Investigational New Drug Application Flashcards
An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug
is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. These three
phases of an investigation are a follows:
(a) Phase 1. (1) Phase 1 includes the initial introduction of an investigational new drug into humans. Phase 1 studies are
typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to
determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses,
and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug’s pharmacokinetics
and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The
total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80.
(2) Phase 1 studies also include studies of drug metabolism, structure-activity relationships, and mechanism of action in
humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease
processes.
(b) Phase 2. Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a
particular indication or indications in patients with the disease or condition under study and to determine the common short-term
side effects and risks associated with the drug. Phase 2 studies are typically well controlled, closely monitored, and conducted in a
relatively small number of patients, usually involving no more than several hundred subjects.
(c) Phase 3. Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence
suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness
and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for
physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects.
What are the FDA’s primary objectives in reviewing an IND in all phases of the investigation?
To assure the safety and rights of subjects
What are the FDA’s primary objectives in reviewing an IND in Phase 2 and 3
help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drugs effectiveness and safety.
What is the central focus of the initial IND submission?
general investigational plan nd protocols for specific human studies
A sponsor shall report in an information amendment essential information on the
IND that is not within the scope of a protocol amendment, IND safety reports, or annual report. Examples of information requiring
an information amendment include:
(1) New toxicology, chemistry, or other technical information; or
(2) A report regarding the discontinuance of a clinical investigation.
An information amendment is required to bear prominent identification
of its contents (e.g., “Information Amendment: Chemistry, Manufacturing, and Control”, “Information Amendment: PharmacologyToxicology”, “Information Amendment: Clinical”), and to contain the following:
(1) A statement of the nature and purpose of the amendment.
(2) An organized submission of the data in a format appropriate for scientific review.
(3) If the sponsor desires FDA to comment on an information amendment, a request for such comment.
(c) When submitted. Information amendments to the IND should be submitted as necessary but, to the extent feasible, not
more than every 30 days.
IND safety reports. The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the
sponsor is providing drug under its INDs or under any investigator’s IND) in an IND safety report of potential serious risks, from
clinical trials or any other source, as soon as possible, but in no case later than _________ calendar days after the sponsor determines
that the information qualifies for reporting
15
The sponsor must submit each IND safety report in a narrative format or on FDA Form
3500A or in an electronic format that FDA can process, review, and archive. FDA will periodically issue guidance on how to
provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files). The
sponsor may submit foreign suspected adverse reactions on a Council for International Organizations of Medical Sciences
(CIOMS) I Form instead of a FDA Form 3500A. Reports of overall findings or pooled analyses from published and unpublished in
vitro, animal, epidemiological, or clinical studies must be submitted in a narrative format. Each notification to FDA must bear
prominent identification of its contents, i.e., “IND Safety Report,” and must be transmitted to the review division in the Center for
Drug Evaluation and Research or in the Center for Biologics Evaluation and Research that has responsibility for review of the IND.
Upon request from FDA, the sponsor must submit to FDA any additional data or information that the agency deems necessary, as
soon as possible, but in no case later than _________ calendar days after receiving the request.
15
The sponsor must also notify FDA of any
unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than __________ calendar days after
the sponsor’s initial receipt of the information.
7
If the results of a sponsor’s investigation show that an adverse event not initially determined to be reportable under
paragraph (c) of this section is so reportable, the sponsor must report such suspected adverse reaction in an IND safety report as
soon as possible, but in no case later than ______ calendar days after the determination is made
15
A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief report of the progress of
the investigation that includes:
(a) Individual study information. A brief summary of the status of each study in progress and each study completed during the
previous year.
(b) Summary information. Information obtained during the previous year’s clinical and nonclinical investigations,
(d) If the investigator brochure has been revised, a description of the revision and a copy of the new brochure.
(e) A description of any significant Phase 1 protocol modifications made during the previous year and not previously reported
to the IND in a protocol amendment.
(f) A brief summary of significant foreign marketing developments with the drug during the past year, such as approval of
marketing in any country or withdrawal or suspension from marketing in any country.
(g) If desired by the sponsor, a log of any outstanding business with respect to the IND for which the sponsor requests or
expects a reply, comment, or meeting.
(a) Individual study information. A brief summary of the status of each study in progress and each study completed during the
previous year. The summary is required to include the following information for each study:
(1) The title of the study (with any appropriate study identifiers such as protocol number), its purpose, a brief statement
identifying the patient population, and a statement as to whether the study is completed.
(2) The total number of subjects initially planned for inclusion in the study; the number entered into the study to date,
tabulated by age group, gender, and race; the number whose participation in the study was completed as planned; and the
number who dropped out of the study for any reason.
(3) If the study has been completed, or if interim results are known, a brief description of any available study results.
(b) Summary information. Information obtained during the previous year’s clinical and nonclinical investigations, including:
(1) A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system.
(2) A summary of all IND safety reports submitted during the past year.
(3) A list of subjects who died during participation in the investigation, with the cause of death for each subject.
(4) A list of subjects who dropped out during the course of the investigation in association with any adverse experience,
whether or not thought to be drug related.
(5) A brief description of what, if anything, was obtained that is pertinent to an understanding of the drug’s actions, including,
for example, information about dose response, information from controlled trials, and information about bioavailability.
(6) A list of the preclinical studies (including animal studies) completed or in progress during the past year and a summary of
the major preclinical findings.
(7) A summary of any significant manufacturing or microbiological changes made during the past year.
what is 312.38
withdrawal of IND
(a) An investigational new drug may be used in a clinical investigation if the following conditions are met:
(1) The sponsor of the investigation submits an IND for the drug to FDA; the IND is in effect under paragraph (b) of this
section; and the sponsor complies with all applicable requirements in this part and parts 50 and 56 with respect to the conduct of
the clinical investigations; and
(2) Each participating investigator conducts his or her investigation in compliance with the requirements of this part and parts
50 and 56.
