Clinical Trials Administrative Start-Up Handbook

SECTION 11

General Information

Information in this section of the Handbook focuses primarily on the investigator's regulatory obligations - both for industry-sponsored clinical trials and for investigator-initiated trials in which the investigator holds the IND/IDE and assumes the responsibilities of both sponsor and investigator.

Note that:

• Aside from the ethical and regulatory responsibilities outlined in this chapter, additional, study-specific responsibilities may derive from other sources, such as the study protocol, the clinical research agreement, any conditions of approval imposed by the FDA or by the Institutional Review Board, institutional policy (such as the research billing compliance policy), and state law.
  
  
• Before enrolling subjects, you may also need to register your study at ClinicalTrials.gov. For complete information about the registration requirements and for detailed instructions about how to register your study, see Registering Studies at ClinicalTrials.gov - FAQs about the FDA/NIH/ICMJE Requirements. Failure to register applicable studies can carry heavy penalties.

Investigator's Responsibilities - A Brief Outline

Overriding all else is this: As the principal investigator, although you may delegate some clinical research duties to other members of your study staff, the ultimate responsibility rests with you. Begin a study only if you are certain that adequate time and resources are available to you.

In general, your responsibilities as an investigator are to:

• Personally conduct or supervise the trial as written in the clinical protocol.
  
• Ensure that all associates and study team members are informed about their duties and obligations.
  
• Understand the investigational agent, including potential risks and side effects.
  
• Ensure that the investigational agent is properly handled, dispensed, and administered.
  
• Monitor and report all adverse events, protocol violations, and unanticipated problems that occur during the study.
  
• Maintain accurate study records, submit data to your study sponsor, if applicable, and make the data available for monitoring and inspection.
• Ensure that the rights, safety, and welfare of human subjects in your study. Obtain IRB approval and informed consent from each subject.
  

Common to clinical research and - in a sense - apart from the regulatory obligations, is a particular ethical problem called the "therapeutic misconception," i.e., the potential confusion on the part of the research subject regarding his or her relationship to the investigator - a confusion that is especially frequent when the investigator is also the subject's physician. One of the investigator's important ethical responsibilities is to explain the difference between the research and the physician/caregiver roles and to avoid confusion by re-emphasizing this distinction throughout the study. In explaining the difference between roles, investigators can explain to subjects that:

• The physician/caregiver role involves interventions that are designed to improve the well-being of the individual patient, are based on the best available medical evidence, and have a reasonable expectation of a successful outcome.
  
  
• The researcher's role, however, involves interventions that are not necessarily designed to provide direct benefit to the participant. Instead, the interventions are designed to contribute to generalizable knowledge, are standardized according to a strictly written protocol, and lead to outcomes that are measured across groups of subjects.

Useful Web resources

The following list is a sample of Web resources that provide more detailed information about investigator responsibilities in clinical research.

• Good Clinical Practice (GCP) Training from the Collaborative Institutional Training Initiative (CITI) at the University of Miami. This is must-read information. The CITI course consists of fourteen training modules, two of which focus especially on investigator responsibilities: Module 5 (for investigator-initiated studies) and Module 6 (for studies sponsored by pharmaceutical or device companies). For access to the modules, follow instructions at the link.
  
  
• Good Clinical Practice Guidelines, International Conference on Harmonization, Topic E6. Although this 63-page reference is entitled "Guidance for Industry," by scrolling to Section 4 you'll find a 23-page description of investigator responsibilities.
  
  
• Investigators' responsibilities in drug studies are described on the FDA's page about Investigational New Drug (IND) Applications. Scroll to Subpart D.
  
  
• Investigators' responsibilities in device studies (both significant risk and non-significant risk devices) are described by the FDA in Device Advice (scroll more than halfway down the page). Also refer to the FDA's Investigators' Responsibilities for Significant Risk Device Investigations.
  
  
• Form FDA 1572, the "Statement of Investigator," is familiar to investigators who have participated in drug or biologic studies that are subject to the IND regulations. It is useful to review page 2 of the form, as it summarizes your responsibilities as an investigator and the commitments that you make to the FDA when conducting FDA-regulated studies. Signing the document, then failing to follow these commitments/responsibilities is a criminal offense.
  
  
• The FDA's Draft Guidance "Protecting the Rights, Safety, and Welfare of Study Subjects - Supervisory Responsibilities of Investigators (published 5/10/07) is a valuable reference, applicable to clinical research generally, not solely to FDA-regulated research. The Draft Guidance focuses especially on clarifying certain investigator supervisory responsibilities and subject protection responsibilities because, during inspections, the FDA has repeatedly identified instances of non-compliance with them. You may want to use this Guidance to build your own "preparedness" checklist. The Guidance helps to clarify such questions as:
  
  
  • What is the appropriate delegation of study-related tasks?
    Your staff must be qualified by education and experience to perform delegated tasks, especially clinical tasks. You should identify, in writing, the education or training that qualifies each staff member to perform the delegated tasks. You should have a back-up plan for who will conduct study procedures in the event that a staff member is unavailable due to vacations or illness, or if a staff member leaves. For forms that can be used to delineate staff roles in your study, go to Useful self assessment checklists.
    
    
  • What is adequate training?
    Your staff must understand the protocol and regulatory requirements and have a plan for training staff. You must anticipate staff turnover and how you will adequately train replacement staff. Here is a sample Staff Training Log that can be tailored to your study.
    
    
  • What constitutes adequate supervision of an ongoing trial?
    You must have a detailed plan (such as SOPs) for the supervision and oversight of the trial. You must have enough time to supervise the trial, especially if the staff is inexperienced or overburdened - or if the trial is complex, with a subject population that is quite ill.
    
    
  • What are the investigator's responsibilities for oversight of other people involved in the conduct of a trial?
    Even if study staff do not report directly to you, you are still responsible for assuring that they are trained and qualified. For example, if the study protocol requires testing with equipment not available at the study site, the investigator is responsible for ensuring that the outside equipment is adequate and that the equipment operators are properly certified.
    
    
  • What is "reasonable medical care" necessitated by participation in a clinical trial?
    Subjects may suffer adverse events or need attention for intercurrent illnesses during the trial. You must be prepared to provide or to refer subjects for appropriate medical care.
    
    
  • What is "reasonable access to medical care?"
    You must be readily available to subjects who are participating in a risky trial, e.g., of a drug with significant toxicity potential.
    
    
  • What sort of protocol violations present unreasonable risks to human subjects?
    You must strictly adhere to the inclusion/exclusion criteria that are specifically intended to exclude subjects for whom the study drug or device poses unreasonable risk.

Useful self-assessment checklists

• Researcher Checklist for Good Clinical Practice (GCP): This tool was developed by the UW Human Subjects Division. It provides a valuable checklist, enabling you to assess whether you understand the regulatory duties and responsibilities of a clinical investigator.

Here are two sample forms for documenting the delegation of responsibilities to study staff:

• Allocation of Research Staff Responsibilities: This tool was also developed by the UW Human Subjects Division. It provides a means for documenting that research staff have been informed about their delegated duties. This tool can be tailored to fit your own study, and should be updated when staff turnover occurs or if staff responsibilities are shifted.
  
  
• Study Site Signature and Delegation of Responsibility form: This tool is similar to the "Allocation" form, above. That is, it provides a means for documenting that research staff have been informed about their delegated duties and must be tailored to fit your own study.

Responsibilities of the Sponsor-Investigator

Usually the clinical investigation of a drug or device is sponsored by the manufacturer that developed it and intends to bring it to market. In such cases, the IND or IDE filing is handled by the sponsor.

A clinical investigator may, however, serve as a sponsor-investigator. A sponsor-investigator is an individual who both initiates and actually conducts, alone or with others, a clinical trial. (Corporations, agencies, or other institutions do not qualify as sponsor-investigators.) In such cases, the IND or IDE filing is handled by the investigator, and the sponsor-investigator assumes the role and responsibilities both of an investigator and of a sponsor.

Resources for Sponsor-Investigators

FDA Web links

Below are some useful FDA links for sponsor-investigators. Note that although some of the guidance information refers to the role and responsibilities of “industry” or “companies,” when you are acting as a sponsor-investigator, these same responsibilities apply to you.

For general FDA information:

• The FDA Home Page
• Good Clinical Practice in FDA-Regulated Clinical Trials: Includes useful guidance documents and information sheets.
• The Drug Approval Application Process

For specific FDA information:

• Information for Clinical Investigators
• Investigational New Drug (IND) Application Process: Includes links to and instructions for completing Form 1571 (IND application) and FDA Form 1572) (Statement of Investigator). Also includes information about the FDA's Pre-IND Consultation Program.
• Device Advice

Other Helpful Web links

• Mentioned previously as a Useful Web resource, Module 5 of the University of Miami's CITI Good Clinical Practice (GCP) Training program includes must-read information about the responsibilities of sponsor-investigators. Information at the referenced Web site explains how to access the module.
  
  
• Another valuable resource is the Web site of the University of Minnesota's IND-IDE Assistance Program (referenced here with permission). Separate links from the Assistance Program's home page present advice about both IND and IDE applications - advice that is generally applicable for sponsor-investigators everywhere (although direct help is, of course, available only to University of Minnesota investigators). Also presented on the site are various templates (protocol writing, case report forms, self-monitoring plans, safety reports, annual reports, transmittal letters, labels, and more) that may be useful to you.

Local assistance

• A formal investigator assistance program does not yet exist at the University of Washington, but investigators may contact Assad Awan, Pharm D, for help and advice with INDs. Dr. Awan is the Director of Investigational Drug Services at Harborview Medical Center and can be reached by phone at (206) 731-5448 or by email.
  
  
• The Fred Hutchinson/University of Washington Cancer Consortium's Research Trials Office has a Regulatory Affairs Office that is available to provide support and advice on investigator-initiated INDs and IDEs to Cancer Consortium member investigators.