Clinical Trials

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. 

 

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 Regulated by the FDA
  • Study involves drugs, devices, or biologics that are regulated by the FDA and meets the FDA definition of an Applicable Clinical Trial (ACT):
    • Trials of drugs and biologics: Controlled, clinical investigations, other than Phase I investigations, of a product subject to FDA regulation, and
    • Trials of devices: Prospective clinical studies of health outcomes comparing an intervention with a device against a control in human subjects (other than small clinical trials to determine the feasibility of a device, or clinical trials to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes); and pediatric postmarket surveillance studies, as required under the Federal Food, Drug and Cosmetic Act.
      
      Checklist for evaluation whether a Clinical Trial or Study is an Applicable Clinical Trial
      

       

• Clinical Trials receiving NIH funding
  • Study receives NIH funding and fits the NIH definition of a Clinical Trial: ‘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.’ 
    
    See NIH Policy and guidance
    
    
• Clinical Trials planning ICMJE Journal publication
  • The study team plans ICMJE journal publication and the study meets the ICMJE definition of a clinical trial: ‘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 relationship between a health-related intervention and a health outcome.’ 
    NOTE:  Registration must occur before the first patient was enrolled.
    
    See ICMJE Policy and guidance
    
    
• Qualifying Clinical Trials billing to the Centers for Medicare and Medicaid Services (CMS)
  
  • CMS requires the National Clinical Trial (NCT) number on all clinical trial-associated claims submitted and is available only by registering at ClinicalTrials.gov. Claims submitted to CMS without the NCT number will be rejected.
  • Definition of a Qualifying Clinical Trial under CMS Clinical Trials Policy:
    • 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).
    • The trial is not designed exclusively to test toxicity or disease pathophysiology and must have therapeutic intent.
    • 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.

Registration on ClinicalTrials.gov is the responsibility of the study sponsor (i.e., IND or IDE holder or the initiator of the study). In many instances, this will be an industry sponsor assuming responsibility for registering a clinical trial for multiple sites. In instances of Investigator Initiated Trials where a USA PI is acting as a sponsor-Investigator, the responsibility for registering qualifying clinical trials on ClinicalTrials.gov falls to the Primary Investigator (PI). The PI may delegate the responsibility for entering information, however the PI remains responsible for its accuracy and the Approve and Release actions which are required every time information is entered into the record.

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.

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.

• Data elements for protocol registration
• Data elements for results reporting

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

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.

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. 

Food and Drug Administration

• Checklist for Evaluating whether a Clinical Trial or Study is an Applicable Clinical Trial
• Summary of Changes effective January 18, 2017

Clinical Trials.gov

• www.ClinicalTrials.gov
• ClinicalTrials.gov FAQs
• Clinical Trials.gov Protocol Registration System
• Training Material 

National Institutes of Health

• FAQs for NIH Grantees
• NIH Implementation of FDAAA
• NIH Requirements for Registering & Reporting

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 (PDF)

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

Principal Investigators 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.

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 Stefanie White for assistance with developing your study budget.

Stefanie White, CCRP
Director, Clinical Trials Office
(251) 445-9834
swhite@southalabama.edu 

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	IND Application: Instructions in 21 CFR 312.22-23 Information for Sponsor-Investigators Submitting Investigational New Drug Applications (INDs) (FDA Guidance) FDA Form 1571 (IND Application Cover Form): Form (PDF)    FDA Form 1572, Statement from Investigator: Form(PDF) | FAQ - Statement of Investigator (FDA Guidance) FDA Form 3674, Certificate of Compliance: Form (PDF) Register the study on ClinicalTrials.gov. If applicable, a written request for charging the cost of the investigational drug to subjects Conflicts of interest (financial disclosures) for all participating investigators 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.	IDE Application: Instructions in 21 CFR 812.20 IDE Approval Process( FDA Guidance) FDA Form 3674, Certificate of Compliance: Form (PDF) Register the study on ClinicalTrials.gov. Conflicts of interest (financial disclosures) for all participating investigators 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.

 

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.

2. 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.

3. Advertisement- Create any advertisements you plan to use for your study. These will need to be approved by the IRB

 

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 IRBNet Specifics section of the Research Compliance and Assurance's webpage. 

Institutional Biosafety Committee

Please review 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
Director, Clinical Trials Office
(251) 445-9834
swhite@southalabama.edu 

 Refer to the ClinicalTrials.gov section above for guidance on submission requirements and compliance.

For inquiries or assistance with submission, contact:

Stefanie White, CCRP
Director, Clinical Trials Office
(251) 445-9834
swhite@southalabama.edu