Columbia University Medical Center (CUMC) / New York-Presbyterian Hospital (NYPH)
Investigator Initiated Research Program

Participating in clinical trials as both investigator and sponsor can be a positive and productive experience for physician researchers and study coordinators.  However, the daily study administration and collection of data can also be a challenge for the people involved.

Before beginning a trial, the investigator may have questions about preparation, documentation and reporting data. The Clinical Trials Office (CTO) is prepared to assist investigators by answering these questions.


Investigator-Initiated Clinical Trial Considerations
IND v. Non-IND Determination
FDA Study Requirements
Adverse Event Reporting for Both IND and Non-IND Studies
CTO Requirements
Summary


Investigator-Initiated Clinical Trial Considerations
  Sponsor Investigator Responsibilities
Study Setting
Study Personnel
FDA Regulations
  Sponsor Investigator Responsibilities
There are several reasons why investigators may choose to act as both sponsor and investigator of a clinical study:

  • Scientific interest in a drug or product
  • An opportunity to contribute to clinical knowledge
  • A potential for publication of study results

As an investigator acting as a sponsor, the investigator is held to the same standards and obligations as any other individual or organization that takes responsibility for and initiates a clinical investigation. These responsibilities include:

  • Writing the protocol and designing the Case Report Form
  • Monitoring the study and reviewing the source documents
  • Drug accountability
  • Submitting safety reports to the FDA
  • Complying with all applicable FDA regulations

Study Setting
Consideration should be given to the organization of your clinical site. There are a number of important issues:

  • The amount of investigator time the study will require
  • The background and training of the study coordinator
  • The involvement of sub-investigators
  • Personnel and time resources for recruiting and screening study patients

Study Personnel
To conduct the study and to meet the requirements of the protocol, identification of the individuals who will be conducting the study on a daily basis is very important.  These persons may include:

  • Research study coordinator
  • Laboratory personnel
  • Research nurses
  • A study observer trained in a specific methodology or medical specialty

In addition, at CUMC/NYPH all study personnel must be certified in Good Clinical Practices.  A discussion with the Departmental Administrator about the allocation of time for each individual who will be devoted to the study, what their specific role will be; a need for additional staff and the resources for hiring additional people are important.

In general the roles and responsibilities of the two key individuals on the study can be defined as follows:

Investigator
  • Identification of potential study patients
  • Medical responsibility for all study patients
  • Active involvement in study startup activities
  • Resource management
  • Accurate reporting of data
  • Reporting adverse drug experiences
  • Directly oversee the administration of the study drug

Study Coordinator
Usually chosen for their scientific or medical training, this individual coordinates all aspects of study implementation at the site. The primary responsibilities of the study coordinator include:

  • Patient recruitment
  • Data collection with detail orientation
  • Completion of Case Report Forms
  • Day to day problem solving

Other resources may also be needed; consideration should be given to the following:

  • Specific diagnostic or therapeutic instruments
  • Nursing service
  • Medical records
  • Radiology facilities
  • Clinical laboratory

FDA Regulations

There are well-defined regulations and guidelines from the FDA that govern the conduct of clinical investigations in the United States. These include Institutional Board Review (IRB) approval and informed consent; it is the investigator’s responsibility to comply with all stated requirements. In addition, if the study requires an IND, the investigator must also follow a number of other regulations. For example, it will be the investigator’s responsibility to communicate with the FDA and to provide, among other things, complete information regarding the investigator’s protocol, the conduct of the investigator’s study, and the experiences of patients exposed to study drug over the entire study course.

The investigator is the sponsor of the study and therefore it will be the investigator’s responsibility to comply with these regulations and guidelines. Accordingly, the investigator must refer to the code of Federal Regulations (CFR) that governs the conduct of clinical investigations. Information about the need for an IND can be found in the 21 CFR Section 312.2
IND v. Non-IND Determination
  In general a study requires an IND if it is intended to support a:

  • New indication
  • Change in the approved route of administration or dosage level
  • Change in the approved patient population (pediatric) or a population at greater or increase of risk (elderly, HIV positive, immunocompromised)
  • Significant change in the promotion of an approved drug

The FDA determines exemption status, i.e., IND or non-IND, after investigator submission of FDA form 1571. The investigator can use the FDA Investigational New Drug (IND) Guidances document for additional information.  Information on animal and previous human studies can be obtained by seeking permission from the original pharmaceutical or device company.  A company generally allows an investigator to cross reference the company’s IND/NDA.

Usually when an IND study is conducted the drug/device is provided free of charge to the patients and the investigator is not billed for the drug/device. However when conducting a non-IND study, the pharmaceutical or device company does not have to provide the drug/device, third party reimbursement may be sought and the drug/device must be deemed medically indicated.
FDA Study Requirements
  Regardless of exemption status, i.e., IND v. non-IND, all studies require the following:

Institutional Review Board (IRB): 21 CFR part 56
The IRB is an integral part of all clinical research. The FDA requires that an appropriately constituted IRB, as described in FDA regulations, review all the research documents and activities directly related to the rights and welfare of the subjects of any proposed clinical research. The FDA further requires the IRB to be sensitive to the composition and viewpoints of the community in which clinical research is to be conducted.

The CUMC IRB fulfills all regulatory requirements and CUMC faculty must submit proposals to the IRB using the RASCAL system. If an investigator needs assistance with the IRB application process, the investigator can seek advice from the Clinical Trials Office Medical Director.

IRB responsibilities include:
  • Review and approve the research protocol and patient informed consent
  • Subsequently review of the study to ensure that the rights and welfare of the study patients are protected
  • Approve the investigator’s qualifications to conduct the study
  • Approve the qualifications of any sub-investigators
  • Approve any announcements used to recruit patients
  • Approve any changes in the research protocol or patient informed consent form before the investigator or any sub-investigators put those changes into effect
  • Review of all safety reports, adverse events, and unexpected events occurring during the course of the study

Patient Informed Consent: 21 CFR part 50
Informed consent must be obtained from all study participants before any screening, treatment or study procedure required by the protocol is done.

  • All patients who have signed a consent form must receive a copy
  • Consent forms are legal documents, and must be kept as part of the permanent study records
  • The principal investigator is the person responsible to fully inform potential study patients about the trial. The written informed consent is helpful in this process, but it should not replace the principal investigator’s responsibility (or that of any sub-investigator) to directly inform potential study patients about all aspects of the trial

Case Report Forms: 21 CFR part 312.62b
Complete documentation is essential to the conduct of the clinical study. FDA regulation clearly states that the investigator is required to prepare and maintain adequate and accurate case histories for each patient, containing all observations and other data pertaining to the trial. Each case report form should contain information consistent with each patient’s medical record.

Case report forms are designed for collecting data defined in the study objectives. Information such as patient number, demographics, medical history and measurements of efficacy and adverse events are recorded on the Case Report Form at the site by investigator, sub-investigator or study coordinator. The following is an example of required documentation:

First visit: entry into each patient’s medical record should include:

  • Date the patient entered the study
  • Patient number
  • Number that correlates with the assigned study drug (if drug is randomized) and any other study drugs that the patient could possibly receive
  • Confirmation of written informed consent
  • Confirmation that the study patient met the inclusion criteria to be enrolled, but none of the exclusion criteria
  • Medications the study patient may have received: all medications should include dates begun and discontinued; the dose received; and the reason it was taken
  • Any diseases being treated and the patient’s health status prior to entry into the study

Subsequent visits: entry should include:

  • Any non-study medications added, changed or discontinued (this should include the date of any medication or dosage change)
  • Any reported complaint or adverse event, the date and time of onset; severity; duration; and any recommendations for treatment and follow up
  • The status of the patient during and after treatment with the study drug
  • Study drug taken
  • Procedures conducted (as relevant)

Final visit: entry should include:

  • a clear statement that the patient’s participation has been completed or terminated
  • the reason for the termination of treatment

Additional FDA Requirements for IND Studies
Investigators must comply with a number of additional FDA requirements before conducting a study that requires an IND. For a comprehensive list of these requirements, please refer to the Code of Federal Regulations, 21 CFR part 312. A summary is provided below.

Submit to the FDA:


Ensure the following:

  • Study Drug Dispensation: Investigators are additionally required to store study medication(s) as recommended on the label in a secured area.  The use of the CUMC Research Pharmacy is required to ensure accurate drug accounting.
  • Collecting Data and Retaining Records: Investigators must identify who will be responsible for the documentation of all data entered in patients’ medical records. Completing Case Report Forms: investigators must also identify who will complete the Case Report Forms. This process can be somewhat time consuming, because data transcription must be legible, complete and accurate.

The FDA requires that the investigator retain study documents for at least two years after the application is approved for the indication for which the drug is being investigated, or two years after the investigation is discontinued and the FDA has been notified.


Adverse Event Reporting for both IND and Non-IND Studies
  During the course of the study, the investigator must keep the FDA informed of any adverse experience associated with use of the drug that is both serious and unexpected in the following manner:

  • Telephone call within 3 days of the occurrence of any unexpected fatal or life threatening event associated with use of the drug.
  • 10 day written report to follow-up on telephone call or to report any other serious, unexpected adverse event associated with use of the drug. This report should identify all previous IND safety reports concerning a similar adverse experience, and should analyze the significance of the adverse experience in light of the previous similar reports.

Investigators should also notify the FDA of adverse events via the MedWatch system forms, available online:
CTO Requirements
  Before initiation of an IND and non-IND study, submit the following documents to the Clinical Trials Office:

  • Study protocol
  • Sample informed consent
  • The principal investigator’s curriculum vitae
  • Copy of the IRB approval letter indicating that both the protocol and the patient informed consent have been reviewed and approved
  • Copy of the IRB approval for any announcement used to recruit patients for the study
  • Signed research agreement

Investigators are also responsible for all FDA requirements noted above.  Copies of all FDA-required documentation must also be submitted to the CTO to ensure CUMC/NYPH compliance with federal standards.


Summary
  Involvement in any clinical trial requires a high degree of motivation and interest on the part of many key people. To make the experience positive and productive for all, the investigator must be able to maintain interest and motivation throughout the progress of the trial. Chances for success will be highest when time is spent assessing the following factors before beginning the study proposal process:

  • Experience
  • Environment
  • Patient population
  • Training of study personnel
  • Time commitment
  • Responsibility as a sponsor

Since a great deal of responsibility will be required of the study coordinator it is therefore critical that the study coordinator be well trained, not only in the specialty relevant to the investigator’s study, but also in the research methodology of that specialty.

Contract Research Organizations (CROs) and various hospitals offer courses in specialty-specific research methodology; general clinical trial methodology courses are available through professional groups such as Drug Information Associates, Regulatory Affairs Professionals Society, and the Association of Research Clinical Professionals at their annual and regional meetings. If you have staffing needs, it may be possible to obtain a trained research coordinator or nurse through an independent contract clinical coordinator group.

By considering these important aspects of study conduct, the investigator will strengthen the commitment of everyone involved through cooperation, communication and knowledge.


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