Recently, the US Food and Drug Administration (FDA) released a new draft guidance document on the content and format of generic drug submissions using the common technical document (CTD).
As reported, FDA’s new draft guidance document, ANDA Submissions — Content and Format of Abbreviated New Drug Applications, is meant to help industry increase the quality of its submissions, the agency said in a Federal Register notice. The agency’s hope is that by helping industry to increase submission quality, it can help it to meet the agency’s obligations under the Generic Drug User Fee Act (GDUFA), which required the agency to approve an increasing number of ANDA submissions within 10 months of submission. Comments on the guidance are due 60 days from the document’s release date.
I. INTRODUCTION
This guidance is intended to assist applicants in preparing abbreviated new drug applications (ANDAs) for submission to the FDA under section 505(j) of the Federal Food, Drug and Cosmetic Act (the FD&C Act) (21 U.S.C. 355(j)). This guidance details the information to be provided in each section of the Common Technical Document (CTD) format for human pharmaceutical product applications and identifies supporting guidance documents and recommendations issued by FDA to assist in preparing the submission.
This guidance identifies the information an applicant should include to ensure that a complete, high-quality application is submitted to FDA. FDA has previously published guidance on the filing process, including the refuse-to-receive standards, which should be reviewed thoroughly to avoid common deficiencies found in ANDA submissions.
II. BACKGROUND
Procedures for ANDAs submissions are set forth in FDA’s regulations in 21 CFR part 314. An ANDA is usually submitted for a drug product that is the same as an already approved drug or listed drug. A listed drug is defined in § 314.3(b) as a new drug product that has an effective approval under section 505(c) of the FD&C Act for safety and effectiveness or under section 505(j) of the FD&C Act, which has not been withdrawn or suspended under section 505(e)(1) through (e)(5) or (j)(5) of the FD&C Act, and which has not been withdrawn from sale for what FDA has determined are reasons of safety or effectiveness (§ 314.161).
An applicant submits an ANDA based on a listed drug, and the previously approved drug product on which the ANDA relies is officially known as the reference listed drug (RLD). A reference listed drug (RLD) is defined as the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its abbreviated application (§ 314.3(b)). FDA lists approved drugs that may be referenced in an ANDA in the Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book). The Orange Book is updated by a monthly cumulative supplement.
On July 9, 2012, GDUFA was signed into law by the President to speed the delivery of safe and effective generic drugs to the public and reduce costs to industry. Under GDUFA, FDA agreed to meet certain obligations as laid out in the GDUFA Commitment Letter. Among these obligations is FDA’s commitment to performance metrics for the review of new ANDAs that are submitted electronically following the electronic CTD (eCTD) format. For example, FDA has committed to review and act on 90 percent of original ANDA submissions within 10 months from the date of submission in Year 5 of the program, which begins on October 1, 2016.
To meet these performance goals, FDA is issuing this guidance to assist ANDA applicants in improving the quality of submissions, to increase the number of original ANDAs acknowledged for receipt upon initial submission, and to decrease the number of review cycles. FDA is committed to providing comprehensive assistance in the early stages of the application process so that an original ANDA will contain all information necessary for FDA to complete its review in one review cycle.
III. CTD FORMAT
The CTD format was developed by the International Conference on Harmonisation (ICH) in an attempt to streamline the variability of submission requirements among Japan, the European Union, and the United States. The CTD collects quality, safety, and efficacy information into a common format that has been adopted by ICH regulatory authorities. As previously stated, only ANDA submissions made electronically following the eCTD format on the date of submission will be subject to the review metric goals described in the GDUFA Commitment Letter. Section 745A(a) of the FD&C Act, added by section 1136 of the Food and Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144), requires that submissions under section 505(b), (i), or (j) of the FD&C Act and section 351(a) or (k) of the Public Health Service Act (42 U.S.C. 262(a) or (k)) be submitted in electronic format specified by FDA, beginning no earlier than 24 months after FDA issues a final guidance specifying an electronic submission format.
When finalized, the guidance for industry Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications will implement the electronic submission requirements of section 745A(a) of the FD&C Act by requiring the eCTD format for ANDA submissions, among other submission types. Applicants are reminded that any record in electronic form submitted to FDA under requirements of the FD&C Act are subject to the provisions of 21 CFR part 11 unless exempted. Part 11 regulations were issued in 1997 to provide criteria for acceptance of electronic records, electronic signature and handwritten signatures executed to electronic records as equivalent to 98 paper records and handwritten signatures on paper
FDA has issued several guidance documents specific to the CTD and eCTD submissions. The information contained in these guidances focuses on the technical aspects of filing a CTD application and should be reviewed thoroughly prior to submitting an ANDA. This guidance addresses the content of the CTD for an original ANDA.
The CTD is comprised of the following modules:
- Module 1: Administrative information;
- Module 2: CTD Summaries;
- Module 3: Quality;
- Module 4: Nonclinical study reports;
- Module 5: Clinical study reports.
A. Module 1 – Administrative Information
1. Forms and Cover Letter
Section 1.1 of the ANDA submission contains several forms.
Contains Nonbinding Recommendations
1.1.2 Also contains copy of the GDUFA user fee cover sheet (FDA Form 3794). 1.2 Contains a cover letter.
1.1.2 Contains the completed, signed Application Form FDA 356h (§ 314.94(a)(1)). Applicants should provide complete contact information, including phone and fax numbers, for the agent stationed at each facility listed in the 356h form, along with detailed descriptions of the type of testing performed at each, where applicable. Applicants will be notified of failure to complete facility and testing information. Failure to provide the requested information in a timely fashion will result in the application being refused for receipt. Applicants may use continuation pages, as necessary.
1.2.1 Contains the completed, signed Form FDA 3674, Certification of Compliance Under 42 U.S.C. 282(j)(5)(B) with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C. 282(j)).
2. Administrative Information
1.3.1.2 Contains a U.S. agent letter of appointment, if applicable. The U.S. agent letter of appointment is a separate document submitted in addition to the U.S. agent’s signature on Form 356h, if applicable. If the applicant does not reside or have a place of business in the United States, an agent that resides or maintains a place of business in the United States must the application (§ 314.50(a)(5)).
1.3.2 Contains the field copy certification (§ 314.94(d)(5)). The applicant will certify that the field copy submitted to the appropriate district office is a true copy of the technical section contained in the archival and review copies of the ANDA.
1.3.3 Contains the debarment certification required under the Generic Drug Enforcement Act of 1992 (section 306(k) and 306(a) and (b) of the FD&C Act (21 U.S.C. 335a(k) and 335(a) and (b))). The applicant must certify that it did not and will not use the services of any debarred persons in connection with the application. The applicant must also list all convictions described in the FD&C Act (section 306(k) and 306(a) and (b)). The applicant may use the following language from section 306(k)(1) for the certification required for section1.3.3:13: (Name of Applicant) hereby certifies that it did not and will not use in any capacity the services of any person debarred under section 306 of the Federal Food, Drug, and Cosmetic Act in connection with this application.
1.3.4 Contains financial certification for any clinical investigator who has no disclosable financial interests in, or arrangements with, any applicant of the covered clinical study (FDA Form 3454) or disclosure statement for each clinical investigator who, or whose spouse or dependent child, had disclosable financial interests in and/or arrangements with any sponsor of the covered clinical study (FDA Form 3455) (21 CFR part 54 and § 54.2(e)).
1.3.5 Contains patent information and certification. Applicants are required to list each patent issued by the U.S. Patent and Trademark Office that claims the drug substance, drug product, or that claims a use of the RLD that is cited by the ANDA (§ 314.94(a)(12)). FDA recommends that when providing patent information, applicants include the expiration date for each patent, whether the RLD is protected by any pediatric exclusivity, and when that pediatric exclusivity will expire.
For each patent listed, the applicant must certify to one of the following paragraphs (§ 314.94(a)(12)(i)(A)(1) through (4)): If the RLD is covered by a patent claiming a method of using the listed drug and the labeling for the drug product for which the applicant is seeking approval does not include any indications that are covered by the use patent, the applicant must also submit a statement explaining that the method of use patent does not claim any of the proposed indications (§ 314.94(a)(12)(iii)). Applicants submitting a Paragraph IV certification will provide the following language from § 314.94(a)(12)(i)(A)(4):
I, (name of applicant), certify that Patent No.(is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of) (name of proposed drug product) for which this application is submitted.
Applicants submitting a Paragraph IV certification must also certify that they will provide notice to the owner of the patent(s) and the holder of the approved application that lists the patent(s) that is/are being challenged (§314.94(a)(12)(i)(A)(4)). The process for notice is provided in section 505(j)(2)(B) of the FD&C Act and § 314.95. Applicants should also submit an exclusivity statement regarding their marketing intentions. This statement is relevant when the generic applicant intends to remove or carve out any protected indication(s) from the labeling in order to gain market entry prior to a use’s expiry.
B. Module 2 – CTD Summaries
1. Quality Overall Summary
2.3Contains the Quality Overall Summary (QOS), which provides an overview of the chemistry, manufacturing, and controls (CMC) section of the application (§314.50(c)(2)(iv)). The QOS summarizes what is known about the drug substance (the active pharmaceutical ingredient (API)) in section 2.3.Sand the drug product in section 2.3.P.Applicants should provide separate information on each drug substance contained in the product in section 2.3.S. All information provided in the summary needs to be accurate and supported by information, data, or justification included in Module 3 or other parts of the application.
Applicants should use the Question-Based Review (QbR) model when writing their summaries. FDA introduced the QbR initiative in 2005 as a tool for the review of the CMC — Drug Substance and Drug Product Quality — sections of the ANDA19 and updated the QbR model to include additional CMC questions from microbiology in 2011. The QbR model assists applicants in developing their QOS by providing specific questions that, when answered, ensure adequate information is submitted for FDA review. FDA has posted the QbR-QOS outlines designed for simple dosage form products (solution or immediate-release solid oral dosage forms) and for sterility assurance of products terminally sterilized by moist heat. FDA has also developed example QOS summaries for controlled-release capsules and immediate-release tablets. Additionally, FDA recommends that applicants refer to the QbR Frequently Asked Questions and the QbR for Sterility Assurance of Terminally Sterilized Products: Frequently Asked Questions for further guidance on completing the QOS, including page limits.
FDA recommends that the QOS be submitted in MS Word and text-based PDF file. If the applicant provides a scanned PDF copy of the QOS, FDA requests that the applicant also submit the QOS in Microsoft Word.
C. Module 3 – Quality
Module 3 contains all of the CMC information necessary to support the application (§ 314.94(a)(9)(i)), including the information supporting and verifying what was summarized in Module 2.3. The specific placement of product quality microbiology information in Module 3 is listed in CDER’s Manual of Policies and Procedures (MAPP) 5040.1 Product Quality Microbiology Information in the Common Technical Document. Any analytical procedure submitted in the summaries of Module 2 should be described in sufficient detail to allow an analyst to reproduce the conditions and obtain results comparable to what is stated in the application. FDA recommends that applicants submit a table of contents for Module 3. It is recommended that applicants review the following guidances for industry to assist in the preparation of Module 3: ANDAs: Impurities in Drug Products, ANDAs: Impurities in Drug Substances, and ANDAs: Stability Testing of Drug Substances and Products.
1. Drug Substance
Section 3.2.S contains the CMC information specific to the drug substance(s) (§ 314.50(d)(1)(i)). For a drug product containing more than one drug substance, the information requested for part “S” should be provided in its entirety for each drug substance. To assist in preparing data for the drug substance section, applicants should review the guidance for industry Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances. 3.2.S.1 Contains general information about the drug substance including: (1) the nomenclature, (2) the structure, and (3) general properties. Section 3.2.S.1 should not include any references to the DMF.
3.2.S.2 Contains information related to each drug substance manufacturer including:
(1) the name and full address of the facility(ies);
(2) contact information for an agent at the facility (phone, fax numbers and email address);
(3) function or responsibility;
(4) the Type II DMF number for the API; and
(5) the Central File Number (CFN), Facility Establishment Identifier (FEI) or Data Universal Numbering System (DUNS) numbers, if known.
The applicant should also provide current good manufacturing practice (cGMP) and/or Debarment Certification of the facility that matches the information provided in FDA Form h. Subsections 3.2.S.2.2 through 3.2.S.2.6 may refer to the DMF. If there is no DMF referenced in the application, detailed information should be provided in these subsections. For a sterile substance for use in a sterile drug product, section 3.2.S.2.2 will include the sterilization process and any in-process controls and section 3.2.S.2.5 will contain the validation of sterilization processes for the drug substance.
3.2.S.3 Contains characterization information for the API. FDA recommends that applicants complete the Summary Tables for the Listing and Characterization of Impurities and Justification of Limits in Drug Substance.
D. Module 4 – Nonclinical Study Reports
ANDAs generally do not contain data that are required for Module 4.
E. Module 5 – Clinical Study Reports
Module 5 contains all of the clinical study report data needed to support the application and demonstrate that the generic is bioequivalent to the RLD (§ 314.94(a)(7)). To facilitate the submission of complete data, FDA develops product-specific guidances, summary data tables (as referenced in section III.B.2 of this guidance), and multiple guidances on biopharmaceutics.
Applicants should use an eCTD Study Tagging File for each study submitted.
1. Complete Study Data
5.2 Contains the tabular listing of the clinical studies submitted in the module.
5.3 Contains the clinical study reports and related information.
5.3.1 Contains the complete study data for the biopharmaceutic studies and the lot numbers and strength of products used in the BE study(ies); and documents the study type. The section will also contain information of in vivo and in vitro studies including, but not limited to:
- Synopsis
- Study report
- Protocol and amendments
- All case report forms
- List of independent ethics committees (IECs) or institutional review boards (IRBs) and consent and/or assent forms
- IRB approval letters for protocol, amendments, and consent/assent forms
- List and description of investigators and sites
- Number of subjects enrolled in each site Signatures of principal or coordinating investigator(s) or sponsor’s responsible medical officer
- Listing of subjects receiving test drug(s) from specified batch
- Randomizations scheme
- Audit certificates and reports
- Documentation of statistical methods and interim analysis plans
- Documentation of interlaboratory standardization methods of quality assurance procedures if used
- Publications based on the study
- Important publications referenced in the report
- Discontinued patients including specific reason for discontinuation
- List of subjects included in the PP (per protocol), (M)ITT (modified/intent-to treat), and safety populations
- List of subjects excluded from the PP, (M)ITT, and safety populations
- Reason for exclusion from the PP, (M)ITT, and safety populations for each subject
- Protocol deviations including specific reason for deviation
- Demographic data
- Drug concentration data
- Treatment compliance rate data
- Individual subject’s response scores/data per visit
- Adverse event listings
- Concomitant medication listings
- Listing of individual laboratory measurements by subject
- Site (identifier)
- Individual subject data listings
- In vivo and/or in vitro BE study datasets
- Summary dataset containing a separate line listing for each subject
- Analysis dataset containing a separate line listing for each visit per subject Individual Analysis datasets (e.g., adverse events, concomitant medications etc.) Analysis programs
- Annotated case report form (CRF)
- Annotated ECG waveform datasets Image files
- Narrative safety reports for serious adverse events
- Source documents
- Clinical raw data/medical records
5.3.1.2 Contains the comparative BA and BE study reports (e.g., fasting studies, fed studies)
5.3.1.3 Contains in vitro-in vivo correlation study reports (e.g., comparative dissolution data).
5.3.1.4 Contains reports of bioanalytical and analytical methods provided in individual study reports. If a method is used in multiple studies, the method and its validation should be included once in section 5.3.1.4 and then referenced in individual study reports.
The data provided in all of these sections support the summary tables submitted in section 2.7. All comparative dissolution data from the in vitro-in vivo correlation study reports should be placed in section 5.3.1.3, while the dissolution summary tables should be placed in section 2.7.
2. Literature References
5.4 Contains copies of any documents referred to in the application. The documents may include published articles, official meeting minutes, or other regulatory guidance or advice provided to the applicant. One copy of all important references cited in the QOS or individual technical reports provided in section 5.3 will also be submitted in this section. FDA recommends that the documents be provided in text-based PDF.