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Regulations in Clinical Research:

Obligations and Responsibilities of


Two of the most important individuals in a clinical trial are

investigators and sponsors. However, being such a crucial part of a
trial also brings many obligations and responsibilities. Although the
sponsor is the one who initiates and finances a trial, the investigator
is the person who conducts it. For this reason, most of the
obligations and responsibilities fall on the investigator as the person
accountable for everything that goes wrong in a trial. Learning these
obligations and knowing how to follow them is a crucial practice that
will ensure compliance in a clinical trial.

For this reason, weve decided to compose this material that will give
you a basic outline of all the rules and regulations that investigators
and sponsors should follow.

After reading this, youll be able to

- Recognize the federal obligations associated with clinical research and


- Learn which are the most common problems at clinical research sites
that occur during an FDA inspection and ways to avoid them;

- Use different methods that will ensure working with compliance with
all protocol requirements and federal regulations;

Defining an Investigator
The Investigator in a clinical trial is the person
whos responsible for the actual conducting of
the study. The study drug is distributed to the
human subjects under the Investigators
immediate directions.

Even though some trials might be led by more

than one individual (a team), still, there has to
be one person whos responsible for the
whole trial and this person will be the study

While were on the subject of defining

Can physicians be investigators?
investigators, there is one common question
YES! Physicians are allowed to be sub-investigators, but
that we feel deserves an answer:
they will only perform the procedures for which they
have the necessary knowledge and medical expertise. So,
not only medical doctors, but also physicians can be

Defining a Sponsor-
Defining a Sponsor
The sponsor of a clinical trial can be not In some cases, one individual can be both
only an individual, but also a company, the initiator of a study and the person
institution, or an organization (such as a who conducts it. This individual will be
CRO) which firstly initiates, and then called a sponsor-investigator. When this is
manages and/or finances the trial. As the case, that individual takes the tasks,
such, the sponsor is usually not the one obligations, and responsibilities of both
who actually conducts the research. This roles - sponsor and investigator. [21 CFR
role is usually carried out by the 312.3]
investigator. Later, well talk more about
the tasks and responsibilities of sponsors
in a clinical trial.

Clinical Studies Legal Framework

Federal Food, Drug, and Cosmetic Act (FD&C Act) - represents a set of
laws which gives authority to the FDA (US Food and Drug Administration) to
supervise, oversee, and inspect the safety of food, drugs, and cosmetics.
- Section 505(i) is where the FDA is given a statutory authority to supervise
and oversee clinical studies in order to test and inspect their effectiveness
and safety.

CFR (Code of Federal Regulations) - a set of regulations under Section

505(i) which outline the authority of the FDA over the clinical studies
conduct. In these regulations are also included:
- Investigator responsibilities;
- Sponsor responsibilities;

Other guidances - as advice that will help investigators and sponsors to

work with compliance and conduct the study according to all regulations;

Main Investigator Responsibilities

As weve said before, clinical investigators are the people who carry out and conduct the
actual research, and as such they have a great number of obligations and responsibilities
to fulfill. Here are some of the most important investigator responsibilities in a trial:


Making sure that the whole
research/investigation is being
conducted in accordance/compliance Ensuring and protecting the rights,
with: well-being, and safety of human
- Form 1572 - Signed Investigator subjects;
- Investigational plan;
- All applicable regulations (below);

Main Investigator Responsibilities


Making sure that the investigational

drugs are controlled; #4

Controlling and making sure that all

requirements regarding reports,
approval, and IRB submission and
#5 review are met, according to 21 CFR 56;

Making sure that all the informed

consent forms are properly obtained
in accordance with 21 CFR 50;

Main Investigator Responsibilities


Keeping/retention of records (21 CFR

- Records of drug disposition; Creating Investigator reports according to
- Case histories; 21 CFR 312.64:
- Relevant data on each subject that - Progress reports which are given to
received the study drug; the sponsor;
- Relevant data on each employee that - Safety reports (reporting any less
controls the investigation; serious adverse events according to a
- (keeping the data 2 years after the previously specified timetable as well
date when the marketing application as urgent reports for any serious or
is approved for the drug - only for the complicated adverse events);
indication that it was researched for); - Giving a final report to the sponsor;
- (keeping the data 2 years after a - Giving a financial disclosure to the
discontinued investigation); sponsor according to 21 CFR 54;
Main Sponsor Responsibilities

According to 21 CFR 312.50, sponsors are responsible for:

Choosing and selecting an

investigator that has the proper Keeping/maintaining an effective IND;
qualifications to lead the trial;

Providing all the necessary Making sure that research is being

information to investigators in conducted according to the general
order to be able to properly investigational plan;
conduct the investigation;

Making sure that both the

Making sure that the whole investigator and the FDA are timely
investigation is properly and informed of any important/relevant
consistently monitored; new adverse events/risks to subjects;

Investigators and the FDA

The FDA has certain expectations that the Investigator must follow.

The most important and basic FDA expectation is

Regulations (CFR)!

Compliance with the CFR means to learn, know, and adhere to all
clinical investigator regulations, and to learn, understand, and
respect all clinical investigator responsibilities.

FDA Expectations

FDA Expectations: Study Oversight

Supervision on how the study is being conducted;

Training of all the study staff;
Delegation of study tasks as appropriate;
Oversight of third parties involvement;

FDA Expectations: Protecting the Rights, Welfare, and Safety of Subjects

Avoid the exposure of subjects to redundant and unneeded risks;

Facilitate and provide medical care for any issues that arise from study participation (adverse events);
Provide medical care for other non-study-related medical problems that can occur during the study;

Statement of Investigator
Form FDA 1572

Investigator Commitments on 1572:

- Notify and inform all subjects that the drugs

will be used for investigational purposes;
- Always conduct or supervise the investigation This statement notes:
- Make sure that all the individuals who are No investigator may participate in
working and assisting with the study conduct an investigation until he/she provides
are always informed of their appropriate the sponsor with a completed, signed
obligations; Statement of Investigator, Form FDA
1572 [21 CFR 312.53(c)].

Investigator Commitments on 1572:

- Ensure that you always follow the exact protocol and do not make any changes before
informing the sponsor, unless human subjects are at risk;
- Make sure that the subjects understood and signed the Informed Consent Form (21 CFR Part
50), ensure IRB review, reports, and approval (21 CFR Part 56);
- Inform the sponsor about any adverse events (21 CFR 312.64); read/understand the IB;
- Ensure that all records are maintained adequately and accurately (21 CFR 312.62) as well as
available for future inspections according to 21 CFR 312.68;
- Ensure the initial and all the other reviews by the IRB and inform them of any research
changes or unexpected issues that could put human subjects at risk, and dont make any IRB-
unapproved changes, unless if its urgently needed to avoid hazards to subjects;
- Work/act in accordance to all other requirements in 21 CFR 312;

Do you need a Form FDA 1572?

This is a common question asked by many foreign clinical studies. Below, youll see the three most
common cases regarding the Form FDA 1572.

A clinical study conducted outside of the U.S. and is not under an IND (investigational new drug

A clinical study conducted outside of the U.S. but is under an IND - THE INVESTIGATOR HAS TO SIGN A
1572 (along with respecting all other FDA IND regulations);

A clinical study with a local law prohibiting the 1572 - FDA WILL EXPECT THAT THE SITE OPERATES AS A

ICH GCP - E6 Good Clinical Practice: Consolidated Guidance

Good Clinical Practice or GCP represents an

international quality standard.

In the case of clinical trials and their safety on

human subjects, GCP follows the guidelines

ICH GCP - E6 Good Clinical Practice: Consolidated Guidance

As the Guideline itself declares:

The guideline was developed with

The objective of this ICH GCP Guideline is to
consideration of the current good clinical
provide a unified standard for the European Union
practices of the European Union, Japan, and
(EU), Japan and the United States to facilitate the
the United States, as well as those of Australia,
mutual acceptance of clinical data by the
Canada, the Nordic countries and the World
regulatory authorities in these jurisdictions.
Health Organization (WHO).

This guideline should be followed when The principles established in this guideline may
generating clinical trial data that are also be applied to other clinical investigations that
intended to be submitted to regulatory may have an impact on the safety and well-being of
authorities. human subjects.

Differences Between FDA regulations and E6 ICH GCP

Sponsor responsibilities: ICH E6

contains more details regarding
monitoring and QA in clinical trials
when compared to FDA regulations;
Signing the informed consent
form: In this area, the FDA
Delegation of activities related to the regulations dont require that
investigational drug: While the FDA the person who conducts the
has no regulation regarding such informed consent process signs
activities, the ICH permits the the form, while ICH-GCP does
investigator to delegate the require this action.
dispensing of study drugs, counseling
of patients, and drug accountability to Delegation of informed consent: The
an appropriate individual; FDA has no specific regulations when it
comes to investigators who delegate
informed consent activities or in other
IRB area: In this section, FDA words - it does not require the
regulations are more investigator to personally conduct the
detailed and with more consent interview. However, ICH E6
requirements; does allow investigators to delegate the
informed consent process to an
appropriate person.
Differences Between FDA regulations and E6 ICH GCP


GCP (Good Clinical Practice) as an official quality standard in all FDA-regulated trials is not
equivalent to good clinical practice in the sense of caring for patients. An example for this are the
FDA requirements in regards of drug accountability, following of the study protocol,
recordkeeping, etc.

Investigators should be careful of the following:

FDA-regulated research standards

Clinical care of patients standards

Academic research standards
Back in History: The Thalidomide tragedy (1961-1962) - A Lesson on
Drug Safety

Thalidomide is a drug which was first introduced in the post-war

period mostly as a safe sedative (among other conditions). This
drug was first spread on the German market, but soon after it also
entered other countries as well as the U.S. It even started selling
as an over-the-counter drug. The tragedy here is that it was also
presumed to be safe for the pregnant mother and her unborn
child, especially once the drug was promoted to help with
morning sickness. However, this wasnt the case. In 1961, doctors
around the globe started associating Thalidomide with birth
defects in babies whose mothers were taking this drug during
pregnancy. Thalidomide caused approximately 10.000 babies
(reported cases) to be born with phocomelia (limbs
malformation), out of which only 50% survived. This tragic case
was the first step that led to a more strict and regulated drug

Back in History: The Thalidomide tragedy (1961-1962) - A Lesson on
Drug Safety

The Food, Drug and Cosmetic Act of 1938 was now proved to have a huge loophole - companies being able to
distribute still unapproved drugs for experimental purposes. This Act also didnt require that the patients are
informed of the fact that a drug still holds an investigational status nor did it require the FDA to be informed of
this experimental use. Another loophole area is the fact that this Act didnt require any kept records such as
keeping track of distribution of the drug. And lastly, the Act didnt require any demonstration of the
effectiveness of a certain drug.

Actions taken to Regulate the Approval Process of Drugs

Kefauver-Harris Drug Amendments IND Regulations of 1963

Act in 1962

Requirements: Requirements:
- FDA has to be informed before a clinical - Current framework of clinical
trial is conducted; research was created;
- FDA is allowed to inspect company - Investigators participating in clinical
records related to clinical research and trials have to be qualified and
development; possess the required scientific
- Drug approval will be now based on training and experience;
both efficacy and safety; - All trials have to be controlled and
- Authority and rulemaking over adequate;
Investigational New Drugs; - Informed Consent forms are
- Rulemaking authority over clinical trials required for all human subjects who
and research; will participate in a clinical trial;
- FDA has the power to stop clinical trials; - Keeping of records is now an
The Investigator as the Person in Charge at the Site

Many parties interested in starting a clinical research site are always wondering who is the person in charge at the
site. We are here to tell you that this person is the investigator!

Not only that the investigator is in charge at the clinical research site, but hes also responsible and held
accountable if things go wrong!

Although sponsors are allowed by the FDA to delegate their actions to CROs (contract research organizations,
investigators are not allowed to delegate their responsibilities and tasks to other outside organizations, individuals,
or site staff.

If the investigator isnt doing his/her job properly, or is delegating tasks that should be performed personally, the
FDA will give penalties for noncompliance (posted on the FDA website). These penalties can be:
- Warning Letters;
- Disqualifications/Restrictions/Debarments;
- Criminal prosecutions/prison/fines;

FDA and ICH requirements for documentation
submitted to the IRB

FDA requirements: ICH requirements:

- Complete documents that the investigator - All written information distributed to subjects;
receives (the protocol, investigators brochure, a - Informed consent forms;
sample of the informed consent form, all - Protocol and all amendments;
advertising materials that are to be distributed); - Advertisement materials;
- Progress reports; - Investigators Brochure;
- Reports of any injuries to subjects; - Information regarding payments/compensations
- Reviewed research proposals and any scientific to subjects;
evaluations; - Current CV and qualifications of the investigator;

Reporting Clinical Trial Results
( )

The U.S. Public Law 110-85 states that a responsible Form FDA 3674 (represents a Certification of
party (usually the sponsor or PI) should register and compliance with some FDA submissions):
report any results of so-called applicable clinical trials
on . anualsForms/Forms/UCM048364.pdf

More information: es/ucm125335.htm

An FDA-required statement in the informed consent:

For more questions regarding registration and results
of clinical trials - NLM Helpdesk:

For compliance and/or enforcement: 25

Conduct sensitive research activities personally!

Supervise all research activities personally!
Respect and follow the current study protocol!
Make sure that everyone who assists the conducting of the study knows their obligations!
Meet all informed consent requirements according to 21 CFR 50 as well as all requirements
concerning IRB review, reporting, and approval!
Always notify the study sponsor AND the IRB in advance and get their approval if you wish to
make any protocol changes!
Make sure that you possess a signed informed consent form for every human subject thats
participating in your trial!
Inform the sponsor about any adverse events that might occur during the study conduct!
Always keep and maintain proper and accurate records and have them ready for inspection
at all times!
Respect every single requirement in 21 CFR 312!
Finally, report all financial worries and interests to the sponsor!


Lose or delete original data entries!

Delegate sensitive and important activities to non-physicians (activities that can
compromise the study participants or protocol)!
Allow any changes to data without a reason why or without checking the originals!
Backdate any informed consent forms and/or signatures!
Make protocol revisions without a written approval from sponsors!
Neglect/omit to secure an IRB approval of all consent form revisions!
Ever use study staff as subjects (participants) in a study!

Compliance vs Non-Compliance: Inspections and Audits at the Site
Compliance vs Non-Compliance: Inspections and Audits at the Site

According to Section 505(k)(2) of the Food, Drug and Cosmetic Act, the
FDA is granted the rights to access, copy, and verify all necessary
records in a clinical trial!

21 CFR 312.68 states that:

An investigator shall upon request from any properly

authorized officer or employee of FDA, at reasonable times,
permit such officer or employee to have access to, and copy
and verify any records or reports

Compliance vs Non-Compliance: Inspections and Audits at the Site

Most Common Questions Asked During an Audit/Interview

(Authority Delegation - WHEN/WHERE/WHO)

- Staff training;
- Informed consent forms of study subjects;
- Pre-screening/Screening of subjects for enrollment;
- Test article receipt - administration/handling/return;
- Reports/safety reports;
- Transcription of data;
- Archiving data;
- Laboratory;

Compliance vs Non-Compliance: Inspections and Audits at the Site

Most Common Slips that Cause Non-Compliance Outcomes - Classification of Compliance

- Lack of supervision and oversight; During an inspection, studies can be separated into
- Insufficient or improper training of study three different groups depending on their level of
staff; compliance with regulations. The results of your
- Inability to protect the safety and well-being inspection can be classified as:
of study subjects;
- Poor investigator involvement in the study; - NAI (no action indicated): working in
- Study staff and investigator being compliance;
overworked, thus unable to perform at their - VAI (voluntary action indicated): small deviation
best; that requires voluntary correction where
- OAI (official action indicated): major/critical
non-compliance which will require FDA

Compliance vs Non-Compliance: Inspections and Audits at the Site

Regulatory Actions for Non-Compliance

- Warning letter;

- Notice of Initiation of Disqualification

Proceedings and Opportunity to Explain

- Disqualification of clinical investigator;

- Criminal Investigation by Office of Criminal

Investigations (OCI);

- Debarment;

Form FDA 483

After the inspection, the FDA will either estimate that theres no action indicated or youll be given an FDA Form 483.
On this form, it is noted that it:

...lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional
observations, and do not represent a final Agency determination regarding your compliance.

The person who receives this FDA Form 483 will have to send back a response to the FDA. This response should be
submitted within 15 days of receiving the 483, no matter how many items and observations it includes. The response
submitted based on this Form should contain either a specific correction timeline or a further explanation and
clarification of the FDA requirements.

By providing the FDA with a good response on the 483, you might be able to prevent receiving a warning letter!

Even though the 483 is to be taken seriously in order to prevent any further complications, it does not represent a
final FDA decision on whether the FD&C Act has been violated in any way. The FDA Form 483 together with all
responses from your site will be then gathered and the FDA will decide if there should be any other actions taken.

Warning Letter

The FDA Warning Letter is an official document that usually follows an inadequate response of FDA Form 483. This
document is defined as:

...a correspondence that notifies regulated industry about violations that FDA has documented during its
inspections or investigations. Typically, a Warning Letter notifies a responsible individual or firm that the Agency
considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug,
and Cosmetic Act (the Act), its implementing regulations and other federal statutes. Warning Letters should only be
issued for violations of regulatory significance, i.e., those that may actually lead to an enforcement action if the
documented violations are not promptly and adequately corrected.

Poor Warning Letter Responses

After this letter is received, you should always aim to give the best answer thats supported by facts.
However, in practice, there have been many wrong responses to this Warning Letter. Heres what not to
- Blaming the study monitor for issues regarding IRB approval;
- Blaming the study coordinator for activities that belong to you as the investigator;
- Enrollment of study participants/subjects based on your (as an investigator) personal opinion,
when these subjects do not meet inclusion criteria;
- Submitting false information to sponsors (such as reporting that youve enrolled subjects who
never showed up, changing and manipulating other subject data, etc.);
- Enrolling ineligible subjects (especially in trials where more serious drugs are involved - oncology
trials) - this can cause serious adverse events and even death;
- Altering the medical records of patients;


Disqualification of the Investigator

According to 21 CFR 312.70, an investigator can be disqualified when:

He/she fails to comply

with FDA requirements The FDA then
repeatedly and/or provides a chance for
deliberately; formal hearing;

The FDA gives timely notice Finally, when all of these options
to the investigator for an are exhausted, the investigator can
informal hearing in order to be disqualified and lose the
explain his/her actions; eligibility to receive investigational
drugs in the future;

Case Study: Paul H. Kornak - Jail time for fraud

Kornak was a VA (Veterans Administration) researcher and study coordinator at the Stratton VA
Medical Center in Albany, New York. He was conducting oncology trials and was altering patients
medical records and blood tests so that they can be enrolled in his trials. However, one of the
patients had a severely impaired liver and kidney function, so when he received the harmful oncology
drugs he died. For this crime, as well as many other fraudulent actions, Paul Kornak was sentenced to
71 months (almost 6 years) in prison, as well as debarred from any further clinical research. His
associate, Dr. Holland, was also given 5 years probation.

Case Study: Paul H. Kornak - Jail time for fraud

Throughout his years of conducting research,

Kornak admitted to altering a minimum of 27
patient records. Furthermore, Kornak was also
posing as a physician, while in reality he never
finished his medical education and training.

This case study should serve as the perfect example

of what not to do to all researchers out here. Every
researcher should know that when it comes to
patients safety and fraud, theyre going to be held
personally accountable and responsible for
everything that goes wrong.

Ensuring Quality Data and Subject Safety in Trials

- Be involved and supervise the trial;

- Select and employ qualified staff;
- Provide proper training to staff members;
- Make sure that your staff only performs activities theyre qualified for;
- Ensure that sub-investigators and staff are involved;
- Consider the human factor when handling systems;
- Try to not handle data too often in order to avoid human errors;
- Try to avoid conflicts of interest;
- Make sure that you estimate the ability of both staff and systems to comply with: protocols, subject
visits, FDA inspections, EDC systems, laboratory testing and data, archiving data, reports to the
sponsor, recordkeeping, drug accountability, etc.;
- Use systems that dont allow space for human errors;

Ensuring Quality Data and Subject Safety in Trials

- Standardize all systems used in order to ease data input and review by all parties;
- Try to simplify the protocol;
- Note all procedures (SOPs) and use checklists whenever possible;
- Double-check all CFRs and consent forms against every change that you notice;
- Create an integrated framework;
- Develop: Data Management Plan, Data and Safety Monitoring Plan, Data Analysis Plan, and Quality
Assurance Plan;
- Train, test, do beta-testing;
- Always have a backup plan regarding floods, disasters, staff turnover, etc.;
- Be careful of unblinding procedures;

Ensuring Quality Data and Subject Safety in Trials

- Gather weekly meetings with your team/staff;

- Be your own audit;
- Implement and use a system that will detect
and correcting errors in real time;
- Follow and audit all changes (who, why, what,
- Close loops and take care of monitoring

FDA Websites for More Information

Running Clinical Trials

FDA Basics for Industry

Sign up for Updates

Replies to Inquiries to FDA on Good Clinical Practice

FDA Inspections of Clinical Investigators - Information sheet

Guidance for Industry - Investigator Responsibilities
FDA Websites for More Information

Investigator-Initiated Investigational New Drug (IND) Applications webpage

FDA Debarment List (Drug Product Applications)

Clinical Investigators- Disqualification Proceedings

List of Warning Letters

FDA Websites for More Information

Regulatory Procedures Manual Section on Warning Letters

Inspection Observations

Inspections Classification Database and Search

Investigators are the most important people in a clinical trial and their attitude and compliance will
affect the quality of the study itself!
Clinical trials are a serious business that brings positive or negative outcomes to people who need
new, safe and effective ways of treatment!
Every investigator, sponsor, coordinator, and all other staff working on a study should be familiar
with working under the appropriate FDA regulations!
GCP (Good Clinical Practices) in clinical research is not equivalent to standard good care of patients!
Both the sponsor and the investigator should know their responsibilities and obligations as well as
their accountability!
Every investigator is in charge at the site and he/she is the one responsible for the whole study
Always follow the appropriate FDA/ICH regulations!
Address and correct all FDA issues in a timely manner in order to prevent further complications!
ALWAYS ensure quality data and maximum safety to your study participants!

As a final note...

We sincerely hope that weve managed to give you

enough information on the regulations and safety
measures regarding clinical trials. Clinical research is an
extremely important field in medicine which should be
taken seriously since it has a great impact on improving
and advancing treatments. To sum up, we now know
that the most important person in a clinical research is
the investigator since he/she is the one whos
conducting the actual study. The investigator carries
almost all accountability when it comes to working in
compliance with rules and regulations. Hopefully, weve
given you an idea of what the main obligations and
responsibilities of a good investigator are and you can
use this in order to improve your study. Finally, in clinical
research its important that we all remember to generate
quality data and take care of the safety and well-being of