compliance with the fda guidances on investigator responsibilities and the form 1572

Compliance with the FDA Guidances on Investigator

Responsibilities and the Form 1572

Presented by

Paul Below, CCRA, CCRTP. Below Consulting, Inc.

About the Speaker

• Clinical research consultant and GCP trainer based in Minneapolis, MN since 2003

• Involved in project management, monitoring, auditing and training for pharmaceutical and medical device client.

• Started career as a study coordinator in 1996

• ACRP CCRA since 2001 and ACRP Credentialed Trainer since 2008

• Adjunct faculty for St. Cloud State University’s Masters Degree Program in Applied Clinical Research

• Past President of the Minnesota Chapter ACRP

Learning Objectives

• Describe the general purpose and history of development of the FDA’s Investigator Responsibilities Guidance for Industry

• Define what the FDA considers to be adequate supervision of study staff and other third parties

• Explain what the FDA considers to be the appropriate delegation and adequate training of study-related tasks

• Examine investigator responsibilities outlined in the guidance for protecting study subjects

• Discuss the FDA’s expectations for how to complete the Form FDA 1572

Copyright © 2011 - P. Below Consulting, Inc. 3

Investigator Responsibilities Guidance

• Final version issued in October 2009

• Initial draft issued May 2007

• Applicable to clinical trials of drugs, biologics, and medical devices

4Copyright © 2011 - P. Below Consulting, Inc.

Guidance Purpose

To clarify for investigators and sponsors the FDA’s expectations concerning investigator responsibilities:

To supervise a clinical study in which some study tasks are delegated to employees or colleagues of the investigator or other third parties

To protect the rights, safety, and welfare of study subjects


About Guidance Documents

• Represents FDA's “current thinking” on ways to comply with the regulations

• Not legally binding• Can use an alternative approach if it satisfies the regulations• The use of the word “should” means something is suggested

or recommended but not required• Non-compliance should not be cited in a FDA Form 483

(“Notice of Inspectional Observations” or written list of discrepancies noted during an FDA inspection)


http://www.fda.gov/RegulatoryInformation/Guidances/ucm122046.htm 7

Investigator Responsibilities

Guidance History

Copyright © 2011 - P. Below Consulting, Inc.

FDA Guidance – Guideline for the Monitoring of Clinical Investigations (January 1988):

“The monitor should visit the investigator at the site of the investigation frequently enough to assure that … the investigator is carrying out the agreed-upon activities and has not delegated them to other previously unspecified staff.”

Guidance History


Guidance History

FDA Guidance – A Guide to Informed Consent – Information Sheet (January 1998):

“The clinical investigator is responsible for ensuring that informed consent is obtained from each research subject before that subject participates in the research study. FDA does not require the investigator to personally conduct the consent interview. The investigator remains ultimately responsible, even when delegating the task of obtaining informed consent to another individual knowledgeable about the research.”


Guidance History

FDA Guidance – ICH Guidelines for Good Clinical Practice (May 1997):

“The investigator should maintain a list of appropriately qualified persons to who the investigator has delegated significant trial-related duties” (Section 4.1.5)

“The investigator should ensure that all persons assisting with the trial are adequately informed of the protocol, the investigational product(s), and their trial-related duties and functions” (Section 4.2.4)


Guidance History

Specific tasks indicated in ICH GCP that can be delegated:

Making trial-related medical decisions

Documenting and explaining protocol deviations

Performing investigational product accountability

Explaining correct use of investigational product and check that subject is following instructions properly

Obtaining informed consent

Making CRF corrections


Recent Warning Letter

“According to the trial staff list for Protocol X, your clinical research coordinators … were delegated responsibilities, including but not limited to, affirmation of inclusion and exclusion criteria and assessment of adverse events, serious adverse events, and study endpoints. You had informed the FDA investigator that as you were inexperienced in conducting clinical trials, you mainly relied on your clinical research coordinators to conduct the study and complete the study’s paperwork. In FDA’s review of the resumes of Mr. X and Ms. X, … these individuals did not appear to be qualified, certified, or significantly medically trained and licensed to be independently making judgments related to determination of eligibility of subjects for enrollment into the study and/or making the determination as to whether or not adverse events were related to the use of the investigational drug.”



“The protocol specified that the person obtaining informed consent must be sufficiently trained on medical issues, so that questions could be adequately addressed. The protocol specifically required that this person have an M.D., Ph.D., or RN degree. .. For all subjects enrolled into this study (Subjects 1001-1008 and 1010-1013), the informed consent document and the assent form for children 10-17 years of age were not obtained by an MD, PhD, or RN, as required by the protocol.”

“For Subjects 1001-1007, X was not administered by the principal investigator or a sub-investigator, as required by the protocol. Instead, the X was administered by a study coordinator, contrary to the criteria specified in the protocol.”



“We note that Ms. X served as the primary study coordinator … and was terminated from your site as of December 4, 2006. We wish to emphasize, however, that as the clinical investigator, it was your ultimate responsibility to ensure that the studies were conducted properly and in compliance with FDA regulations to protect the rights, safety, and welfare of study subjects. We note that the monitors from two different studies notified you on multiple occasions that Ms. X was failing to follow the protocols and/or incorrectly completing certain study-related tasks. Among the tasks identified by the monitors were those for which she had not been delegated authority. The fact that you permitted her to continue as study coordinator despite these repeated notices indicates your failure to conduct the study in accordance with the investigational plans and the lack of adequate supervision on your part.”



“In a written affidavit signed by you during the FDA inspection, you noted that you thought the training provided by the monitors to you and your study coordinators was sufficient, and that if there were problems, the monitors would let you know. You further asserted that you did not know that you had to supervise the study and ensure that the study coordinators were correctly doing such things as completing source records and case report forms, filling out adverse event and hospitalization forms, and notifying the IRB and sponsor on time.”


Supervision of the Study



• Drugs/Biologics (21 CFR Part 312): Investigators commit themselves to personally conduct or supervise the investigation

• Medical Devices (21 CFR Part 812): Investigators commit themselves to supervise all testing involving human subjects



• Common practice for investigators to delegate certain study-related tasks to employees, colleagues or other third parties (entities not under direct supervision of the investigator)

• When tasks are delegated, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated

• The investigator is accountable for regulatory violations resulting from failure to adequately supervise the conduct of the clinical study


Adequacy of Supervision

FDA focuses on four major areas to assess “adequacy”: Are individuals who are delegated tasks qualified to

perform such tasks?

Did the study staff receive adequate training on how to conduct the delegated tasks and were provided with an adequate understanding of the study?

Is there adequate supervision and involvement by the investigator in the ongoing conduct of the study?

Is there adequate supervision or oversight of any third parties involved in the conduct of the study?


Appropriate Delegation

Individuals delegated tasks should be qualified by education, training, and experience (and state licensure where relevant) to perform the delegated tasks



Appropriate delegation is especially important for tasks considered clinical or medical in nature such as:

Evaluating study subjects to assess clinical response to an investigational therapy (i.e., global assessment scales)

Providing medical care to subjects during the course of the study



• Most clinical/medical tasks require formal medical training and may also have licensing or certification requirements (may vary by jurisdiction such as states or countries)

• Licensing requirements should be taken into account when delegating specific tasks

• In all cases, qualified physician (or dentist, when appropriate) should be responsible for all trial-related medical decisions and care (ICH GCP section 4.3.1)


Texas Statutes Scope of Practice

• Physicians: Texas Occupations Code (151-167). Special section on delegation of certain medical tasks (Chapter 157). Available at: http://www.statutes.legis.state.tx.us/Docs/OC/htm/OC.157.htm

• Physician Assistants: Texas Occupations Code (204.202) – Scope Of Practice. Available at: http://law.onecle.com/texas/occupations/204.202.00.html


Texas Statutes Scope of Practice

• Advanced Practice Nurses: Guidelines for Determining APN Scope of Practice. Available at: http://www.bon.texas.gov/practice/apn-scopeofpractice.html

• Registered Nurses: Texas Administrative Code (Rule 217.11) – Standards of Nursing Practice

• General nursing practice information available at: http://www.bon.texas.gov/practice/gen_practice.html



During inspections of sites, FDA has identified the following tasks that have been inappropriately delegated:

Screening evaluations including obtaining medical histories and assessment of inclusion/exclusion criteria

Physical examinations

Evaluation of adverse events

Assessment of primary study endpoints

Obtaining informed consent



• The protocol may specify the qualifications of individuals to perform certain protocol-required tasks

• The protocol must be followed even if state law permits individuals with different qualifications to perform the task



If the state allows nurse practitioners or physician assistants to perform physical examinations under supervision of a physician, but the protocol specifies that physical examinations must by done by a physician, then a physician must perform such exams.



• Investigators should maintain a list of appropriately qualified persons to who significant trial-related duties have been delegated (ICH GCP section 4.1.5)

• The list should also include: Description of the delegated tasks

Identification of dates on involvement in the study

Identification of the training that individuals have received that qualifies them to perform the delegated tasks (can refer to an individual’s CV on file)

• Separate lists should be maintained for each study conducted


Appropriate Training

Investigator should ensure there is adequate training for all staff participating in the study including new staff hired after the study has begun to meet unanticipated workload or replace staff



Staff should be:

Familiar with purpose of the study and protocol

Have adequate understanding of the specific details of the protocol and investigational product needed to perform assigned task

Aware of regulatory requirements and acceptable standards for conduct of clinical trials and human subjects protection

Competent to perform or trained to perform delegated tasks

Informed of pertinent changes during conduct of trial



If the sponsor provides training, the investigator should ensure that their staff receive the sponsor’s training or receive the training materials from that training that is pertinent to the staff’s role in the study


Supervision of Study Conduct

• Each study site should have a distinct individual identified as the investigator who has supervisory responsibilities

• Investigators should have sufficient time to conduct and supervise the study (ICH GCP section 4.2.2)



• Sub-investigators should report directly to the investigator

• The Investigator should have authority to terminate the sub-investigator’s involvement in the study

• Sub-investigators should not be delegated the primary supervisory responsibility for the site



The following factors may affect the ability of the investigator to adequately supervise the study:

Inexperienced staff Demanding workload for staff Complex trials Large number of subjects enrolled at the site Seriously ill subject population Conducting multiple concurrent studies Conducting study from a remote location or at

multiple sites


Supervision Plan

The investigator should develop a plan for supervision that might include the following elements:

Routine meetings with staff to review trial progress, adverse events, and protocol amendments

Routine meetings with sponsor’s monitors Procedure for the timely correction and documentation

of problems identified Procedure for documenting or reviewing performance

of delegated tasks in a satisfactory and timely manner (e.g., observation of the performance of selected assessments or independent verification by repeating selected assessments)


Supervision Plan

Investigator plan (continued): Procedure for ensuring that the consent process is

conducted per 21 CFR part 50 Procedure for ensuring that information in source

documentation is accurately captured on CRFs Procedure for dealing with data queries and

discrepancies identified by the sponsor monitor Procedure for ensuring study staff comply with the

protocol, adverse event assessment and reporting requirements

Procedure for addressing medical and ethical issues that arise during the course of the study in a timely manner


Supervision of Third Parties

• Investigators should take steps to ensure that staff not under their direct employ (e.g., site management organization [SMO] employees) are qualified and have received adequate training

• Investigators should be “particularly cautious” when SMOs complete source documents, CRFs, investigational product accountability records and IRB correspondence)

• A sponsor who retains an SMO shares responsibility for the quality of work performed by the SMO



If outside staff performance of study-related tasks is not adequate and cannot be made satisfactory, the investigator should document the deficiencies in writing to the staff member’s supervisor and inform the sponsor



• Many critical study functions are performed by parties not involved in direct patient care or under direct control of the investigator such as lab testing, radiologic assessments, and ECGs

• When these services are retained by the sponsor, the sponsor is responsible for ensuring that these parties are competent and are fulfilling their study responsibilities



When an investigator retains outside services for testing with special equipment or expertise not available at the site, the investigator should take steps to ensure that the facility is adequate (e.g., has required certifications or licenses)



• The investigator may also institute procedures to ensure that records coming from outside facilities are authentic and accurate particularly if the assessments are crucial to the evaluation of efficacy, safety of an invention, or decision to include or exclude subjects

• Investigators should carefully review external reports for results that are inconsistent with clinical presentation

• If investigators detect possible errors or that results from a central laboratory or testing facility may be questionable, they should contact the sponsor immediately


Medical Device Considerations

Field clinical engineers (device sponsor employees) should be supervised by the investigator because they have the potential to bias the outcome of the study, affect the quality of research data, and/or compromise the rights and welfare of the human subjects


Medical Device Considerations

• The field clinical engineer’s activities should be described in the protocol

• If the field clinical engineer has face-to-face contact with subjects or conducts activities directly affecting the subject, those activities should be described in the informed consent


Protecting Study Subjects


Primary Physician Notification

• The investigator should inform the subject’s primary physician about the subject’s participation in the trial (if they have a primary physician and agree to the disclosure)

• ICH GCP section 4.3.3 previously only “recommended” the above


Study Related Medical Care

• During the subject’s participation, the investigator or designated sub-investigator should ensure that reasonable medical care is provided to the subject for any adverse event, including clinically significant laboratory values, related to trial participation (ICH GCP section 4.3.2)

• Subjects should receive appropriate medical evaluation and treatment until resolution of any emergent condition related to the study intervention even if the follow-up period extends beyond the end of the study


Non-Study Related Medical Care

• The investigator should inform the subject when medical care is needed for conditions or illnesses unrelated to the study intervention or the disease under study (ICH GCP section 4.3.2)


• The subject should also be advised to seek appropriate care from the physician who was treating the illness prior to the study or assist the subject in obtaining needed medical care

Investigator Availability

• Investigators should be available to subjects during the study for medical care related to study participation

• “Particularly important” when the study drug has a significant toxicity or abuse potential

• For study drugs with potentially fatal toxicity, the investigator should be readily available by phone or other electronic communication 24 hours a day and in reasonably close proximity to subjects (not in another state or on prolonged travel)


Investigator Availability

• Subjects should be clearly educated on the possible need for investigator contact and provided all contact information (phone numbers, email addresses) in writing

• Prior to undertaking a study, prospective investigators should consider their availability to the extent needed given the nature of the trial

• During any period of unavailability, the investigator should delegate responsibility for medical care to a specific qualified physician who will be readily available to subjects during that time


Protocol Violations and Subject Risk

• Failure to comply with the protocol sometimes exposes subjects to unreasonable risks


• For example, enrolling subjects who violate certain study inclusion & exclusion criteria or failing to perform safety assessment intended to detect drug toxicity are considered failures to protect the rights, safety and welfare of human subjects

• Investigators should minimize these risks by closely adhering to the study protocol

Form FDA 1572


Form FDA 1572 Guidance

• Final version issued in May 2010

• Applicable to clinical trials of drugs and biologics (but NOT medical devices)


What is the Form FDA 1572?

An agreement signed by the investigator to provide certain information to the sponsor and assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic


When should the 1572 be signed by the investigator?

• Whenever a sponsor selects a new investigator to participate in a clinical trial being conducted under an IND, the sponsor must obtain a completed and signed 1572 before permitting the investigator to begin participation in the trial (21 CFR 312.53(c))

• The investigator should sign the form only after being given “enough information” to be informed about the study and to understand their commitments

• Having “enough information” typically means that the investigator has read and understands the protocol and investigator’s brochure and is familiar with the human subjects protection and GCP regulations


Must the investigator be a physician?

• NO - The regulations do not require that the investigator be a physician

• Sponsors are required to select only investigators qualified by training and experience as appropriate experts to investigate the drug (21 CFR 312.53(a))

• In the event the clinical investigator is a non-physician, a qualified physician (or dentist, when appropriate) should be listed as a subinvestigator for the trial and should be responsible for all trial-related medical (or dental) decisions


What are the minimum qualifications of an investigator?

• The regulations do not specify the minimum requirements nor do the regulations specify what qualifications an investigator must have in order to be considered qualified by training and experience to conduct a clinical investigation

• Sponsors have discretion in determining what qualifications, training, and experience will be needed

• Qualifications should include familiarity with human subject protection regulations (i.e., 21 CFR Parts 50 and 56) and GCP regulations (i.e., 21 CFR Part 312) and standards (e.g., ICH E6) for the conduct of clinical studies


Does the 1572 need to be submitted to FDA?

• NO - Although the sponsor is required to collect the 1572 from the investigator, FDA does not require the form to be submitted to the agency

• Many sponsors submit the 1572 to FDA, however, because it collects, in one place, information that must be submitted to FDA under 21 CFR 312.23(a)(6)(iii)(b)


When must a 1572 be updated?

• If there are changes to information contained on a signed 1572 (e.g., an IRB address change, the addition of new sub-investigators, the addition of a clinical research lab), the investigator should document the changes in the clinical study records and inform the sponsor of these changes, so that they can appropriately update the IND

• The 1572 itself does not need to be revised nor a new form completed and signed by the investigator. The sponsor can accumulate certain changes and submit this information to the FDA in an information amendment or a protocol amendment


Must investigators outside of the United States sign a 1572?

• If a foreign clinical study is conducted under an IND, then all FDA IND regulations, including the requirement to obtain a signed 1572, must be met

• In addition, investigators are responsible for complying with the applicable laws and regulations of the country in which the study is being conducted, regardless of whether the study is being conducted under an IND.

• FDA recommend that sponsors obtain signed, written statements from investigators acknowledging their commitment to comply with local laws and requirements


Must a new 1572 be signed when the OMB expiration is reached?

NO - There is no need to prepare and sign a new 1572 when the OMB expiration date has been reached


Does FDA expect a double-sided 1572?

• NO - Either a double-sided or two-page document is acceptable

• However, FDA recommends that if a two-page document is used that it be stapled so that there is no question about what form the investigator signed


Does the 1572 need to be typed?

• NO - It is acceptable to print the blank form from FDA’s website and hand-write or type the information onto the form

• Typed forms are preferable because they are usually more legible

• The completed form must be signed and dated by the investigator (either by hand or using an acceptable electronic method)


How should an investigator’s name appear on the 1572?

• Section #1 should contain the investigator’s full legal name (e.g., name on the investigator’s birth certificate or marriage certificate)

• Titles, degrees, and/or professional qualifications may follow the investigator’s legal name, if desired


What address should be entered into Section #1?

• The address where the investigator can be reached by mail or in person should be entered in Section #1 of the 1572

• Usually, this corresponds to the investigator’s work or business address

Can co-investigators be listed in Section #1?

• The term “co-investigator” is not defined in FDA regulations

• Under 21 CFR 312.3(b), each co-investigator is an investigator and must sign a separate 1572

• It is acceptable to have more than one investigator at a single site (each of whom has signed a 1572)


Does the CV need to be updated during a clinical study?

NO - FDA regulations do not require a CV or other statement of qualifications to be updated during a clinical study


Are CVs required to be signed and dated?

• NO - FDA regulations do not require a CV to be signed and dated

• The investigator's dated signature on the 1572 is sufficient to attest to the accuracy of the CV or other statement of qualifications submitted with the 1572


What qualifies as a research facility for Section #3?

• Section #3 is intended to identify facilities where study activities will be conducted and data will be generated

• This includes facilities where subjects will be seen and study procedures performed

• Other sites may also be listed (e.g., research lab where IP is prepared, storage facility where IP is kept, or a location where tissue specimens are collected)


If subjects are seen at more than one site, should all sites be listed?

• YES - The names and addresses of each of the study sites should be identified in Section #3

• However, if the protocol specifies that the investigative product can be administered at a subject’s home, the subjects' home addresses do not have to be listed on the 1572


What qualifies as a clinical laboratory for Section #4?

Section #4 is intended to identify clinical laboratories or testing facilities directly contributing to or supporting the clinical study


Should satellite labs doing additional testing be listed?

• If a laboratory is sending samples to a satellite or other contract labs for additional testing, it is not necessary to list these facilities

• It is only necessary to list the primary laboratory, provided that laboratory can trace the samples to each of the satellite and/or contract labs where the tests were performed


Who should be listed as a sub-investigator in Section #6?

• The purpose of Section #6 is to capture information about individuals who will assist the investigator and make a direct and significant contribution to the data

• The decision to list an individual depends on whether he/she is performing significant clinical trial-related duties


Who should be listed as a sub-investigator in Section #6?

• In general, if an individual is directly involved in the performance of procedures and the collection of data required by the protocol, that person should be listed


• If the protocol notes that each subject needs to visit a specified internist who will perform a full physical to qualify subjects for the clinical investigation, that internist should be listed in Section #6

Should research nurses or residents be listed in Section #6?

• Hospital staff, including nurses, residents, or fellows and office staff who provide ancillary or intermittent care but who do not make a direct and significant contribution to the clinical data, do not need to be listed individually

• It is not necessary to includein this section a person with only an occasional role in the conduct of the research, (e.g., an on-call physician who temporarily dealt with a possible adverse effect or a temporary substitute for any research staff)


Should residents on rotation be listed in Section #6?

• For staff residents on rotation, it may be difficult to prospectively identify those individuals who might perform specified protocol procedures or collect clinical data. Specific names of the rotational staff do not have to be listed in Section #6

• Instead, the names ofrotational individuals and the procedures they are expected to perform should be included in the clinical study records


Should a pharmacist be listed in Section #6?

• The decision about whether to list a pharmacist is a matter of judgment, dependent upon the contribution that the individual makes to the study.

• For example, a research pharmacist may prepare test articles and maintain drug accountability for many clinical studies that are ongoing concurrently at an institution.

• Because the pharmacist would not be making a direct and significant contribution to the data for a particular study, it would not be necessary to list the pharmacist as a sub-investigator in Section #6, but he/she should be listed in the investigator’s study records.


Should a study coordinator be listed in Section #6?

• Generally, a coordinator has a greater role in performing critical study functions (I.e., recruits subjects, collects and evaluates study data, and maintains study records) and making direct and significant contributions to the data


• Therefore, the research coordinator should usually be listed in Section #6 of the 1572

Are CVs necessary for sub-investigators in Section #6?

• NO - The regulations at 21 CFR 312.53(c)(1)(viii) require only that sub-investigators’ names be listed in Section #6 of the 1572

• The investigator must ensure that all associates, colleagues, and employees assisting with the conduct of the clinical investigation are aware of their obligations including complying with the IND regulations


Questions


compliance with the fda guidances on investigator responsibilities and the form 1572

Documents

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