NDA Submission Process Flashcards

Question

CTD Module 4- Safety/Nonclinical

Answer 1

Table of contents Study Reports -Pharmacology -Animal Pharmacokinetics -Toxicology -Local Tolerance -Other Studies Literature References

Answer 2

5.1 Table of Contents for Clinical Study Reports and Related Information 5.2 Tabular Listing of all Clinical Studies 5.3 Clinical Study Reports and Related Information 5.3.6 Reports of Post-marketing Experience (including all significant safety observations) 5.3.7 Case Report Forms and Individual Listings (case report tabulations) Located with the study reports and accessed via a study tagging file (more on this later) 5.4 Literature References

Answer 3

-Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication -Study Reports of Uncontrolled Clinical Studies -Reports of Analyses of Data from more than One Study (including any formal integrated analyses, meta-analyses and bridging analyses) -Other Study Reports

Answer 4

-Tabulations of individual patient data from all clinical studies required (per 21 CFR 314.50(f)(1) this is safety data but in reality, all data) -Case report tabulations (all individual patient data) are submitted electronically as datasets (SAS Transport files) and referenced from/with CSR -Datasets MUST be submitted per CDISC Standards (SDTM and ADaM) -Discuss at pre-NDA meeting if there are questions

Answer 5

-CRFs are submitted as PDF files regardless of whether they were paper or electronic Audit trail or Data Edit Documentation required -After initial NDA/BLA – must submit any other CRFs that FDA requests within 30 days

Answer 6

1.Each patient who died during a clinical study, and 2.Each patient who dropped out a study due to an AE, whether believed to be drug-related or not -including patients receiving comparative drugs or placebo 3.Discuss need for additional CRFs at pre-NDA meeting

Answer 7

1. Must list all patents that claim the drug substance, product or method of use for the drug to be listed by FDA -Information published by FDA in Orange Book (Approved Drug Products with Therapeutic Equivalence Evaluations) 2. Submit on Form FDA 3542a Patent Information Submitted With the Filing of An NDA, Amendment, or Supplement

Answer 8

1. Only applies to 505(b)(2) and 505(j) 2. Must certify to lack of, expiration of, non-infringement of, or invalidity of any patents not owned by applicant -314.94(a)(12) -No form exists, just written certification

Answer 9

BLAs are subject to additional regulations (21CFRPart 600): Subpart B--Establishment Standards § 600.10 - Personnel. § 600.11 - Physical establishment, equipment, animals, and care. § 600.12 - Records. § 600.13 - Retention samples. § 600.14 - Reporting of biological product deviations by licensed manufacturers. § 600.15 - Temperatures during shipment. Subpart C--Establishment Inspection § 600.20 - Inspectors § 600.21 - Time of inspection. § 600.22 - Duties of inspector. Filed with 356h form and M3

Answer 10

Certification that applicant did not and will not use services of any person or firm who has been debarred under the Generic Drug Enforcement Act of 1992 in connection with the application -Required for all NDAs and BLAs, not just ANDAs

Answer 11

1.Not required in electronic submission -District Office will have access to the entire submission 2.Legacy purpose was to certify that the copy of Modules 1,2 & 3 sent to FDA District Office is true and accurate copy of those sections included in the NDA/BLA

Answer 12

Documents payment of PDUFA application fee – by wire transfer See FDA website for directions on completing user fee cover sheet (Form FDA 3397) online

Answer 13

For trials covered by 21 CFR 54, certification of: Investigators with no financial disclosures (Form 3454) Investigators with financial disclosures (Form 3455) For trials that included investigators with disclosures, must explain measures taken to minimize potential bias Forms FDA 3454 and 3455

Answer 14

-This should be done during the IND phase -FDA reviews proposed trade names for the potential for product mix-ups or other confusion that could lead to medication errors Part of safety risk assessment of product -Sponsor can get feedback from FDA on choice of trade name

Answer 15

Per the Food and Drug Administration Safety and Innovation Act (FDASIA), a sponsor who will be submitting an NDA or BLA is required to submit an initial Pediatric Study Plan (PSP) within 60 calendar days after the date of the end-of-Phase 2 meeting or such other time as may be agreed upon between the Secretary and the applicant -includes a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration (21 USC 355c(a) and (e))

Answer 16

-an outline of the pediatric study or studies that the applicant plans to conduct Including study objectives and design, age groups, relevant endpoints, and statistical approach); -Any request for a deferral, partial waiver, or waiver, if applicable goes in Module 1

Answer 17

1. Module 3 Impurities Methods and Process Validation Executed batch records 2. Module 4 Nonclinical datasets (SAS xpt) Per CDISC SEND model Carcinogenicity and/or Repeat Dose Toxicity

Answer 18

1. CRTs and CRFS – discussed above 2. Integrated Summaries for Efficacy and Safety (ISE and ISS) - (meta) analyses for efficacy and safety Normally these are placed in M5.3.5.3 However a separate ISE and/or ISS may not be required when the information can be incorporated into Module 2.7.3 and 2.7.4 Rare Diseases/Orphan Drugs Refer to FDA Guidance in eCTD area of website 3. Discuss plans with FDA at pre-NDA/BLA meeting

Answer 19

1Electronic transmission - through the Electronic Submission Gateway (ESG) 2.For applications > 10 GB, may also submit physical media to the Central Document Room, Beltsville, MD

Answer 20

1.Content PLANNING is KEY *Understand US Requirements *Inventory product information *Assign accountability 2.Allow for adequate TIME *Authoring, review and approval *Quality assurance on documents and data *Compilation and publishing 2.Communicate with Stakeholders

Answer 21

1.FDA’s central point for accepting secure electronic submissions via Internet 2.Automated validation; staff do not open or review submissions 3.Route validated submission to correct Center or Office for review

Answer 22

1.Technical When using ESG - Automated Validation tool Identifies and rates the severity of any errors found for reviewability of the electronic submission Runs a check of file formats, bookmarks and hypertext links 2. Manual Division quality checks on content are done within 45/60 day “window” for the purposes of FILING; official start of clock occurs after this is complete TOC, Datasets, Missing Information/Files

Answer 23

1. Enables use of e-mail with link to submission, logs and codes submission into DARRTS (Document Archiving Reporting Regulatory Tracking System) 2. FDA Regulatory Project Manager (RPM) receives both e-mail and DARRTS inbox notice, clicks on links in DARRTS, and assigns submission to reviewers(s) 3. Assigned reviewers receive both e-mail and DARRTS inbox notice and can then access submission directly

Answer 24

1. Accept the NDA/BLA for Filing -File or refuse to file (RTF) -Determination made by 45/60 days The application is sufficiently complete to permit a substantive review RTF Reasons Missing sections, missing datasets or missing required studies or required certifications Lack of organization per Guidance Does not contain an English translation of parts of the NDA/BLA Datasets not per standards 3. Review the application (if filed) Different Review Timelines Priority Review vs. Standard Technical reviews performed by Review Team Communications with sponsor Advisory committee decision 4. Agency Action Approval Complete Response

Answer 25

1.Standard (S) or Priority (P) review from date of filing (not submission) 2.Classified by the review Division within 60 days after receipt of the application -Applicant will receive the classification in filing letter 3.While FDA makes determination at the time of filing, applicant can provide scientific rationale for priority review in NDA cover letter

Answer 26

Standard Review = 10 months Priority Review = 6 months

Answer 27

An NDA/BLA application (or efficacy supplement) for a drug or biologic that treats a serious condition AND if approved, would provide a significant improvement in safety or effectiveness A few types of applications automatically qualify for priority review by statute EX: Qualified Infectious Disease Product

Answer 28

Good Review Management Principles and Practices for New Drug Applications and Biologics License Applications -Guidance to provide recommendations to industry and review staff on good review management principles and practices (GRMPs) for the review of NDAs, BLAs, or efficacy supplements/supplements with clinical data -For FDA review staff; describes planning and conducting review, factors to consider

Answer 29

Drug establishment registration information -Allows FDA to identify all manufacturing facilities involved in producing drugs that are in commercial distribution in the US Drug listing information -Helps FDA maintain a catalog of all drugs in commercial distribution in the US

Answer 30

Owners/operators of registered establishmentS must submit list of every drug in commercial distribution within 5 days of beginning the manufacturing or processing of drugs and biological products Updates must be submitted every subsequent June and December or, at the discretion of the registrant, when any change occurs

Answer 31

1.Sponsor’s manufacturing facilities Verify the accuracy and completeness of the manufacturing information Evaluate manufacturing controls and pre-approval batches Evaluate cGMP Collect samples for analysis including method validation and verification 2.Clinical trial sites

Answer 32

1.Issue Approval letter (314.105) 2.Issue Complete Response (Action) letter (314.110) 3.Reasons for Refusal to Approve an NDA (314.125) 4.Common reasons include CMC – specifications, manufacturing (GMP), device (if applicable) Clinical – data issues, not following GCP Safety concerns – nonclinical or clinical

Answer 33

Enables commercial distribution as of date of approval letter

Answer 34

1Letter describes why the Agency will not approve the application in its present form for one or more reasons 2.Applicant must take action: Resubmission addressing deficiencies Withdrawal of application Request opportunity for hearing to discuss further steps

Answer 35

Amendment – FDA’s request for more information Not the same as a supplement

Answer 36

to the deficiencies in Action letter