IND Application Subparts Quick & Dirty

drug-safetyThe U.S. Code of Federal Regulation (CFR), Title 21 Food and Drugs, Chapter 1 Food and Drug Administration (FDA), Department of Health and Human Services, Sub chapter D Drugs for Human Use, part 312 Investigational New Drug (IND) Application outlines the regulation around new drug development and clinical research. Specifically part 312.3 defines, “Clinical investigation means 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.”

Part 312 is made up of subparts A through I. Here’s a quick look at what’s included in each of those subparts.

Subpart A – General Provisions: The Scope of the general provisions section is to outline the procedures and requirements governing the use of investigational new drugs, including the procedures and requirements for the INDs submission and review by the FDA.  The Applicability section informs which specific clinical investigations these requirements applies to. The Definitions and interpretations of the terms applied include: clinical investigation, Contract Research Organization, FDA, IND, Independent ethics Committee (IEC), Investigational new drug, Investigator, marketing application, Sponsor, Sponsor-Investigator, and Subject. The Labeling of an investigational new drug section includes specific language and requirements for the package of an investigational new drug intended for humans. The Promotion of Investigational drugs section states that INDs cannot be misrepresented as “safe and effective”, “commercially distribute” or a part of a “prolonging” of an investigation. Charging for the investigational drugs under an IND section outlines the criteria for, the allowable duration, and the applicable recoverable costs. The criteria for waivers of applicable requirements are outlined in the Waivers section.

Subpart B – Investigational New Drug Application: The Requirement for an IND section outlines which clinical investigations are subject to submit an IND application. The Phases of an investigation  for a clinical investigation are “generally divided into three phases” and “conducted sequentially”. The purpose and typical number of subjects afor the different phases are outlined here. General principles of the IND submission section goes through the FDA’s primary objectives when reviewing the IND, the amount of information to be submitted, their central focus, and generally the set format. The IND Content and format section (exceptions for Phase I) outlines the required content for submission and format order: cover sheet, table of contents, introductory statement, Investigational Brochure (IB), Protocol (see draft strategy guide), Chemistry, manufacturing, and control information, pharmacology and toxicology information, Previous human experience, Additional information, and Relevant information. Protocol amendments section outlines impacting events within the life cycle of a protocol that would require an amendment of that protocol to be submitted for review. The IND safety reporting section defines the important applicable terms: Adverse Event, Life-threatening Adverse Event or Life-threatening suspected adverse Reaction, Serious Adverse Event or Serious Suspected Adverse Reaction, Suspected adverse Reaction, Unexpected Adverse Event or Unexpected Suspected Adverse Reaction. Also included in this section is the sponsor’s requirements for the review of safety information and the reporting requirements for IND safety reports. The Annual reports section states the sponsor is required to “submit a brief report of the progress of the investigation” this is to be done “within 60 days of the anniversary date that the IND went into effect”. The report contents are outlined in this section and include: individual study information, summary information, a description of the investigational plan, possible revised IB, possible significant protocol changes, summary of significant foreign marketing developments, and any possible outstanding IND business in respect to the FDA. The last section being Withdrawal of an IND outlines the notification requirements if an IND is withdrawn.

Subpart C – Administrative Actions: The General Requirements for use of an investigational new drug in a clinical investigation section states the conditions in which a new drug may be used in a clinical investigation, and when the IND can be anticipated as goes into effect and contingently the IND can be shipped to the named investigators. The FDA Comment and advice on an IND deficiencies are included in this section, stating when, how this communication can be expected and the required action for “comments” versus “advice” versus a “clinical hold”. Clinical holds and requests for modifications are defined in this section along with sponsor response process and options. Termination is  defined in this section along with sponsor response process and options. Inactive status is defined in this section along with the process that can be either initiated by the FDA, or on the request of the sponsor. Meetings are explained in this section as “frequently useful in resolving questions and issues raised during the course of a clinical investigation”, along with possible reasons to request one. Dispute resolution are similarly explained in this section as viewed by the FDA reviewing divisions to be done “as quickly and amicably as possible through the cooperative exchange” for different outlined scenarios.

Subpart D – Responsibilities of Sponsor and Investigators: The General responsibilities of sponsors are outlined in this first section. The terms of Transferring obligations to a contract research organization are then stated in the following section and that they must be stated in writing. The Selecting investigators and monitors section outlines the requirements for the sponsor when they are selecting these participating parties. The Emergency research under 50.24 section outlines the sponsor responsibilities for monitoring investigators with an exception under 50.24. The Informing investigators section states the sponsors required commitment to keep the investigator informed of new observations an discoveries especially concerning safety. The Review of ongoing investigators section outlines the sponsors responsibility to monitor and evaluate participating investigators along with any required action for non-compliance. The Recordkeeping and record retention section outlines sponsor responsibilities in terms of drug shipment records to the investigator, financial interest, along with the required duration for record retention and test article. The Inspection of sponsor’s records and reports section outlines FDA rights to inspection of clinical investigation records, including drug shipment and control records. The Disposition of unused supply of investigational drug outlines the sponsor’s responsibilities for drug control once the investigation is discontinued or terminated. The General responsibilities of investigators are stated in this section as “ensuring that an investigation is conducted according to the signed investigator statement” and in accordance with parts 50 and 56 including “obtain the informed consent of each human subject to whom the drug is administered”. The Control of the investigational drug states “that investigator shall administer the drug only to subjects under the investigator’s personal supervision”. The Investigators record keeping and retention outlines responsibilities in respect to the disposition of drug, case histories, and record retention. The Investigator reports outlines responsibilities to submit to the sponsor required progress report, safety reports, final report, and financial disclosure reports. The Assurance of IRB review outlines the investigator responsibility to assure that the IRB complies with its responsibilities to the clinical study review and oversight. The Inspection of investigator’s records and reports states the FDA’s right to inspect participant investigator’s records and reports. Handing of controlled substances states the associated responsibilities “if the investigational drug is subject to the Controlled Substances Act”. The Disqualification of a clinical investigator outlines the process and procedure for the possible disqualification of an identified clinical investigator.

Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses: The Purpose section states “the purpose of this section is to establish procedures designed to expedite the development, evaluation, and marketing of new therapies intended to treat persons with life-threatening and severely-debilitating illnesses, especially where no satisfactory alternative therapy exists.” The Scope outlines which drugs this applies to along with definitions for section terms. Early Consultation section refers to drug development lifecycle stages in which meeting to consult with the FDA is appropriate. The Treatment protocols section states “If the preliminary analysis of phase 2 test results appears promising, FDA may ask the sponsor to submit a treatment protocol to be reviewed”. The Risk-benefit analysis in review of marketing application for drugs to treat life-threatening and severely debilitation illnesses section outlines to process and procedures for this specific review. The Phase 4 studies section outlines possible FDA request for additional post marketing studies concurrent with marketing approval. The Focused FDA regulatory research section outlines the possibility of a request for these types of additional studies. The Active monitoring of conduct and evaluation fo clinical trials section states “For drugs covered under this section, the Commissioner and other agency officials will monitor the progress of the conduct and evaluation of clinical trials and be involved in facilitating their appropriate progress.” The Safeguard for patient safety states for drugs covered under this section “All of the safeguards incorporated within parts 50, 56, 312, 314, and 600 of this chapter designed to ensure the safety of clinical testing and the safety of products following marketing approval apply”.

Subpart F – Miscellaneous: The section Import and export requirements outline those in terms of shipment of the investigational product. The Foreign clinical studies not conducted under an IND section states the conditions in which the FDA will accept support for an IND or application for marketing approval. The Availability for public disclosure of data and information in an IND section outlines the terms in the FDA’s disclosure agreement with the sponsor. The Address for correspondence includes appropriate divisions and their associated address for correspondence. The Guidance documents section states the availability of various FDA guidance documents to assist with compliance with certain requirements.

Subpart G – Drugs for Investigational Use in Laboratory Research Animals or In Vitro Tests: The section, Drugs for investigational use in laboratory research animals or in vitro tests outlines the provisions associated with FDA “Authorization to ship”, “Termination of authorization to ship”, “Disposition of unused drug”.

Subpart H – Reserved

Subpart I – Expanded Access to Investigational Drugs for Treatment Use: The General section outlines the scope of “this subpart contains requirements for the use of investigational new drugs and approved drugs where availability is limited by a risk evaluation and mitigation strategy (REMS) when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition; and defines both: immediately life-threatening disease or condition and serious disease or condition. The Requirements for all expanded access uses section outlines the FDA “criteria, submission requirements, safeguards, and beginning treatment information set out” as applicable to all expanded access uses described in this subpart.” The Individual patients including for emergency use section outlines the FDA criteria in which the “FDA may permit an investigational drug to be used for the treatment of an individual patient by a licensed physician.” The Intermediate size patient populations section outlines criteria in which the “FDA may permit an investigational drug to be used for the treatment of a patient population smaller than that typical of a treatment IND or treatment protocol.” The Treatment IND or treatment protocol section criteria in which the “FDA may permit an investigational drug be used for widespread treatment use.”