Clinical Trials

There are several definitions for a clinical trial. The University of South Alabama follows the definition provided by the National Institute of Health (NIH). Per the NIH, a clinical trial is 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. It is important to note that not all human subject research is considered a clinical trial.

If you are approached by a pharmaceutical company to conduct a clinical trial or if you want to develop an Investigator-Initiated clinical trials please contact the Director of Clinical Trials.

Wendy Blount, RN, MSN
Director, USA Health Clinical Trials
(251) 445-9834
wlblount@health.southalabama.edu

▼   Regulations

Clinical trials that use a product that is regulated by the Food and Drug Administration (FDA) must follow FDA regulations. Additionally, clinical trials must adhere to the principles of Good Clinical Practice, most important of which is ICH E6: Good Clinical Practice- Consolidated Guidance. Below are important links to review prior to starting any clinical trials.

FDA Regulations Relating to Good Clinical Practice and Clinical Trials

ICH Guidance Documents

ICH E6: Good Clinical Practice- Consolidated Guidance

The below information is vital information to conducting clinical trials at the University of South Alabama. 

▼   Training

Personnel conducting clinical trials require additional training. Training requirements can be found on the Training webpage. All key personnel and investigators should take the required training. Key personnel are any research personnel that significantly contribute to the integrity of the research date. Examples of key personnel include coordinators and Investigators. Pharmacist should be considered key personnel when an investigational product is involved.

▼   Investigational New Drug (IND)

Numerous clinical trials that use a drug governed by the Food and Drug Administration (FDA) require an Investigational New Drug (IND) application to be filed with the FDA. The person or entity that files the IND is considered the Sponsor.

The Sponsor is ultimately responsible for all aspects of the study. Such responsibilities are clearly defined in the federal regulations.

University of South Alabama’s Investigators should be sure to consider all the required Sponsor responsibilities before submitting an IND. Investigators should refer to the IND Guidance for comprehensive information about INDs.  

▼   Data & Safety Monitoring for Clinical Trials

Overview

Data and safety monitoring is intended to protect the safety of research participants and ensure the integrity of the research data. All studies involving human subjects require some level of monitoring.

Federal regulations require appropriate provisions be in place to adequately monitor the data collected and ensure the safety of research subjects. The NIH requires data and safety monitoring for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); and efficacy, effectiveness, and comparative trials (phase III). The method and level of data and safety monitoring should be commensurate with the degree of risk of harm to subjects and the size and complexity of the study.

Data Safety Monitoring Plans (DSMP)

A DSMP is a written plan for monitoring research data and the safety of study participants. DSMPs are required for clinical studies involving more than minimal risk. A DSMP ordinarily appears in the study protocol and assures there is a plan and system for appropriate oversight of the study. The DSMP should delineate who is responsible for reviewing and reporting adverse events, to whom they will be reported, and on what schedule this monitoring and reporting will occur. The DSMP should also explicitly indicate whether or not there will be a formal data safety monitoring board (DSMB). Though every study involving more than minimal risk will have a DSMP, only a subset of studies will have a DSMB.

Data Safety Monitoring Board (DSMB)

A DSMB is a formally convened group charged with reviewing data and endpoints on a timeline set forth in a protocol's DSMP. These groups are made up of members from different disciplines who are knowledgeable and experienced in the responsible conduct of research. Membership must include experts in biostatistics and the medical field under study.

The following is a list criterion for the use of a DSMB:

  • Multi-site clinical trials with interventions that entail risk(s) to participants
  • If the trial is evaluating mortality or another major endpoint, such that inferiority of one treatment arm has safety as well as effectiveness implications.
  • Any research done in an emergency setting where the informed consent requirement is waived.
  • All phase III clinical trials with the exception of behavioral and nutritional studies
  • Phase I or II trials that involve blinding
  • The trial includes vulnerable population and is greater than minimal risk
  • When it would be ethically important for the trial to stop early if the primary question addressed has been definitively answered, even if secondary questions or complete safety information were not yet fully addressed.
  • When there is prior information suggesting the possibility of serious toxicity with the study treatment
  • Studies that do not meet the above criteria, but are required by the funding source to be reviewed by a DSMB.

Investigators are required to report on the progress of the study at a frequency established in the DSMP and approved by the DSMB. Investigators should complete and submit the applicable form(s) listed under resources.

Resources

SOP 1206: Data Safety Monitoring Board policy

Reporting Forms:

▼   ClinicalTrials.gov

The Food and Drug Administration states that certain studies must be reported on the public website, clinicaltrials.gov. The submission requirements are outlined in Section 801 of the Food and Drug Administration Act (FDAAA 801) issued in 2007.

FDA Clinicaltrials.gov Resources

In September 2016, NIH issued a final policy to promote broad and responsible dissemination of information from NIH-funded clinical trials through ClinicalTrials.gov. Under this policy, every clinical trial funded in whole or in part by NIH is expected to be registered on ClinicalTrials.gov and have summary results information submitted and posted in a timely manner, whether subject to FDAAA 801or not. This policy is effective for applications for funding, including grants, other transactions, and contracts submitted on or after January 18, 2017. For the NIH intramural program, the policy applies to clinical trials initiated on or after January 18, 2017.

NIH News Release: HHS takes steps to provide more information about clinical trials to the public (September 16, 2016)

For Assistance with Clinicaltrials.gov reporting please contact:

Wendy Blount, RN, MSN
Director, USA Health Clinical Trials
(251) 445-9834
wlblount@health.southalabama.edu

Stefanie White, CCRP
Associate Director, Research Quality Assurance and Improvement
(251) 460-7573
swhite@southalabama.edu

▼   Why it’s important

Clinical trials must be placed in a public database, ClinicalTrials.gov, as mandated by federal agencies.  The trials are required to be registered when they begin and updated throughout the life of the study.  Additionally, study results must be provided upon completion of the study.  Monetary penalties can be applied by the agencies if the requirements are not met. 

 

▼   Recent changes – January 18, 2017

The revised requirements to register applicable clinical trials now also apply to trials funded by NIH, whether they or not they are FDA-regulated. The expanded regulations also include increased penalties for noncompliance. Furthermore, several scientific journals have specified they will not publish clinical trials which have not registered.

▼   Applicable Clinical Trials
  • Clinical trials funded by in whole, or in part, by National Institute of Health

Definition of Clinical Trial as determined by the NIH:

A research study in which one or more human subjects are prospectively assigned to one or more interventions to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.”

This definition encompasses phase 1 trials of FDA-regulated drug and biological products, small feasibility studies of FDA-regulated device products, and study of any intervention not regulated by the FDA, (i.e., behavioral interventions)

  • Trials that meet the clinical trial definition of the International Committee of Medical Journal Editors (ICMJE) that the investigator may publish.

Definition as determined by ICJME:

Any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Health-related interventions include any intervention used to modify a biomedical or health-related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes). Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events. Purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) will not require registration.   NOTE:  Registration must occur before the first patient was enrolled.

  • Qualifying clinical trials that will render claims for items/services to the Center for Medicare and Medicaid Services.

The National Clinical Trial (NCT) number must be included on claims for items and services provided in clinical trials that are qualified for coverage as specified in the "Medicare National Coverage Determination (NCD) Manual," Section 310.1.

Definition of a Qualifying Clinical Trial under CMS Clinical Trials Policy:

  1. The subject or purpose of the trial is the evaluation of an item or service that falls within a Medicare benefit category (e.g., physicians' service, durable medical equipment, diagnostic test) and is not statutorily excluded from coverage (e.g., cosmetic surgery, hearing aids).
  2. The trial is not designed exclusively to test toxicity or disease pathophysiology and must have therapeutic intent.
  3. Trials of therapeutic interventions must enroll patients with diagnosed disease rather than healthy volunteers, although trials of diagnostic interventions may enroll healthy patients to have a proper control group.
  • Applicable Clinical Trials per FDAAA:

Trials of Drugs/Biologics: Controlled, clinical investigations of a product subject to FDA regulations, other than Phase I. This may include interventional studies with dietary supplements.

Trials of Devices: Prospective controlled trials with health outcomes, which compares an intervention with a device against a control, other than small feasibility studies. Includes Pediatric post-market surveillance studies.

Applicable Clinical Trials under FDAAA also meet one of the following conditions:

Checklist for Evaluating whether a Clinical Trial or Study is an Applicable Clinical Trial

  • The trial has one or more sites in the U.S.
  • The trial is conducted under an FDA Investigational New Drug Application (IND) or Investigational Device Exemption (IDE) application
  • The trial involves a drug, biologic, or device that is manufactured in the U.S. or its territories and is exported for research

    FDAAA requirements for registration exclude the following (unless funded   either in whole, or in part by NIH):
  • (Non-serious/life-threatening) Phase 1 drug trials, including studies in which 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 (e.g., behavioral interventions)
  • Non-interventional (observational) clinical research, such as cohort or case control studies
▼   Who is the Responsible Party for Registering Trial and Study Results?

The responsible party is considered to the study sponsor (i.e, IND or IDE holder or the initiator of the study) or a sponsor-designated PI who is responsible for conducting the study, and has access to and control over the clinical data to analyze the data and publish the results.

The USA PI should consult with industry sponsor to assure that posting of a trial is in accordance with terms of the study contract. A sponsor whom provides study drug only typically does not accept the registration/results reporting responsibilities.

▼   Registration and Reporting Results

ClinicalTrials.gov Registration Guide

  • Initial Registration:  No later than 21 days after enrollment of first subject
  • Interim updates:  The record must be updated annually (even if nothing has changed) until the final results are reported. NOTE: Specific type of changes must be reported within 30 days.
  • Reporting Results: No later than one year after the trial’s primary completion date.  This is the date when the final subject was examined or received an intervention for the purposes of collection of data for primary outcomes.
▼   What specific information is provided to Clinical Trials.gov?

Specific information on the data elements required by FDA and NIH for registration reporting is located on the ClinicalTrials.gov Protocol Registration System information website.

▼    Responsibilities of the PI

The PI can delegate the responsibility for entering information for purposes of registration, updates and reporting of results, however, the PI remains responsible for:

  • The accuracy of the information
  • The Approve and Release actions which are required every time information is entered into the record
▼    Informed Consent Requirements

Federal regulations require that consent forms included the following statement, without revision.  This is included in the USA standard consent template:

A description of this clinical trial will be available on http://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.

▼   Penalties for failure to register a clinical trial

Failure to register, or provide incomplete/false information (including updates subsequent to initial registration) may include monetary penalties of up to $10,000 per incident and/or per day, non-compliance notification from the FDA, and for federal sponsored studies, the withholding or recovery of grant funding.

NIH grantees are required to certify compliance with registration/reporting requirements in grant applications and progress reports. 

▼   Investigator-Initiated Clinical Trials

Investigator-Initiated Studies (IIS), also called Investigator-Initiated Trial (IIT), are clinical studies initiated and managed by a non-pharmaceutical company researchers, like individual investigators or institutions. The researcher is responsible for the legal and regulatory responsibilities of the trial sponsor for the conduct and management of the study as defined by all applicable laws and regulations.

Investigators should contact the Director of Clinical Trials for assistance with study development.

Wendy Blount, RN, MSN
Director, USA Health Clinical Trials
(251) 445-9834
wlblount@health.southalabama.edu

Maintaining compliance can be a challenge since these trials are not overseen by a sponsor and monitoring team.  The Office of Research Compliance and Assurance have tools, guidance, practices that can help you at all time-points of your study. For assistance with monitoring of Investigator-Initiated studies please contact:

Stefanie White, CCRP
Associate Director, Research Quality Assurance and Improvement
(251) 460-7573
swhite@southalabama.edu

Below are the steps that you need to take to start-up and manage an IIS trial. Some steps can be done simultaneously, while others need to be done chronologically.

▼   STEP 1: WRITE THE PROTOCOL

Below is a link to a protocol template. It is not required that you use this template. Clinical research protocol templates are widely available on the internet.  E6(R2) Good Clinical Practice: Integrated Addendum[BW3]  outlines the necessary information for a clinical trial protocol and protocol amendments in section 6. It is highly suggested that your compare your finished protocol with section 6 of the above guidance to ensure that all components of the protocol are described. 

Protocol Template

▼   STEP 2: DETERMINE THE FEASIBILITY

It is vital that the logistics and the feasibility be assessed for an IIS. Protocols should be sent to the following individuals to determine the feasibility of an IIS protocol:

Winona (Wendy) Blount, RN, MSN
Director, USA Health Clinical Trials
USA Health Clinical Trials Office
(251) 445-9834 office
wlblount@health.southalabama.edu

Stefanie White, CCRP
Assoc. Director, Research Quality Assurance and Improvement
Office of Research Compliance and Assurance
(251) 460-7573 office
swhite@southalabama.edu

Principal Investigator’s should also start discussing the protocol with departments that they plan to utilize. These departments will also be able to provide feedback on the feasibility of the protocol.

▼   STEP 3: DETERMINE THE BUDGET

This step can be started while the feasibility step is in progress. However, the budget should not be finalized until Step 2 has been completed.

The budget will vary greatly from study to study and will depend on numerous factors. Please contact Wendy Blount for assistance with developing your study budget.

Winona (Wendy) Blount, RN, MSN       
Director, USA Health Clinical Trials         
USA Health Clinical Trials Office            
(251)445-9834 office
wlblount@health.southalabama.edu   

▼   STEP  4: DETERMINE IF AN IND OR IDE IS NEEDED
Investigational New Drug (IND)- The United States Food and Drug Administration's Investigational New Drug program is the means by which a Sponsor (the person who takes responsibility for the study and drug- NOT the funding source) obtains permission to start human clinical trials and to ship an experimental drug across state lines before a marketing application for the drug has been approved.

Please refer to the IND Guide Book for information on conducting a study with an IND.

Investigational Device Exemption (IDE)- allows an investigational device to be used in order to collect safety and effectiveness data required to support a premarket approval (PMA) application or a 510(k) submission to Food and Drug Administration (FDA).

  INVESTIGATIONAL DRUGS - IND INVESTIGATIONAL DEVICES - IDE
FDA REGULATIONS  21 CFR 312 21 CFR 812
GUIDANCE/RESOURCES Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND (FDA Guidance)
FDA Website
Significant Risk and Nonsignificant Risk Medical Device Studies (FDA Information Sheet; Includes examples of SR and NSR devices)
FDA Website
INITIAL FDA PAPERWORK FOR APPLICATIONS
  1. IND Application: Instructions in 21 CFR 312.22-23
    1. Information for Sponsor-Investigators Submitting Investigational New Drug Applications (INDs) (FDA Guidance)
  2. FDA Form 1571 (IND Application Cover Form): Form ( PDF) | Instructions
  3. FDA Form 1572, Statement from Investigator: Form(PDF) | FAQ - Statement of Investigator (FDA Guidance)
  4. FDA Form 3674, Certificate of Compliance: Form (PDF)
    1. Register the study on ClinicalTrials.gov.
  5. If applicable, a written request for charging the cost of the investigational drug to subjects
  6. Conflicts of interest (financial disclosures) for all participating investigators
    1. Financial Disclosure by Clinical Investigators (FDA Guidance)
The FDA paperwork is not required to be submitted to the IRB. After submission, the FDA will respond within 30 days. All documentation received from the FDA must be kept on file.
  1. IDE Application: Instructions in 21 CFR 812.20
    1. IDE Approval Process( FDA Guidance)
  2. FDA Form 3674, Certificate of Compliance: Form( PDF)
    1. Register the study on ClinicalTrials.gov.
  3. Conflicts of interest (financial disclosures) for all participating investigators
    1. Financial Disclosure by Clinical Investigators (FDA Guidance)

Sponsor-Investigators are encouraged to contact the FDA to obtain further guidance prior to the submission of an IDE application through the Pre-IDE Submission Process.

The FDA paperwork is not required to be submitted to the IRB. After submission, the FDA will respond within 30 days. All documentation received from the FDA must be kept on file.

This step can be done at the same time as STEP 3. It is advised to wait until STEP 2, the feasibility assessment, is complete as it can result in changes to the protocol.

▼   STEP 5: COMPLETE REGULATORY DOCUMENTS
 

The following documents should be created.

  1. Informed Consent Form- Please refer to the Informed Consent page for more information on creating the Informed Consent.
  1. Case Report Forms- The case report form is the tool used by the sponsor of the clinical trial to collect data from each participating patient. The CRFs can be electronic or paper. These forms should collect data points that support the objective(s) of the study, as well as, gather data for subject safety.
  1. Advertisement- Create any advertisements you plan to use for your study. These will need to be approved by the IRB
▼   STEP 6: SUBMIT TO THE IRB AND OTHER REGULATORY BOARDS
 

Institutional Review Board

All research involving human subject must be approved by the Institutional Review Board BEFORE you enroll any subjects or gather any data. Any IIS research must go through the University of South Alabama IRB; it cannot go through WIRB.

For more information on how to submit to the IRB, please review the Getting Started section of the Research Compliance and Assurance’s webpage.

Institutional Biosafety Committee

Please review the Getting Started section of the Biosafety webpage to see if your study requires IBC approval.

Data Safety Monitoring Board

A Data and Safety Monitoring Board (DSMB) is an independent group of experts that advises the sponsor and the study investigators. The members of the DSMB serve in an individual capacity and provide their expertise and recommendations. The DSMB evaluates research data on an ongoing basis to assure participant safety and study integrity. The DSMB periodically reviews study data and unanticipated problems and makes recommendations based on their reviews along with assessing the performance of overall study operations and any other relevant issues, as necessary. The following is a list criterion for the use of a DSMB:

  • Multi-site clinical trials with interventions that entail risk(s) to participants
  • If the trial is evaluating mortality or another major endpoint, such that inferiority of one treatment arm has safety as well as effectiveness implications.
  • Any research done in an emergency setting where the informed consent requirement is waived.
  • All phase III clinical trials with the exception of behavioral and nutritional studies
  • Phase I or II trials that involve blinding
  • The trial includes vulnerable population and is greater than minimal risk
  • When it would be ethically important for the trial to stop early if the primary question addressed has been definitively answered, even if secondary questions or complete safety information were not yet fully addressed.
  • When there is prior information suggesting the possibility of serious toxicity with the study treatment
  • Studies that do not meet the above criteria, but are required by the funding source to be reviewed by a DSMB.

If you have any questions about using a DSMB or if you need assistance determining if your study requires a DSMB, please contact:

Stefanie White, CCRP
Associate Director, Research Quality Assurance and Improvement
Office of Research Compliance and Assurance
swhite@southalabama.edu
Ph: (251) 460-7573

▼   STEP 7: REPORT ON CLINICALTRIALS.GOV
 

More information to come. Please contact Stefanie White for more information.

Stefanie White, CCRP Associate Director, Research Quality Assurance and Improvement
Office of Research Compliance and Assurance
swhite@southalabama.edu
Ph: (251) 460-7573