SOCRA_21 CFR 312

"Unexpected" is if it not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application.

Unexpected adverse event or unexpected suspected adverse reaction

This part does not apply to the use in the practice of medicine for an unlabeled indication of a new drug product or of a licensed biological product

Unlabeled indication definition

Investigational New Drug Application

What is 21 CFR 312

an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. Subjects cannot get investigational drug during a hold. No new subjects may be recruited and patients already in the study should be taken off therapy involving the investigational drug.

What is a clinical hold?

1) Drug Substance 2) Drug Product 3) A brief general description of the composition, manufacture, and control of any placebo used in a controlled clinical trial 4) Labeling 5) Environmental analysis requirements

What is included in Chemistry, manufacturing, and control information in an IND?

1) New protocol 2) Changes in a protocol (change in risk, scope of investigation, scientific quality of the study) 3) New Investigator (submit within 30 days) 4) Content and format

When should someone submit a protocol amendment?

**The sponsor should submit to FDA's reviewing division at least 1 month in advance of the meeting with the following information: 1) A brief summary of the clinical studies to be submitted in the application 2) A proposed format for organizing the submission, including methods for presenting the data 3) Information on the status of needed or ongoing pediatric studies 4) Any other information for discussion at the meeting

"Pre-NDA" and "pre-BLA" meetings

1) Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted 2) Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival

"life threatening" means:

1) 30 days after FDA received the IND; or 2) On earlier FDA authorization to ship the drug

A sponsor may ship an investigational new drug to investigators named in the IND:

2 years

A sponsor shall retain the records and reports required by this part for X years after a marketing application is approved for the drug.

5 working days

A sponsor who determines that its investigational drug presents an un reasonable and significant risk to subjects shall discontinue those investigations that present the risk, notify FDA, all IRBs and all investigators who have at any time participated in the investigation of the discontinuance. The sponsor shall discontinue the investigation as soon as possible, and in no event later than X working days.

1) An explanation why the sponsor's compliance with the requirement is unnecessary or cannot be achieved 2) A description of an alternative submission or course of action that satisfies the purpose of the requirement 3) Other information justifying a waiver (FDA may grant a waiver if it finds that the sponsor's noncompliance would not pose a significant and unreasonable risk to human subjects of the investigation and that one of the following is met:1) The sponsor's compliance with the requirement is unnecessary for the agency to evaluate the application, or compliance cannot be achieved 2) The sponsor's proposed alternative satisfies the requirement or 3) The applicant's submission otherwise justifies a waiver

A waiver request is required to contain at least one of the following:

any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.

Adverse Event

1) 30 days after FDA receives the IND, unless FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold 2) On earlier notification by FDA that the clinical investigations in the IND may begin. FDA will notify the sponsor in writing of the date it receives the IND

An IND goes into effect:

1) The sponsor of the investigation submits an IND for the drug to FDA 2) Each participating investigator conducts his or her investigation in compliance with the requirements of this part and parts 50 and 56

An investigational new drug may be used in a clinical investigation if the following conditions are met:

Needs to be submitted within 60 days of the anniversary date that the IND went into effect. 1) Individual study information 2) Summary information 3) A description of the general investigational plan for the coming year to replace that submitted 1 year earlier 4) If the investigator brochure has been revised, a description of the revision and a copy of the new brochure. 5) 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. 6)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 7) A log of any outstanding business with respect to the IND for which the sponsor requests or expects a reply, comment or meeting

Annual reports should include:

The applicability of this part to in vivo bioavailability studies in humans

Bioavailability indication definition

1) There is reasonable evidence the investigation that is not designed to be adequate and well-controlled is impeding enrollment in, or otherwise interfering with the conduct or completion of, a study that is designed to be an adequate and well-controlled; 2) Insufficient quantities of the investigational drug exist to adequately conduct both the investigation that is not designed to be adequate and well-controlled and the investigations that are designed to be adequate and well-controlled 3) The drug has been studied in one or more adequate and well-controlled investigations that strongly suggest lack of effectiveness 4) Another drug under investigation or approved for the same indication and available to the same patient population has demonstrated a better potential benefit/risk balance 5) The drug has received marketing approval for the same indication in the same patient population 6) The sponsor of the study that is designed to be an adequate and well-controlled investigation is not actively pursuing marketing approval of the investigational drug with due diligence

Clinical hold of any study that is not designed to be adequate and well-controlled

any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice

Clinical investigation definition

a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the FDA

Contract research organization (CRO)

A sponsor shall ship investigational new drugs only to investigators participating in the investigation

Control of drug

If all investigations covered by an IND remain on clinical hold for 1 year or more, the IND may be placed on inactive status by FDA

Conversion of IND on clinical hold to inactive status

Whenever FDA concludes that a deficiency exists in a clinical investigation that may be grounds for the imposition of clinical hold FDA will, unless patients are exposed to immediate and serious risk, attempt to discuss and satisfactorily resolve the matter with the sponsor before issuing the clinical hold order

Discussion of deficiency

Is designed primarily for IND;s involving new molecular entities or major new uses of marketed drugs, a sponsor of any IND may request and obtain an end of phase 2 meeting

Eligibility for "end of Phase 2" meetings

1) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug 2) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product 3) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product 4) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 and with the requirements for informed consent 5) The investigation is conducted in compliance with the requirements.

Exemptions (1-The clinical investigation of a drug product that is lawfully marketed in the US is exempt from the requirements of this part if all the following apply):

An investigational new drug may be exported from the USA for use in a clinical investigation under any of the following conditions: 1) An IND is in effect for the drug, the drug complies with the laws of the country to which it is being exported, and each person who received the drug is an investigator in a study submitted to and allowed to proceed under the IND 2) The drug has valid marketing authorization in Australia, Canada, Israel, Japan, New Zealand, Switzerland, South Africa or in any country in the European Union or the European Economic Area and complies with the laws of the country to which it is being exported 3) The drug is being exported to Australia, Canada, Israel, Japan, New Zealand, Switzerland, South Africa, or to any country in the European Union or the European Economic Area, and complies with the laws of the country to which it is being exported, the applicable provisions. Drugs exported under this paragraph that are not the subject of an IND are exempt from the label requirement 4) The person exporting the drug sends a written certification to the Office of International Programs, Food and Drug Admin, at the time the drug is first exported and maintains records doc

Exports Requirements

1) Any of the conditions for phase 1 2) The investigational plan or protocol(s) is not reasonable as a bona fide scientific plan to determine whether or not the drug is safe and effective for use 3) There is convincing evidence that the drug is not effective for the purpose for which it is being investigated

FDA may propose to terminate an IND during Phase 2 or 3 if FDA finds that:

Ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation. Obtain the informed consent of each human subject,

General responsibilities of investigators:

1) Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury 2) The clinical investigators named in the IND are not qualified by reason of their scientific training and experience to conduct the investigation described in the IND. 3) The investigator brochure is misleading, erroneous, or materially incomplete 4) The IND does not contain sufficient information to assess the risks to subjects of the proposed studies 5) The IND is for the study of an investigational drug intended to treat a life-threatening disease or condition that affects both genders and men or women with reproductive potential who have the disease or condition being studied are excluded from eligibility because of a risk or potential risk from use of the investigational drug of reproductive toxicity or developmental toxicity.

Grounds for Clinical hold of a Phase 1 study under an IND:

1) Any of the conditions in Phase 1 2) The plan or protocol for the investigation is clearly deficient in design to meet its stated objectives

Grounds for Clinical hold of a Phase 2 study under an IND:

1) FDA may place a proposed expanded access IND or treatment use protocol on clinical hold if it is determined that: A) The pertinent criteria in subpart I of this part for permitting the expanded access use to begin are not satisfied or B) The expanded IND or expanded access protocol does not comply with the requirements for expanded access

Grounds for Clinical hold of a Phase 3 study under an IND

1) Human subjects would be exposed to an unreasonable and significant risk of illness or injury 2)The IND does not contain sufficient information required to assess the safety to subjects of the clinical investigations 3) The methods, facilities, and controls used for the manufacturing, processing, and packing of the investigational drug are inadequate to establish and maintain appropriate standards of identity, strength, quality, and purity as needed for subject safety 4) The clinical investigations are being conducted in a manner substantially different than that described in the protocols submitted in the IND 5) The drug is being promoted or distributed for commercial purposes not justified by the requirements of the investigation 6) The IND , or any amendment or report to the IND, contains an untrue statement of a material fact or omits material information required by this part 7) The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences or fails to make any other report required 8) The sponsor fails to submit an accurate annual report of the investigations 9) The sponsor fails to comp

Grounds for termination of an IND in Phase 1

FDA may, on its own initiative, issue guidance on the applicability of this part to particular investigational uses of drugs. On request, FDA will advise on the applicability of this part to a planned clinical investigation

Guidance definition

1) 2 YEARS 2) 1 YEAR The sponsor shall have 30 days to respond as to why the IND should continue to remain active. *An IND that remains on inactive status for 5 years or more may be terminated

If no subjects are entered into clinical studies for a period of __ years or more under an IND, or if all investigations under an IND remain on a clinical hold for __ year or more, the IND may be placed by FDA on inactive status.

An investigational new drug offered for import into the USA complies with the requirements of this part if it is subject to an IND that is in effect and 1) The consignee in the USA is the sponsor of the IND 2) The consignee is a qualified investigator named in the IND 3) The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the investigational drug, and the IND identifies the consignee and describes what actions the consignee will take with respect to the drug

Imports Requirements

The clinical hold order may be made by telephone or other means of rapid communication or in writing. The clinical hold order will identify the studies under the IND to which the hold applies, and will briefly explain the basis for the action. As soon as possible, and no more than 30 days after the imposition of the clinical hold, the Division Director will provide the sponsor a written explanation of the basis for the hold.

Imposition of clinical hold

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 4) List of subjects who dropped out during the investigation in association with any adverse experience, whether or not thought to be drug-related 5) A brief description of what 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

In an Annual Report, what is included in the Summary Information?

a review panel that is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection. An institutional review board (IRB) of this chapter and subject to the requirements of part 56 of this chapter, is one type of IEC

Independent ethics committee (IEC)

At least 1 month in advance of an end of Phase 2 meeting, the sponsor should submit background information on the sponsor's plan for Phase 3, including summaries of the Phase 1 and 2 investigations, the specific protocols for Phase 3 clinical studies, plans for any additional nonclinical studies, plans for pediatric studies, including a time line for protocol finalization, enrollment, completion, and data analysis, or information to support any planned request for waiver or deferral of pediatric studies, and tentative labeling for the drug.

Information regarding "end of Phase 2" meetings

1) Cover sheet 2) A table of contents 3) Introductory statement and general investigational plans 4) - 5) Investigator's brochure 6) Protocols 7) Chemistry, manufacturing, and control information 8) Pharmacology and toxicology 9) Previous human experience with the investigational drug

Investigational New Drug Application in the following order:

a new 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. The term "investigational drug" and "investigational new drug" are deemed to be synonymous for purposes of this part

Investigational new drug definition

An investigator shall provide the sponsor with an adequate report shortly after completion of the investigator's participation in the investigation.

Investigator Final Reports

The clinical investigator shall provide the sponsor with sufficient accurate financial information to allow an applicant to submit complete and accurate certification or disclosure statements. The investigator shall promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following the completion of the study.

Investigator Financial disclosure reports

The investigator shall furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained. The sponsor is required to submit annual reports to FDA on the progress of the clinical investigations.

Investigator Progress reports

An investigator must immediately report to the sponsor any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event. The investigator must record nonserious adverse events and report them to the sponsor according to the timetable for reporting specified in the protocol.

Investigator Safety Reports

an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. "Subinvestigator" includes any other individual member of that team

Investigator definition

-Investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. -maintain adequate records of case histories and observations and other data pertinent to the investigation -Maintain and retain records for 2 years following the date a marketing application is approved

Investigator recordkeeping and record retention

"Caution: New Drug--Limited by Federal (or United Staes) law to investigational use."

Labeling of an investigational new drug needs to have a statement saying...

an occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.

Life-Threatening adverse event or life-threatening suspected adverse reaction

an application for a new drug submitted or a biologics license application for a biological product submitted under the Public Health Service Act.

Marketing application definition

1) A signed investigator statement containing a) The name and address of the investigator b) The name and code number of the protocol(s) in the IND identifying the study(ies) to be conducted by the investigator c)The name and address of any medical school, hospital, or other research facility where the clinical investigation(s) will be conducted d) The name and address of any clinical laboratory facilities to be used in the study e) The name and address of the IRB that is responsible for review and approval of the study(ies) f) A commitment by the investigator that he or she: 1) only make changes in a protocol after notifying the sponsor 2) comply with all requirements regarding the obligations of clinical investigators 3) Will personally conduct or supervise the described investigation 4) Will inform any potential subjects that the drugs are being used for investigational purposes and will ensure that the requirements relating to obtaining informed consent and IRB review and approval are met 5) Will report to the sponsor adverse experiences that occur in the course of the investigation(s) 6) Has read and understands the information in the investigator's brochure, including the potent

Obtaining information from the investigator (Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following)

1) If FDA proposes to terminate an IND, FDA will notify the sponsor in writing, and invite correction or explanation within a period of 30 days. 2) The sponsor's request for a regulatory hearing must be made within 10 days of the sponsor's receipt of FDA's notification of non-acceptance. Immediate termination of IND is possible if there is substantial danger to the health of individuals.

Opportunity for sponsor response to termination of IND

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 gain early evidence on effectiveness. 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. 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.

Phase 1 Clinical Trial

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. This phase is typically well-controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects.

Phase 2 Clinical Trial

This phase study expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting the 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. Usually includes several hundred to several thousand subjects.

Phase 3 Clinical Trial

to determine the safety of proceeding to Phase 3, to evaluate the Phase 3 plan and protocols and the adequacy of current studies and plans to assess pediatric safety and effectiveness, and to identify any additional information necessary to support a marketing application for the uses under investigation

Purpose of "End of Phase 2" meetings

1) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug that is subject to 312.2 2) A sponsor shall not begin a clinical investigation subject to 312.2 until the investigation is subject to an IND which is in effect in accordance with 312.40 3) A sponsor shall submit a separate IND for any clinical investigation involving an exception from informed consent under 50.24. Such a clinical investigation is not permitted to proceed without the prior written authorization from FDA. FDA shall provide a written determination 30 days after FDA receives the IND or earlier.

Requirement for an IND

A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug

Selecting investigators

Results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. The event may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples are allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization or the development of drug dependency or drug abuse.

Serious adverse event or serious suspected adverse reaction

A person may export an investigational new drug provided that he or she: 1) Provides a written statement explaining why compliance with each such paragraph is not feasible or is contrary to the best interests of the individuals who may receive the investigational new drug 2) Provides a written statement from an authorized official of the importing country's government. The statement must attest that the official agrees with the exporter's statement; explain that the drug is to be stockpiled solely for use of the importing country in a national emergency; and describe the potential national emergency that warrants exportation of the investigational new drug under this provision 3) Provides a written statement showing that the Secretary of Health and Human Services (the Secretary) or his or her designee, agrees with the findings of the authorized official of the importing country's government.

Situations where the investigational new drug is to be stockpiled in anticipation of a national emergency

a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.

Sponsor definition

an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those applicable to an investigator and a sponsor.

Sponsor-Investigator definition

a human who participates in an investigation, either as a recipient of the investigational new drug or as a control. A subject may be a healthy human or a patient with a diease.

Subject definition

any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable possibility" means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse reaction, which means any adverse event caused by a drug.

Suspected adverse reaction

1) name, address, and telephone number of the sponsor, the date of the application, and the name of the investigational new drug 2) Identification of the phase or phases of the clinical investigation to be conducted 3) A commitment not to begin clinical investigations until an IND covering the investigations is in effect 4) A commitment that in IRB that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of each of the studies in the proposed clinical investigation and that the investigator will report to the IRB proposed changes in the research activity in accordance with the requirements of part 56 5) A commitment to conduct the investigation in accordance with all other applicable regulatory requirements 6) The name and title of the person responsible for monitoring the conduct and progress of the clinical investigations 7) The name(s) and title(s) of the person(s) responsible under 312.32 for review and evaluation of information relevant to the safety of the drug 8) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, a statement containing the n

What is included in an IND cover sheet

1) A brief description of the drug substance and the formulation, including the structural formula, if known. 2) A summary of the pharmacological and toxxicological effects of the drug in animals and, to the extent knownin humans 3) A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans 4) A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies 5) A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug

What is included in an Investigator's Brochure

1) A statement of the objectives and purpose of the study 2) The name and address and a statement of the qualifications of each investigator, and the name of each sub investigator 3) The criteria for patient selection and for exclusion of patients and an estimate of the number of patients to be studied 4) A description of the design of the study, including the kind of control group to be used, if any, and a description of methods to be used to minimize bias on the part of subjects, investigators, and analysis. 5) The method for determining the dose(s) to be administered, the planned max dosage, and the duration of individual patient exposure to the drug 6) A description of the observations and measurements to be made to fulfill the objectives of the study 7) A description of clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug in human subjects and to minimize risk.

What is included in the protocol section of an IND

should be held before major commitments of effort and resources to specific Phase 3 tests are made. The scheduling of an of Phase 2 meeting is not, however, intended to delay the transition of an investigation from Phase 2 to 3.

What is the timing for "end of Phase 2" meetings

Immediately, but no later than 15 calendar days.

When does an IND safety report of potential serious risks need to be reported to a sponsor?

Immediately, but no later than 15 calendar days.

When does an IND safety report of potential serious risks need to be reported to the FDA?

Immediately, but no later than 7 calendar days

When does an unexpected fatal or life-threatening suspected adverse reaction report need to be submitted to the FDA?