21 CFR 312 – Investigational new Drug Applications

T/F: When a sponsor transfers some or all of it’s obligations to a CRO, the CRO is required to comply with all regulations designated as sponsor requirements for the transfered obligations.

Controlled trials evaluating the effectiveness of multiple doses of a drug in patients would be considered as what phase of the investigation?
Phase II

What phase of a study typically evaluates the pharmacokinetics of a drug in normals?
Phase I

When a sponsor receives information from an IRB regarding public disclosure of research, what action must the sponsor take?
Submit copies of the information disclosed to both the IND file and the Dockets Management Branch of the FDA.

Studies which provide an overall evaluation of a drug and an adequate basis for physician labeling would be considered as what phase of the investigation?
Phase III

To whom may a sponsor provide investigational drugs?
Investigators participating in the clinical investigations under the IND.

What statement must the label of all investigational drugs bear?
“Caution: New Drug – Limited by Federal law to investigational use”

Who must specifically be named on the FDA Form 1572?
1. Investigator
2. Institution where the investigation will be conducted
3. Clinical lab to be used in the study
4. IRB responsible for review and approval
5. Sub-investigators who will assist the investigator

What information must an investigator provide study subjects regarding the drug they may receive?
That the drug is being used for investigational purposes.

Who has the responsibility for ensuring that an IRB that complies with the requirements of 21 CFR 56 will provide review and approval of an investigation?
The Investigator

What actions must an investigator take to make changes in a study protocol?
1. Inform the sponsor, request the change, and obtain a protocol amendment, if required
2. Inform the IRB, and request review and approval of the amendment
3. Modify the consent form, if required, and obtain the IRB approval
4. Inform study patients of the pertinent changes, and obtain new informed consent, if applicable

Give an example of the type of information required to be filed as an information amendment to an original IND application.
New technical information such as a toxicolocy or chemistry; reports regarding discontinuation of a clinical investigation.

What is the FDA’s preferred filing frequency for information amendments by sponsors?
At intervals of 30 days.

What is the FDA’s definition of the term “associated with the use of the drug” with respect to evaluation of AE’s?
There is a reasonable possiblity that the experience may have been caused by the drug.

What types of experiences does the FDA classify as serious adverse drug experiences in clinical trials? Any event that results in…
1. Death
2. A life-threatening drug experience
3. Inpatient hospitalization or prolongation thereof
4. Significient or persistent disability
5. Congenital anomoly or birth defect
* Important medical events may also be serious events

What additional information is availabe from thr FDA that applies to and supports interpretation of the FDA regulations?
FDA guidance documents which support interpretation of the regulations are available from both the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research.

What is the FDA’s definition of disability, as it relates to SAE’s?
A substantial disruption of a person’s ability to conduct normal life functions.

What is the FDA criterion which classifies an adverse drug experience as unexpected?
Any adverse experience, the specificity or severity of which is not consistent with the current Investigator Brochure, or other designated document when an Investigator Brochure is not required.

Unless the FDA notifies a sponsor that investigations in an IND are subject to a clinical hold, how soon may a soposnr being a clinical investigation after filing the IND?
30 days after the FDA receives the IND submission.

Generally, sponsors may request FDA comment and advice on which components of an IND submission?
1. Adequacy of technical data to support an investigational plan.
2. Design of a clinical trial.
3. A determination of whether proposed investigations are likely to produce the data and information needed for an NDA.

Reasons for the FDA to impose a clinical hold for a Phase I, II, or III investigation:
1. Subjects would be exposed to unreasonable and significant risk of ilness or injury
2. Unqualified investigators
3. Inadequate Investigator Brochure
4. IND lacks safety data
5. Gender bias on subject elegibility

If enrollment in a sponsored, adequate and well-controled investigation is being impeded by a treatment-IND investigation, what action may the FDA take?
The FDA may place the treatment-IND on clinical hold

T/F: Resumption of clinical investigators which were subject to a clinical hold must always be issued in writing by the FDA to a sponsor.
False – If permitted in the clinical hold order, investigators may be resumed as soon as the deficiencies are corrected. Resumption notification for clinical hold cases requiring sponsor response, may be made by telephone or other rapid communication means.

For what length of time must all clinical investigations under an IND remain on hold prior to the FDA converting the IND to inactive status?
One year or more

If a sponsor fails to inform the FDA of all SAE’s, what is the most significant action the FDA may take relative to the IND?
Termination of the IND

On what grounds may the FDA terminate an IND immediately, without opportunity for sponsor response?
If the FDA concludes that continuation of the investigation presents a substantial danger to the health of individuals.

If an IND is placed on inactive status by the FDA, what action must the sponsor take with drug supplies?
Arrange with all investigators for the return or other proprt method of disposal of the investigational drug.

At what point in the clinical development process of a drug does the FDA encourage meetings with an IND sponsor?
At the end of Phase II and prior to NDA submission

End of Phase II meeting between FDA and a sponsor are generally reserved for what type of IND?
IND’s involving new molecular entities or major new uses of marketed drugs.

Purposes of Pre-NDA or Pre-BLA meetings between a sponsor and the FDA:
1. To uncover any major unresolved problems.
2. To identify studies on which the sponsor will rely to establish effectiveness.
3. To identify the status of ongoing or needed studies, to assess pediatric safety and effectiveness.
4. To acquaint FDA reviewers with the technical content.
5. To discuss statistical analysis methods.
6. To determine the optimal approach for presenting and formatting of NDA date.

Who at the FDA is responsible for issuing a clinical hold?
The Division Director with responsibility of review of the IND

When the FDA approves a shipment of a drug for emergency use from a telephone request, what additional requirement typically is made of the sponsor?
The sponsor must make an appropriate IND submission as soon as practicable after receiving the approval.

T/F: Filingh a seperate IND with the FDA is required if a sponsor elects to conduct investigations involving waiver of informed consent in emergency research.

What are the labeling requirements for investigational drugs with respect to sagety or effectiveness of the product?
The lable can bear no misleading statement and shall not represent that the drug is safe or effective for the purposes for which it is being investigated.

T/F: A promotional claim is acceptable on investigational drug supply labeling, provided the claim was previously approved by the FDA.
False – Promotional claims may not appear on investigational drug supply labels.

Describe the FDA requirement for charging for investigational drugs under an IND.
Charging under an investigational drug IND is not permitted without prior written approval from the FDA. Written explanation of why charges are necessart and not a normal cost of doing business is required.

T/F: Charging a reasonable amount for investigational drugs under a treatment IND is permissable provided certain criteria are met and there is no commercialization or promotion involved.

T/F: All of the safeguards incorporated in the FDA regulations regarding informed consent, IND, NDA, and Biologics also apply to drugs intended to treat life-threatening or severely debilitating illness.

Criteria necessary for importing investigational new drugs into the US:
The Consignee is:
1. The US sponsor of the IND.
2. A qualified investigator named in the IND.
3. The domestic agent of a foreign sponsor, who is responsible for the control and distribution of the drug and is so indentified in the IND.

Name two individuals who may submit a request for authotization to the FDA to export investigational drug outside the US.
1. The person in the US who seeks to export the drug, or
2. An authorized official of the Government of the country to which the drug is proposed to be shipped

Name the international doctrine of ethical principles that is the standard requirement for acceptance of foreign studies in support of an IND or NDA.
The Declaration of Helsinki

In general, the FDA accepts foreign studies not conducted under an IND, provided what conditions are present? Provided the studies are:
1. Well designed
2. Well conducted
3. Performed by qualified investigators
4. Conducted in accordance with ethical principles acceptable to the world community.

T/F: The FDA may disclose the existance of an IND, even if it has not previously been made public.

T/F: Some clinical investigations involving an in vitro diagnostic biologic product may be exempt from the IND regulations if it is used only to confirm a diagnosis made by another medically established diagnostic product or procedure.

T/F: Clincial research on blood grouping serum, reagent RBC’s and anti-human globulin are generally exepmt from the FDA’s IND Regulations.

T/F: Use of a marketed drug or biologic product for an unlabeled indication in the practice of medicine is not subject to IND regulations.

What is the definition of a CRO, according to the FDA’s IND regulations.
A person working with the sponsor as an independent contractor who assumes one or more of the obligations of the sponsor.

What types of products are generally subject to the IND regulations?
Investigational new drugs, biological drugs, and biological products used in vitro for diagnostic purposes that are to be used in a clinical investigation.

How much time does the FDA have to provide a sponsor with a written approval to proceed with an IND that involves waiver from informed consent due to emergency conditions?
30 Days

What phase of clinical investigation includes a study that evaluates security-activity relationships or mechanism of action in humans?
Phase I

Two conditions under which the FDA can place an IND on inactive status:
1. If no subjects are entered into clinical trials for a period of 2 yrs or more under the IND
2. If all investigations under the IND remain on clinical hold for a period of more than one year.

What is the FDA’s primary objectives when reviewing an IND regarding Phase I?
Safety Assessment

What is the FDA’s primary objectives when reviewing an IND regarding Phase II & III?
Safety/Efficacy – and to help assure scientific evaluation

What is the FDA’s primary objectives when reviewing an IND regarding all phases?
Assure the rights and safety of subjects.

List the general responsibilities of sponsors:
1. Select qualified investigators, providing them with information to properly conduct the trial.
2. Ensure proper monitoring.
3. Ensure the study is conducted in compliance with the protocol.
4. Maintain an effective IND.
5. Ensure FDA and investigators are provided full safety information.

How soon does a sponsor have to submit a new investigator amendment to an IND?
30 days following the addition of the investigator.

Sponsors are required to maintain an ongoing review of safety information from which sources?
Any foreign or domestic source including clinical epidemiology, and animal investigations, commercial marketing experience, scientific literature reports, and unpublished scientific papers, and reports from foreign regulatory authorities not previously reported to the FDA.

What is the time requirement for fliing IND safety reports with the FDA?
ASAP and never later than 15 calendar days after the sponsor’s initial receipt of the information.

How soon must the FDA be notified of a fatal or life-threatening adverse experience which is associated with use of a drug?
By telephone or facsimile, no later than 7 calendar days after sponsor receipt of the information, followed by a written report no later than 15 calendar days after initial receipt of the information by the sponsor.

For the purposes of filing IND safety reports with the FDA, what is the definition of a :life-threatening event”?
The patient was at immediate risk of death from the reaction as it occurred.

Who must approve modifications on the reporting format or frequenct of IND safety reports to a sponsor deviating from the regulations?
The Division Director at the FDA.

When are sponsors required to file follow-up information for IND safety reports?
As soon as the relevant information is available.

If a sponsor evaluates an adverse event and determines that it is reportable as an IND safety report, but it was not originally reported as such, how long does the sponsor have to report the event as an IND safety report?
ASAP, but in no event later than 15 calendar days after the determination is made.

T/F: If a sponsor submits an IND safety report, it is assumed by the FDA that the drug caused or contributed to the event, unless it is specifically denied by the sponsor.
False – Mere submission of a report under the IND safety report requirements does not reflect conclusion, by the sponsor or FDA, that the drug caused or contributed to the reported event.

What is the time frame in which a sponsor must file an IND annual report?
Within 60 days of the anniversary date that the IND went into effect.

What are the required elements to be reported for each individual study reported in an IND annual report?
1. Study title, identifier an dpurpose, description of patient population and completion status.
2. Total number of subjects (Initially planned for inclusion, Entered to date, Who completed as planned, Dropped for any reason.)
3. Brief description of any interim or final analysis results, if available.

Name specific clinical adverse experience summary items required in an IND annual report:
1. Most frequent and most serious adverse experiences by body system.
2. IND safety reports submitted w/I thepast year
3. list of subjects who died with cause of death
4. list of subjects who dropped due to an adverse experience.

T/F: Summary information for clinical trials activity within the past year is required in the IND annual report, while results or pre-clinical studies are not.
False – Pre-clinical summary information for studies completed of conducted within the past year must be included in the IND annual report.

For what type of studies do FDA officials intend to monitor study progress and evaluation to facilitate appropriate progress of the trials?
Drugs intended to treat life-threatening or severely debilitating illnesses.

What should be the main focus of an initial IND submission?
The general investigational plan and the protocols for specific human studies.

Name the factors that determine the amount of information that must be submitted in an IND.
1. Novelty of the drug
2. Extent to which the drug has been previously studied
3. Known or suspected risks
4. Particular developmental phase

Fda form 1571 requires the names and titles of two persons with specific functions. Who are they?
1. The person responsible for monitoring the conduct and progress of the evaluation
2. The person responsible for review and evaluation of safety information for the drug.

T/F: FDA Form 1571 contains a statement that an IRB that complies with the requirements of 21 CFR 56 will be responsible for review of all studies conducted under the IND.

Name the elements required in the general investigational plan of an original IND application.
1. Rationale for the drug or study.
2. Indication(s).
3. General evaluation approach.
4. Types of trials to be conducted in the first year.
5. Estimated number of patients to be studied in the first year.
6. Any anticipated risks of particular severity or seriousness.

Describe the level of detail required for Phase I protocols vs Phase II & Phase III protocols.
Phase I may be less detailed and more flexible than Phases 2 and 3. Phase I should outline the plan, specify the number of patients, describe safety measures and include a dosing plan. Phases 2-3 should be very detailed, and will generally not permit unanticipated protocol changes.

Required sections in a clinical research protocol for a study conducted under an IND:
1. objectives and purpose
2. name, address, and qualifications of investigators and of the reviewing IRB
3. inclusion/exclusion criteria
4. study design
5. dosing information
6. planned observations and measurements
7. clinical procedures to evaluate safety

Required content elements in the Chemistry, Manufacturing, and Controls section of an original IND Application. Information on:
1. Drug Substance
2. Drug Product
3. Placebo composition if applicable
4. Labeling
5. Environmental analysis requirements

The pharmacology and toxicology section of an original IND application requires the names and qualifications of the individuals who performed what tasks?
Those who evaluated the results of pre-clinical studies and concluded it was reasonably safe to begin the proposed clinical investigations.

Results of pre-clinical studies on abuse potential and drug dependence are required in the original IND application for which classes of drugs?
Psychotrophic substances or any other drug with abuse potential.

What are the FDA’s requirements for translation and inclusion of documents in an IND application which are not English?
A complete English translation must be included as well as a copy of the original publication in the foreign language.

Name the three categories of protocol amendments which require a sponsor to undate the original IND application:
1. New Protocols
2. Changes in a protocol
3. New investigators

T/F: During the investigator selection process, sponsors are required to obtain a commitment from an investigator to provide financial disclosure statements before, during, and for one year after the completion of a study.

When a sponsor is conducting investigations under 21 CFR 50.24, in emergency research conditions, what information must the sponsor promptly file with the FDA, under the IND?
Information received from the IRB concerning the public disclosure required by the regulation.

What information document must a sponsor provide to an investigator prior to beginning an investigation?
Investigator Brochure

What is a sponsor’s obligation relative to review of a patient data in an ongoing investigation?
The sponsor must review and evaluate safety and efficacy data as it is obtained from the investigator.

What records must a sponsor maintain regarding investigational drug supplies?
Records of receipt, shipment or other disposition of the drug, which should include the name of the investigator, as well as the date, quantity, and batch or code mark of each shipment.

What records are sponsors required to retain regarding financial interests of it’s investigators?
1. Complete and accurate records showing any financial interest paid to investigators by the sponsor of the study
2. Complete and accurate records concerning all other financial interests of the investigator in compliance with 21 CFR 312.87

How long must a sponsor retain records of clinical investigators?
Two years after a marketing application is approved, or if an application is not approved for the drug, two years after the shipment and delivery of the drug for investigational use is discontinued and the FDA has been notified.

T/F: Sponsors are required to reserve samples of any test article and reference standards used in bioequivalence or bioavailability studies, yet are not required to release these samples to the FDA.
False – Sponsor is requested to release these samples to the FDA upon their request.

What authority does the FDA have regarding inspection of sponsor records?
The FDA may have access to, inspect, copy, and verify any records and reports relating to a clinical investigation at reasonable times.

Who may inspect records of investigational drugs that are also controlled substances?
The FDA and the DEA of the US Dept of Justice

What precautions must a sponsor take regarding storage of investigational drugs that are also controlled substances?
Ensure the drug is stored in securely locked, or substantially constructed cabinet or other securely locked, substantially constructed enclosure, access to which is limited to prevent theft or diversion of the substance into illegal channels of distribution.

Under what conditions may an investigator dispose of investigational drug?
Only under written authorization by the sponsor; the sponsor must also ensure that the disposition method will not expose humans to risks from the drug.

What records must be maintained by investigators for investigational drug supplies?
Records of drug disposition including dates, quantities, and use by study subjects.

For how many years must an investigator retain records of investigational drug supplies and study subject case records?
Two years after NDA approval, or if an NDA is not approved, two years after the investigation has been discontinued and the FDA has been informed.

What types of reports is an invsestigator obligated to provide to the sponsor of a study?
1. Progress Reports
2. Safety Reports
3. Final Reports
4. Financial Disclosure Reports

What information must an investigator provide to a sponsor regarding financial interests?
Sufficient, accurate information to allow the sponsor to file required reports with the FDA, and any changes to their financial interests during or for one year after the close of the study.

Information which an investigator must promptly report to the reviewing IRB:
1. All changes in the research
2. All unantacipated problems involving risk to human subjects or others

If an investigator is disqualified by the FDA, what impact might this event have for the sponsor?
Data from disqualified investigators may be eliminated from NDA consideration, and ultimately result in the FDA’s failure to approve the NSA. Further, for approved drugs, data from disqualified investigators could result in withdrawl of marketing approval by the FDA.

T/F: Once the FDA disqualifies an investigator, he or she may never again receive investigational drug.

What is the basic premise, relative to risk, of the IND regulations regarding drugs intended to treat life-threatening and severely debilitating disease?
Physicians and patients are generally willing to accept greater risk or side effects from drugs intended to treat these types of illnesses.

What are the criteria for life threatening diseases or conditions to which special IND regulations apply for clinical trials? Diseases or conditions:
1. Where the likelihood of death is high unless the disease is interrupted
2. With outcomes where the end point of the clinical trial analysis is survival.

What is the FDA’s definition of a “severely debilitating” disease?
A disease or condition that my cause irrerersible morbidity.

What types of early consultation meetings are usually available for IND’s to evaluate life-threatening or severely debilitating illnesses?
1. A pre-IND meeting to review animal data or study design, to discuss Phase I trial designs or data presentations in the IND.
2. An end-of-Phase I meeting to discuss the design of Phase 2 trials.

For what purpose might the FDA undertake docused regulatory research?
To evaluate critical rate-limiting aspects of the drug development process in facilitating the development of therapies to treat life-threatening or severely debilitating illnesses.

What form specifies the content and order of an IND submission?

If a clinical hold order is issued by telephone, how soon thereafter must the FDA provide the sponsor with a written explanation of the basis for the clinical hold?
30 Days

T/F: The FDA may place a treatment IND on clinical hold if a sponsor is not pursuing marketing approval with dur diligence.

When a clinical hold order is issued by the FDA for an ongoing study, what actions must the sponsor take?
Notify all investigators to stop recruitment, remove subjects from the drug, unless specifically permitted to continue the ongoing patients, in the interest of safety.

T/F: When a licensed medical practitioned files a TX IND with the FDA, the investigator becomes a sponsor-investigator, even though the sponsor may be supplying the drug.

Only a sponsor may interrupt a treatment IND investigation if inadequate supplies are available to support it as well as concurrent controlled trials.
False – The FDA may also place the treatment-IND on clinical hold under these circumstances.

T/F: For treatment IND’s, the investigator is responsible for reporting safety information directly to the FDA.

Who may bring consultants to an end of phase II meeting?
Both the FDA and the sponsor.

What clinical items must a sponsor provide the FDA at least one month in advance of an end of phase II meeting?
A summary of Phase I and II investigations, specific protocols for phase III, plans for any pediatric studies or requests for waiver or deferral of pediatric studies, and tentative labeling for the drug.

T/F: The FDA may place a treatment IND or treatment protocol on clinical hold if a comparable or satisfactory alternative therapy or drug becomes available for patients with condirions intended to be treated in the investigation.

What is the proper sequence of actions a sponsor should take when attempting to resolve an administrative or procedural dispute with the FDA?
1. Attempt to resolve the dispute with the reviewing division of CDER or CBER, beginning with the assigned Consumer Safety Officer. (CSO).
2. If the dispute is not resolved via the CSO, seek resolution via an ombudsman.

What is the proper sequence of actions a sponsor should take when attempting to resolve a scientific or medical dispute with the FDA?
1. Discuss the matter directly with the responsible reviewing officials.
2. If unresolved, request a meeting with the reviewing officials, and management representatives.

A revised copy of an Investigator Brochure in an IND annual report must be accompanied by what additional information?
A description of the revisions.

What does the phrase emergency use of an investigational drug imply, in the FDA’s IND regulations?
Use of a drug in an emergency situation for which an IND application has not yet been filed.

T/F: The terms “treatment protocol” and “treatment IND” are interchangeable and mean the same thing.
False – A treatment protocol is sponsored by a sponsor, while a treatment IND is sponsored by a liscensed medical practitioned who becomes a sponsor-investigator.

T/F: Serious or life-threatening diseases in patients for whom no alternative drug or comparable therapies are available may be evaluated outside of sponsor-planned clinical trials in a treatment protocol.

T/F: “Treatment use” protocols are generally used once a drug’s initial safety in Phase II trials has been demonstrated.

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