CITI training

What must you file before conducting human clinical trials with an experimental drug?
IND application (Form FDA 1571)
During the clinical development phase of the IND process, what must sponsors do?
Maintain current IND application by amending IND with new Form FDA 1571 and providing FDA with:
safety updates
copies of new protocols
FDA 1572
Annual Progress reports
this document notifies FDA of relevant changes in investigators conducting clinical trials under the IND.
Form FDA 1572
What is the timeline of drug development?
Preclinical trials, IND Submission,
Clinical Development (Phase I-III), NDA submission,
Marketing (Phase IV)
When does a sponsor submit the IND?
Prior to clinical development phases (human trials). *30 day process.
What is the NDA?
New Drug Application, submitted prior to Phase IV marketing phase.
How long does the NDA submission take?
6 months – 2 years.
What is determined for a drug in the preclinical phase
Pharmacokinetics and bioavailability Outcome shows promise of safety and efficacy warranting additional studying.
How long does FDA have to review IND submission?
30 days
How long is the clinical development phase (Phase 1-III) in process for IND?
6-7 years.
Determine the trial phase:
– Assess toxicity
– Determine drug’s PK and PD profiles
– Determine doses resulting in sufficient biological level of drug
Phase I
Determine the trial phase:
– Determine drug’s effectiveness (primary goal)
– Determine long-term drug safety
– Confirm findings
Phase III
Determine the trial phase:
– Determine drug’s short-term risk (safety) (primary goal)
– Examine preliminary effectiveness of drug
Phase II
Determine the trial phase from the subject population:
Controlled studies enrolling limited numbers of patients
Phase II
Determine the trial phase from the subject population:
Controlled and uncontrolled studies (but typically placebo-controlled and double-blinded) enrolling larger patient numbers.
Phase III
Determine the trial phase from the subject population:
Normal healthy volunteers unless toxicity prevents exposure (e.g, cancer drugs). In this, case patients with end-stage disease might be enrolled.
Phase I
If an IND application is submitted and the FDA has not contacted the physician within 30 days after acknowledging receipt, can the trial start?
Yes, one of two conditions must be met.
1. 30 days elapsed since FDA received IND application and no hold as been placed.
2. Correspondence has ben received from FDA allowing the trial to start.
What must be provided to investigators before they beginning conducting trials at their site?
Protocol and Investigator’s Brochure
What regulation must a PI comply with in order to use an edc system for a clinical trial?
21 CFR Part 11
21 CFR 56.115(b)
21 CFR 312.57
21 CFR 312.62
21 CFR 812.140
What happened because of the concern and confusion regarding interpretation of Part 11in 2003.
FDA withdrew all the guidance documents related to Part 11, while re-examining.
They then issued: Guidance for Industry: Part 11, Electronic Records; Electronic Signatures-Scope and Application (2003) and Guidance for Industry: Computerized Systems Used in Clinical Investigations (2007). ** The 2007 guidance “supplements the 2003 guidance”
Development of most new drugs from discovery to marketing approval usually takes:
9 years or more
The first randomized, controlled study of an experimental drug versus aspirin for postoperative pain control will enroll 55 patients in each arm. Which of the following best describes the clinical phase of this study?
Phase 2
Adults with more than a 12-month history of migraines were assigned randomly in a double-blinded study to receive treatment with experimental drug X (10 or 20 mg/day) or placebo. The primary efficacy measure was the reduction in severity of the migraine attacks. Enrollment was 1200 subjects. Which of the following best describes the clinical phase of this study?
Phase 3
Long-term toxicology of an experimental drug in animals most likely refers to which part of drug development?
Pharmacokinetics and pharmacodynamics of a new formulation of an investigational drug most likely refers to which clinical phase of a study in humans?
Phase 1
For a Phase 1 new drug study in humans, what is the primary source of the data included in the initial Investigator’s Brochure?
Preclinical data
What is ICH’s more specific name?
International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use.
what is the goal of the ICH?
to minimize redundant research. and standardize technical guidelines and requirements.
Define the term: an individual, or judicial or other body, authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedures involved in the research
Legally Authorized Representative (LAR)
an unplanned excursion from the requirements of the protocol that is not implemented or intended as a systematic change.
Protocol Deviation (or Violation)
What are the 6 regulatory and pharmaceutical industry groups that have representatives working for ICH?
-European Commission (EC)
-European Federation of -Pharmaceutical Industries’ Association (EFPIA)
-Ministry of Health, Labor, and Welfare, Japan (MHLW)
– Japan Pharmaceutical Manufacturers Association (JPMA)
– US Food and Drug Administration (FDA)
– Pharmaceutical Research and Manufacturing of America (PhRMA)
How do the World Health Organization (WHO) and the European Free Trade Association (EFTA) [represented by Swissmedic, and Health Canada participate with ICH?
As observers.
How is the ICH governed?
a Steering Committee
Who supports the ICH?
the ICH Secretariat
Who provides the ICH secretariat?
The International Federation of Pharmaceutical Manufacturers Association (IFPMA)
How many seats on the Committee does each of the 6 working groups of ICH have?
who nominates other nonvoting participants to attend ICH steering Committee meetings?
The observer groups (WHO, Health Canada, and EFTA)
Is the ICH GCP regulation or guideline?
Depends, several countries adopted it as law, but the U.S FDA adopted it only as guidance. (Federal Register, Vol. 62, MAY 9, 1997)
What are the four main categories covered by ICH guidelines?
Q: Quality topics (chemical and pharmaceutical assurance)
S: Safety topics: in vitro and in vivo preclinical research
E: Efficacy topics: relating to research in human subjects
M: Multidisciplinary topics: those that do not fit uniquely into one of the above categories.
What are the expert working groups responsible for?
developing specific guidelines.
* The ICH then provides an efficient process and format to standardize the new requirements across agencies and countries.
ICH E6 guideline pertains specifically to what
the conduct of clinical research to support marketing applications for drugs.
Provides a unified standard for designing, conducting, recording, and reporting research involving human subjects.
ICH E6 guideline for good clinical practice.
What are the two important goals of the ICH E6 standard?
To assure that
1: The rights, well-being, and confidentiality of trial subjects are protected.
2: Trial data are credible.
Where do the ethical principles followed by ICH GCP guidelines originate from?
the Declaration of Helsinki
What ethical principles stem from the Declaration of Helsinki?
in notes….
If planning to market drugs outside the US, what guidance must a PI follow while conducting the clinical trial?
ICH E-6 Good Clinical Practice.
Can an employee at the research site be witness to a patient’s consent?
No, they are involved in the trial. Witness must be “a person who is independent of the trial, who cannot be unfairly influenced by people involved in the trial”
What must a witness do before the consent process starts?
Read the consent form and other written information provided to the participant. They must also determine whether the participant has any other questions and should sign the impartial witness signature block on the consent document.
If following ICH guidelines who all should sign the consent form between the subject, witness, and person obtaining consent.
All of them.
Oversee research involving human subjects to assure the protection of their rights, safety, and welfare.
FDA or ICH: requires the consent form to include a statement that “monitors, auditors, the IRB/IEC, and the regulatory authorities will be granted access to the subject’s original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject is authorizing such access
FDA or ICH: Treatment alternatives only need to be listed in the consent form
FDA or ICH: requires that the potential benefits and risks of the alternatives should also be included in the consent form.
What does the ICH E6 guidelines require in a consent form for treatment arms.
Description of each arm, the likelihood of being assigned to each of the study arms, and an explanation of ” the subject’s responsibilities”
Does FDA require description in consent if research provides no expected benefit?
No, only an explanation of expected benefits of the research?
What does ICH require in terms of benefits in the ICF?
If there is no intended clinical benefit to the subject, Section 4.8.10(h) requires that the subject be made aware.
Consent form should describe the anticipated prorated payments to subjects (recommended for FDA as well)
Is assent required for both FDA and ICH?
Yes, and the consent of the parents.
Define Assent
The agreement of someone who cannot consent for his or herself.
When is there a valid reason not to require assent?
FDA vs. ICH when enrolling an adult who is unable to consent for him or herself.
ICH E6 requires assent along with permission from their LARs. Not required by FDA.
Only subjects who are able to consent for themselves are allowed to enroll in non-therapeutic research studies (a trial in which there is no anticipated direct clinical benefit to the subject.
When can ICH allow subjects to be enrolled that cannot consent for themselves? (Exceptions)
studies where:
– the objectives cannot be met without including these subjects.
the foreseeable risks to the subject are low as is the negative impact.
– the study is not illegal AND
The IRB/IEC has specifically agreed to include these subjects.
FDA requires Investigator to inform the subject’s primary physician about the subject’s participation in the trial if subject has a PCP and if the subject agrees to the primary physician being informed.
False, this is a requirement of ICH E6 guidelines.
FDA or ICH requirement:
IRB/IEC is required to review
-written ICF and updates
– trial protocols/amendments
– subject recruitment procedures (advertisements)
– written information to be provided to subjects
– IBs
Safety information
Info about payments and compensation to subjects
– CVs and qualifications
– any other docs IRB/IEC may require to fulfill its responsibilities
ICH E6 Guideline. FDA not clear in requirements for IRB/IEC review of documents.
Per FDA requirements, what is required of the IRB/IEC?
to review the consent form (21 CFR 56.109) and to keep “copies of all research proposals reviewed, scientific evaluations, if any, that accompany the proposals, approved sample consent documents.
A primary purpose of the ICH is to:
– require publication of negative trial results.
– develop mandatory worldwide regulations for drug development.
– require FDA registration of worldwide clinical trials.
– minimize the need for redundant research
Minimize the need for redundant research.
The ICH GCP guidelines:
– set standards for the design, conduct, monitoring and reporting of clinical research.
– guarantee that a submission in any ICH region will be approved for marketing.
– require certification of clinical research sites and investigators
– replace FDA regulations for internationally conducted studies of drugs that will be marketed in the U.S.
Set standards for the design, conduct, monitoring and reporting of clinical research.
The ICH E6 GCP describes standards that apply to:
-Investigators, sponsors, and IRBs.
– Research sponsors only
– Investigators only
– IRBs only
Investigators, sponsors, and IRBs.
In the United States, following the ICH E6 GCP is:
– Voluntary for FDA-regulated drug studies.
– Mandatory for studies conducted outside the United States.
– Mandatory for investigational device studies.
– Mandatory for drug studies.
Voluntary for FDA-regulated drug studies
The FDA will apply:
– The ICH E6 GCP standards
– The Code of Federal Regulations
– Local IRB requirements
– State law where the sponsor’s headquarters are located.
The code of federal regulations
What is the legal status of ICH in the U.S.?
It is a guideline
Regarding subject signature on consent forms, which is true about dates?
Both the FDA and ICH require
ICH requires a witness when enrolling illiterate subjects, true or false?
Regarding probability of assignment to trial arms in consent forms, which is true?
Only ICH recommends.
When is there “Sponsor-investigators”
Investigator-initiated trials of investigational drugs.
Who addresses the role of “Sponsor-investigators?”
means in addition to producing the drug, the company also supplies the investigator with the drug for use in the study
Drug Supplier/Manufacturer
means the entity who takes responsibility for and initiates a clinical investigation. The sponsor can be any legal entity, including a company, an academic organization, or an individual. The intent of the sponsor’s IND is to allow testing for marketing approval of the drug. These are generally considered commercial or corporate INDs. Note: the sponsor is often but not always the entity that funds the clinical research.
means an individual who both initiates and conducts the clinical investigation and under whose immediate direction the investigational drug is being administered, used, or dispensed. The sponsor-investigator assumes all of the responsibilities of the sponsor as well as all the responsibilities of an investigator as outlined in the Form FDA 1572 (see the module, Investigator Obligations in FDA-Regulated Research). Usually, the intent of the sponsor-investigator trial is to gain scientific knowledge without seeking market approval for the drug. These are considered investigator-initiated or sponsor-investigator trials.
Usually, the intent of the sponsor-investigator/investigator-initiated trial is to
gain scientific knowledge without seeking market approval for the drug.
the regulation stating: exception from informed consent for emergency research
21CFR 50
What can Investigators reference when unsure if an IND is required for a study of an approved drug?
IND exemptions for studies of lawfully marketed drug or biological products for the treatment of cancer OR seek opinion from FDA.
Form FDA ______: Statement of the Invesitgator
Form FDA ____: Investigational New Drug Application, NDA
detailed requirements for the content and format of an IND can be found in
21 CFR 312
what can be cross-referenced when the manufacturer of an IND already has an active IND for the drug being studied?
Chemistry, manufacturing, and controls (CMC) information
Pharmacology and toxicology information
Previous human experience with the drug
Form: contractual agreement between the sponsor and FDA.
FDA 1571
21 CFR 56
The content for an IND for studies of marketed products is the same as the content for studies of new drugs, with the following exception:
a copy of the approved labeling (including the package insert) can be provided in lieu of the Investigator’s Brochure.
what are the three types of protocol amendments?
-new sponsor protocol
-a change in an existing protocol when the entire sponsor protocol is not revised
– identifying and adding new investigator to a study
submitted when new toxicology, chemistry, or other technical information is available. Study discontinuation is also submitted as this.
Information amendments
When do Annual Reports need to be submitted to the FDA?
within sixty (60) days of the anniversary date that the IND went into effect.
The following are purposes of what:
-The rights and well-being of human subjects are protected.
-The reported trial data are accurate, complete and verifiable from source documents.
-The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirements.
Trial monitoring
When the sponsor-investigator holds the IND for an investigational drug he or she is responsible for annual reporting of which one of the following to FDA?
A. IND renewal application
B. Adverse Event Summary Report, but only from unblinded portions of studies (“open-label IND safety report”)
C. IND report
D. Marketing plan (i.e. annual updated projection of sales and profits)
C. IND report
Which of the following is a criterion for determining if a study of an approved drug is exempt from the require of an IND?
A. The study intends to invoke an exception from informed consent.
B. The study involves a route of administration that significantly increases the risks to the patient.
C. The study is not intended to be reported to FDA to support a new indication or support a labeling change.
D. The study intends to involve more than 100 patients in a study.
C. The study is not intended to be reported to FDA to support a new indication or support a labeling change.
Which of the following reports must be filed using an FDA Form 1572?
A. Annual Reports
B. Addition of a new investigator
C. Protocol amendments
B. Addition of a new investigator.
the tool used to record data collected during a clinical trial
CRF, case report form
document that includes information needed for potential subjects to have sufficient info to provide informed consent to participate in a clinical trial. The FDA regulations and ICH E6 describe the information that must be included in the consent form.
Informed Consent Document
any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects.
” Assure the protection of the rights and welfare of the human subjects.
All info in original records and certified copies of original records of clinical findings ETc
source data.
Initial documentation of data in a clinical study and includes recorded observations, laboratory reports, medical records, etc.
Source Document.
This agreement is a contract that defines both the terms of study conduct and the financial agreements
CTA (Clinical Trial Agreement)
When is it necessary for an investigator to complete and sign a new 1572?
– when participating in a new protocol that has been added to the IND
– When a new investigator is added to the study.
What needs to be done when there are other changes to information contacted on a signed and dated 1572? (IRB/IEC address change, addition of a clinical research lab)
investigator should document the changes in the clinical study records and inform the sponsor of the changes, so that the sponsor can appropriately updated the IND.
ICH or FDA, requires submission of up to date curriculum with changes?
clinical trials of drugs or devices from which the data will be submitted to the FDA to support a marketing application or relied upon by the FDA to establish effectiveness.
“covered clinical studies”
For purposes of financial disclosures, the term (blank) includes anyone who is directly involved in the treatment or evaluation of research subjects. The term also includes the spouse and each dependent child of the (blank).
21 CFR 54
Financial Disclosure by Clinical Investigators
The investigator’s financial interests with the pharmaceutical company (sponsor) or to the outcome of the clinical investigation is reported directly to the FDA by:
A) The investigator’s institution
B) The investigator
C) The IRB
D) The sponsor
D. The sponsor
In completing Form FDA 1572, Statement of Investigator, the Investigator agrees to:
A) Maintain a contract with the sponsor
B) Maintain records indefinitely
C) Report to the FDA any adverse events that occur.
D) Conduct or supervise the investigation personally
D. Conduct or supervise the investigation personally.
Form FDA 1572, Statement of Investigator, is legally binding between the Investigator and the:
A) Subjects
B) Sponsor
The investigator must report adverse events to the:
A) Subject
B) Sponsor
D) IRB only
B) Sponsor
When must the investigator update the IRB about the progress of a trial?
A) During the conduct of the study and at termination
B) During the conduct of the study only
C) Never
D) At study termination only
A) During the conduct of the study and at termination
Which of the following is an investigator’s commitment to the sponsor?
A) Submit documents to sponsor for yearly approval to continue the study
B) Retain study documents for 3 years after study completion at the site
C) Provide the financial disclosure document directly to FDA
D) Submit a new FDA form 1572 to sponsor as needed
D) Submit a new FDA form 1572 to sponsor as needed
“…any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries”
Biological Product (Biologic)
“…a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use” (ICH GCP E6 Section 1.33).
Investigational Drug
“…a new drug, antibiotic drug, or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes” (21 CFR 312.3).
Investigational New Drug (IND)
Which of the following is an important component of drug accountability?
A) Environmental controls
B) Drug shipping and disposition records
C) Patent expiration date
D) Manufacturer’s compounding procedures
Drug shipping and disposition records
Who has ultimate responsibility for an investigational product?
Investigational product dispensing or administration info for the sponsor is recorded on the:
Case Report Form
The packaging of investigational drugs should ideally
A) look like a marketed product
B) allow subjects to identify placebo pills
C) be designed to help with subject compliance
D) be attractive so the study coordinators will use it
be designed to help with subject compliance
Where is info on storage requirements for the investigational product usually found?
A) on the product code-breaker label
B) In the CRF directions
C) In the drug accountability log
D) In the study protocol
in the study protocol
A 46-year-old man is currently enrolled in a Phase 3 study of a drug for severe diabetic neuropathy. While the study is ongoing, a new drug becomes commercially available that may have equal or greater benefit to the subject. The investigator should do which of the following?
Discuss the pros and cons of both the investigational drug and the commercially available drug and then allow the subject to decide whether to withdraw from the research to take the new drug
Which of the following statements in a consent form is an example of language that appears to waive a subject’s rights?
I waive any possibility of compensation for injuries that I may receive as a result of participation in this research.
An investigator is confronted with a life-threatening situation that necessitates using a test article in a human subject who is unable to provide informed consent and there is no time to obtain consent from the individual’s legal representative. Under the FDA regulations, which of the following describes the best course of action for the investigator:
The investigator and another physician who is not part of the study team agree that the situation necessitates the use of the test article and the IRB will be notified later.
Under which circumstance does the FDA allow verbal consent prior to participation in a research study?
The study is minimal risk.
Which of the following should take place during periodic site visits?
Identification of protocol violations
Which of the following best describes when the majority of CRF data are verified against source record information?
Periodic site visits.
When should the sponsor-monitor conduct the most detailed review of the study protocol with the site’s study staff?
Site initiation visit.
The FDA requires retention of investigational drug study records for:
At least 2 years after the investigational drug’s approval by the FDA.
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