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Product Applications (including Investigational Applications) - Background

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Background

Investigational Applications/Notices
FDA receives and reviews applications seeking permission to conduct clinical investigations of unapproved human drugs (including unlicensed biological products) and significant-risk medical devices.  To conduct certain clinical investigations of a human drug or biological product, a sponsor (either an individual or a company) must submit an Investigational New Drug Application (IND).  An IND for a human drug or biological product goes into effect 30 days after it is submitted to FDA, permitting the initiation of the proposed investigation in human subjects, unless FDA informs the sponsor of the IND that it has been placed on “clinical hold.”  FDA may place an IND on clinical hold before initiation of the investigation for several reasons, including if the Agency determines subjects would be exposed to an unreasonable and significant risk of illness or injury, or if the investigation does not otherwise comply with the regulations governing INDs. 

FDA can suspend an IND after a study has begun by putting it on clinical hold for the same reasons FDA can put it on hold before it begins.  FDA may terminate an IND, among other reasons, if subjects would be exposed to an unreasonable and significant risk of illness or injury, the studies are being conducted in a manner substantially different from the protocols, or the sponsor is no longer complying with the regulations governing INDs.  An IND under which no subjects are entered into any clinical studies for a period of 2 years or more, or all of the investigations are on clinical hold for 1 year or more, may be placed on inactive status.  A sponsor may also voluntarily withdraw an IND.

To conduct a clinical investigation on a significant-risk medical device, a sponsor must submit an Investigational Device Exemption (IDE).  A proposed investigation of a significant-risk medical device in humans may begin: (1) 30 days after FDA receives an IDE, unless FDA notifies the sponsor that the investigation may not begin or (2) when FDA has approved the IDE.  An IDE may be disapproved, among other reasons, because there is reason to believe that the risks to subjects are not outweighed by the anticipated benefits, or because the investigation does not otherwise comply with the regulations governing IDEs.  After a study has begun, FDA generally may withdraw approval of an IDE for the same reasons it may disapprove it. 

The information required for an IND or IDE varies depending on a number of factors, including the phase of clinical development, the known or suspected risks with the product, or the novelty of the product under investigation.  Generally, the investigational application includes, among other things:

  • Information about the nature of the product or device,
  • Manufacturing information,
  • Reports of prior investigations and marketing experience with the product,
  • Animal pharmacology and toxicology studies (for INDs only),
  • The investigational plan and protocol for the proposed study or studies,
  • Information on the qualifications of the clinical investigators, and
  • Commitments to obtain informed consent from research subjects, to obtain review of the study by an Institutional Review Board, and to adhere to the applicable regulations.

After an IND or IDE goes into effect, the following information is required to be submitted to or filed in the IND or IDE:

  • Safety reports submitted by the sponsor, including reports of serious and unexpected adverse events in human subjects participating in the study or studies;
  • Progress reports on the clinical study and, if a study is completed, a brief description of the results of the study; and
  • Letters reflecting FDA actions on the application.

Prior to shipment of a new animal drug for clinical investigational use in animals, the sponsor of an investigation must submit to FDA a “Notice of Claimed Investigational Exemption for a New Animal Drug” (NCIE) containing certain information about the study.  The information required in an NCIE includes, among other things:

  • Identity of the new animal drug,
  • Labeling and other pertinent information to be supplied to the investigators,
  • Name and address of each clinical investigator, and
  • Approximate number of animals to be treated (or if not available, the amount of new animal drug to be shipped).

This information is maintained in an investigational new animal drug (INAD) file FDA can terminate an exemption that permits shipment of a new animal drug for clinical investigational use in animals if FDA finds that the sponsor of the investigation has failed to comply with any of the conditions governing exemptions, continuing the investigation would be unsafe or otherwise contrary to the public interest, or the drug is being used, or has been used for purposes other than bona fide scientific investigation.  In such instances, FDA will notify the sponsor and permit the sponsor to have an opportunity to correct.  If the sponsor fails to correct, prior to terminating the exemption, the sponsor will be given an opportunity for a hearing before the FDA.

Current Disclosure Policies for INDs, INAD files and NCIEs, and IDEs:  At the present time, FDA generally does not disclose any information about the existence, status, or contents of an investigational application or exemption submitted to the Agency, until the product has been approved, licensed, or cleared.  Generally, FDA’s regulations prohibit it from disclosing that it has INDs, INAD files or NCIEs, or IDEs in-house, unless the existence of the INDs, INAD files or NCIEs, or IDEs has been publicly acknowledged by the sponsor.  FDA’s regulations prohibit it from disclosing any of the information in or about the IND, INAD file or NCIE, or IDE, including whether it has put an IND on clinical hold, whether it has terminated an IND or an investigational exemption for a new animal drug, whether it has approved, disapproved, or withdrawn an IDE, or whether the IND has been voluntarily withdrawn by the sponsor or placed on inactive status.

FDA regulations create limited exceptions to this general prohibition on the release of information about IDEs: (1) FDA may release a summary of selected portions of the safety and effectiveness data in a pending application if: (a) the existence of the application has been disclosed and (b) the information is relevant for public consideration of a specific pending  issue; and (2) upon request, a detailed summary of information concerning the safety and effectiveness of banned devices that are the subject of the IDE will be disclosed.

FDA regulations also create limited exceptions regarding the release of information about INDs and INAD files and NCIEs: (1) the Commissioner of FDA may release summaries of selected portions of safety and effectiveness information in a pending application if: (a) the existence of the application has been publicly disclosed and (b) the information is relevant for public consideration of a specific pending  issue; and (2) safety and efficacy information from INDs and INAD files is required to be disclosed under certain circumstances, unless extraordinary circumstances exist.  In practice, the first exception is rarely invoked for information in INDs and INAD files and NCIEs, and the second has been difficult to implement. 

With the passage of the Food and Drug Administration Amendments Act (FDAAA) in 2007, sponsors became subject to expanded requirements (found in Title VIII of FDAAA) to publicly disclose information about certain clinical trials being conducted by them.  The sponsors are required to submit this information to ClinicalTrials.gov. 

ClinicalTrials.gov, a federally mandated databank for certain drug, biological product, and medical device clinical trials, provides the public with access to basic information about these clinical trials.  The site includes information about, among other things:

  • The disease or condition being studied
  • The drug or therapy under study
  • A summary of the purpose of the study
  • The recruiting status of the trial
  • Criteria for patient participation
  • The location of the trial and specific contact information
  • Study design
  • The phase of the trial (for drugs and biological products).

In most cases involving certain drug clinical trials, this information is posted online shortly after the first patient is enrolled in the trial.  Title VIII of FDAAA also includes provisions for considering whether clinical trial results should be submitted to ClinicalTrials.gov for unapproved products.

FDA will continue to work with the National Institutes of Health/U.S. National Library of Medicine (NIH/NLM) to implement the provisions in Title VIII of FDAAA and ensure that companies are complying with existing requirements in the law.

The International Committee of Medical Journal Editors (ICMJE) also requires that clinical trials be registered in a public clinical trials registry before an article is considered for publication in an ICMJE member journal.  The ICMJE policy requires clinical trial registration, at the time of patient enrollment, or earlier.  Significant, well-respected journals are members of ICMJE, including the Journal of the American Medical Association (JAMA), the New England Journal of Medicine (NEJM), and The Lancet. 

In addition, PhRMA has issued principles encouraging the posting of certain clinical trials and results information on a public registry.  PhRMA’s “Principles on Conduct of Clinical Trials” provides that member companies “commit to the timely submission and registration on a public database of summary information about all clinical trials that we conduct involving the use of our marketed or investigational products in patients.”  The principles explain that 21 days after patient enrollment is an appropriate standard for timely submission of the clinical trial to a public database. 
Finally, companies sometimes disclose, on company Web sites and in press releases, the company’s product development pipeline, including the product’s stage of development (e.g., for drugs, Phase 1, 2, or 3). 

Marketing Applications
FDA receives and reviews applications seeking permission to market human drugs, animal drugs, biological products, and significant-risk medical devices.  To obtain permission to market a human drug, the manufacturer must submit a New Drug Application (NDA) for an innovator drug, or an Abbreviated New Drug Application (ANDA) for a generic drug.  To obtain permission to market a biological product, the manufacturer must submit a Biologics License Application (BLA).  To obtain permission to market a medical device, a manufacturer must submit either a Premarket Approval Application (PMA) or a 510(k), unless the device is exempt from premarket notification requirements.  To gain permission to market an animal drug, a manufacturer must submit a New Animal Drug Application (NADA) for an innovator drug, or an Abbreviated New Animal Drug Application (ANADA) for a generic drug.

The contents of a marketing application vary somewhat depending on the type of application, but generally include:

  • Proposed labeling for the product, which includes proposed indications and how the product is to be administered;
  • Information about the components, physical characteristics, and/or chemistry of the product;
  • Information about how the product will be manufactured;
  • Marketing history of the product, if any; and
  • Information from all relevant laboratory, animal and clinical studies supporting the approval or clearance of the application.

Depending on the type of marketing application, the investigational application may also be incorporated by reference.

If the marketing application for a drug, biological product, or device is not accepted for filing by FDA because the Agency determines the application is not sufficiently complete to allow for substantive review of the application, FDA sends a “refuse to file,” “refuse to accept,” or “refuse to receive” letter to the sponsor of the application, depending on the type of application.  These letters are not sent in response to 510(k) submissions.

If, after reviewing an application, FDA determines that it cannot approve or clear the application in its current form, FDA sends a letter informing the sponsor of this decision.  For NDAs, BLAs, and ANDAs, this letter is called a “complete response” letter.  For NADAs and ANADAs, this letter is called a “refuse to approve” letter.  For PMAs, it is called a “not approvable” letter.  For 510(k)s, it is called an “additional information  (AI)” letter. 

In some cases, a sponsor may voluntarily withdraw a pending application before FDA has reached a final determination.  If no activity is seen on an application for some period of time and it appears no work is being done or will be undertaken by the sponsor on a pending application, it may be considered abandoned.

If, after reviewing an application, FDA determines that the application meets the requirements for approval (for NDAs, ANDAs, NADAs, ANADAs, BLAs, or PMAs) or clearance (for 510(k)s), FDA sends a letter informing the sponsor of this decision.  Additionally, for NADAs and ANADAs, FDA publishes in the Federal Register a regulation prescribing the conditions under which the new animal drug may be used and sends the applicant a copy of the proposed Federal Register publication. 

If, after the product is approved, FDA determines that the product no longer meets the requirements for marketing approval, e.g., is no longer safe and effective, FDA may send a notice informing the sponsor that FDA intends to withdraw approval or licensure, and offering the sponsor an opportunity for a hearing.  A sponsor may also voluntarily request that FDA withdraw the approval, license, or clearance of an application.

Current Disclosure Policies for Marketing Applications.  FDA does not disclose the existence of a marketing application for a drug, biological product, or a premarket approval application for a device unless the application has been previously publicly disclosed or acknowledged by the sponsor.  FDA does not disclose the existence of a 510(k) for a device unless the device is on the market or the submitter of the 510(k) has disclosed its intent to market the device. 

FDA's regulations generally prohibit the release of information from or about a pending application.  As a result, FDA generally cannot disclose that it has issued a “refuse to file,” “refuse to accept,” “refuse to receive,” or “additional information (AI)” letter to the sponsor of the application.  If the marketing application cannot be approved or cleared, FDA does not disclose the complete response, not-approvable, refuse to approve, or “not substantially equivalent (NSE)” letters. 

If and when the drug application, biologics license application, or premarket approval application for a device is approved, the refuse to file/accept/receive letter and the correspondence informing the sponsor that the application cannot be approved in its current form are publicly available, with appropriate redactions.  But additional information letters sent to the sponsor of device applications are not released once the device is cleared and NSE letters are not released, even if the sponsor re-submits a 510(k) for the same device that is later cleared by FDA.

There are limited exceptions to the general prohibition on release of information from or about a pending application.  FDA may release summaries of selected portions of safety and effectiveness information in a pending application if the existence of the application has been publicly disclosed or acknowledged by the sponsor, if relevant for public consideration of a specific pending issue.  This exception is most commonly invoked when an advisory committee meeting is held to consider an application prior to its approval or clearance.  Also, under the Best Pharmaceuticals for Children Act (BPCA) (which applies to human drug applications) and the Pediatric Research Equity Act (PREA) (which applies to both human drugs and biological products), FDA must release clinical, clinical pharmacology, and statistical reviews of pediatric studies within a statutorily defined time frame regardless of whether the application has been approved. 

Because FDA’s regulations generally prohibit the release of information from or about unapproved applications, FDA generally does not disclose the fact that a sponsor has withdrawn or abandoned a drug or device application, or biologics license application before it is approved.  FDA also does not disclose the fact that a sponsor has withdrawn or abandoned a 510(k) application before it is cleared.  However, the FDCA and FDA regulations require FDA to disclose non-summary safety and efficacy information from certain NDAs, INDs, and ANDAs, as well as from certain NADAs, INADs files, NCIEs, and ANADAs, in certain limited circumstances, upon request, unless “extraordinary circumstances” exist.  In practice, these provisions have been difficult to implement.

Some companies disclose on company Web sites, in press releases, and in calls with investors when an application has been filed by FDA for review.  Securities and Exchange Commission (SEC) filings that companies are required to submit also may include information about marketing applications submitted to FDA.