Meeting Principal Investigator Obligations
Form FDA 1572
The principal investigator (PI) must submit a signed and dated Form FDA 1572 (Statement of Investigator) to the sponsor before a sponsor is permitted to allow an investigator to participate in an FDA-regulated study. In signing the 1572, the investigator agrees to “… ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulation” (21 CFR 312.60). After the investigator has signed the 1572, the sponsor forwards it to FDA. This two-page document requests information specific to the investigative site and requires documentation of the qualifications of the investigator. The 1572 states the investigator’s commitments and is considered a contract between FDA and the investigator.
NOTE: Only studies conducted under an IND require a 1572. Observational and postmarketing studies do not require a 1572.
Investigational Device Regulations
Regulations differ somewhat for device studies. For example, an investigator completes an Investigator Agreement instead of a 1572. Regulations 21 CFR 50, 54, and 56 still apply, but in addition, 21 CFR 803, 812 and 814 govern investigational device studies. Specifically, investigator obligations can be found in 21 CFR 812.
- I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of
- I agree to personally conduct or supervise the described investigation(s).
- I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed con sent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.
- I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 64.
- I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the
- I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above.
- I agree to maintain adequate and accurate records in accordance with 21 CFR 62 and to make those records available for inspection in accordance with 21 CFR 312.68.
- I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
- I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312.
Study Conduct. 21 CFR 312.53( c) The investigator will personally conduct or supervise the investigations.
Note: This responsibility cannot be delegated.
Human Subject Protection. 21 CFR 312.60
The investigator is responsible for protecting the rights, safety, and welfare of subjects under the investigator’s care.
Investigator’s Brochure (IB). 21 CFR 312.53( f), ICH 4.1.2
The investigator will read the IB and understand the potential risks and side effects of the drug.
Investigational Drug. 21 CFR 312.59, 21 CFR 312.61, 21 CFR, 312.62(a) ICH 4.6
- Administer the drug only to subjects under the investigator’s personal supervision or under the supervision of a subinvestigator responsible to the investigator
- Give investigational drug only to those authorized to receive it
- Maintain adequate records of the disposition of the investigational drug, including dates, quantity, and use by subjects
- Return unused supplies of the drug to the sponsor, or otherwise provide for their disposition under § 312.59
- Ensure the person dispensing or administering drug has been properly trained to do so and is in compliance with any local or state laws (e.g., RN must have a doctor’s order to dispense or administer drugs).
- If alternative disposition is used, obtain written permission from sponsor.
Controlled Substances. 21 CFR 312.69
Store in securely locked, substantially constructed enclosure. Take adequate precautions to prevent theft or diversion into illegal channels of distribution.
Subject Medical Records and Other Source Documents. 21 CFR 312.62 (b), 21 CFR 312.68
Prepare and maintain adequate and accurate case histories that record all observation s and other pertinent data required by the sponsor. Make the records available for inspection to any properly authorized officer of FDA (21 CFR Part 312.68).
Record Retention. 21 CFR 312.62( c)
Maintain records (study files) for the study for 2 years after study discontinuation, drug approval, or drug disapproval. Note: Some studies conducted under ICH Guidelines may require storage as long as 15 years. ICH 4.9.5.
Investigator Reports. 21 CFR 312.64, 21 CFR 54, ICH 4.10,4.11, 4.13
Submit reports to sponsor at times required by regulations and the sponsor:
- Progress reports
- Safety reports: adverse events (AE) and serious adverse events (SAE)
- Final report at study end
- Financial disclosure*
*Financial disclosure applies to the investigator and all those listed on the 1572. It also applies to spouses and dependent children of those disclosing.
Adverse Experiences. 21 CFR 312.64(b), ICH 4.11
Report adverse events (AEs) to the sponsor in accordance with 21 CFR Part 312.64.
Follow sponsor requirements for expedited reporting of serious AEs (SAE). Sponsor will define SAE criteria and time frames for reporting in the study protocol.
IRB. 21 CFR 56, 21 CFR 312.66, ICH 4.4
- Assure that the IRB is in compliance with 21 CFR Part 56
- Obtain IRB initial and continuing review and approval of the study
- Promptly report all changes in the research activity and unexpected risks to subjects or others to IRB
- Do not make any changes in the research without IRB approval, except when necessary to eliminate a hazard to a subject
Protocol Compliance. 21 CFR 312.66, ICH 4.5
Changes to the protocol to be made only after receiving sponsor and IRB approval except to eliminate hazard to human subjects.
Note: If departure from the protocol does occur, the nature of the departure and actions taken to prevent recurrence must be documented in study files.
Informed Consent and IRB Requirements. 21 CFR 50, 21 CFR 56, ICH 4.8
- Obtain consent in compliance with 21 CFR 50 and 56
- Obtain IRB approval of the informed consent prior to implementing the consent process with any subject
- Obtain informed consent before enrolling subject in study
- Provide subject with sufficient time to make decision about participating in study
- Ensure subject understands language in the consent form and the consent contains all the required elements
- Consent should not contain any language that is exculpatory or waives or appears to waive any of the subject’s rights
Investigative Staff. 21 CFR 312.53( g), ICH 4.1.5
Ensure that staff are qualified, capable and trained to perform their study-related responsibilities. Keep personnel informed of study-related information and changes.
Maintain records documenting how staff members were trained to perform their duties (e.g., on-site training by team member, through their licensing, etc.) Maintain records on protocol-specific training.
Investigator Disqualification. 21 CFR 312.70
Investigator may be disqualified for repeated or deliberate failure to comply with regulations or submitting false information to the sponsor.
The primary responsibility of the study coordinator (SC) or clinical research coordinator (CRC) is to ensure the smooth progress of the study from start-up to close-out through the day-to-day coordination of study operations. Although the PI delegates many duties to the SC (and these delegated duties should be documented), the PI remains responsible, legally and ethically, and accountable for study operations and outcomes. The SC must comply with all the regulations that apply to the PI, and ensure the PI is informed and up-to-date on study subject and study-related issues.
The role and general responsibilities of the SC will depend on the allocation of responsibilities at the investigative site and the types of studies the site will be conducting. For example, some facilities may allocate budget preparation and negotiation to another individual or department. There are no specified educational requirements for study coordinators, although many have a clinical background and/o r nursing degree. The PI must be realistic about what expectations are placed on the SC, and hire the right person to fulfill those expectations. The more the SC is qualified to do (e.g., phlebotomy, blood pressures, ECGs, etc.), the less he or she will be dependent on the investigator.
Common Study Coordinator Tasks
- Marketing the site/securing studies
- Assessing the protocol
- Training study staff
- Preparing and negotiating study budgets
- Preparing and submitting documents to the IRB
- Interacting with sponsor, IRB, office staff, niche providers, other department personnel
- Tracking study budget, payments
- Maintaining regulatory files
- Documenting communication and study progress
- Documenting subject study visits
- Resolving queries on study data
- Transcribing source information to CRFs
- Coordinating, preparing for, and participating in monitoring visits, audits, and inspections
- Ordering study supplies and drug as needed
- Recruiting subjects
- Developing and coordinating advertising
- Screening subjects for eligibility
- Discussing study and conducting consent process
- Scheduling study assessments and visits
- Ensuring all visits, tests, and procedures are completed in required time intervals
- Interviewing and evaluating subjects at appropriate intervals
- Reviewing laboratory and clinical information for signs of adverse events
- Identifying, documenting, reporting and following up on adverse events
- Maintaining drug accountability
- Dispensing investigational product per protocol and under PI supervision
- Obtaining, preparing, and shipping biological specimens
- Coordinating study subject reimbursement
Hiring the Right Study Coordinator
The ideal SC is one who has clinical research experience, is able to conduct the procedures the site will be performing most frequently, and possesses the qualities listed below. When hiring an SC, write a job description identifying the minimum qualifications necessary and the activities the SC will be expected to perform. Also consider any licensure restrictions and state and local laws (e.g., is a licensed practical nurse allowed to draw blood?)
Desirable Qualities in a Study Coordinator
- Scientific/medical background
- Clinical research experience
- Strong communication skills
- Excellent organizational skills
- Good interpersonal skills with patients
- Creativity and resourcefulness
- Ability to work independently
- Good problem solving skills
- Strong conflict resolution/negotiation skills
- Ability to work flexible hours
- Good computer skills
Caution: With a competent and capable study coordinator, the PI will be able to delegate responsibilities with confidence. However, there are some study-related responsibilities that cannot be delegated:
- Overall responsibility and accountability for the study
- The Form FDA 1572 : Only the PI can sign
- Determining relatedness (causality) of an adverse event to the investigational product
- Medical decisions, diagnoses, assessments and physical These can only be done by a qualified medical doctor, unless otherwise stipulated by state law. For instance, some state licensing laws will allow a nurse practitioner or a physician’s assistant to conduct physical exams. Although the law may allow it, some sponsors will want only a qualified physician to conduct physical exams.