Chapter Seventeen

Investigational Drugs

Bambi Grilley

Learning Objectives

After completing this chapter, the reader will be able to

• List the major legislative acts that led to the current system of drug evaluation, approval, and regulation used in the United States (U.S.).

• List the steps in the drug approval process.

• List the components of an investigational new drug application (IND).

• Recognize the difference between a commercial IND, a treatment IND, an emergency use IND, and an individual investigator IND.

• Define orphan drug status and list the advantages of classifying a drug as an orphan drug.

• List all of the requirements (as specified by the Office of Human Research Protections [OHRP]) for an institutional review board (IRB).

• Prepare appropriate reviews of protocols for use by the IRB or other review committees when they evaluate new protocols.

• Describe the type of support that is necessary for clinical research, including (but not limited to):

    a. Ordering drug supplies for ongoing clinical trials

    b. Maintaining drug accountability records as required by the Food and Drug Administration (FDA)

    c. Preparing drug and protocol data sheets for use by health care personnel in the hospital

    d. Preparing pharmacy budgets for sponsored clinical research

    e. Aiding investigators in designing and conducting clinical trials in their institution

    f. Assisting investigators in initiating and conducting clinical trials (including emergency use INDs)

Key Concepts

Introduction

It is estimated that $802 million is spent to get a new drug product to market in the United States.^1,2 Although there is some controversy surrounding these estimates, more recent research indicates this number may be even higher, costing on average $868 million and ranging from $500 million to more than $2 billion.^3,4 Previous data have indicated that for every 4000 products synthesized in the lab, only five will ever be tested in humans and only one of those will ever reach the market.⁵ Currently the Pharmaceutical Research and Manufacturers of America (PhRMA) database is tracking 2900 new medicines in development with more than $49 billion invested in research and development (R&D) in 2011.⁶ This should be compared to 35 novel drugs approved by the Food and Drug Administration (FDA) in 2012.⁷ The FDA is the federal agency that decides which drugs, biologics, and medical devices are marketed in the United States. In fact, the FDA monitors the manufacture, import, transport, storage, and sale of $1 trillion worth of goods annually.⁸ The centers of the FDA involved in regulating drugs, biologics, and medical devices used in humans are as follows:

     • Center for Biologics Evaluation and Research (CBER)

     • Center for Drug Evaluation and Research (CDER)

     • Center for Devices and Radiological Health (CDRH)⁹

Since this book deals with drug related information, this chapter will concentrate only on the regulations associated with CBER and CDER.

Since 1940, more than a 1000 new molecular entities (NMEs) have been approved in the United States.¹⁰ It is very important that the clinical trials upon which the FDA will base their decisions be both scientifically accurate and complete. Pharmacists can play an important role in ensuring that the clinical trials conducted at their institutions meet the goals set forth by the study sponsor, the local investigator, and ultimately the FDA.

Currently, most research conducted on investigational drugs is performed in medical schools, hospitals, and organizations specifically designed to conduct clinical research trials. In some institutions, a pharmacist will be hired specifically to handle investigational drugs. More frequently, however, this role falls to other health care providers. To successfully manage investigational drugs, this individual or team of individuals must be a bookkeeper, inventory control manager, and, most importantly, an information disseminator. Before proceeding, it is necessary to define a number of terms that will be used in this chapter.

Definitions

Biologics license application (BLA): A biologics license application is a submission that contains specific information on the manufacturing processes, chemistry, pharmacology, clinical pharmacology, and the medical effects of the biologic product. It is a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce.¹¹

Clinical investigation: Any experiment in which a drug is administered or dispensed to one or more human subjects. An experiment is any use of a drug (except for the use of a marketed drug) in the course of medical practice. Although there are many other definitions, this is the FDA’s definition and would seem the appropriate one to use given the nature of this topic. Please note that the FDA does not regulate the practice of medicine and prescribers are (as far as the agency is concerned) free to use any marketed drug for off-label use.¹²

Commercial IND: An IND for which the sponsor is usually either a corporate entity or one of the institutes of the National Institutes of Health (NIH). In addition, CDER may designate other INDs as commercial, if it is clear the sponsor intends the product to be commercialized at a later date.¹³

Control group: The group of test animals or humans that receive a placebo (a dosage that does not contain active medicine) or active (a dosage that does contain active medicine) treatment. For most preclinical and clinical trials, the FDA will require that this group receive placebo (commonly referred to as the placebo control). However, some studies may have an active control, which generally consists of an available (standard of care) treatment modality. An active control may, with the concurrence of the FDA, be used in studies where it would be considered unethical to use a placebo. A historical control is one in which a group of previous patients is compared to a matched set of patients receiving the new therapy. A historical control might be used in cases where the disease is consistently fatal (i.e., acquired immunodeficiency syndrome [AIDS]). (Refer to Chapter 4 for additional information on control groups.)¹⁴

Contract research organization (CRO): An individual or organization that assumes one or more of the obligations of the sponsor through an independent contractual agreement.¹²

Drug master file (DMF): A submission to the FDA that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.¹⁵

Drug product: The final dosage form prepared from the drug substance.¹⁶

Drug substance: An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body.¹⁶

Food and Drug Administration (FDA): The agency of the U.S. government that is responsible for ensuring the safety and efficacy of all drugs on the market in the United States.⁸

Good clinical practice (GCP): A standard for the design, conduct, monitoring, analyses, and reporting of clinical trials that provides assurance that the results are credible and accurate, and that the rights of study subjects are protected.¹⁷

Institutional review board (IRB): A committee of reviewers that evaluates the ethical implications of a clinical study protocol.^18,19

Investigational new drug: A drug, antibiotic, or biologic that is used in a clinical investigation. The label of an investigational drug must bear the statement: “Caution: New Drug—Limited by Federal (or U.S.) law to investigational use.”¹²

Investigational new drug application (IND): A submission to the FDA containing chemical information, preclinical data, and a detailed description of the planned clinical trials. Thirty days after submission of this document to the FDA by the sponsor, clinical trials may be initiated in humans, unless the FDA places a clinical hold. When the FDA allows the studies to proceed, this document allows unapproved drugs to be shipped in interstate commerce.¹²

Investigator: The individual responsible for initiating the clinical trial at the study site. This individual must treat the patients, ensure that the protocol is followed, evaluate responses and adverse reactions, ensure proper conduct of the study, and solve problems as they arise.¹²

New drug application (NDA): The application to the FDA requesting approval to market a new drug for human use. The NDA contains data supporting the safety and efficacy of the drug for its intended use.^12,16

New molecular entity (NME): A compound that can be patented and has not been previously marketed in the United States in any form.²⁰

Regulatory project manager (RPM): This will be the sponsor’s (see below) primary FDA contact person. Each application that is submitted is assigned a regulatory project manager (RPM). Contact information for the RPM is provided in the letter sent to the applicant acknowledging receipt of the application. If the RPM is changed during the course of the review, the applicant is notified by the new RPM.²¹

Sponsor: An organization (or individual) who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, government agency, academic institution, private organization, or other organization.¹²

Sponsor-investigator: An individual who both initiates and conducts a clinical investigation (i.e., submits the IND and directly supervises administration of the drug as well as other investigator responsibilities).¹²

Subject: An individual who participates in a clinical investigation (either as the recipient of the investigational drug or as a member of the control group).¹²

History of Drug Development Regulation in the United States

For more than a century after the Declaration of Independence, drug products were not regulated in the United States. Available drugs were often ineffective, but some were addictive, toxic, or even lethal. During this same period, physicians were not licensed and nearly anyone could practice medicine. The public was, for the most part, responsible for using common sense when evaluating which products they would use.

The evolution of drug regulations in this country is a study in human tragedy. Crises have instigated the development of many of the laws regulating drug development, preparation, and distribution.

The first federal law developed to deal with drug quality and safety was the Import Drug Act of 1848. This law was passed after it was discovered that American troops involved in the Mexican War had been supplied with substandard imported drugs. The act provided for the inspection, detention, and destruction or reexport of imported drug shipments that failed to meet prescribed standards.

The Pure Food and Drugs Act was passed in 1906. This law required that drugs not be mislabeled or adulterated and stated that they must meet recognized standards for strength and purity. Mislabeling in this context only referred to the identity or composition of drugs (not false therapeutic claims). False therapeutic claims were prohibited with the passing of the Sherley Amendment in 1912.

In 1937, the drug sulfanilamide was released. This drug showed promise as an anti-infective agent and was prepared as an oral liquid. The vehicle used for this preparation was diethylene glycol (a sweet-tasting solvent similar to ethylene glycol, which was used as an automobile antifreeze). A total of 107 people died after taking this preparation. Within 1 year of this tragedy, the Food, Drug and Cosmetic Act of 1938 was enacted. This law required that the safety of drugs, when used in accordance with the labeled instructions, be proven through testing before they could be marketed. It was in this law that the submission of an NDA to the FDA was first described. The NDA was required to list the drug’s intended uses and provide scientific evidence that the drug was safe. If after 60 days the FDA had not responded to the manufacturer regarding the NDA, the manufacturer was free to proceed with marketing of the product.

In 1951, the Durham–Humphrey Amendment was passed. This law divided pharmaceuticals into two distinct classes:

     1. Over-the-counter (OTC) medications that could be safely self-administered.

     2. Prescription () medications that had potentially dangerous side effects and, therefore, required expert medical supervision.

This law required the following statement be added to the labels for all prescription medications: “Caution: Federal Law prohibits dispensing without a prescription.”

In 1962, another drug tragedy occurred that resulted in additional regulations. In that year, an inordinate number of pregnant women in Western Europe gave birth to children with severe deformities. These deformities were related to the use of the drug thalidomide. Although U.S. consumers were not directly affected by this tragedy, because thalidomide had not been released in the U.S. market, it was a compelling reason for the legislature to develop stronger laws regarding the testing of new drug products. The Kefauver–Harris Drug Amendment was passed the same year. This law specified that the manufacturer had to demonstrate proof of efficacy, as well as safety, prior to marketing any new drug. Additionally, this law required that drug manufacturers operate in conformity with Current Good Manufacturing Practices (CGMP). Finally, it stated that the FDA had to formally approve an NDA before the drug could be marketed.²²

There are numerous other laws and regulations that affect drug products in the United States, but those mentioned above provide the legal foundation for the current regulation of drug products in the United States. Based on these laws, the FDA has assumed a large role in assessing the safety and efficacy of drug products prior to their distribution in the United States.

As stated, the goal of the FDA is to provide American consumers with safe and effective drugs, biologics, and devices.⁸ Extensive debate regarding the need to reform the FDA has been ongoing in the United States for years. Critics of the FDA have long claimed that the approval process for drugs in the United States is too costly and time consuming.^23,24 Interestingly, however, data show that the FDA leads the world in the first introduction of new active substances. Using data from fiscal year (FY) 2012, of the 32 novel drugs approved by the FDA and also approved in other countries, 75% of those drugs were approved by the FDA first.⁷ Nevertheless, over the past two decades, the FDA and the federal government have initiated many reforms and initiatives designed to address these criticisms. Included in these reform acts are the Prescription Drug User Fee Act of 1992 (PDUFA), which was reauthorized in 1997 and 2002, and the Food and Drug Administration Modernization Act of 1997 (FDAMA). PDUFA redefined the timeframes for NDA reviews and established revenues to fund the increased demands created by the new timeframes.²⁰ The FDAMA, which reauthorized PDUFA in 1997, was much broader in scope and impacted not only the drug approval process, but also other aspects of the practices of pharmacy and medicine.²⁵ The Food and Drug Administration Amendments Act (FDAAA), which was signed into law in 2007, further expanded PDUFA to provide the FDA with additional resources to conduct timely and comprehensive reviews of new drugs in the United States.²⁶

Aside from looking at review times, the FDA has also been concerned about the increasing difficulty in drug and biologic develepment. To attempt to address this issue, the FDA launched a new initiative in March 2004 called the Critical Path Initiative. The Critical Path Initiative is the FDA’s attempt to facilitate modernization of the sciences and improve regulatory decision making. They have been working with the public, the pharmaceutical industry, other regulatory agencies, and academia to identify projects they feel are most likely to help the drug development process from test tube to bedside.²⁷

Finally, the FDA has undertaken many information technology initiatives to facilitate the regulatory review process. Included in these initiatives is the development of systems allowing for electronic submission, management, and review of regulatory information.²⁸ Overall, the goal of the initiatives is to review priority drugs in 6 months and standard drugs within 10 months.²⁹ Other attempts by the FDA to increase availability of investigational drugs to patients will be discussed later in this chapter.

First initiated in response to components of FDAMA, the National Institutes of Health (NIH) developed a Web-based system that offers information about ongoing clinical trials for a wide range of diseases and conditions. The system allows potential study subjects to search for studies for particular diseases and identify treatment centers that offer enrollment into those studies. Requirements for postings have become more stringent over the past 5 years.³⁰ Most recently, in 2007 FDAAA required more types of trials to be registered, additional trial registration information, and submission of summary results including adverse events for certain trials.²⁶ The site is available at http://clinicaltrials.gov. Study sponsors are required to verify that the study is posted on the ClinicalTrials.gov Web site as part of the IND submission process through submission of a Form 3674.³¹

Increasingly, drug companies are involved in global drug development. Historically, the regulatory requirements for drug approval varied from country to country, resulting in a significant amount of time and money being spent to receive multiple approvals. For this reason, the International Conference on Harmonization (ICH) has brought together officials from Europe, the United States, and Japan to develop common guidelines for ensuring the quality, safety, and efficacy of drugs. The FDA has been very involved in the development of the ICH guidelines. The ultimate goal of these guidelines is to provide pharmaceutical firms a method to ensure simultaneous submission and rapid regulatory approval in the world’s major markets. This would minimize duplication of effort, improve efficiency, and increase the quality and consistency of medical treatments available to patients worldwide.³²

For gene therapy products, review and approval by the National Institutes of Health Office of Biotechnology Activities (NIH/OBA) and local Institutional Biosafety Committee(s) are required in addition to review and approval by the FDA and IRB (discussed below). Submission requirements for the NIH/OBA are similar to those mandated by the FDA (covered later in this chapter). The review process for gene therapy products is a separate topic that will not be further addressed in this chapter. Individuals interested in regulatory requirements of gene therapy products can refer to review articles such as “Gene Transfer: Regulatory Issues and Their Impact on the Clinical Investigator and the GMP facility” published in Cytotherapy in 2003.³³

In addition to the regulatory review of investigational drugs by the FDA, research protocols are also reviewed for ethical appropriateness by IRBs. The formalized process for protecting human subjects began with the Nuremberg Code. This code was used to judge the human experimentation conducted by the Nazis around the middle of the twentieth century. The Nuremberg Code states that “the voluntary consent of the human subjects is absolutely essential.” The code goes on to specify that the subject must have the capacity to consent, must be free from coercion, and must comprehend the risks and benefits involved in the research.³⁴ The Declaration of Helsinki reemphasized the above points and distinguished between therapeutic and nontherapeutic research. This document was first developed in 1964 and has been revised multiple times, most recently in 2008.³⁵

The NIH, as part of the Department of Health and Human Services (DHHS), used these two documents to develop its own policies for the Protection of Human Subjects in 1966. These policies were raised to regulatory status in 1974 and established the IRB as a mechanism through which human subjects would be protected. The Belmont Report, released in 1978, further delineates the basic ethical principles underlying medical research on human subjects.³⁶ Title 45 Part 46 of the Code of Federal Regulations (CFR), which was released in 1981, was designed to make uniform the protection of human subjects in all federal agencies.¹⁸ Title 21 Part 50 (approved in 1980) of the CFR sets forth guidelines for appropriate informed consent and Title 21 Part 56 (approved in 1981) of the CFR sets forth guidelines for the IRB.^19,37 Copies of these regulations can be obtained on the Internet at http://www.gpoaccess.gov/cfr/index.html

These two documents are used by the FDA and the DHHS to evaluate the ethical conduct of clinical trials in the United States. Further information regarding the role of the IRB will be presented later in this chapter.

The Drug Approval Process

The drug approval process in the United States is standardized by FDA review. It consists of preclinical testing and Phase I-IV of clinical testing. The first step in the drug approval process is preclinical testing. This testing is conducted either in vitro or in animals. Before filing an IND, the sponsor must have developed a pharmacologic profile of the drug, determined its acute and subacute toxicity, and have sufficient information regarding chronic toxicity to support the drug’s use in humans.³⁸

After the preclinical testing is completed, the sponsor will file an IND with the FDA. The IND is the application by the study sponsor to the FDA to begin clinical trials in humans. Most often, the sponsor is a pharmaceutical company, but occasionally an individual investigator will file an IND and serve as a sponsor-investigator. An investigator IND is submitted when a physician plans to use an approved drug for a new indication (i.e., one that is outside the package labeling) or on occasion, for an unapproved product or for an NME. The IND requirements for the sponsor-investigator are the same as those for any other sponsor. For that reason, no differentiation will be made in the following discussion of the drug approval process.

An IND is not required if the drug to be studied is marketed in the United States and all of the following requirements are met:

     1. The study is not to be reported to the FDA in support of a new indication.

     2. The study does not involve a different dose, route, or patient population that increases the risk to patients.

     3. IRB approval and informed consent are secured.

     4. The study will not be used to promote the drug’s effectiveness for a new indication.

The FDA has developed a guidance document specifically to assist in determining whether or not an IND is required. However, in situations where it is unclear whether an IND is required or not, a call to the FDA is the best way to determine the appropriate way to proceed.³⁹

In recent years there have been several therapeutic products developed that depend on the use of an in vitro companion diagnostic device (or test) for its safe and effective use. It is important to note that in this situtation, the in vitro device should be approved or cleared concurrently by FDA for the use indicated in the therapeutic product labeling. To be clear, this might require the study of the diagnotic device under an investigational device exemption (IDE) while the therapeutic product is being studied under an IND. If the diagnostic device and therapeutic product are to be studied together to support their respective approvals (or clearance in the case of a device) both products can be studied in the same investigational study if the study has been developed and conducted in a manner that meets both IND and IDE regulations.⁴⁰ One other interesting issue related to devices is the use of a mobile app (i.e., a software application on a mobile platform such as an iPhone, Android, Windows tablet, or BlackBerry) for the diagnosis of disease, or the cure, mitigation, treatment or prevention of disease or to affect the structure of function of the body. In these situations, the mobile app can be considered to be a medical device subject to IDE regulations.⁴¹ IDE regulations and components will not be further discussed in this chapter; however, the applicable regulations can be found in 21CFR812 and the FDA has extensive guidance regarding these products and their development.

An IND application needs to contain the following information:

       1. Cover sheet: Form 1571 (available at the FDA Web site under Forms, http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm). This form identifies the sponsor, documents that the sponsor agrees to follow appropriate regulations, and identifies any involved CRO. This is a legal document.

       2. Table of contents

       3. Introductory statement: States the name, structure, pharmacologic class, dosage form, and all active ingredients in the investigational drug; the objectives and planned duration of the investigation should be stated here.

       4. General investigational plan: Describes the rationale, indications, and general approach for evaluating the drug, the types of trials to be conducted, the projected number of patients that will be treated, and any potential safety concerns; the purpose of this section is to give FDA reviewers a general overview of the plan to study the drug.

       5. Investigator’s brochure: An information packet containing all available information on the drug including its formula, pharmacologic and toxicologic effects, pharmacokinetics, and any information regarding the safety and risks associated with the drug. It is important that this brochure be kept current and comprehensive; therefore, it should be amended as necessary. The investigator’s brochure may be used by the investigator or other health care professionals as a reference during the conduct of the research study.

       6. Clinical protocol

           • Objectives and purpose: A description of the purpose of the trial (a typical Phase I objective would be to determine the maximum tolerated dose of the investigational drug, whereas a typical Phase III objective would be to compare the safety and efficacy of the investigational drug to placebo or standard therapy).

           • Investigator data: Provides qualifications and demographic data of the investigators involved in the clinical trial (may be presented on form 1572 (available at the FDA Web site under Forms, http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm).

           • Patient selection: Describes the characteristics of patients that are eligible for enrollment in the trial and states factors that would exclude the patient.

           • Study design: Describes how the study will be completed; if the study is to be randomized, this will be described here with a description of the alternate therapy.

           • Dose determination: Describes the dose (with possible adjustments) and route of administration of the investigational drug; if retreatment or maintenance therapy of patients is allowed, it will be detailed in this section.

           • Observations: Describes how the objectives stated earlier in the protocol are to be assessed.

           • Clinical procedures: Describes all laboratory tests or clinical procedures that will be used to monitor the effects of the drug in the patient; the collection of this data is intended to minimize the risk to the patients.

           • IRB approval for protocol: Documentation of this approval is not required as part of the IND application process; however, form 1571 does state that an IRB will review and approve each study in the proposed clinical investigation before allowing initiation of those studies.

       7. Chemistry, manufacturing, and control data

           • Drug substance: Describes the drug substance including its name, biological, physical, and chemical characteristics; the address of the manufacturer; the method of synthesis or preparation; and the analytical methods used to ensure purity, identity, and the substance’s stability.

           • Drug product: Describes the drug product including all of its components; the address of the manufacturer; the analytical methods used to ensure identity, quality, purity, and strength of the product; and the product’s stability.

           • Composition, manufacture, and control of any placebo used in the trial: The FDA does not require that the placebo be identical to the investigational drug; however, it wants to ensure that the lack of similarity does not jeopardize the trial.

           • Labeling: Copies of all labels and labeling used for the drug substance or product, and packages as it will be provided to each investigator. Labels in this context meaning the information affixed to product and used to identify the contents while labeling in this context relates to product information including prescribing information.

           • Environmental assessment: Presents a claim for categorical exclusion from the requirement for an environmental assessment (a statement that the amount of waste expected to reach the environment may reasonably be expected to be nontoxic).

       8. Pharmacology and toxicology data

           • Pharmacology and drug disposition: Describes the pharmacology, mechanism of action, absorption, distribution, metabolism, and excretion of the drug in animals and in vitro.

           • Toxicology: Describes the toxicology in animals and in vitro.

           • A statement that all nonclinical laboratories involved in the research adhered to Good Laboratory Practice (GLP) regulations.

       9. Previous human experience: Summary of human experiences, which includes data from the United States and, where applicable, foreign markets. Known safety and efficacy data should be presented (especially if the drug was withdrawn from foreign markets for reasons of safety or efficacy).

     10. Additional information: Other information that would help the reviewer evaluate the proposed clinical trial should be included here. For example, if a drug has the potential for abuse, data on the drug’s dependence and abuse potential should be discussed in this section.³⁸

The letter of authorization (LOA) to cross reference a drug master file, investigational new drug application, or new drug application (referred to in item nine on page one of Form 1571) is required when the investigational product (or some component of the investigational product) being used in the research is being supplied by a manufacturer other than the study sponsor. The original holder of the IND/NDA/DMF prepares the LOA. An LOA is frequently required when two companies are working together toward development of a product.⁴²

The IND should be amended as necessary. There are four types of documents that may be used to amend the IND. They are as follows:

       1. Protocol amendments: Submitted when a sponsor wants to change a previously submitted protocol or add a new study protocol to an existing IND.⁴³

       2. Information amendments: Submitted when information becomes available that would not be presented using a protocol amendment, IND safety report, or annual report (example: new chemistry data).⁴⁴

       3. IND safety reports: Reports clinical and animal adverse reactions; reporting requirements depend on the nature, severity, and frequency of the experience. The following definitions are used to help evaluate adverse reactions.

           • Suspected adverse reaction: An adverse reaction for which there is evidence to suggest a causal relationship between the drug and the adverse event.

           • Serious adverse event or serious suspected adverse reaction: An event that results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based on appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

           • Unexpected adverse event or unexpected suspected adverse reaction: An adverse reaction that is not listed in the current labeling for the drug product. This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the event because of greater severity or specificity.

                  For serious and unexpected, fatal, or life-threatening suspected adverse reactions, the sponsor is required to notify the FDA by telephone or fax within 7 calendar days after the sponsor receives the information. The sponsor must also submit a written report within 15 calendar days. For clinical and nonclinical adverse reactions that are both serious and unexpected, the sponsor must notify the FDA in writing within 15 calendar days. The written reports should describe the current adverse event and identify all previously filed safety reports concerning similar adverse events. The written report may be submitted as a narrative or as Form 3500A.^45,46

           4. Annual reports: Submitted within 60 days of the annual effective date of an IND; it should describe the progress of the investigation including information on the individual studies, summary information of the IND (summary of adverse experiences, IND safety reports, preclinical studies completed in the last year), relevant developments in foreign markets, and changes in the investigator’s brochure.⁴⁷

Each submission to a specific IND is required to be numbered sequentially (starting with 000). A total of three sets (the original and two copies) of all submissions to an IND file (whether a new IND or revisions to an existing IND) are sent to the FDA.³⁸

Once submitted to the FDA, the IND will be forwarded to the appropriate review division based on the therapeutic category of the product. Examples of the different divisions include oncology products, hematology products, anti-infective products, and medical imaging products. Following submission, the IND and clinical trial will be assigned to a review team that includes:

     • The project manager

     • A chemistry, manufacturing, and controls (CMC) reviewer

     • A nonclinical pharmacology/toxicology reviewer

     • A clinical reviewer and

     • Other reviewers as needed (e.g., statisticians, epidemiologists, site inspectors, patient representatives)²¹

The FDA has 30 days after receipt of an IND to respond to the sponsor. The sponsor may begin clinical trials if there is no response from the FDA within 30 days.⁴⁸ The FDA delays initiation of a new study or discontinues an ongoing study by issuing a clinical hold. Clinical holds are most often used when the FDA identifies an issue (through initial review or through later submissions) that the agency feels poses a significant risk to the subjects. After this issue has been satisfactorily resolved, the clinical hold can be removed and the investigations can be initiated or resumed.⁴⁹

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