Contents

2.9 - REGULATORY SUBMISSIONS

Subchapter 2.9 provides information on the procedures for obtaining information and filing applications with the agency. These will be covered by Center. The filing and registration requirements are directed by the FD&C Act and its implementing regulations. They are filed, in most cases, by industry (e.g.: drug registration, LACF registration and process filing, ANDA's, etc.).

2.9.1 - CENTER FOR DRUG EVALUATION AND RESEARCH (CDER)

The FD&C Act and its regulations require the filing of certain forms by firms which produce human drugs and drug related products. The requirements and procedures for these are described below.

2.9.1.1 - Registration and Listing

Owners or operators of all drug establishments not exempt under Section 510(g) of the FD&C Act [21 U.S.C. 360 (g)] or 21 CFR 207.10, that engage in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs, including blood products, and biologicals, are required to register each such establishment and to submit a list of every drug in commercial distribution, whether or not the output of such establishment or any particular drug so listed enters interstate commerce. Briefly, first time registration, re-registration and updates are accomplished by submitting an FDA 2656 (Registration of Drug Establishment/Labeler Code Assignment ). The drug listing and subsequent June and December updating shall be on form FDA 2657 (Drug Product Listing) or form FDA 2658 (Registered Establishments Report of Private Label Distributors).

Registration and Listing is required whether or not interstate commerce is involved. Detailed registration and listing instructions appear in 21 CFR 207.

An establishment shall register on the form FDA 2656 (Registration of Drug Establishment/Labeler Code Assignment) and list on form FDA 2657(Drug Product Listing) or form FDA 2658 (Registered Establishments Report of Private Label Distributors). The forms may be obtained online at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html.

General information and questions can be addressed by: Phone: 301-210-2840, Mail: Food and Drug Administration, Center for Drug Evaluation and Research, Drug Registration and Listing (HFD-337), 5600 Fishers Lane, Rockville, MD 20857, or e-mail: DRLS@cder.fda.gov. See IOM Exhibit 5-12 for types for drug operations that require registration and listing.

2.9.1.2 - Investigational New Drug Application (IND)

An application which a drug sponsor must submit to FDA before beginning tests of a new drug on humans. The IND contains the plan for the study and is supposed to give a complete picture of the drug, including its structural formula, animal test results, and manufacturing information. Detailed instructions for the submission of IND's can be found in 21 CFR 312.

2.9.1.3 - New Drug Application (NDA)

A New Drug Application is an application requesting FDA approval to market interstate commerce a new drug for human use. The application must contain among other things, data from clinical studies needed for FDA review from specific technical viewpoints, including chemistry, pharmacology, biopharmaceutics, statistics, and anti-infectives, microbiology. Detailed instructions for the submission of NDA's can be found in 21 CFR 314.

2.9.1.4 - Abbreviated New Drug Application (ANDA)

A simplified submission permitted for a duplicate of an already approved drug. ANDAs are for products with the same or very closely related active ingredients, dose form, strength, administration route, use, and labeling as a product already shown to be safe and effective. An ANDA includes all the information on chemistry and manufacturing controls found in a new drug application (NDA), but does not have to include data from studies in animals and humans. It must, however, contain evidence the duplicate drug is bioequivalent to the previously approved drug. Information concerning the submission of ANDA's can be found in 21 CFR 320.

2.9.2 - CENTER FOR DEVICES AND RADIOLOGICAL HEALTH (CDRH)

The FD&C Act, its amendments, and the regulations promulgated under the Act, require the filing of certain forms and submission of certain data by those involved in the production (and in some cases the use) of medical devices and radiological products. Within the CDRH, the Division of Small Manufacturers, International and Consumer Assistance (HFZ-220) has been charged with responsibility for providing information and assistance to industry in complying with these requirements. The general requirements are discussed below, as are several issues unique to CDRH submissions.

2.9.2.1 - Device Registration and Listing

Section 510 of the FD&C Act [21 U.S.C. 360] and 21 CFR 807 describe the establishment registration, device listing, and premarket notification requirements and specify conditions under which establishments are exempt from these requirements.

Manufacturers of finished devices (including device specification developers, reprocessors of single use devices), repackers and relabelers, foreign exporters and initial importers of medical devices, are required to register their establishments by submitting a form FDA 2891. After initial submission, annual registration is accomplished by use of the Center for Devices and Radiological Health (CDRH) computer generated FDA 2891(a). Component manufacturers are not required to register if the components are sold to registered device establishments for assembly into finished devices. Registration and listing is required, however, if the component is labeled for a health care purpose and sold to medical or clinical users. Optical laboratories, clinical laboratories, dental laboratories, orthotic and prosthetic appliance assemblers, hearing aid dispensers and others who, using previously manufactured devices, perform a service function for physicians, dentists, other licensed practitioners or their patients, are exempt from establishment registration if they are located in the United States. X-ray assemblers are exempt from establishment registration. An exemption from registration does not exempt an establishment from inspection under Section 704 of the FD&C Act [21 U.S.C. 374].

Each establishment, except initial importers of medical devices, required to register must list their devices. Device listing is accomplished using a form FDA-2892; the same form is used to update listing information.

All foreign manufacturers are required to notify FDA of the name, address, telephone and fax numbers, and e-mail address of their United States agent. The United States agent must reside or have a physical place of business in the United States. Post office boxes, answering services and machines are not allowed.

Establishments are required to register and list, even if interstate commerce is not involved. Foreign establishments must register, list and submit a United States agent notification prior to exporting to the United States. See IOM Exhibit 5-13 for types of medical device operations, which require registration and listing.

An establishment must initially register on the form FDA 2891, and list on form FDA 2892 which may be obtained from:

1. FDA Internet site: http://www.fda.gov/cdrh/reglistpage.html .
2. CDRH, Division of Small Manufacturers, International and Consumer Assistance (HFZ-220), 1350 Piccard Drive, Rockville, MD 20850, 800-638-2041 ext. 102 or 301-443-6597 ext. 102. Please note this is an automated publications' request line. Caller must leave name, address, phone number and publications needed.

A sample United States agent notification letter may be obtained from:

1. FDA Internet site: http://www.fda.gov/cdrh/reglistpage.html.
2. CDRH, Division of Small Manufacturers, International and Consumer Assistance (HFZ-220), 1350 Piccard Drive, Rockville, MD 20850, 800-638-2041 ext. 102 or 301-443-6597 ext. 102. Please note this is an automated publications' request line. Caller must leave name, address, phone number and publications needed.

General information and policy questions can be addressed by:

1. Sending an e-mail message to RLPROGRAM@ cdrh.fda.gov.
2. Writing to or calling Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance/Division of Program Operations, Registration and Listing Program (HFZ-308), 9200 Corporate Blvd., Rockville, MD 20850, 301-827-4555, press 3, then 2.

2.9.2.2 - Investigational Device Exemption (IDE) Regulation

The IDE regulation in 21 CFR 812 contains requirements for sponsors, Institutional Review Boards (IRBs) and Clinical Investigators. Additional requirements are found in 21 CFR 50, Informed Consent, and 21 CFR 56, IRB's. All Sponsors of device clinical investigations must have an approved IDE, unless specifically exempted by the regulation. Sponsors who have an approved IDE are exempt from requirements on labeling, registration and listing, premarket notification, performance standards, premarket approval, GMPs except the design control provisions, banning of devices, restricted devices, and color additives.

Provisions for obtaining an IDE, and the sections of the regulations, with which sponsors, investigators, and IRBs must comply, differ according to the risks posed by the device. Sponsors of nonsignificant risk devices must obtain IRB approval, and are subject to a limited number of provisions; sponsors of significant risk (See 21 CFR 812.3(m).) investigations are subject to the entire regulation.

There are investigations, described in 21 CFR 812.2(c) that are exempt from the IDE regulation. Exempted investigations apply to devices and diagnostics, which meet the criteria in the regulation. These devices are, however, still subject to other regulatory requirements of the Act, such as labeling, premarket approval of Class III devices, and GMPs (as stated in the preamble to the IDE regulation).

A Sponsor who knows a new device is not "substantially equivalent" to a preamendment device, or who is not sure if a device is "substantially equivalent" without conducting a clinical investigation, must obtain an approved IDE to conduct the clinical investigation. After collecting clinical data, a sponsor who desires to market a device must either submit a premarket notification (510k) or premarket approval application to FDA. A premarket notification may be submitted if the sponsor believes the data supports a finding of substantial equivalence.

Certain radiation-emitting electronic devices that are investigational are also subject to radiological health regulations, 21 CFR 1000 through 1050.

Transitional devices, must have an approved IDE in order to be investigated.

Sponsors, Monitors, IRBs, Investigators, and Non-Clinical Toxicological Laboratories will be covered under the Bioresearch Monitoring Program. FDA has the authority to inspect and copy records relating to investigations. Records identifying patients by name will be copied only if there is reason to believe adequate informed consent was not obtained, or investigator records are incomplete, false, or misleading.

2.9.2.3 - Premarket Notification - Section 510(k)

The Medical Device Amendments of 1976 require device manufacturers to notify the CDRH at least 90 days before commercially distributing a device. This is known as a "Premarket Notification" or a "510(k)" submission. "Commercial distribution", for practical purposes, means the device is held for sale. These 510(k) requirements do not apply to Class I devices unless the device is intended for a use which is of substantial importance in preventing impairment of human health, or to any Class I device that presents a potential unreasonable risk of illness or injury. See section 510(l) of the FD&C Act [21 U.S.C. 360(l)].

A manufacturer must submit a Premarket Notification to FDA in any of the following situations:

1. Introducing a device into commercial distribution for the first time.
2. Introducing a new device or product line for the first time, which may already be marketed by another firm.
3. Introducing or reintroducing a device with significant changes or modifications affecting the safety or effectiveness of the device. Such changes or modifications could relate to design, material, chemical composition, energy source, manufacturing method, or intended use.

These requirements do not apply to "custom devices." A "custom device" is a device made exclusively for, and to meet the special needs of, an individual physician or health professional, or for use by an individual patient named in the order of a physician or dentist (such as specially designed orthopedic footwear). A "custom device" is not generally available in finished form for purchase; and is not offered through labeling or advertising for commercial distribution.

Refer to IOM Exhibit 5-13 for types of medical devices, which require 510(k) submissions. The investigator should document for CDRH review failures to submit required 510(k)s.

2.9.2.4 - Premarket Approval

Class III devices are required to undergo premarket approval in accordance with the provisions of Section 515 of the FD & C Act [21 U.S.C. 360e]. Premarket approval for a device is initiated with the submission of an application to FDA. Prior to approval of a premarket approval application (PMA), or a supplemental PMA, FDA has the authority to inspect the applicant's facilities and those records pertinent to the PMA.

Compliance Program Guidance Manual 7383.001 contains specific guidance on performing PMA pre-approval and post-approval inspections.

Inspections of manufacturing facilities are usually required prior to approval of a Premarket Approval Application. A full GMP inspection may not be necessary if there has been a recent satisfactory inspection covering a device similar to the PMA device.

Requests for PMA inspections issue from HFZ-306. The assignments will request the firm be inspected for compliance with the GMP regulations, and with their commitments in the PMA.

2.9.2.5 - Classification of Devices

All medical devices subject to the FD&C Act will be classified as either Class I, Class II, or Class III medical devices.

Manufacturers who have questions regarding the classification of a device can write CDRH under Section 513(g) of the FD&C Act [21 U.S.C. 360c (g)] and request an opinion as to the status of the device.

2.9.2.5.1 - Class I

Class I - General - Devices for which general controls (i.e., the controls in Sections 501, 502, 510, 516, 518, 519 and 520 of the FD&C Act [21 U.S.C. 351, 352, 360, 360f, 360h, 360i, and 360j]) provide reasonable assurance of safety and effectiveness.

2.9.2.5.2 - Class II

Class II - Special Controls - Devices for which the general controls, by themselves, are insufficient to provide reasonable assurance of safety and effectiveness of the device, and for which there is sufficient information to promulgate special controls, necessary to provide such assurance.

2.9.2.5.3 - Class III

Class III - Premarket Approval - Devices which:

1. Cannot be placed into Class I or II because insufficient information exists to provide assurance of safety and effectiveness, and cannot be placed into Class II because too little data exists to support the promulgation of special controls, and
2. Are purported or represented to be for use in supporting or sustaining human life, or for a use which is of substantial importance in preventing impairment of human health, or
3. Presents a potentially unreasonable risk of illness or injury.

Unless they are determined substantially equivalent to devices distributed prior to the 1976 Medical Device Amendments, devices proposed for marketing after May 28, 1976, fall automatically into Class III. Class III medical devices marketed before May 28, 1976, and the substantially equivalent devices marketed after that date, remain subject to the premarket notification requirements until required to have an approved PMA. Petitioners can request to have such devices reclassified into Class I or II. Transitional devices, those regulated as new drugs before May 28, 1976, are automatically assigned to Class III.

2.9.2.6 - Requests for GMP Exemption and Variances

Section 520f(2)(A) of the FD&C Act [21 U.S.C. 360j (f)(2)(A)] allows manufacturers, trade organizations, or other interested persons to petition for exemption or variance from all or part of the GMP. Filing a petition does not defer compliance with the GMP requirements, and petitions will not be processed while an investigation is ongoing, or while regulatory action is pending.

Some Class I devices have been exempted from the GMP through the classification process. Each classification panel was required to consider the Class I devices reviewed by that panel and recommend if they should be exempt from the GMP. Devices exempted from the GMP by the classification process are published in classification regulations in the Federal Register.

Devices labeled or otherwise represented as sterile are not eligible for exemption from the GMP regulation. A sterile device is subject to all GMP requirements pertinent to sterility and sterilization processes.

No exemptions will be granted from 21 CFR 820.198 - Complaint Files, which requires the device manufacturer to have an adequate system for complaint investigation and follow-up. This Policy extends to 820.180 - General Requirements, which gives authorized FDA employees access to complaint files, device related injury reports, and failure analysis records for review and copying. When FDA has granted a manufacturer an exemption from one or more GMP requirements, the manufacturer still has the responsibility to implement appropriate quality control measures to assure the finished device has the quality it purports to possess, as stated in Section 501(c) of the FD&C Act [21 U.S.C. 351 (c)]. A manufacturer who has been granted a GMP exemption is still subject to inspection under Section 704(a) of the FD&C Act [21 U.S.C. 374 (a)], and may be subject to regulatory action if devices are adulterated or misbranded.

2.9.2.7 - Medical Device Reporting

The Medical Device Reporting (MDR) regulation and the changes mandated by the Safe Medical Devices Act of 1990 (SMDA) is a mandatory information reporting system. It requires manufacturers, importers, and users of medical devices to report to FDA certain adverse experiences caused or contributed to by their devices. This program is administered by the Center's Office of Surveillance and Biometrics. The regulation requires a report be submitted to FDA whenever a manufacturer or an importer becomes aware of information that its device:

1. May have caused or contributed to a death or serious injury, or
2. Has malfunctioned and, if the malfunction recurs, is likely to cause or contribute to a death or serious injury.

Under the Safe Medical Devices Act of 1990, user facilities must report device-related deaths to FDA and to the manufacturer, if known. User facilities must also report device-related serious illnesses and injuries to the manufacturer, or to FDA if the manufacturer is unknown. In addition, SMDA also requires user facilities to submit to FDA, on an annual basis, a summary of all reports submitted.

The CDRH Division of Small Manufacturers International and Consumer Assistance and the Office of Surveillance and Biometrics should be contacted for further guidance about the MDR regulation. Inspections for compliance with the MDR regulation are conducted following the guidance contained in the Compliance Program 7382.845 - Inspection of Medical Device Manufacturers. When reviewing the manufacturer's complaint files, look for complaints, which are reportable, and have not been reported by the manufacturer.

2.9.2.8 - Radiation Reporting

Prior to introduction of products into commerce, manufacturers of radiation-emitting electronic products must submit radiation safety Product Reports if the product is listed and marked in Table 1 of 21 CFR 1002.1. (Non-medical radiation products have NO registration and listing requirements, but the same type of information is included in these reports.) These are premarket documents but there is no timeframe for review and manufacturers do not have to wait for clearance. However, these documents must be processed by CDRH, Office of Compliance to provide rapid import entry of electronic products. Radiation Product Reports provide technical specifications, how products comply with standards, and radiation testing and quality control programs to support the firm's (self)-certification of compliance of each product.

In addition, manufacturers must file annual reports (if specified in Table 1), defect or noncompliance reports when appropriate (similar to recall notices), and accidental radiation occurrence reports when appropriate (similar to, and sometimes replaced by, Medical Device Reports (MDRs)).

2.9.3 - CENTER FOR BIOLOGICS EVALUATION AND RESEARCH (CBER)

The requirements for the registration and licensing of biological products fall under both the Public Health Service Act (PHS) and the FD&C Act.

2.9.3.1 - Registration and Listing

See also IOM 5.7.3.

CBER provides industry with registration and listing forms, FDA 2830, Blood Establishment Registration and Product Listing, and FDA 3356, Establishment Registration and Listing for Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps). Instructions for completing these documents are on the reverse side of these forms along with establishment and product definitions. Registration forms are available through the district office and through CBER's Office of Communication, Training and Manufactures Assistance, and from the CBER website. Registration and listing is required whether or not interstate commerce is involved. (See IOM 5.7.3)

2.9.3.1.1 - Human Blood and Blood Products

Human Blood and Blood Products:

1. Who must register - Section 510 of the FD&C Act and 21 CFR 607 delineate the requirements and exemptions relating to the registration of establishments engaged in the collection, manufacturing, preparation, or processing of human blood or blood products. Registration and listing are required whether or not interstate commerce is involved. Fixed blood collection sites that have supplies or equipment requiring quality control or have an expiration date, e.g., copper sulfate, centrifuges, etc., or are used to store donor records, must register. Temporary collection sites, to which all blood collection supplies are brought on the day of collection and are completely removed from the site at the end of the collecting period (except beds, tables, and chairs) and blood mobiles, are not required to register. All Military blood bank establishments are required to register. (MOU with Department of Defense [Federal Cooperative Agreements Manual] Regarding Licensure of Military Blood Banks.) Brokers, who take physical possession of blood products, such as in storage, pooling, labeling, or distribution, are required to register. Blood establishments located outside of the United States that import or offer for import blood products into the U.S. are required to register with FDA. They must also provide the name of the United States agent, the name of each importer, and each person who imports or offers for import these blood products.
2. When to register - Establishments must register within five days after beginning operations and must submit a list of blood products they distribute commercially. They must register annually thereafter.
3. How to register - Owners or operators of blood establishments register using the Form FDA 2830. Refer to Compliance Policy Guide (CPG) 230.110 for additional information on registration. These persons may complete and submit Form FDA 2830 on the Internet or may submit a paper form.
4. Where to mail completed paper forms - Mail completed legible forms to: Food and Drug Administration, Center for Biologics Evaluation and Research, Division of Blood Applications (HFM-370), 1401 Rockville Pike, 200N, Rockville, MD 20852-1448.

5. General Information and Questions:
   Phone: 301-827-3546

   Email: bloodregis@cber.fda.gov