Professional Documents
Culture Documents
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.
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After reading this, youll be able to
- 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;
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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.
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Defining a Sponsor-
Defining a Sponsor
Investigator
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.
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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.
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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:
#1
#2
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;
Statement
- Investigational plan;
- All applicable regulations (below);
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Main Investigator Responsibilities
#3
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Main Investigator Responsibilities
#6
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Investigators and the FDA
The FDA has certain expectations that the Investigator must follow.
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.
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FDA Expectations
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Statement of Investigator
Form FDA 1572
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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;
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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
application) - THE INVESTIGATOR DOESNT NEED TO SIGN A 1572;
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
NON-IND SITE;
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ICH GCP - E6 Good Clinical Practice: Consolidated Guidance
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ICH GCP - E6 Good Clinical Practice: Consolidated Guidance
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.
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Differences Between FDA regulations and E6 ICH GCP
REMEMBER!!!
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.
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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.
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Actions taken to Regulate the Approval Process of Drugs
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
obligation;
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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;
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FDA and ICH requirements for documentation
submitted to the IRB
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Reporting Clinical Trial Results
( www.ClinicalTrials.gov )
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 http://www.fda.gov/downloads/AboutFDA/ReportsM
on www.ClinicalTrials.gov . anualsForms/Forms/UCM048364.pdf
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DONT!
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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!
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Compliance vs Non-Compliance: Inspections and Audits at the Site
- 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;
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Compliance vs Non-Compliance: Inspections and Audits at the Site
- 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
necessary;
- OAI (official action indicated): major/critical
non-compliance which will require FDA
involvement;
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Compliance vs Non-Compliance: Inspections and Audits at the Site
- Warning letter;
- Debarment;
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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.
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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.
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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
respond:
- 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;
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Disqualification of the Investigator
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;
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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.
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Case Study: Paul H. Kornak - Jail time for fraud
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Ensuring Quality Data and Subject Safety in Trials
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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;
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Ensuring Quality Data and Subject Safety in Trials
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FDA Websites for More Information
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FDA Websites for More Information
Inspection Observations
http://www.fda.gov/ICECI/EnforcementActions/ucm250720.htm
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CHECKLIST
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
conduct!
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!
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As a final note...
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