CHAPTER § 1.01 FDA Regulation of Investigational New Drugs

• Jurisdiction: United States

§ 1.01 FDA Regulation of Investigational New Drugs

[1] Introduction

Before placing a pharmaceutical on the market in the United States, a manufacturer must receive approval from the U.S. Food and Drug Administration ("FDA" or "the Agency"). FDA's authority to control the introduction and removal of new drugs in interstate commerce is delegated by Congress through the Federal Food, Drug & Cosmetic Act ("FDCA").¹ Two of FDA's primary concerns in considering an application for approval are: "[w]hether the drug is safe and effective for its proposed use(s), and whether the benefits of the drug outweigh its risks."² FDA answers these questions by reviewing the results of clinical trials, when the investigational drug is administered to humans and tested for safety and effectiveness. Clinical trial results "comprise the single most important factor in the approval or disapproval of a new drug."³

While the goal of a clinical trial is to evaluate a new drug, FDA's "overriding consideration" is the safety of the human subjects enrolled in the trial.⁴ As a result, FDA heavily regulates and monitors the clinical trial process, both to ensure that each trial is scientifically sound to generate the necessary data, and to ensure that human subjects are reasonably safe and treated respectfully. FDA recognizes that each new drug has the potential to treat, prevent, or diagnose a specific disease or condition differently, more effectively, or more safely than what is currently on the market. Each new drug also has the potential to introduce harm and substantial risks. One of FDA's most difficult challenges is to balance the need to allow new drugs onto the market as quickly as possible with the need to fully understand the intended and unintended effects of the drug on human health.

This section describes the regime through which FDA regulates clinical trials for new pharmaceuticals.

[2] Investigational New Drug Application

After preclinical work is completed (i.e., nonclinical studies in the laboratory and in animal models), and the "sponsor"⁵ is ready to test the new drug in human subjects, the sponsor must submit to FDA an investigational new drug application ("IND").⁶

Technically, an IND is a request for an exemption from the federal law that prohibits the introduction of unapproved new drugs into interstate commerce.⁷ To be permitted to transport or distribute unapproved drugs across state lines for use in clinical trials, manufacturers must submit IND applications to FDA for review and approval.⁸

There are two categories of INDs: (1) commercial and (2) research (noncommercial). Commercial INDs, the focus of this section, are submitted by companies whose ultimate goal is to market the drug for purchase. However, many INDs are actually approved for non-commercial research, including Investigator INDs, Emergency Use INDs, and Treatment INDs.⁹

FDA grants an IND when the sponsor provides sufficient preclinical data showing that a drug is "reasonably safe for initial use in humans" and "exhibits pharmacological activity that justifies commercial development."¹⁰ Preclinical data usually includes animal pharmacology and toxicology studies. An IND is required to include, among other things: (a) manufacturing information to "ensure that the company can adequately produce and supply consistent batches of the drug," (b) detailed protocols¹¹ of proposed clinical studies to determine "whether the initial-phase trials will expose subjects to unnecessary risks," and (c) information on investigators to assess whether the investigators "are qualified to fulfill their clinical trial duties."¹² FDA has issued written guidance on the appropriate content and format of INDs.¹³

After a sponsor submits an IND, FDA has 30 calendar days to review the submission. If FDA notes any problems with the application, it may place the IND on a "clinical hold."¹⁴ If the sponsor has not heard from FDA within the 30 days, the sponsor may begin clinical trials on day 31, unless a clinical hold has been imposed on the sponsor. Where a clinical hold has been imposed, the sponsor cannot begin a clinical trial until notified by FDA that the hold has been lifted.¹⁵ FDA is also authorized to notify sponsors before the 30-day mark that an IND is granted.¹⁶

[3] Sponsor Responsibilities and Compliance

Clinical trial sponsors take responsibility for and initiate clinical investigations, but generally do not actually conduct the investigations (unless the sponsor is a sponsor-investigator).¹⁷ FDA regulations outline specific clinical trial related responsibilities for sponsors, including staffing the trial with qualified clinical investigators, monitoring the trial's progress, ensuring compliance with the investigational plan and protocol, maintaining the IND, notifying the FDA about adverse effects and risks of the investigational drug, and maintaining adequate records of the trial.¹⁸

[a] Selecting and Informing Investigators

Sponsors are responsible for selecting qualified investigators and for assuring that investigators clearly understand and accept their regulatory obligations.¹⁹ Sponsors must obtain a signed investigator agreement from each investigator and provide the investigators with a brochure that contains: a description of the drug substance and formulation; a summary of the known pharmacological effects, toxicological effects, pharmacokinetics, and biological disposition of the drug in both animals and humans; a summary of data obtained from previous clinical trials concerning safety and effectiveness; and a description of potential risks and side effects that are anticipated based on prior experience with the drug or similar drugs, as well as any precautions or monitoring to be undertaken when using the drug.²⁰ Throughout the course of the clinical investigation, the sponsor must also inform all investigators of new observations, including adverse effects of the drug, by distributing "periodically revised investigator brochures, reprints or published studies, reports or letters to clinical investigators, or other appropriate means."²¹

[b] Monitoring Progress of Investigation

Sponsors are also responsible for monitoring the progress of clinical investigations.²² For example, if a sponsor discovers that an investigator is not properly complying with the IND protocol, the sponsor must either take steps to ensure the investigator's future compliance or terminate the investigator's participation in the clinical trial.²³ The sponsor must also review safety information as reported by the investigators and file safety and annual reports with FDA as appropriate.²⁴ If the sponsor determines that the "investigational drug presents an unreasonable and significant risk to subjects," the sponsor must terminate the clinical trial within 5 days of making this determination and must notify FDA, the Institutional Review Board ("IRB"), and all investigators participating in the trial.²⁵

[c] Filing Reports

FDA requires sponsors to notify the Agency of certain changes to the clinical trial information, to file IND safety reports for certain serious and unexpected suspected adverse events, and to file annual reports of the progress of the investigation.²⁶ Sponsors must file protocol amendments with FDA if they plan to: implement a new protocol; change an existing Phase 1 study protocol²⁷ in a way "that significantly affects the safety of subjects"; change an existing Phase 2 or 3 protocol in a way that "significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study"; or add a new investigator.²⁸

Sponsors are required to monitor and to review safety information related to the investigational drug and to report certain adverse events associated with the investigational drug to both FDA and investigators in IND safety reports.²⁹

FDA also requires sponsors to file annual reports on the progress of the clinical investigation.³⁰ These reports must be filed within 60 days of the yearly anniversary of the IND's effective date and must include summaries of: the status of each study; serious adverse events; IND safety reports filed; subject deaths; subject drop-outs due to adverse events; information learned regarding the investigational drug's actions (e.g., dose response and bioavailability information); preclinical findings; and significant manufacturing or microbiological changes.³¹ The IND annual report should also contain a description of the investigational plan for the upcoming year, copies of any revised investigator brochures, descriptions of any protocol changes not reported in a protocol amendment, and a summary of any developments in foreign marketing activities.³²

Sponsors are required to file information amendments for all other essential information that is not covered by the protocol amendments, IND safety reports, or annual reports.³³ Examples of such essential information include new information regarding the drug's toxicology or chemistry and the discontinuance of an investigation.³⁴

[d] Record Keeping

Sponsors must keep comprehensive records related to the clinical trial that include information regarding the receipt, shipment, and disposition of the investigational drug.³⁵ The sponsor's records should also contain information regarding any financial interest paid to investigators and any other investigator financial interests.³⁶

These records must be kept for 2 years after the drug receives marketing approval, or for 2 years after the investigation is discontinued.³⁷ The sponsor must also allow FDA to access or copy the records and must provide copies of the records upon written request.³⁸

[e] Delegation of Obligations

Sponsors may delegate any or all of their regulatory obligations to a Contract Research Organization ("CRO").³⁹ Transfer of responsibility must be described in writing.⁴⁰ The CRO then assumes legal responsibility to follow the regulations regarding any obligation it agrees to undertake.⁴¹

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