Process Maps: IND and IDE Submissions
FDA’s Center for Drug Evaluation and Research (CDER) is responsible for regulating manufacturing, testing and importation of pharmaceutical drugs in the US. This includes new drug approvals, abbreviated new drug approvals (generics), over-the-counter drugs, animal drugs and biologics.
A drug is defined as:
- article intended for use in diagnosis, cure, mitigation, treatment, or prevention of the disease;
- articles (other than food) intended to affect the structure or any function of the body;
- articles intended to be used as components of any of the above.
Below is a brief summary of regulatory requirements for clinical research involving drugs, biologics or dietary supplements.
3.1.1 Preclinical Regulatory Requirements
Preclinical testing begins after a potential drug has been identified in the lab. Preclinical testing involves lab and animal studies that evaluate the drug’s toxic and pharmacologic effects. Preclinical studies are also subject to the FDA regulations known as Good Laboratory Practices (GLP), 21 CFR 58. The GLP regulations specify minimum standards in such areas as personnel, facilities, equipment and operations.
Pre-clinical studies not performed under GLP conditions may not be accepted by the FDA. Recognition of this fact is particularly important for academic drug development.
Please see “Roadmap for Academic Health Centers to Establish Good Laboratory Practice-Compliance Infrastructure”, Acad. Medicine, 2012 87(3):279-284
Preclinical testing includes pharmacokinetics, the study of how the drug moves through living organisms. Researchers examine absorption, distribution, metabolism and excretion (also abbreviated as ADME) to ensure that the drug reaches its intended target and passes through the body properly. In addition to the biological tests, researchers conduct chemistry tests to establish the drug's purity, stability and shelf life. Manufacturing tests are conducted to determine the feasibility of producing the drug on a large scale and to explore dosing, packaging and formulation (e.g., pill, inhaler, injection).
At the preclinical stage, the FDA will generally ask, at a minimum, that sponsors: (1) develop a pharmacological profile of the drug; (2) determine the acute toxicity of the drug in at least two species of animals, and (3) conduct short-term toxicity studies ranging from two weeks to three months, depending on the proposed duration of use of the substance in the proposed clinical studies.
3.1.2 Investigational New Drug (IND) Application (21 CFR Part 312)
After preclinical testing is completed, a sponsor or sponsor-investigator (see below) files an IND with FDA prior to beginning any human testing. An IND is a request for FDA authorization to administer an investigational drug to humans. Such authorization must be secured prior to interstate shipment and administration of any unapproved drug.
The application must show results of preclinical experiments; the chemical structure of the compound; how it is thought to work in the body; any side effects found in animal studies; and how the compound is manufactured (chemistry, manufacturing and controls section). The IND must also include a detailed clinical trial plan, including how, where and by whom the studies will be conducted.
Based on the information of the IND application, the FDA will determine if there is sufficient evidence to support initial human testing. The sponsor must wait 30 days after submitting the IND to the FDA for review. At the end of the 30 day review period, unless the FDA identifies a potential safety problem involving the use of the drug and asks for a delay, the sponsor may begin the proposed clinical testing.
Clinical Trials Resource Group houses a website that provides step-by-step guide to how to file an IND (http://www.ucdmc.ucdavis.edu/clinicaltrials/IND/index.html). However, we highly recommend contacting Clinical Trials Group for consultation regarding INDs or IND Exemptions. The team’s qualified staff also prepares FDA filings on contractual basis.
3.1.3 Special IND subtypes.
Expanded Access of Investigational Drugs: Treatment IND (21 CFR 312.320)
A treatment IND allows patients, whose need for treatment outweighs the risks (e.g. life-threatening illness), to obtain access to investigational treatment prior to completion of pivotal clinical trials. The FDA will allow an investigational drug to be used under the Treatment IND if there is preliminary evidence of drug efficacy, which means that Phase III clinical trials with this drug must be well underway. Typically, such patients are not eligible for the on-going trials, and no alternative therapy is available. Such IND requires IRB review and Informed consent. The list of approved Treatment INDs is posted on the FDA website.
Expanded Access of Investigational Drugs: Group C Treatment IND
Group C drugs are Phase III cancer drugs that have shown evidence of reproducible efficacy. These drugs are distributed by the NIH under NCI protocols. Treatment is a primary objective, but safety and effectiveness data are still collected. FDA generally grants the waver from the IRB review requirements.
Expanded Access of Investigational Drugs: Single-patient INDs (Emergency Use and non-emergency use)
The need for investigational drug may arise in an emergency situation that does not allow for IND submission and IRB review. A physician who wishes to administer an investigational drug under the Expanded Access: Single-Patient program is responsible for procuring the drug from the sponsor, securing IRB approval and providing informed consent consistent with standard FDA rules (subject to emergency use exceptions provided in those rules), reporting adverse drug events to the sponsor, and maintaining accurate drug accountability and patient case history records. A physician who is unable or unwilling to meet these demands should not proceed. For detailed description of how a single-patient IND is executed at UC Davis, see UC Davis Policy and Procedure P&P1509.
For more details see: http://www.ucdmc.ucdavis.edu/clinicaltrials/IND/index.html (under “New! Expanded Access to Investigational drugs”)
3.1.4 New Drug Application (NDA)
After clinical trials have been completed demonstrating safety and effectiveness, the drug sponsor will submit a New Drug Application (NDA) to the FDA for a license to market the drug for a specified indication. NDAs contain all of the information about all of the studies, including preclinical testing, all clinical trials, dosing information, manufacturing details and proposed labeling for the new medicine. Most academic drug development efforts do not progress to this stage.
At NDA submission stage, FDA scientists review all the results from all the studies carried out over the years and determine if they show that the medicine is safe and effective enough to be approved. During this review, the FDA determines what the labeling should be and whether the sponsor can manufacture it properly and consistently. Once the drug is approved, it becomes available for physicians to prescribe for the indication approved by the FDA. The review process takes approximately 18 months.
3.1.5 Determine if your Study is Exempt from IND Requirements
Many academic investigators will want to conduct a clinical study with an already approved drug. This is often done to establish efficacy in a new disease indication. FDA provides provisions for conducting studies of lawfully marketed drugs through the use of an IND exemption. A clinical investigation of a drug is exempt from the IND requirements if all of the criteria for an exemption in 21CFR312.2(b) are met:
- The investigational drug is lawfully marketed in the United States;
- The investigation is not intended to be reported to the FDA as a well-controlled study in support of a new indication for use of the drug product;
- The investigation is not intended to support a significant change in advertising to an existing lawfully marketed prescription drug product;
- 4. 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;
- The investigation will be conducted in compliance with the requirements for institutional review set forth in FDA regulations 21 CFR 56, and requirements for informed consent as set forth in FDA regulations 21 CFR 50;
- The investigation will be conducted in compliance with FDA regulations 21 CFR 312.7: Promotion and charging for investigational drugs.
Thorough documentation is required to support this exemption criterion and may include prior publications or other public disclosures. If such evidence cannot be provided, a physician should submit a research IND (limited in scope) to the FDA. The physician is now considered sponsor-investigator.
FDA Guidance: Investigational New Drug Applications (INDs)—Determining whether Human Research Studies can be conducted without an IND
3.1.6 Is IND required for studies with dietary supplements?
Many clinical studies of academic investigators evaluate the effect of dietary supplements on the disease or physiological parameters. Some of these studies may require an IND submission. If the dietary supplements are investigated for diagnosis, cure, mitigation, treatment, or prevention of disease and are used to affect the structure or function of the body, then the dietary supplement will be considered a drug for the purposes of this study.
The study will be the subject to the same regulations as any other unapproved drug. Specifically, the FDA will be paying particular attention to the composition of the dietary supplement, its origin and manufacturing processes. When preparing the INDs for dietary supplements, make sure that the supplement manufacturer is willing to provide this information.
FDA's Center for Devices and Radiological Health (CDRH) is responsible for regulating manufacturing and importation of medical devices sold in the United States. In addition, CDRH regulates radiation-emitting electronic products (medical and non-medical) such as lasers, x-ray systems, ultrasound equipment, microwave ovens and color televisions.
If a product is labeled, promoted or used in a manner that meets the definition in section 201(h) of the Federal Food Drug & Cosmetic (FD&C) Act, it will be regulated as a medical device. A device is: "an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals,
intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.
This definition provides a clear distinction between a medical device and other FDA regulated products such as drugs. If the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug. In cases where it is not clear whether a product is a medical device , contact the CDRH to make a determination.
3.2.1 Device Classification
The FDA has established classifications for approximately 1,700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. Each of these generic types of devices is assigned to one of three regulatory classes (Class I, Class II and Class III) based on the level of control necessary to assure the safety and effectiveness of the device. The device classification defines the regulatory requirements for an approval of a new device. Regulatory control increases from Class I to Class II to Class III.
Device classification depends on the intended use of the device and also upon indications for use. In addition, classification is risk based, that is, the risk the device poses to the patient and/or the user is a major factor in the class it is assigned. Examples:
Class I devices: elastic bandages, examination gloves, and hand-held surgical instruments.
Class II devices: powered wheelchairs, infusion pumps, and surgical drapes.
Class III devices: implantable pacemaker pulse generators and coronary stents.
To find the classification of your device, as well as whether any exemptions may exist, you need to find the regulation number that is the classification regulation for your device. One of the ways to accomplish this is to go directly to the classification database and search for a part of the device name (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf)
Once you have identified the correct classification regulation go to the device panel (medical specialty) to which the device belongs.
The search will provide you with the Device Classification and the appropriate CFR regulation. If the device is not classified, you can research similar devices on the FDA website (PMA and 510(k) databases) or use pre-IDE consultation for the FDA determination.
FDA Guidance: Frequently Asked Questions About Medical Devices
3.2.2 Significant Risk vs Non-significant Risk
Devices used on human subjects to conduct investigations of safety and effectiveness are considered “Investigational Devices” (Section 520(g) of FDCA).
Significant Risk (SR) device presents a potential for serious risk of health, safety and welfare of a subject, and:
Examples of SR devices include sutures, cardiac pacemakers, hydrocephalus shunts, and orthopedic implants. Conversely, non-significant risk (NSR) device studies do not pose a significant risk to patients. Non-significant risk should not be confused with “minimal risk”, a term used by the FDA to classify studies. Examples of NSR devices include most day-wear contact lenses and lens solutions, ultrasonic dental scalers, and foley catheters.
SR devices must meet all regulatory requirements set in 21 CFR 812, including the requirement for approval by both IRB and the FDA before commencing the study. Significant risk devices require submission of an investigational device exemption (IDE) to CDRH (see below).
NSR device studies may commence without FDA approval, based solely on the IRB approval. However, the sponsor-investigator must follow abbreviated IDE requirements, which are, in essence, the same requirements as regular IDE only without FDA submission (21 CFR 812.2 (b)). The IRB acts as a surrogate overseer for the FDA.
FDA Guidance Significant Risk and Non-significant Risk Medical Device Studies can be used to help classify a device.
3.2.3 Investigational Device Exemption (IDE) (21 CFR Part 812)
IMPORTANT: the clinical study of a new indication for an already marketed device falls under the IDE regulation.
An investigational device exemption (IDE) is a regulatory submission to the CDRH. If approved, it allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data.
- Study approved by an institutional review board (IRB). If the study involves a significant risk device, the IDE must also be approved by FDA;
- informed consent from all patients obtained and documented;
- the device is labeled “CAUTION- Investigational Device. Limited to investigational use only;”
- Sponsor-investigator complies with monitoring requirements;
- Records and reports are maintained;
- Investigator cannot promote or commercialize (charge for) the device.
A step-by-step guidance on IDE preparation can be found on Clinical Trials website: http://www.ucdmc.ucdavis.edu/clinicaltrials/IND/index.html
Two important elements of the guidance are:
- FDA is approval of an early feasibility study, including some first-in-human studies, may be based on less nonclinical data than would be expected for other types of studies (e.g., traditional feasibility or pivotal).
- The introduction of new approaches to facilitate timely device and clinical protocol modifications during an early feasibility study, while still maintaining compliance with FDA human subject protection requirements, including obtaining informed consent and Institutional Review Board (IRB) (or ethics committee) oversight.
3.2.4 Abbreviated IDE
Studies of non-significant risk devices are subject to abbreviated IDE requirements. An IDE submission to the FDA is not required under the abbreviated requirements, but the requirements for labeling, informed consent, monitoring, records and reports, and promotional practices contained in FDA regulations still apply (21 CFR 812.2(b)). In addition, the concept of “non-significant risk” to determine whether abbreviated IDE procedures are appropriate should not be confused with “minimal risk” to determine whether expedited IRB review is appropriate. For a device study to be eligible for expedited IRB review, it must be a non-significant risk device AND present no more than minimal risk to the subject (ref. 21 CFR 56.110).
Requirements under abbreviated IDE (see appendix 2 for more details):
3.2.5 IDE Exemptions
Some studies may be exempt from the IDE regulations. The exemption criteria is explained in 21 CFR 812.2(c), and briefly summarized below:
3.2.6 Emergency Use of Unapproved Device
If this situation is encountered, act in accordance with UCDMC P&P 1509 “Emergency Treatment of an Investigational Drug, Device or Biologic (FDA Regulated Products) in a Life Threatening Situation.”
An unapproved medical device is a device that is utilized for a purpose, condition, or use for which the device requires, but does not have, an approved application for premarket approval (510(k)) or an approved IDE. Emergency use is permitted if the treating physician determines that:
- The patient has life-threatening condition that needs immediate treatment
- No generally acceptable alternative treatments exist
- Because of an immediate need there is no time to use existing procedures for CDRH approval
Next, the treating physician needs to undertake the following protective measures:
- An independent assessment by an uninvolved physician
- Informed consent from the patient or legal representative
- Approval of the IRB Chair
- Approval from the IDE sponsor, if any
- Prior FDA approval for shipment or emergency use of the investigational device is not required, but the use should be reported to the FDA by the IDE sponsor via a supplement within 5 working days from the time the sponsor learns of the use
Note that if a physician, who is faced with an emergency situation contacts the FDA to discuss his/her patient’s condition, the FDA will only act in an advisory role, rather than in an approving role. The responsibility for making the decision as to whether the situation meets the emergency use criteria and whether the unapproved device should be used lies with the physician.
FDA Guidance: Emergency use Authorization of Medical Products
3.2.7 Compassionate use of Investigational Devices
This type of use is NOT an emergency use. Compassionate use request to utilize an investigational device in the mitigation, diagnosis and treatment of a serious disease requires an IDE Supplement. The sponsor or investigator has to submit the protocol for use of the device in a single patient or a group of patients. In order to permit this use, CDRH will review the following information:
- No comparable alternative treatment exists
- Sufficient evidence of safety
- Clinical use will not interfere with ongoing clinical investigations
3.2.8 Treatment Use
This type of use is NOT an emergency use. A request for Treatment Use of an investigational device in the mitigation, diagnosis and treatment of a serious disease requires a Treatment IDE Submission. If approved, Treatment IDE enables a wider group of patients to receive the investigational device for the same indication as it is being studied under the sponsor IDE. Treatment IDE will remain open even after the sponsor trial has been completed. The following provision have to be met:
- Device is investigated in a controlled clinical trial under IDE for the same use
- Sponsor is actively pursuing market approval
- No comparable alternative treatment exists
- Clinical use will not interfere with ongoing clinical investigations
- Sufficient evidence of safety and effectiveness
FDA Guidance: Expanded Access to Investigational Drugs for Treatment Use — Qs & As; http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf
3.2.9. PMA vs 510(k)
Premarket approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Due to the level of risk associated with Class III devices, FDA needs to see sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). The content of PMA is similar to the NDA for new drugs, and contains manufacturing sections, pre-clinical laboratory studies and clinical investigations.
Some devices (from Class I or Class II) may be able to be approved under a different pathway colloquially called 510(k). The name refers to requirements outlined in section 510(k) of Food, Drug and Cosmetics Act. If the device is considered substantially equivalent to one or more similarly marketed devices (known as “predicate”devices), a claim of substantial equivalence can be made. A claim of substantial equivalence does not mean the new and predicate devices must be identical. Substantial equivalence is established with respect to intended use, design and other parameters.
3.2.10 Humanitarian Use
HUD (Humanitarian Use Device) designation requests are the first step in seeking marketing approval of a HUD. The second step is a submission of a Humanitarian Device Exemption (HDE) application to the Center for Devices and Radiological Health (CDRH) or to the Center for Biologics Evaluation and Research (CBER).
HUD is a “medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year.” (21 CFR 814.39(n)). The request for HUD designation is described in the FDA Guidance “Designating Humanitarian Use Devices”
If the request is granted, the investigator proceeds with the submission of HDE. An HDE is similar in both form and content to a premarket approval (PMA) application, but is exempt from the effectiveness requirements of a PMA. An HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. The application, however, must contain sufficient information for FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury, and that the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Additionally, the applicant must demonstrate that no comparable devices are available to treat or diagnose the disease or condition, and that they could not otherwise bring the device to market.
Investigator means 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. "Sub-investigator" includes any other individual member of that team (21 CFR 321.3).
Sponsor means a person who takes responsibility for and initiates a clinical investigation (21CFR312.3). 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.
Sponsor-Investigator means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed (21CFR312.3). The term does not include any person other than an individual. If an academic investigator submits an IND or IDE and is the principal investigator, the investigator is the Sponsor-Investigator and he/she is responsible for regulatory compliance.
Academic investigators sometimes equate the term “Sponsor” with the source of the study funding. In fact, there are two types of sponsors: regulatory sponsor and financial sponsor. The regulatory sponsor is the person/entity who initiates and takes responsibility for a clinical investigation. The regulatory sponsor submits the IND or IDE and is responsible for communications with the FDA. The regulatory sponsor may be a pharmaceutical company, a private or academic organization, or an individual.
A financial sponsor may be a company, a department, a non-profit or a government agency. If a pharmaceutical (or device) company is supplying a drug (or device) for an academic study, but will not be submitting the IND or IDE, the company is not the regulatory sponsor. For commercial INDs, the financial and regulatory sponsors are usually the same (i.e. the pharmaceutical or device company).
Helpful delineation of the ownership of the study processes (adapted from the UCOP Office of General Counsel)
Investigator (or University)
Injuries and indemnifications
Sponsor pays (except when caused by the institution or Pi non-compliance, negligence or misconduct
Institution pays (except for product defects)
Sponsor owns CRFs and reports provided by sponsor; UC owns medical records and other data
UC owns protocol, documents, research results, data
Sponsor owns patentable inventions conceived and reduced to practice; UC owns everything else
UC owns all inventions and IP
Grants, Institution, Department
Sponsor-Investigator responsibilities under an IND or IDE are covered in 21 CFR Part 312 (for drugs) and 21 CFR Part 812 (for devices). Also see FDA Guidance “Investigator Responsibilities – Protecting the Rights, Safety and Welfare of Study Subjects”, and ICH E6 (GCP)–Section 4 (http://ichgcp.net/4-investigator).
Below is a brief summary of the responsibilities and available resources for Sponsor-Investigators under an IND:
21CFR part 50 details sponsor obligations Sponsors are responsible for:
Additional specific responsibilities of sponsors are described elsewhere in this part
§312.53-Selecting investigators and monitors
§312.54- Emergency Research under 50.24 of this chapter
§312.55- Informing Investigators
§312.56- Review of ongoing investigations
§312.57-Recordkeeping and record retention
§312.58- Inspection of sponsor’s records and reports
§312.59 Disposition of unused supply of investigational drug
21CFR part 64 details investigator obligations. Investigators are responsible for:
Additional specific responsibilities of clinical investigators are set forth in this part and in parts 50 and 56 of this chapter.
§312.61-Control of the investigational drug
§312.62- Investigator recordkeeping and record retention
§312.64- Investigator reports
§312.66- Assurance of IRB review
§312.68-Inspection of investigator’s records and reports
§312.69- Handling of controlled substances
§312.70- Disqualification of a clinical investigator.
A helpful checklist of the FDA regulations along with corresponding onsite documents can be found at http://www.partners.org/phsqi/ToolsPage.htm
See http://www.ucdmc.ucdavis.edu/clinicaltrials/Training/2013ctcalendar.html for a detailed presentation of Sponsor-Investigator responsibilities under an IND.
CTSC Clinical Trials Resource Group is available to help with IND/IDE preparation, submission, and maintenance http://www.ucdmc.ucdavis.edu/clinicaltrials/IND/index.html
The process and format for submitting an IND application is defined in 21 CFR 312.23, “IND Content and Format.” For a complete guide on IND/IDE submissions, see http://www.ucdmc.ucdavis.edu/clinicaltrials/IND/index.html
The process and format for submitting an IDE application is defined in 21 CFR 812.20, and can be found on CTSC website: http://www.ucdmc.ucdavis.edu/clinicaltrials/IND/index.html.