retention/Recruitment
• Collaborating with Ancillary Depts

Cindy Casaceli, MBA
DirectorClinical Trials Coordination Center
Center forHealth + Technology (CHeT)
University of Rochester
(585) 273-4239
• Clinical Trial Operations
• Trial budgets/Per subject fee
• Data Management
• Data sharing/Data mining
• eConsent
• Telehealth
• Mobile technologies

Sarah Wong, PhD, CCRP
Clinical Research Manager, Neurology
UCSF Movement Disorders and Neuromodulation Center
San Francisco VA Medical Center
(415) 353-7885
(415) 353-9060 (Fax)
• Clinical Trials Operations
• Project Management

Melissa A. Kostrzebski
Senior Project Manager
Clinical Trials Coordination Center
Center for Health + Technology (CHeT)
University of Rochester
(585) 273-4239
melissa.kostrzebski@chet.rochester.edu
• Clinical Trial Operations
• Project Management Monitoring
• Telehealth
• Sensor Technologies
• Protocol and Consent Development
• Recruitment and Outreach
• Data entry / query management

Ray James, BS, RN
Boston University School of Medicine
Department of Neurology
Parkinson Disease and Movement Disorder Center
72 East Concord Street, C3
Boston, MA 02118
(617) 638-7745
(617) 638-5354 (Fax)
• Research Nursing activities
• PD Medications
• Motor function assessments
• Retention/Recruitment
• Preparationfor Monitor Visits
• Cross-Disciplinary Coordination
• Managing Study Budgets
• Training New Research Staff
• Visit Preparation and Source Creation
• SOP development
• Monitoring Preparation

April Langhammer, BA, CCRP
University of Kansas Medical Center
3599 Rainbow Blvd.
Kansas City, KS 66160
(913) 588-6989 (office)
alanghammer@kumc.edu
• Source document creation
• Regulatory preparation

Julia Spears, CCRC
The University of Toledo, Dept. of Neurology
Gardner-McMaster Parkinson Research Center
3000 Arlington Avenue, MS 1083
Toledo, OH 43614-2598
(419) 383-6728 (office)
(419) 383-3063 (fax)
(419) 450-9793 (cell)
julia.spears@utoledo.edu
• Budget development and negotiation
• Study start-up / essential documents
• Regulatory management
• Consent form development
• WIRB submissions
• Data entry / query management
• CRO/CRA and Sponsor relations
• Site template development (Regulatory and source)

Alistair Glidden, BA
Center for Health + Technology
University of Rochester
• Digital and decentralized/virtual trials, including participant and investigator support for telemedicine
• Subject recruitment, including social media advertising and video production
• Training and onboarding new staff
• Database design, including general considerations (question/response/report structure) and specific guidance (REDCap)atea

Education & Training

The Parkinson’s Foundation and Parkinson Study Group have partnered on patient engagement in research design and implementation for ten years. As part of this partnership, we are pleased to provide training resources for study coordinators.

Our first resource contains three videos:

Research Education
1. An introductory video to the research process
2. An overview of patient engagement in research
3. An introductory video to our patient engagement in research work

Stay tuned for more resources on how research is conducted. By the end of this year, the Parkinson’s Foundation will launch a free, open access, online course covering topics including information on ethics and informed consent, analyzing and interpreting research and recruiting representative populations into research.Patient Engagement in Research.

Learn more about the Parkinson’s Foundation’s patient engagement in research program here. Our methodology of patient engagement can be found here. Examples of our Research Advocacy program work on bringing in representative populations to research can be found here and here. To join our efforts, contact Karlin Schroeder, Associate Vice President, Community Engagement, kschroeder@parkinson.org or (646) 388-7641.

THE RESEARCH PROCESS VIDEOS

More videos coming soon!

Patient Engagement in Research
Community Based Research
Patient Engagement in Research
Ethics

ADDITIONAL EDUCATION & TRAINING RESOURCES

Download this presentation here.
The Research Clinic Simulation
OfficialCMCLogo-16x9
Chicago Movement Coalition Website

Telemedicine

We're pleased to be able to offer these telemedicine resources to our coordinators, courtesy of the Center for Health + Technology at the University of Rochester.

GOING VIRTUAL

Telemedicine for Parkinson’s: A Clinician’s Guide

Telemedicine for Parkinson’s: A Live Demonstration

AN INTRODUCTION TO TELEMEDICINE

Video 1: A Brief Introduction to Telemedicine
Video 2: An Introduction to Telemedicine
Video 3: A Comprehensive Introduction to Telemedicine

TRAINING MATERIALS

A guide for Conducting Virtual Research Activities

Additional resources can be found on the University of Rochester’s website here.

Funding, Budget & Contracts

Components of a Budget

Start-up Fees

  • Pharmacy
    • $300 Federally funded and investigator-initiated studies
    • $3000 Sponsored studied
  • IRB, sponsored research only

Clinical Care Expenses

Study Team Effort

Indirect Costs

  • Non-federally funded
  • Federally funded

PHARMACY FEES

FACILITIES & ADMINISTRATIVE RATES

**Check institutional rates as these vary by institution

Clinical Trials: From Concept to Implementation

Download this presentation here.

Regulatory Information

GUIDELINES FOR CREATING A REGULATORY BINDER

General Guidance for Using the Regulatory Binder:

  • The Regulatory Binder should be assembled at the beginning of the study, prior to enrollment.
  • Keep the Regulatory Binder current and up-to-date.
  • Customize the binder to meet the specific needs of your protocol:
  • This Regulatory Binder is a template. Include only sections pertinent to your protocol. Omit unused sections and add sections as needed. See “Applicable Regulatory Binder tabs” below for more information.
  • Add additional tabs and/or documents to each section as needed.
  • Identify an individual(s) responsible for maintaining the binder. Ensure that this person is listed as the Primary Contact in the IRB system to ensure that all IRB correspondence and documents are received/filed in a timely manner. •Store binder in a safe and secure location, but accessible to authorized study staff at all times.
  • Participant-specific documentation and information, e.g., signed consent forms, test results, and completed case report forms, should be maintained separately in a participant-specific binder/file. Study material containing identifiable information should be stored in a secure location or protected manner.
  • If documentation is maintained in a separate location or electronically, include a signed and dated note-to-file in the designated binder section explaining where the file is kept and who maintains them.

APPLICABLE REGULATORY BINDER TABS

1. General Research Studies
Examples include but are not limited to: Questionnaire studies, minimal risk drug studies

a. Protocol/Amendments+
b.Consent/HIPAA+
c. IRB/xIRB*+
d. Training+
e. Case Report Forms (CRFs)+
f. Lab+
g. Instructions for Use (IFU) +
h. Recruitment +
I. CV/Medical Licenses +
j. ParticipantMaterials +
k .Delegation Log+
l. Screening/Enrollment Log+
m. CLIA/CAP/ Lab Certificates +
n. Package Insert
o. Miscellaneous

2. FDA-Regulated Drug Studies
(in addition to #1, maintain the following tabs)
Examples include but are not limited to: Clinical trials, IND submission studies

a. Financial Disclosure ^
b. Study Shipment Supplies^
c. Monitor Log & Letters ^
d. 1572^
e. Investigator Brochure^
f. FDA Submissions^
g. Investigational Product Shipment^
h. Investigational Product AccountabilityLog ^
i. SAE/IND Reports (non-UPIRSO)^
j. SAE/IND worksheets^
k. Correspondence^

3. FDA-Regulated Device Studies
(in addition to #1, maintain the following tabs)
Examples include: Investigational device studies, IDE submission studies

a. Financial Disclosure ^
b. Study Shipment Supplies^
c. Monitor Log & Letters ^
d. FDA Submissions^
e. Investigational Product Shipment^
f. Investigational Product AccountabilityLog ^
g. Investigator Agreement^
h. Correspondence ^

4.Sponsored Research Studies
(in addition to #1, possibly #2 and/or #3, maintain the following tabs)
Examples include: Studies with external funding

a. Sponsor Contact
b. Sponsor Newsletters
c. (Sponsor)Correspondence

Comments
* external IRB (both commercial or non-commercial)
^ use to maintain documents required for FDA-regulated research
+ use to maintain documents to meet Good Clinical Practice (GCP)

FORM 1572

The 1572 is an investigator’s signed contract with the FDA, agreeing to uphold federal clinical study obligations. No investigator may participate in an investigation until a 1572 is signed. Device studies use an Investigator’s Agreement Form, which is the equivalent to the 1572.

The PI agrees to personally conduct or supervise the described investigation. The PI agrees to maintain adequate and accurate records in accordance with 21 CRF 312.62 and to make those records available for inspection in accordance with 21 CRF 312.68. The PI ensures that all associates, colleagues, and employees assisting in the conduct of the study are informed regarding their obligation to meet all commitments of the study.

  • Name and address of the investigator
  • Education, training, and qualifications of investigator
  • Address of research facilities and clinical laboratories
  • Name and address of the IRB
  • Name of co-investigators and research staff
  • Protocol number and title
  • Commitments
  • Signature
  • Date

GUIDELINES AND REGULATIONS

Federal Regulations

  • Code of Federal Regulations (CFR)
    • CFR Title 46 Part 46: Outlines federal policy for the protection of human subjects in research, establishing mandates for institutional review boards (IRBs) and additional protections for vulnerable populations.
    • CFT Title 21 Part 50: Specifies that research on human subjects at institutions that hold Federal wide Assurances (FWAs) requires IRB review; this CFR specifies the minimum level of review for different types of research.

International Guidance

  • International Conference on Harmonization – Good Clinical Practice (ICH GCP E6)

Local

  • Institutional (IRB) versus Central IRB (usually selected by sponsor but can be WIRB, Quorum or others)

INSTITUTIONAL REVIEW BOARD

The Institutional Review Board (IRB) was established in accordance with federal regulations governing the use of human subjects in research. 

The IRB reviews and surveys research to ensure the protection of the rights and welfare of all research subjects. 

Investigators cannot initiate or  change research protocols until they have received IRB approval.

GOOD CLINICAL PRACTICE TRAINING

All faculty or staff listed on a protocol with the IRB must have documentation of training (may be specific requirements at institution)

Required: CITI Web Based Training or other similar program

Required: GCP for Clinical Trials with Investigational Drugs and Medical Devices (U.S. FDA focus) is suitable for individuals proposing to conduct clinical trials of drugs and devices primarily in the U.S. and/or who would prefer a more U.S. FDA-centric curriculum.

Recommended: Clinical Research Coordinator (CRC)

CITI Program’s CRC course provides a foundational training specifically focusing on operational and regulatory elements necessary for the ethical conduct of clinical research, while at the same time it is specifically tailored for the needs of clinical research professionals. It offers learners a foundation that expands beyond but is directly connected to the Human Subjects Research (HSR) and Good Clinical Practice (GCP) ICH training.

ADDITIONAL TRAINING

  • Protocol specific training

    • Expectations for clinical and research specific procedures, such as laboratory assessments, EKG, vitals, etc.

    • Expectations for standardized and non-standardized study data collection methods or assessments, such as questionnaires

    • Sponsor specific training for EDC, Specialty assessments, diary training, specific assessment devices (these may take place at Investigator meeting but most often by additional training modules/webinars)

  • Shipment of Hazardous Materials (IATA)

  • Blood Borne Pathogens

HELPFUL RESOURCES AND LINKS

Study Start Up

IRB SUBMISSION

All IRB submissions are done electronically using the institutional IRB system or a Central IRB as allowed by the institution (such as WIRB, Quorum)

  • IRB submissions will not be approved without an approved budget from the Office of Sponsored Research (OSR) (sequence depends on institution)
  • The following documents are included in the with the IRB submission:
    • Protocol
    • Budget (Department/Institutional requirements)
    • Investigator’s Brochure
    • Recruitment Materials
    • Informed Consent
    • Research Supplemental Submission (if applicable)

THE IRB: WHAT YOU NEED TO KNOW

  • You must complete CITI training prior to being added to a protocol
  • You must be added to a protocol with the IRB prior to obtaining patient consent or doing any protocol related tasks
  • You must have documented training on each protocol
  • No study procedures can be completed prior to obtaining informed consent
  • Unanticipated Problems: If you encounter a serious event that meets the following criteria, work with your PI to report the SAE to the IRB:
    • Unexpected
    • Related or possibly related
    • Suggests the research places subjects or others at risk of unknown harm

RESEARCH RESPONSIBILITIES

  • Contract: Contracts analyst OSR, Coordinator, Investigator, Sponsor
  • Budget: OSR, Coordinator &/or Regulatory specialist
  • Informed Consent: Coordinator &/or Regulatory specialist
  • Regulatory: Coordinator &/or Regulatory specialist
  • IRB Submission: Coordinator &/or Regulatory specialist

CRITICAL REGULATORY DOCUMENTS

  • CDA executed
  • 1572
  • CVs for all research staff involved in the study (signed and dated within 2 years)
  • Medical Licenses
  • Protocol
  • Amendments
  • Investigator’s Brochure
  • Protocol Signature Pages
  • Critical Correspondence
  • Test Article Records and Drug Accountability
  • Delegation of Responsibility Log
  • IND Safety Reports
  • Laboratory Certifications
  • Laboratory Reference Ranges
  • Lab Director’s CV and License
  • Telephone Logs
  • Site Signature Logs
  • Monitoring Log
  • Financial Disclosures
  • Conflicts of Interest
  • Enrollment & screening logs

Investigator’s Meeting: Prior to study recruitment many sponsors hold IM to train, cover AE and SAE reporting, lab procedures, certify investigators and/or staff in assessments and provide a background on the sponsor and protocol. These may be in person meetings or via Webinar or combined with the Site Initiation Visit (SIV).

Site Initiation Visit (SIV): Following the IM and prior to study start-up, sponsors will hold the SIV to train, cover AE and SAE reporting, lab procedures, certify investigators and/or staff in assessments, collect regulatory documents, verify the Delegation of Authority log and answer questions all site personnel may have about the conduct of the study.

SCREENING & ENROLLMENT

The protocol will specify when a subject is considered enrolled in a study.

  • Screening and enrollment logs to be maintained and provided to sponsor per protocol.
    • Separate enrollment log with complete subject identification is necessary, to be filed in regulatory binder but not released to sponsor as it includes subject PHI.
  • Signature on informed consent before any study related procedures are completed.
  • Randomization per protocol
  • Treatment dispensed per protocol (if a treatment trial)

Questions to Ask when deciding whether to volunteer for research

CONSENT PROCESS DOCUMENT

It is critical to document the consent process for your site.

Some sites include in subject EDC chart or have a separate consent process document including that the subject has had time to review the ICF, all questions were answered and the subject received a copy of the signed consent document for their records.

Example of a Consent Process Document

Required Elements of Informed consent

  • Information must be provided to the subject in a language and level understandable to the subject (7th grade level)
  • Introduction
  • Study involves research
  • Purpose of research
  • Duration of subject involvement in the study
  • Description of study procedures
  • Identification of any experimental procedures
  • Potential risks/ discomforts
  • Potential benefits to subjects or others
  • Alternative procedures or treatments (that are already available to the potential subject)
  • Confidentiality of subject records (e.g. access to sponsor, FDA)
  • Compensation for injury and treatment in event of emergency
  • Who subject can contact
  • Participation is voluntary
  • New-March 7, 2012: “A description of this clinical trial will be available on https://www.clinicaltrials.gov/ , as required by U.S. Law. This web site will not include information that can identify you. At most, the web site will include a summary of the results. You can search this web site at any time.”
  • Unforeseen risks statement
  • Reasons for involuntary termination
  • Additional costs to subject
  • Consequences of decision to withdraw (e.g. impact on their health, treatment, personal welfare etc.)
  • New findings will be communicated
  • Approximate number of subjects in the study
  • Payments to the subject are to be included in the document and when they will be paid (e.g. incentive, travel costs etc.)*

ROUTINE MONITORING VISITS

  • Based on CRO/sponsor requirements study monitors will be asked to come to the site generally within 2 weeks of initial enrollment then every 4-6 weeks. These requirements vary from sponsor to sponsor, may be impacted by enrollment numbers and phase of study.
  • Frequency of visits may decrease in the open extension phases of study.

RESEARCH DRUG/INVESTIGATIONAL PRODUCT

  • Drug storage: Investigational drugs will be stored in the appropriately secured location (i.e. refrigerated or frozen compounds). Accurate and complete drug accountability records MUST be maintained.

    • Investigational drugs, which are dispensed to patients, shall be dispensed only by authorized personnel (under the supervision of the study physician or registered nurse) and in accordance with all state and federal, and institutional regulations as required by law. 

  • Investigational Drug Disposal: Investigational drugs shall be returned or destroyed according to the protocol and drug company policy. If destroyed on site follow your institutional or facility policies for hazardous waste.

  • Temperature logs: All logs for drug cabinets, refrigerator and freezer must be maintained and available for review by the sponsor or designees. Some sites use and institutional research pharmacy and the logs are maintained there.

  • Study Drug Blind Envelopes: In a separate binder, appropriate personnel have access to the blind envelopes for all studies. These blind envelopes are maintained until retrieval by study monitor at closeout. Sometimes these blinds are on the I/P container itself rather than a separate folder. They are however, available to designated study personnel in the event of an emergency. Every effort is made to keep the studies blinded and the sponsor is notified before the blind is broken.

RESEARCH SOP’S

It is important to develop site-specific Research SOP’s.

  • Include record retention policies, location of offsite storage if applicable, drug destruction policies and plan, specific location of temperature logs and archives of these, maintenance of equipment logs (annual recalibration)

  • Outline site-specific responsibilities for research requirements

  • Disaster Plan if one is applicable

ACCESS FOR MONITORS

Access for monitors to patient electronic records may be based on institutional requirements. Some will have certified copies of the patient records printed and dated and provided by the coordinator. Other sites may actually allow sponsor designees “read-only” access to patient records.

  • Submit requests 2-3 weeks in advance

    • Monitor full legal name

    • Date of Birth

    • Last four digits of Social Security Number

    • IRB approval letter

    • Department

    • Start date for access

  • EPIC: 1 year (varies by institution)

  • Powerchart: 90 days

    • Signed Confidentiality Agreement

Clinical Trials 101

Research & Clinical Trials

What is research?

Research is defined by the Department of health and Human Services as a systemic investigation, including research, development, testing and evaluation designed to develop and contribute to generalizable knowledge.

Generalizable

  • Hypothesis is tested
  • Research outcomes are shared
Systemic

  • Defined procedure for data collection process
  • Primary and secondary endpoints are defined prior to data analysis
  • Data is gathered and then analyzed

TYPES OF RESEARCH

Interventional

  • A study that uses an intervention to modify the health of the subjects
  • Administration of a drug or device; medical procedure
  • Manipulation of the environment intended to change the course of a subject’s medical condition

Observational

  • A study without clinical intervention (i.e. survey or questionnaire)
  • An evaluation of patient condition (i.e. PPMI)
  • An assessment of data collected on an individual or group of patients (i.e. PPMI)
Clinical Trials

Sponsor

  • The person, company, or group who wrote the protocol and takes responsibility for the initiation, management, reporting, and document preparation of the trial, as per FDA requirements.

Funder

  • Source of funding to support the conduct of the trial; funding may come from the sponsor or another source.

Human Subjects

  • A human subject is a living individual about whom an investigator obtains data through intervention or interaction or identifiable private information.
  • HIPAA regulations cover research on all human subjects, living or deceased.
  • Identifiable specimens or records of deceased subjects may require approval by the IRB.

Industry Sponsored

  • Protocols for a clinical investigation that are written and initiated by a person or agency outside of the institution
  • The person or agency does not actually conduct the investigation, but pays clinical investigators for their participation
  • The external sponsor takes responsibility for the initiation, management, reporting, and document preparation of the trial

Investigator Sponsored

  • Protocols for a clinical investigation are initiated and conducted by the same person, usually a faculty member
  • Investigator initiated trials carry the same regulatory requirements as industry-sponsored trials, so the investigator takes on ALL sponsor responsibilities
  • Funding sources could be externally funded, grant funded, or unfunded

Grant-funded Clinical

  • A clinical investigation that is funded by the NIH or other granting agencies
  • Subject to further restrictions and requirements that are placed on all federally funded project
  • NIH uses activity codes (e.g. R01, R43, etc.) to differentiate the wide variety of research-related programs they support
Primary Investigator

An individual who actually conducts a clinical investigation, i.e. under whose immediate direction the test article is administered

PI RESPONSIBILITIES

21 CRF 312.60
An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation. An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in 50.23 or 50.24 of this chapter

21 CRF 812.100
An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under the investigator’s care, and for the control of devices under investigation. An investigator also is responsible for ensuring that informed consent is obtained in accordance with part 50 of this chapter. Additional responsibilities of investigators are described in subpart G.

Eligible to serve as the PI

  • Curators
  • Instructors
  • Librarians
  • Non-tenure-track research and clinical faculty
  • Tenure-track faculty
  • Senior research investigators

Case-by-case Determination

  • Adjunct faculty
  • Visiting faculty
  • Visiting scholars
    Contact the Associate Vice President for Research via email to request permission for such faculty. Please include your CV. If approval is granted, upload the confirmation email as a supporting document into the eIRB+ application.

NOT eligible to server as the PI

  • Postdoctoral fellows
  • Research assistants
  • Graduate students
  • Research associates
  • Undergraduate students

The Clinical Trial Process

Clinical Trials: From concept to Implementation
Pre-Clinical Drug Discovery

Compounds are extracted from natural substances or synthesized in the lab and analyzed for therapeutic value

Pre-clinical testing:

  • Pharmacology
    • Pharmacodynamics
    • Pharmacokinetics
  • Toxicology
  • Animal testing
Pre-Clinical Testing

Pharmacodynamics: the observed effect resulting from a certain drug concentration

Pharmacokinetics: Describes the drug concentration-time courses in body fluids resulting from administration of a certain drug dose

  • Absorption
  • Distribution
  • Metabolism
  • Excretion

Toxicology: Tests the toxicological effects of an agent, including carcinogenicity

Animal Studies: Common animal models for studying compound safety and efficacy include mice, rats, pigs, dogs, and monkeys

Research & Development Statistics

The average cost of R&D for every successful drug is $800,000,000 – $1,000,000,000

For every 5,000-10,000 compounds in the R&D pipeline, 1 receives FDA approval

The Pharmaceutical Research Manufacturers of America (PhRMA) estimates that only 5 in 5,000 compounds that enter pre-clinical testing make it to human testing, and 1 of those 5 might be safe and effective enough to reach pharmacy shelves

Essential Elements of a Protocol

Objectives
Objectives should be clearly stated as a hypothesis to be tested

Background
Sufficient background information should be included so that the rationale for the study is clear

Patient Eligibility Criteria
Inclusion and Exclusion criteria should be explicitly stated

Pharmaceutical Information
Information should include product description, storage requirements, stability, route of administration, and toxicity information

Managing Bias

Controlled Trials

  • Study Drug vs. Placebo
  • Similar Age and Weight
  • Same Stage of Disease

Randomization

  • Subjects are randomly assigned to a specific arm of the study
  • The investigator does not control randomization

Blinding

  • Single Blinding: the patients do not know whether they are receiving study drug or placebo
  • Double Blinding: the patients, investigators, study staff, and data analysts do not know whether they are receiving study drug or placebo

Clinical Trial Blinding

Human behavior is influenced by what we know or believe. In research there is a particular risk of expectation influencing findings, most obviously when there is some subjectivity in assessment, leading to biased results. Blinding (sometimes called masking) is used to try to eliminate such bias.

Double blind: usually refers to keeping study participants, those involved with their management, and those collecting and analyzing clinical data unaware of the assigned treatment, so that they should not be influenced by that knowledge.

Double-Dummy: two active compounds, blinding is possible using this method. For example, if we want to compare two medicines, one presented as green tablets and one as pink capsules, we could also supply green placebo tablets and pink placebo capsules so that both groups of patients would take one green tablet and one pink capsule.

Single blind trials: (where either only the investigator or only the patient is blind to the allocation) are sometimes unavoidable.•Open (non-blind) trials. In trials of different styles of patient management, surgical procedures, or alternative therapies, full blinding is often impossible.

The FDA considers blinded clinical trials ethical if they meet the following criteria:

  • Patients are fully informed of the protocol and treatment options
  • Treatments cannot be denied that could prevent irreversible injury or alter survival
  • ontinuous monitoring looks for negative or positive results
Investigational New Drug (IND)

IND Submission Contents

  • Introductory statement
  • Investigational plan
  • Investigator’s brochure
  • Protocol
  • Pharmacology information
  • Toxicology information
  • Summary of previous experiments
  • Chemistry, manufacturing, and control information
  • Form 1571

When to Submit an IND

  • New indication
  • Significant change in marketing
  • A new route of administration
  • Dosage level change
  • New subject population
  • Changes that significantly increase the risks associated with use of the investigational product

The FDA will notify the PI of approval via formal correspondence containing an IND number and a date of approval. All correspondence and original submission materials should be maintained in the regulatory binder.

Includes information and cautions derived from pre-clinical research

Serves as the official labeling for an investigational drug prior to FDA approval; subsequently, the approved package insert becomes the official labeling

Phase 1
  • Determine Safe Dose Range
  • Toxicity Levels
  • Pharmacodynamics
  • Pharmacokinetics
  • Dose Limiting Toxicity (DLT)
  • Maximum Dose Tolerated (MDT)

OBJECTIVES

  • Determine Safe Dose Range
  • Toxicity Levels
  • Pharmacodynamics
  • Pharmacokinetics
  • Dose Limiting Toxicity (DLT)
  • Maximum Dose Tolerated (MDT)
Phase 2
  • Evaluation of safety and disease treatment effects
  • 100-300 subjects
  • Specific disease condition
  • Continued research regarding safety and less common side effects

OBJECTIVES

  • Determine disease response to study drug
  • Drug-drug interaction
  • Efficacy at various doses
  • Patient Safety
Phase 3
  • Treatment evaluation
  • Thousands of subjects
  • Multi-center design
  • Treatment vs. Placebo
  • Controlled
  • Study intervention compared to or combined with standard treatment

OBJECTIVES

  • Compare study interventions to standard treatment for disease
  • Phase III information used for drug labeling
  • Data is analyzed and findings are submitted to the FDA
New Drug Application
  • Submission requesting FDA approval to market a new drug
  • Review of all pre-clinical and clinical trial data
  • Assess safety and efficacy
  • FDA may audit sites to verify data submitted in the NDA
  • If approved, the drug can be marketed and sold to the public under the FDA guidelines for marketing and distribution
Phase 4
  • Post-marketing studies
  • Long-term safety
  • Affects on different cohorts
    • Dosing
    • Race
    • Gender
  • The sponsor must continue to report Adverse Events (AEs) and finding to the FDA via MedWatch Forms

If dangerous side effects are found, the drug is taken off the market or a Black Box may be added

The Impact of Research

Scientific Research has produced substantial social benefits. It has also posed some troubling ethical problems.

— Belmont Report, 1979

Berlin Code of Ethics: World’s first official regulation of human experimentation, barring non-therapeutic interventions without voluntary consent, as well as experiments on minors and others judged vulnerable or incompetent.

The Nuremberg Code: International code of ethics established in response to inhumane Nazi human experimentation during WWII. The Nuremberg Code established four principles:
▫ Informed Consent
▫ Absence of Coercion
▫ Properly formulated scientific experimentation
▫ Beneficence towards experiment participants

Kefauver-Harris Drug Amendments: Passed to ensure drug efficacy and greater drug safety; drug manufacturers are required to prove to the FDA effectiveness of their products before marketing them and tests for safety during pregnancy are required before a drug can receive approval for sale in the U.S. As a result, the FDA is given closer control over investigational drug studies and FDA inspectors were granted access to additional company records.

Declaration of Helsinki: A statement of ethical principles stating that in medical research on human subjects, considerations related to the wellbeing of the human subject should take precedence over the interests of science and society. This document is widely considered the cornerstone of human research ethics.

The Belmont Report: The National Research Act led to the Belmont Report, which outlined 3 basic principles:
▫ Respect for persons
▫ Beneficence
▫ Justice

International Conference on Harmonization (ICH): Good Clinical Practice (GCP) set as the international standard, providing public assurance that trial subjects are protected.

PRINCIPALS OF THE BELMONT REPORT

Respect for persons: Informed Consent

  • Individuals should be treated as autonomous agents… capable of deliberation about personal goals and of acting under the direction of such deliberation
  • Persons with diminished autonomy are entitled to protection.
  • Requirements to acknowledge autonomy and the requirement to protect those with diminished autonomy.

Beneficence: Benefits in research should outweigh the risks

  • Do not harm the human subject.
  • Maximize possible benefits.
  • Minimize possible harm.

Justice: Equality in selection and opportunity to participate in research

  • Each person should have equal share according to:
    • Individual need
    • Individual effort
    • Societal contribution
    • Merit
Guidelines and Regulations

FEDERAL REGULATIONS

Code of Federal Regulations (CFR):

  • CFR Title 46 Part 46: Outlines federal policy for the protection of human subjects in research, establishing mandates for institutional review boards (IRBs) and additional protections for vulnerable populations.
  • CFT Title 21 Part 50: Specifies that research on human subjects at institutions that hold Federal wide Assurances (FWAs) requires IRB review; this CFR specifies the minimum level of review for different types of research

INTERNATIONAL GUIDANCE

International Conference on Harmonization: Good Clinical Practice (ICH GCP E6)

LOCAL GUIDANCE

Institutional (IRB) versus Central IRB (usually selected by sponsor but can be WIRB, Quorum or others)

Institutional Review Board

The Institutional Review Board (IRB) was established in accordance with federal regulations governing the use of human subjects in research.

The IRB reviews and surveys research to ensure the protection of the rights and welfare of all research subjects.

Investigators cannot initiate or change research protocols until they have received IRB approval.

Good Clinical Practice Training

All faculty or staff listed on a protocol with the IRB must have documentation of training (may be specific requirements at institution)

Required: CITI Web Based Training or other similar program

Required: GCP for Clinical Trials with Investigational Drugs and Medical Devices (U.S. FDA focus) is suitable for individuals proposing to conduct clinical trials of drugs and devices primarily in the U.S. and/or who would prefer a more U.S. FDA-centric curriculum.

Recommended: Clinical Research Coordinator (CRC)CITI Program’s CRC course provides a foundational training specifically focusing on operational and regulatory elements necessary for the ethical conduct of clinical research, while at the same time it is specifically tailored for the needs of clinical research professionals. It offers learners a foundation that expands beyond but is directly connected to theHuman Subjects Research (HSR) andGood Clinical Practice (GCP) ICH training.