From my understanding, all countries under the ICH define and report Adverse Events the same way. Are there any other items/ideas within clinical research that all ICH countries have the same process for?

The subject source should document when the site was notified and how the site was notified of the serious adverse event. This information is needed to verify that the site is compliant with the requirement to report serious adverse events within 24 hours of notification to the sponsor.

The informed consent discussion should always be documented in the subject source. It is important for it to be noted that study procedures were not performed until after the informed consent was signed and that the subject was given a signed copy of the informed consent.

Ensuring that the data is not obstructed is critical to maintaining the audit trail. A good rule of thumb to remember is the ALCOA guideline. Data should always be "attributable, legible, contemporaneous, original and accurate." Anyone should be able to review the data and understand the flow of events. It is always best to err on the site of caution and provide documentation for any event that may pose a question later. If everyone follows these guidelines, we can ensure the integrity of the data.

How often does a monitor find onsite that Principal Investigators are not reporting AEs to the Sponsor or IRB?

This also includes the investigator. A principal investigator may be on a review board, however, they are not allowed to vote on submitted matters.

I got into this debate the other day at work. If the Sponsor delivers the IB to the CRO who then delivers them to the sites. Who is responsible for the content of the IB? Does this account for a transfer of responsibility? I personally don't think so.

This documented transfer is often times referred to as a TORO (Transfer of Regulatory Obligations) and the only items that can be transferred to a CRO are further outlined in 21 CFR 312.52.

I like it that this document includes both Audit/Inspection as they can often times be confused. Regulatory agencies only conduct Inspections.

I've also heard of this referred to as an "Expected Adverse Event." Has anyone else heard this term before?

ICH Tripartite Guideline was agreed upon by the US, EU, and Japan for Good Clinical Practice (GCP) under the Efficacy category.

The ICH CTD is simplified into the 5 different modules as depicted in the CTD triangle. Simplistically, Module 1 includes the administrative and labeling requirements of the submission. Module 2 a table of contents of modules 2 through 5 and an overview of the technical date in modules 3 through 5. Module 3 includes a table of contents for module 3 and data on CMC. Module 4 includes a table of contents for module 4 as well as the reports for the nonclinical data. Finally, Module 5 contains the bulk of the information whjch is the table of content and data for the clinical study reports (in human studies).

Module 1 is neither a part of the ICH or the CTD. This is information that may or may not be requested depending on which agency the product is getting filed with. Module 2 really applies to all of the following ICH portions, as it is a summary of the specific information in the following modules: M4Q(R1) Quality per ICH or Module 3; M4S(R2) Safety per ICH or Module 4; and M4E(R1) Efficacy per ICH or Module 5.

The ICH guidelines categories for each CTD Module are listed below:

Module 1: Contains administrative information and prescribing information. Module 2: Contains an overview and summary of modules 3 - 5. Module 3: Contains ICH M4Q(R1) - This code is for Quality. Module 4: Contains ICH M4S(R2) - This code is for Safety (non-clinical study reports). Module 5: Contains ICH M4E(R1) - This code is for Efficacy (clinical study reports).

Source:

http://www.ich.org/products/ctd.html

Module 1 is not harmonized as it is region specific. Module 2: ICH M4Q(R1) Quality Overall Summary (QOS) -- summarizes data in Modules 3,4, and 5. Module 3: ICH M4Q(R1) Quality -- contains Chemistry, Manufacturing and Controls (CMC) information Module 4: M4S(R2) Safety -- includes information regarding pharmacology, pharmacokinetics, and toxicology. Module 5: M4E(R1) Efficacy -- contains study reports

Module 1 contains administrative information and prescribing information Module 2 contains an overview and summary of modules 3 - 5 Module 3 contains ICH M4Q(R1) - This code is for Quality Module 4 contains ICH M4S(R2) - This code is for Safety (non-clinical study reports) Module 5 contains ICH M4E(R1) - This code is for Efficacy (clinical study reports)

https://via.hypothes.is/http:/www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/CTD_triangle.pdf

M4 represents the CTD (the fourth multidisciplinary category addressed by the ICH). The E, S, and Q represent the specific topics the ICH addresses: efficacy, safety, and quality. R states the revision number.

• Module 1 contains region-specific information; for the US this is Form 356h, prescribing information and risk evaluation and mitigation strategy)
• Module 2 ICH Quality Overall Summary (QOS), which consists of a summary and overview of the following three modules
• Module 3 contains ICH M4Q(R1), which consists of quality information
• Module 4 contains ICH M4S(R2), which consists of safety information
• Module 5 contains ICH M4E(R1), which consists of efficacy information

Any and all patent information about the drug needs to be disclosed in the NDA because it helps determine or protect the applicant from whether or not the drug included in the NDA might infringe on a patent.

"of this section for each patent that claims the drug or a method of using the drug that is the subject of the new drug application or amendment or supplement to it and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product"

The CTD relates because in module 1 of the CTD is the same information requested for patent information on the NDA, in the same format.

I think that all of the definitions are important to understand when putting together an application to the FDA. Some definitions, I think don't really need much explanation such as Act, Applicant, FDA, Drug Product, Drug Substance, and Specification. On the other hand, applicants will need to know what type of application they are filing, and then the subsequent aspects or requirements for each type of application. For example, an NDA will not require any type of reference listed drug or RLD. Some terms apply to both ANDAs and NDAs, such as approval letter, class 1 and class 2 resubmission, and complete response letter, just to name a few.

The following must be disclosed when submitting patent information.

A) New Drug application number B) Name of new drug application sponsor C) Trade name (or proposed trade name) of new drug D) Active ingredient(s) of new drug E) Strength(s) of new drug F) Dosage form of new drug G) United States patent number, issue date, and expiration date of patent submitted H) The patent owner's name, full address, phone number and, if available, fax number and e-mail address I) The name, full address, phone number and, if available, fax number and e-mail address of an agent or representative who resides or maintains a place of business within the United States authorized to receive notice of patent certification under sections 505(b)(3) and 505(j)(2)(B) of the act and §§314.52 and 314.95V J) Information on whether the patent has been submitted previously for the new drug application K) Information on whether the expiration date is a new expiration date if the patent had been submitted previously for listing L) Information on whether the patent is a product-by-process patent in which the product claimed is novel M) Information on the drug substance (active ingredient) patent N) Information on the drug product (composition/formulation) patent O) Information on each method-of-use patent P) Whether there are no relevant patents that claim the drug substance (active ingredient), drug product (formulation or composition) or method(s) of use, for which the applicant is seeking approval and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product Q) Signed verification R) Information on whether the applicant, patent owner or attorney, agent, representative or other authorized official signed the form; the name of the person; and the full address, phone number and, if available, the fax number and e-mail address

CTD is related to 314.53 as CTD is the format the NDA application should be submitted and this particular section is information that is included in the NDA application.

Source:

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The terms that I feel are important to understand before submitting are applicant, application, act, abbreviated application, approval letter, resubmission, complete response letter and specification. It is crucial that the applicant truly understands what is needed prior to submitting, in addition, understanding which application is needed. The next section the application would need to thoroughly understand is Section 314.50.

There is a difference between a patent and exclusivity. A patent can be granted anywhere along the development cycle and can last up to 20 years. Exclusivity is the exclusive marketing rights granted upon approval and certain criteria must be met. Exclusivity can last anywhere from 180 days to 7 years. Frequently asked questions on patents and exclusivity. (2014, July 18). Retrieved October 12, 2015, from http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079031.htm

The following items must be disclosed when submitting patent information: A. New Drug Application (NDA) number B. Name of new drug application sponsor C. Trade name (or planned name) D. Active ingredient(s) E. Strength(s) of new drug F. Dosage form G. US patent number, issue date, and expiration date of patent submitted H. Patent owner's name, address, phone number and if available fax number and email address I. Agent of Representative in the US's name, address, phone number and if available fax number and email address J. If the patent has been submitted before K. If the expiration date is new or from a previous patent L. Information on whether the product is novel M. Information on drug substance N. Information on drug product O. Information on method of use P. Confirmation there are no relevant patents that claim the drug substance, drug product, or methods of use, for which the applicant is seeking approval with respect to which a claim of patent infringement could be asserted Q. Signed verification R. Information on who signed the form their name, address, phone number, and if available fax number and email address.

The CTD is the format in which NDAs should be completed. According to the CTD information from 314. 53 regarding patent information and certification is included in Module 1 of the NDA.

It is essential that the applicant understands the difference between an application and an abbreviated application. While an application and an abbreviated application are very similar in definition, an abbreviated application is just that abbreviated. Thus meaning that all the aspects of an application are not included in an abbreviated application. In an application there must be a statement that confirms the type of application, such as original application, 505(b)(2) application, resubmission, or a supplement to an application; whereas in an abbreviated application, this statement is not included. It is also important to comprehend the different types of applications and when they should be used prior to starting one to ensure the correct type will be submitted.

§314.53 Submission of patent information

The items that need to be disclosed are:

1. New drug application number
2. Name of new drug application sponsor
3. Trade name
4. Active ingredient(s)
5. The strength of the new drug
6. The dosage form
7. The patent number
8. The patent owner's full name, phone number, address, e-mail address, and fax number (if available).
9. Information on any previous submissions
10. Information on the expiration date
11. Information on whether the patent is a product-by-process patent
12. Information on the drug substance
13. Information on the drug product
14. Information on each method-of-use
15. The approved drug product or methods of use
16. A signature verifying that the submitted information if accurate
17. Signatures of all other authorized personnel and full name, address, phone number, e-mail, and fax number (if available)

This relates to the CTD format because §314.53 informs the applicant on what is needed to submit an NDA and the CTD format provides support for an NDA submission.

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§314.3 Definitions

I believe the most important terms an applicant needs to understand prior to submission are: Complete response letter, Class 1 resubmission, Class 2 resubmission, and Resubmission.

The Complete response letter allows the applicant to fully understand what needs to occur prior to approval.

Although Class 1 resubmission and Class 2 resubmission are both application resubmissions, the applicant should understand why the FDA is requesting a resubmission.

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The information required is as follows:

• NDA number
• Name of NDA sponsor
• Trade name of new drug
• Active ingredient(s) of new drug
• Strength(s) of new drug
• Dosage form of new drug
• Approval date of NDA or supplement
• patent number, issue date, and expiration date of patent submitted
• The patent owner's name, full address, phone number and, if available, fax number and e-mail address
• The name, full address, phone number of an agent or representative who resides or maintains a place of business within the United States authorized to receive notice of patent certification
• Information on whether the patent has been submitted previously for the new drug application
• Information on whether the expiration date is a new expiration date if the patent had been submitted previously for listing
• Information on whether the patent is a product-by-process patent in which the product claimed is novel
• Information on the drug substance (active ingredient) -Information on the drug product (composition/formulation)
• Information on each method-of-use
• Whether there are no relevant patents that claim the approved drug substance (active ingredient), the approved drug product (formulation or composition) or approved method(s) of use and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product
• A signed verification
• Information on whether the authorized official signed the form; the name of the person; and the full address

This relates to the CDT as much of this information is required for a submission in CDT format. Specifically, name of Sponsor, active ingredients, strength(s) of new drug, and dosage information.

The most important defined terms to understand prior to submission, in my opinion are Abbreviated Application and Application and specifically how they relate to each other and are different from each other. There are different requirements for each of these applications. The Abbreviated Application is outlined in Subpart C and is only applicable to certain drug products. I also think that it is important to highlight the differences between Class 1 Resubmissions and Class 2 Resubmissions. Class 1 Resubmissions are more minor in nature whereas, Class 2 Resubmissions requirereview in front of an advisory committee.

What must be disclosed? How does 314.53 relate to the CTD?

Note the definitions for the application. What terms are important to understand before starting the application?

The ICH guideline categories for each CTD Modules provide harmonized structure and format for presenting information on a new drug. The codes and what they mean are; • Module 1) MR (R3) Overall organization of the CTD. Administrative information and prescribing information and specific to each region.<br> • Module 2: M4Q (R1) Quality overall summary (QOS), and M4E (R1) Clinical overview and clinical summary – efficacy. • Module 3 M4Q (R1) Quality. • Module 4: M4S (R2) Safety. • Module 5: M4E (R1) Efficacy. Reference: ICH harmonization for better health. CTD M4: The common Technical Document. http://www.ich.org/products/ctd.html. Accessed October 11, 2015.

Definitions: The electronic Code of Federal Regulations Title 21, Chapter 1, Subchapter D, Part 314.3 contains a list of definitions. There are many terms that are listed in the regulation for applications for FDA approval to market a new drug. A general understanding of these terms is needed in order to ensure an appropriate and accurate application process is completed. It would be the applicant’s best interest to be familiar with all definitions in order to better understand the application process for a new drug

Electronic Code of Federal Regulations Title 21, Chapter 1, Subchapter D, Part 314.3 defines an applicant as: “Applicant means any person who submits an application or abbreviated application or an amendment or supplement to them under this part to obtain FDA approval of a new drug or an antibiotic drug and any person who owns an approved application or abbreviated application.” The definition includes those who already own an approved application or abbreviated application and not just those who are applying for the first time.

Form FDA 356h is the form that should be completed and signed. It provides the reviewer with general information about the applications such as how the applicant can be reached, a description of the investigational product under review, sections included in the application, a certification statement, and etc.

The applicant would be the person who signs the Form FDA 356h, or has signed a previous form belonging to an approved product.

The application form is Form FDA 356h. It includes a checklist that must be completed by the applicant. When the applicant signs the form and submits it to the FDA, they are declaring that all the information included in the application is true and accurate to their knowledge. FDA Regulatory Affairs, 3rd Ed. Mantus and Pisano, pgs 88-92. 2014.

The application form that is to be completed and signed by the applicant is the New Drug Application (NDA).

Source:

https://via.hypothes.is/http:/www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=5f43ccac24cd09c8a658dbde866225b5&mc=true&n=pt21.5.314&r=PART&ty=HTML#se21.5.314_13

Applicant means any person who submits an application or abbreviated application or an amendment or supplement to them under this part to obtain FDA approval of a new drug or an antibiotic drug and any person who owns an approved application or abbreviated application.

Source:

https://via.hypothes.is/http:/www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=5f43ccac24cd09c8a658dbde866225b5&mc=true&n=pt21.5.314&r=PART&ty=HTML#se21.5.31413

The applicant is anyone who submits an application or abbreviated application or an amendment or supplement to them in order to obtain FDA approval or any person who owns an approved application or abbreviated application.

The application form that is to be completed and signed by the applicant is the New Drug Application (NDA).

(a) Application Form

The required form the FDA wants completed and signed is the New Drug Application (NDA). The application can be a resubmission, an amendment, or a supplement.

https://via.hypothes.is/http:/www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=5f43ccac24cd09c8a658dbde866225b5&mc=true&n=pt21.5.314&r=PART&ty=HTML

applicant

The applicant is anyone who submits an application to the FDA to gain approval of a new drug.

https://via.hypothes.is/http:/www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=5f43ccac24cd09c8a658dbde866225b5&mc=true&n=pt21.5.314&r=PART&ty=HTML

a) Application Form

Form 356h must be completed and signed with each submission. http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM321897.pdf

The Application Form refers to the application described under §314.50, which would be the NDA.

The applicant is "the person who submits an application or abbreviated application or an amendment or supplement to them under this part to obtain FDA approval of a new drug or an antibiotic drug and any person who owns an approved application or abbreviated application."

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What are the ICH guidelines categories for each CTD Module? Example: Module 5 contains ICH M4E(R1)

What do these codes mean?

Who is the applicant? Hint: Go back to 21 CF 314.3 Definitions.

What is the required form the FDA wants completed and signed?