Fecal Microbiota for Transplantation: Safety Communication- Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms

Fecal Microbiota for Transplantation: Safety Communication- Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms

admin No Comments

[Posted 06/13/2019]

AUDIENCE: Patient, Healthcare Professional

ISSUE: The FDA is now aware of bacterial infections caused by multi-drug resistant organisms (MDROs) that have occurred due to transmission of a MDRO from use of investigational fecal microbiota for transplantation (FMT):

  • Two immunocompromised adults who received investigational FMT developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E.coli). One of the individuals died.
    • FMT used in these two individuals were prepared from stool obtained from the same donor.
    • The donor stool and resulting FMT used in these two individuals were not tested for ESBL-producing gram-negative organisms prior to use. After these adverse events occurred, stored preparations of FMT from this stool donor were tested and found to be positive for ESBL-producing E. coli identical to the organisms isolated from the two patients.

RECOMMENDATION: Patients considering FMT to treat C. difficile infection should speak to their health care provider to understand the potential risks associated with the product’s use.

Healthcare providers must obtain adequate consent for the use of FMT from the patient or his or her legally authorized representative. The consent should include, at a minimum, a statement that the use of FMT to treat C. difficile is investigational and a discussion of its potential risks. FDA is informing members of the medical and scientific communities and other interested persons of the potential risk of transmission of MDROs by FMT and the resultant serious adverse reactions that may occur. 

  • Donor screening with questions that specifically address risk factors for colonization with MDROs, and exclusion of individuals at higher risk of colonization with MDROs.
  • MDRO testing of donor stool and exclusion of stool that tests positive for MDRO. FDA scientists have determined the specific MDRO testing and frequency that should be implemented.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:

  • Complete and submit the report Online
  • Download form  or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[06/14/2019 – Safety Communication – FDA]

http://www.fda.gov/safety/medwatch-safety-alerts-human-medical-products/fecal-microbiota-transplantation-safety-communication-risk-serious-adverse-reactions-due

Pharmacy Compounding Advisory Committee Roster

admin No Comments

Applying for Membership on FDA Advisory Committees

As part of the Food and Drug Administration’s (FDA’s) ongoing efforts to recruit qualified experts with minimal conflicts of interest who are interested in serving on FDA advisory committees, FDA is requesting nominations for members to serve on its advisory committees. More info (Posted 2/27/2007)

Current Number of Vacancies = 1

Note, one or more vacancies may be in the nomination process or a final appointment may have been made.

http://www.fda.gov/advisory-committees/pharmacy-compounding-advisory-committee/pharmacy-compounding-advisory-committee-roster

Dean Obeidallah Wins $4.1M In Defamation Suit Against Neo-Nazi Website

admin No Comments

NPR’s Michel Martin speaks with comedian Dean Obeidallah, who this week was awarded $4.1 million in damages for defamation from the neo-Nazi website, The Daily Stormer.

MICHEL MARTIN, HOST:

Continuing the conversation about new technologies, this week, lawmakers debated how to deal with information generated by artificial intelligence, which they fear could be used to smear candidates and interfere with elections. A comedian and commentator named Dean Obeidallah decided to tackle this conduct the old-fashioned way. He sued his defamers, and he won. This week, a judge ruled that the publisher of the neo-Nazi site The Daily Stormer must pay Obeidallah $4.1 million for falsely portraying him as a terrorist. Here to tell us more is Dean Obeidallah. He’s with us from our bureau in New York. Welcome. Thanks so much for joining us.

DEAN OBEIDALLAH: Thank you.

MARTIN: So let me just remind everybody again exactly what happened. What was your specific complaint against The Daily Stormer and its publisher, Andrew Anglin?

OBEIDALLAH: Well, what they did to me and what they wrote about me requires going backwards slightly a little bit. I wrote an article on May 31, 2017, for The Daily Beast, where I’ve been writing weekly for a few years. And in that article, I used the term white supremacist terrorism. And I said, why will Donald Trump not use the term white supremacist terrorism? Because this is three months before Charlottesville. There was already a spike in white supremacist violence going on.

And that so upset Andrew Anglin at The Daily Stormer, the publisher and founder. He wrote an article the next day smearing me. He fabricated tweets that made it look like I was tweeting that I was the mastermind of the bombing, I was cheering for it and I did it the name of Allah and my faith as a Muslim. And they looked exactly real, with retweets and likes and then directed his readership at The Daily Stormer to confront me was the exact term.

MARTIN: And what happened? Did people think this was you?

OBEIDALLAH: Well, yes.

MARTIN: And did people confront you?

OBEIDALLAH: The Daily Stormer readers clearly thought it was me from the comments that were directed at me that very clearly said that I hope – Dean better hope he dies of natural causes before we get him, things like we should hang him from an elm tree. And in their comments, they clearly saw – thought I was a terrorist. And just so it’s clear for people, The Daily Stormer is not your average white supremacist neo-Nazi publication, if there is such one. It is one where readers go to, they exchange information. They animate each other into action.

And readers of The Daily Stormer have committed acts of violence. James Jackson, who I wrote about that May 2017 article, came to New York in March from Maryland to start a race war and killed an elderly African American man and thankfully was arrested before he could kill others. And others have read this publication. So when they say confront you there, it’s not a normal publication saying, go challenge his opinions. It is direct action, encouraging people to literally confront me and to commit acts of violence.

MARTIN: OK. But I’m just curious about why, if you feel that these people are promoting and fomenting violence, why isn’t this a criminal matter as opposed to a civil matter? I mean, a civil matter is between two private parties, and the only consequence could be money, right? That’s the only way it can be a remedy. But if you feel that this group is actually encouraging violence, why isn’t this a criminal complaint?

OBEIDALLAH: It would be a harder case to prove from a criminal point of view because the direct – just as a lawyer, I can say, I mean, speech is protected and has more protections in the criminal setting. So to be charged criminally with inciting violence, you must directly say, go get this person at this place.

MARTIN: Go get him.

OBEIDALLAH: And we’re going to get him. And we’re going to kill him. Instead, it was slightly more ambiguous. But clearly, from a civil point of view, these tweets and this language was not protected by the First Amendment.

MARTIN: Before we let you go, how do you feel? I mean, I know this has not been a – this has not been a pleasant couple of years…

OBEIDALLAH: No.

MARTIN: …Dealing with this and being – first of all, just being falsely defamed for having associated with something, you know, so heinous and then being maligned in this way. I mean, was at least that moment in court when the judge ruled in your favor, like, how did that feel?

OBEIDALLAH: No, that felt great. Did it make up? I can’t go back to my life pre-June 1, 2017, where I’m getting smeared. And as a Muslim, being attacked with the worst anti-Muslim trope you can say is that I’m a Muslim and I’m a terrorist. So it was very painful. It was painful to have friends and family express concerns. It was painful to contact security at Daily Beast and my radio channel to say, hey, we might be visited by white supremacists coming to kill me. And they might kill innocent people I work with. That was all horrible.

But through this all, I’ve never once questioned doing this. This is the right thing to do. It’s the thing we have to do. And I’m happy we got the judgment. And we’re going to continue. And I hope it inspires others and gives them a roadmap to say, don’t be silent. There are lawyers who will represent you – I’m not kidding – free of charge for this kind of work to make it clear that we’re not going to cower from these people. We’re going to sue them. We’re going to win. We’re going to get their money.

MARTIN: That’s Dean Obeidallah. He’s the host of “The Dean Obeidallah Show” on Sirius XM. He’s a columnist for The Daily Beast. And he’s a comedian and a former lawyer. Dean, thanks so much for talking to us.

OBEIDALLAH: Thanks for having me on, Michel. I appreciate it.

Copyright © 2019 NPR. All rights reserved. Visit our website terms of use and permissions pages at www.npr.org for further information.

NPR transcripts are created on a rush deadline by Verb8tm, Inc., an NPR contractor, and produced using a proprietary transcription process developed with NPR. This text may not be in its final form and may be updated or revised in the future. Accuracy and availability may vary. The authoritative record of NPR’s programming is the audio record.

Provided By NPR

Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act

admin No Comments

Docket Number:
FDA-2018-D-1067
Issued by:

Guidance Issuing Office

Center for Drug Evaluation and Research

The Food and Drug Administration (FDA or the Agency) is announcing the availability of a final guidance for industry entitled “Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act.” This guidance describes policies that FDA intends to use in evaluating bulk drug substances nominated for use in compounding under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for inclusion on the list of bulk drug substances that can be used in compounding under section 503B.


Submit Comments

You can submit online or written comments on any guidance at any time (see 21 CFR 10.115(g)(5))

If unable to submit comments online, please mail written comments to:

Division of Dockets Management (HFA- 305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

All written comments should be identified with this document’s docket number: FDA-2018-D-1067.

http://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-bulk-drug-substances-nominated-use-compounding-under-section-503b-federal-food-drug-and

Product Development Under the Animal Rule

admin No Comments

Docket Number:
FDA-2009-D-0007
Issued by:

Guidance Issuing Office

Center for Drug Evaluation and Research

Center for Biologics Evaluation and Research

The Food and Drug Administration (FDA or Agency) is announcing the availability of a guidance for industry entitled “Product Development Under the Animal Rule.” When human efficacy studies are not ethical and field trials are not feasible, FDA may rely on adequate and well-controlled animal efficacy studies to support approval of a drug or licensure of a biological product under the Animal Rule. This guidance finalizes the 2014 revised draft guidance for industry “Product Development Under the Animal Rule.” It is intended to help potential stakeholders (industry, academia, and government) understand FDA’s expectations for product development under the Animal Rule.


Submit Comments

You can submit online or written comments on any guidance at any time (see 21 CFR 10.115(g)(5))

If unable to submit comments online, please mail written comments to:

Division of Dockets Management (HFA- 305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

All written comments should be identified with this document’s docket number: FDA-2009-D-0007.

http://www.fda.gov/regulatory-information/search-fda-guidance-documents/product-development-under-animal-rule

Drug Master Files (DMFs)

admin No Comments

Any of the following Type II DMFs:

  • used to support only NDAs or INDs
  • API intermediates
  • material used in the preparation of APIs 
  • drug product manufacturing intermediates
  • drug products.

See also Slide 48 in CDER’s Small Business Assistance Office Webinar entitled “Drug Master Files (DMFs) under Generic Drug User Fee Amendments (GDUFA)

See also the following Web sites:

The list of DMFs that have passed the Completeness Assessment and are available for reference by ANDAs under GDUFA is available at Type II Drug Master Files – Available for Reference List.

This is the only notification that the DMF has passed the Completeness Assessment.

Currently, the list is updated weekly.

DMFs for APIs submtted under GDUFA that have passed the Administrative review (have an active status) and have had the user fee paid are placed in the queue for a Completeness Assessment.  It is not necessary for there to be an LOA for the DMF to undergo a Completeness Assessment review.  The time frame for the Completeness Assessment depends on workload and may take a number of weeks.

Pre-assignment of DMF Numbers (Category 3)

DMF holders wishing to submit an electronic DMF must obtain a pre-assigned number.  See “Requesting a Pre-Assigned Application number.”  DMF holders can request a pre-assigned number for a paper DMF as well.

Companies wishing to obtain a pre-assigned DMF number for a Type V DMF should obtain clearance to file a Type V DMF (with the exception of a DMF for information regarding manufacturing site, facilities, operating procedures, and personnel for sterile manufacturing plants which do not require clearance.) See Type V DMFs below.  For Type V DFMFs that do not require clearance the request for a pre-assigned number should specify what the DMF covers e.g., Sterile Processing Facility.

Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application (Category 1)

DMFs should be submitted following the Common Technical Document (CTD) format recommended in the “Guidance for Industry  M4Q: The CTD – Quality” (CTD-Q) and the “Draft Guidance for Industry Submitting Marketing Applications According to the ICH-CTD Format —General Considerations” (CTD Guidance).

A Manual of Policies and Procedures (MAPP 5015.10) covering reviewer responsibilities for review of applications submitted using the Question-based Review (QbR) format has been issued.  All Type II DMFs for Drug Substances and Drug Products may be submitted using the QbR format, although this is not required.

  • Conversion to CTD

Companies may convert an existing paper DMF in non-CTD format to paper CTD format.  In such cases DMF holders are advised to submit an amendment containing all sections specified in the CTD format that are applicable to the material covered by the DMF.  Each section should be complete and contain up-to-date information.  For drug substances and excipients all sections of 3.2.S in Module 3 and of 2.3.S in Module 2 should be submitted.   For drug products all sections of 3.2.P in Module 3 and of 2.3.P in Module 2 should be submitted.  If there are any changes in the technical content of the DMF as a result of the reformatting, e.g. addition of new information, the cover letter for the new submission should specify what areas of technical information have been changed.

DMFs in CTD format should follow the recommendations in the Appendix “Granularity” the ICH Harmonised Tripartite Guideline:  Organisation Of The Common Technical Document For The Registration Of Pharmaceuticals For Human Use:  M4.  This supersedes the recommendation in the DMF Guidance.

For conversion of a paper DMF to electronic CTD format, see Electronic DMF.

It is not necessary to submit all Modules i.e. it is not necessary to submit Module 4 and 5.  However, Module 1 and all Sections within Modules  2 and 3 S or P (as appropriate) should be submitted for ALL types of DMFs. 

DMF holders submitting DMFs for Sterile Manufacturing can consult the following Guidances

Products manufactured at separate facilities do not need to be filed as separate DMFs unless the manufacturing processes are different.  Note that the Initial CA Guidance contains recommendations regarding the submission of DMFs for multiple processes.

Module 1 should contain the following information

  • Section 1.2  

According to the DMF Guidance (Section IV.B.1.c), the Statement of Commitment is:

“A signed statement by the holder certifying that the DMF is current and that the DMF holder will comply with the statements made in it.“

  • Section 1.3:    Administrative Information
    • 1.3.1 Contact/sponsor/Applicant information
      • 1.3.1.1 Change of address or corporate name
        Can be used to supply addresses of DMF holder.
      • 1.3.1.2 Change in contact/agent
        Can be used to supply the name and address of contact persons and/or agents, including Agent Appointment Letter.
      • 1.3. Debarment Certification.
  • Section 1.4:    Reference Section
    • 1.4.1 – Letter of Authorization (LOA)
      Submission by the owner of information, giving authorization for the information to be used by Authorized Party.  An Agent Appointment Letter is NOT an LOA and should not be called “Letter of Authorization” and should not be submitted in Section 1.4.1.

    • 1.4.2 – Statement of Right of Reference
      This section should be completed in an application (IND, NDA, ANDA, or DMF) submitted by the Authorized Party that references a DMF. It should contain a copy of the Letter of Authorization from the holder giving the Authorized Party permission to reference the DMF.  If a DMF holder references other DMFs a list of those DMFs can be provided in this section, similar to Section 30 on Form 356h used for NDAs and ANDAs. This is not the same as the list of authorized parties to be provided in 1.4.3.

    • 1.4.3 – List of authorized persons to incorporate by reference
      This is a list of companies for whom LOAs have been submitted to the DMF. This list should be submitted in DMF annual reports.

This does NOT mean a list of individuals within the DMF holder’s company who are authorized to submit information to the DMF.

As stated in 21 CFR 314.420(d):

“The drug master file is required to contain a complete list of each person currently authorized to incorporate by reference any information in the file, identifying by name, reference number, volume, and page number the information that each person is authorized to incorporate.”

The term “reference number” means any code or number used by the holder to identify a particular item in a DMF, where applicable.

English Translations of DMF in a Foreign Language (Category2)

FDA regulations (21 CFR.1(a)(1)) state:

“If any part of the application is in a foreign language, an accurate and complete English translation shall be appended to such part.”

The same is true for DMFs.

Debarment Certification for DMF Holders (Category 3)

According to the Draft Guidance for Industry: Submitting Debarment Certification Statements, DMF Holders are included in the category of “Persons whose services were used in any capacity in connection with the application” required under Section 306(k)(1) of the Food Drug and Cosmetic Act.  DMF holders may include a Debarment Certification statement in their DMF.

TYPES OF DMFs

Type I DMFs (Category 1)

Type I DMFs are no longer accepted per a Final Rule published January 12, 2000 (65 FR 1776). See Type V DMFs below.

Holders of Type II, III, and IV DMFs do not need to place information regarding facilities, personnel or general operating procedures in these DMFs.  Only the addresses of the DMF holder and manufacturing site and contact personnel should be submitted. See Administrative Information in a DMF.

Type II DMFs (Category 1)

Note that GDUFA includes requirements for Type II DMFs for Active Pharmaceutical Ingredients (APIs).

Drug Product and Drug Product Intermediate 

Type II DMFs for drug products should be submitted in the format for “Drug product” in the Guidance for Industry  M4Q: The CTD – Quality. (Category 3) 

It is not necessary to include a Methods Validation Package (3.2.R.3).  Methods Validation information should be submitted in Section 3.2.P.5.3.

Separate DMFs should be submitted for drug substances and drug products.

Active Pharmaceutical Ingredient (API) (Category 4)

The term ‘active pharmaceutical ingredient’ means (SEC.744A(2) in GDUFA):

(A) a substance, or a mixture when the substance is unstable or cannot be transported on its own, intended—

(i) to be used as a component of a drug; and
(ii) to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human body; or

(B) a substance intended for final crystallization, purification, or salt formation, or any combination of those activities, to become a substance or mixture described in subparagraph (A)”

Type III DMFs (Category 1)

The applicable Guidance for Type III DMFs is the Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics:  Chemistry, Manufacturing, and Controls Documentation  and Questions and Answers.  (Category 3)

A Manual of Policies and Procedures covering reviewer responsibilities for review of Type III DMFs has been implemented.  MAPP 5015.5  CMC Reviews of Type III DMFs for Packaging Materials.  This MAPP instructs reviewers to look for information regarding many packaging materials in the application (IND, NDA, or ANDA) for the drug product that utilizes the packaging material before reviewing the DMF.  Much of the information needed for review can be provided directly to the applicant for inclusion in the application, thereby avoiding the need to review the DMF.

CTD format:  Single components and materials of construction may be submitted as if they were drug substances i.e., the preparation of the item should be in S.2.  An assembled container closure systems may be treated as if it were a drug product e.g. the Materials of construction would be in P.1, the finished packaging material release specification would be in P.5. 

Type IV DMFs (Category 3)

See relevant section in the DMF Guidance.  CTD format: Single entities may be submitted as if they were drug substances e.g., the preparation of the item should be in S.2.  Mixtures e.g., as flavor mixtures, may be treated as if it were a drug product, i.e.. the Components and Composition would be in P.1, the finished material release specification would be in P.5.

If toxicology studies are submitted in the same DMF (in paper) as the CMC information, they should be in a separate volume or volumes, although it is preferable for holders to submit such information as a separate Type V DMF.  Toxicology studies in an electronic DMF for an excipient should be submitted in the appropriate module.  See also the Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients.

Note that, in keeping with the recommendation in the DMF Guidance, components of flavor mixtures should include a CFR citation, where applicable, in addition to any other reference, e.g. GRAS or FEMA references.

Type V DMFs (Category 3)

As specified in 21 CFR 314.420(a)(5), DMF holders wishing to submit a Type V DMF must obtain clearance from the FDA (See below for an exception to this requirement for sterile processing facilities). Prospective Type V DMF holders should send their request to dmfquestion@cder.fda.gov, including the following:

    1. An explanation of the necessity for filing the information in a Type V DMF
    2. The proposed Subject (Title) of the DMF
    3. The rationale for not submitting the information in an IND, NDA, or ANDA.
    4. The clinical division that will be reviewing the information, if applicable.

Information regarding manufacturing site, facilities, operating procedures, and personnel for sterile manufacturing plants can be filed as a Type V DMF without clearance.  The Subject field should specify what the DMF covers e.g., “Sterile Processing Facility.”

See Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products

Administrative Information in a DMF (Category 3)

The elements of the administrative information that should be in a DMF are:

  • The name and address of the holder
  • The name and address of manufacturing facility
  • For the contact person:
    • Name
    • Mailing Address
    • Telephone number
    • Fax number
    • E-mail address
  • The name and address of the agent (if applicable)
  • For the contact person at the agent (if applicable):
    • Name
    • Mailing Address
    • Telephone number
    • Fax number
    • E-mail address
  • Statement of Commitment

The appointment of an Agent is optional.  See discussion below under Agents.

Submission of Amendments, Annual Reports, and Letters of Authorization (Category 3)

To facilitate processing of documents that are submitted to an existing DMF, list the Submission Type and the Category/Subcategory of the Amendment (Supporting Document) in bold type in the header on the Cover Letter (transmittal letter).  See list below.  More than one Submission Type/Category/Subcategory can be used but all should be listed. 

Example:  If updated stability data is submitted at the same time as a Letter of Authorization, the heading of the Cover Letter should state:

Letter of Authorization
Original: Quality/Stability

Important New Information: Annual Reports for DMFs in eCTD can be submitted on the same date as any other submission but they must have a different Sequence Number.

FDA’s database is structured as follows:

Application:

Submission

Amendment (called “Supporting Document”) in the database

Amendments (Supporting Documents) are named by a Category and Subcategory

For the Application Type “Drug Master File” the Submission Types are:

  • Original:  Amendments containing changes to technical information are filed in the “Original” submission and the Category/Subcategory should be specified in the header of the Cover Letter.  A new DMF does not need a “Category/Subcategory” designation by the holder.  See Categories and Subcategories below.
  • Annual Report: There is only one Category with two Subcategories:
    • Annual Report
    • Amendment
  • Letter of Authorization: There is only one Category with two Subcategories:
    • Letter of Authorization
    • Withdrawal of Authorization
  • General Information (Reactivation, Closure Request, Administrative Information)
    • Categories of Amendments (Supporting Documents) in General Information 

Categories of Amendments (Supporting Documents) in Original Submission:  

Category: Quality

Subcategories under Quality Category (with corresponding CTD Sections, where applicable).   Applicable Section in modules 2 and 3   Changes to a Subsection not specifically listed below should be reported as the next level up e.g. changes in Control of Materials (S.2.3) should be reported as Manufacture Information S.2. Subcategory
New item:  Additional item e.g. flavor added to a multi-item DMF  
Controls Information (specifications)  S.4 and P.5
Dissolution Data (Usually applies to drug product only) P.5
Facility Information (changes in manufacturing and or testing sites) S.2.1 and P.3.1
Formulation Information  (Usually applies to drug product only) P.1 and related sections
Lot Release (batch analysis) S.4.4 and P.5.4
Manufacture Information S.2 and P.3
Microbiology Information  
New Strength (Usually applies to drug product only) P.1 and related sections
Quality (Not covered by other subcategories)  
Packaging Information (Applies to packaging of the material that is the subject of the DMF e.g. plastic bags for packaging a bulk drug substance in a Type II DMF) S.6 and P.7
Stability Information S.7 and P.8
Response to Information Request  
Response to Deficiency Letter   
Response to Complete Response Letter  

Category: Non-clinical

  • Non-clinical
  • Carcinogenicity Information

Submissions that cover multiple DMFs should have a copy submitted for each DMF.

When a change is made to one part of a DMF the entire DMF does not need to be resubmitted.  For DMFs in CTD format, the entire changed “Document” (Section) should  be submitted e.g. a change in the material used in the synthesis should be included in a resubmission of Section S.2.3.

All submissions should be paginated within the submission.  Pages that replace an already-numbered page from a previous submission should also contain the page number in the current submission (e.g. a page replacing Page 10 in the original submission may be page 14 in the new submission).  For DMFs in CTD format, only the pages within the changed “Document” (Section) are subject to re-numbering.

No pages are ever physically replaced in a paper DMF.

Response to Overdue Notice Letter

A response to an Overdue Notice Letter (ONL) to retain activity of a DMF should be identified as an Annual Report and contain the information listed below for an Annual Report.  Additional administrative and technical information may be included as amendments.  As noted above, Annual Reports submitted at the same time as amendments in eCTD must have separate Sequence Numbers.  A submission that states that an update will be submitted in the future is not sufficient to retain the Active status of a DMF.

 

REPORTING CHANGES TO A DMF (Category 2)

Any addition, change, or deletion of information in a DMF is required to be submitted to the DMF.  In addition the DMF holder must notify each person authorized to reference the DMF (authorized party) (See 21 CFR 314.420(c))  There are no reporting categories for DMFs.  All changes must be reported as amendments.  The DMF holder should notify each authorized party of the nature of the changes, providing as much detail as is consistent with the confidentiality agreement between the DMF holder and the authorized party, so that the authorized party can determine how to report the changes in their approved NDA or ANDA.  See 21 CFR 314.70 and related Guidances.

Also Guidance for Industry:  Changes to an Approved NDA or ANDA and the Q&A
CMC Postapproval Manufacturing Changes Reportable in Annual Reports (Draft Guidance)

ELECTRONIC DMFs (Category 3)

The FDA has published a Final Guidance, Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (5/15/2015) regarding electronic submissions.  See the Guidance for further information regarding requirements for electronic DMF submissions (eCTD Guidance).  The Guidance applies to ALL DMFs, whether or not they are being referenced by an application.  The compliance date for submitting a DMF in electronic format is May 5, 2018.

All electronic submissions must have an application number.  For a new DMF, the holder must request a pre-assigned number in order to populate the US Regional.xml.   The ECTD format provides the backbone for the submission and a guide as to where to place information.  It is not necessary to submit modules that are not applicable to the subject of the DMF e.g. it is not necessary to submit Module 4 and 5 for a Type II DMF for a drug substance.  For new electronic DMFs, all Sections within Modules 1, 2 and 3 should be submitted.  DMF holders are encouraged to submit all subsequent submissions electronically after the initial electronic submission.  See also Electronic Common Technical Document (eCTD).  Electronic signatures are accepted for electronic DMFs.

Electronic DMFs may be submitted either through the Gateway or by sending a disc (one copy) to the Central Document Room at the address provided above.  DMF holders are reminded of the following requirement in the ECTD Guidance:

  • “For all submissions that are 10 gigabytes (GB) or smaller, you must use the FDA ESG .For submissions that are greater than 10 GB, refer to the FDA technical specification “Specification for Transmitting Electronic Submissions using eCTD Specifications.”

See Specification for Transmitting Electronic Submissions using eCTD.

It is not necessary for a DMF holder to submit a form with the DMF for automated processing.  The DMF will be automatically processed in the absence of a form.  If a DMF in eCTD format is flagged with a validation error due to the form heading element not being included in the index.xml when there is no physical form in the eCTD directory, the DMF holder should ignore the error message and continue to submit. 

CONVERSION OF PAPER DMFS TO ELECTRONIC DMFS (Category 3)

An existing DMF number may be used when converting a paper DMF to electronic format.  If the existing number is 4-digits, e.g. 1234, the DMF holder should pad left with zeroes to convert to a 6-digit format, e.g. 001234.  There is no requirement to submit or resubmit DMFs in electronic format.  However, if a paper DMF is converted to eCTD format, and there are any changes in the technical content of the DMF as a result of reformatting, e.g. addition of new information, the cover letter for the new submission should specify what areas of technical information have been changed.  The numbering of the submissions should start with 0001.

LETTERS OF AUTHORIZATION (Category 2)

All Letters of Authorization (LOAs) should be submitted in two copies to the DMF, if the DMF is in paper format.  If the DMF is in CTD format, whether in paper or eCTD, the LOA should be submitted in Section 1.4.1.  A copy of the LOA must then be sent by the DMF holder to the Authorized Party (company or individual authorized to incorporate the DMF by reference).  Failure to submit the original LOA to the DMF may result in a delay in review of the DMF. LOAs should specify the name of the specific item being referenced and the date of the submission of information about that item. The LOA should not be called a “Letter of Access.”

An LOA should be submitted even if the DMF holder is the same company as the authorized party.

LOAs should NOT be submitted with original paper DMFs (unless the DMF has received a pre-assigned number) because the LOA should contain the DMF number. Therefore, if there is no pre-assigned number, DMF holders should wait before submitting an LOA until they have received an acknowledgment letter containing the DMF number.

It is not necessary to reissue LOAs if there have been no changes in the holder, authorized party, subject of the DMF or item referenced.

If the holder changes its name, whether this represents a change in ownership or not, new LOAs should be submitted to the DMF and copies sent to the authorized party(ies). 

If an authorized party changes its name, the new authorized party should request a new LOA from the DMF holder.  Failure to do so may result in a delay in review of the DMF.

If there has been a name change, it is not necessary to submit a Withdrawal of Authorization Letter for the holder or authorized party’s previous name.

If a company has a Master File submitted to another Center in the FDA, e.g. a Biologics Master File (MF) submitted to the Center for Biologics Evaluation and Research, the Letter of Authorization should be submitted to the Master File in that other Center rather than CDER.

  • LOA Template

Note: The “Subject” field in the Letter Templates refers to the Subject of the DMF, not the Item within the DMF being referenced. The Item name should be included in the body of the letter.

AGENTS (Category 2)

There is no regulatory requirement for an agent for any DMF, foreign or domestic. An agent for DMF purposes is not the same as an agent for the purposes of the Drug Listing and Registration System. (DRLS).  Holders should not include the name of the agent for Registration purposes in the DMF unless the same person or company is the agent for both the DMF and DRLS.  Also note that in the US, the process of “Registration” applies ONLY to “registering” an establishment with the FDA.

All “Agent Appointment Letters” for DMFs should be signed by the holder. FDA recommends that such letters include the phrase “appoint AGENT NAME as the agent for DMF” rather than “authorize AGENT NAME to act as the agent for DMF,” since the latter can be confused with a “Letter of Authorization.”

Agents for DMF purposes are not required to be located in the United States, although this is recommended.

An “Agent Appointment Letter” may be included in an original DMF.

If possible, the word “Agent” should be used for the legal entity (whether a company or an individual) who is authorized to act on behalf of the DMF holder.  The word “Representative” or “Contact Person” should be used for an individual who is employed by the Agent or Holder as the contact point for FDA.

If a company acting as an Agent changes its name, the DMF holder should issue a new Agent Appointment Letter.

A different agent can be appointed for different DMFs submitted by the same holder.

HOLDER NAMES (Category 2)

When the company that owns a DMF (DMF holder) changes its name, whether through sale of the company or simply a change in the company’s name, the DMF holder must notify FDA.  See Section VII.E. in the DMF Guidance for further recommendations on the procedure for transferring ownership.  A change in the name of a company for registration purposes under DRLS will not change the DMF holder name.

When a DMF is transferred from one company to another, the original holder should submit an administrative amendment stating that they are TRANSFERRING the DMF to the new holder.  The new holder should then submit an administrative amendment stating that they are ACCEPTING the DMF from the former holder.

If the holder changes names, whether this represents a change in ownership or not, new LOAs should be submitted to the DMF and copies sent to the authorized party. 

If the authorized party changes its name the new authorized party should request a new LOA from the DMF holder.  Failure to do so may result in a delay in review of the DMF.

It is not necessary to submit a Withdrawal of Authorization Letter for the holder or authorized party’s previous name.

A DMF holder is expected to retain a complete reference copy that is identical to, and maintained in the same chronological order as, their submissions to FDA (See Section IV.D.1 in the DMF Guidance).  Therefore the old owner of the DMF is expected to transfer that copy to the new owner of the DMF.

In general FDA expects the manufacturer to be the holder. If a manufacturer (Company A) of a MATERIAL wishes to have the DMF submitted by another company (Company B) and Company B wishes to act as the holder, the DMF should include statements from both companies that Company B takes full responsibility for all the information in the DMF and for all the processes and testing performed by the manufacturer.

If Company B changes its name, whether through an internal name change or a through sale of the company, the new holder should notify the FDA of the name change.  This submission should contain a statement that the new holder of the DMF takes full responsibility for all the information in the DMF and for all the processes and testing performed by the manufacturer.

ANNUAL REPORTS (Category 2)

According to the DMF Guidance, Annual Reports are NOT to be used to report changes in the DMF.  As noted above, Annual Reports submitted at the same time as amendments in eCTD must have separate Sequence Numbers.

The Annual Report should contain (for Cover Letter see Templates below):

1. An administrative page containing the Administrative Information specified above (Administrative Information in a DMF)

AND   2. One of the following

  • Date(s) of the amendment(s) reporting changes since the last Annual Report or the original DMF filing date, whichever is most recent.

Or

  • A statement that no amendments have been submitted since the last Annual Report or the original DMF filing date, whichever is most recent.

AND   3. One of the following:

  • A complete list of all parties authorized to make reference to the DMF, identifying by name, reference number, volume, date, and page number the information that each person is authorized to incorporate by reference and the date of the LOA. 

Or

  • A statement that there are no Authorized Parties.

AND   4. List of all parties whose authorization has been withdrawn

Note that the DMF Guidance uses the terms “Annual Update” and “Annual Report” interchangeably.  All submissions of Annual Reports should be labeled “Annual Report.”  The term “Annual Update” should not be used.

Note that the Annual Report should contain a COMPLETE list of Authorized Parties, even if the list of Authorized Parties is unchanged.

BIOLOGICS MASTER FILES (Category 3)

Master Files submitted in support of products regulated by the Center for Biologics Evaluation and Research (CBER) should be submitted as MFs.  See the CBER web site for the products regulated by CBER.

BINDERS (Category 2)

See FDA IND, NDA, ANDA, or Drug Master File Binders

The “binders” are actually covers.  These may be ordered from the U.S. Government Printing Office (GPO) Web site: http://bookstore.gpo.gov/ or by calling 202-512-1800 to speak with a GPO customer service representative.  The binders may be obtained from another supplier, provided they meet the requirements specified on the GPO Web site.

The direct links for online ordering are

One copy of the DMF should use the blue cover and one should use the red cover.

Fasteners must be obtained separately. Use 2 Piece Prong Fasteners, 8 1/2″ Center to Center, 3 1/2″ Capacity.  Binders should be used for all subsequent submissions to FDA that are more than 10 pages.

If a DMF is submitted using any other kind of binder, it should be a loose-leaf type of binder so that the pages can be removed and placed in FDA-approved binders.  DMFs should not be submitted as “bound” books.

FEES (Category 4)

GDUFA requires DMF fees for Type II DMFs for drug substances (Active Pharmaceutical Ingredients (APIs)) used to support Abbreviated New Drug Applications (ANDAs).  See definition of API above.

Since GDUFA does not apply to any other type of DMF or to Type II DMFs used to exclusively support NDAs or INDs, there are no fees for these types of DMFs.

FORMS  (Category 2)

Certain forms are required for submission of NDAs and INDs.  However there are no forms required or available for DMFs, except for the forms discussed above under Binders and the Generic Drug User Fee Cover Sheet.  The latter applies only to Type II DMF submitted to support ANDAs under GDUFA.

CONFIDENTIALITY OF DMFs (Category 2)

The public availability of the contents of DMFs is covered in 21 CFR 314.430(g).  There are no “open” or “closed” parts of DMFs filed with the FDA.  The decision as to how much information DMF holders share with their authorized parties is a business decision between the parties involved and is not covered by FDA regulations or Guidances.  All requests for information about DMFs beyond that provided in the Drug Master File lists above must be made through the CDER Freedom of Information Web site.

FILING DMFs AND PATENT EXPIRATION AND EXCLUSIVITY ISSUES (Category 2)

DMFs may be filed at any time.  The Patent Expiration date and the Exclusivity Expiration dates listed in the Orange Book have no impact on DMF filing.  The submission of Abbreviated New Drug Applications (ANDAs) that reference DMFs is subject to the regulations regarding filing of ANDAs.

ENVIRONMENTAL ASSESSMENTS (Category 2)

Since DMFs are neither approved nor disapproved, there is no need to file an Environmental Assessment. However the DMF should contain a commitment by the firm that its facilities will be operated in compliance with applicable environmental laws.

REORGANIZATION OF A DMF (Category 1)

The advice in the Guidance does not apply.  It is not necessary to consult with FDA before reorganizing a DMF.

REQUEST FOR CLOSURE OF A DMF BY THE HOLDER (Category 2).

It is not necessary to include a statement that “the holder’s obligations as detailed in Section VII have been fulfilled,” as recommended in the DMF Guidance.  It is sufficient to include a statement that all of the parties authorized to reference the DMF have been notified that the DMF is being closed.

LETTER TEMPLATES AND COVER LETTERS (Category 2)

Note that a “Transmittal Letter” and a “Cover Letter” are the same thing.

See Drug Master File Letter Templates below.

All submissions should have a Cover Letter. 

Drug Master File Lists

Drug Master File Letter Templates

http://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs

Endocrinologic and Metabolic Drugs Advisory Committee Roster

admin No Comments

Applying for Membership on FDA Advisory Committees

As part of the Food and Drug Administration’s (FDA’s) ongoing efforts to recruit qualified experts with minimal conflicts of interest who are interested in serving on FDA advisory committees, FDA is requesting nominations for members to serve on its advisory committees.

Current Number of Vacancies = 0

Note, one or more vacancies may be in the nomination process or a final appointment may have been made.

http://www.fda.gov/advisory-committees/endocrinologic-and-metabolic-drugs-advisory-committee/endocrinologic-and-metabolic-drugs-advisory-committee-roster

Opioid Maker Insys Admits To Bribing Doctors, Agrees To Pay $225 Million Settlement

admin No Comments

Insys, the maker of fentanyl-based Subsys, agreed to a $225 million settlement with the federal government to resolve criminal and civil investigations of the company’s role in the opioid crisis. Reuters hide caption

toggle caption

Reuters

Insys, the maker of fentanyl-based Subsys, agreed to a $225 million settlement with the federal government to resolve criminal and civil investigations of the company’s role in the opioid crisis.

Reuters

Insys Therapeutics, an opioid manufacturer, has agreed to pay $225 million to settle the federal government’s criminal and civil investigations into the company’s marketing practices. As part of the settlement, Insys Therapeutics admitted to bribing doctors to prescribe their opioid painkiller.

Last month, a federal jury in Boston found five top Insys Therapeutics executives guilty of racketeering conspiracy for these same practices. Now, the federal government is holding the company accountable.

In the agreement, the drug maker admitted to orchestrating a nationwide scheme in which they set up a sham “speaker program.” Participating doctors were not paid to give speeches, but to write prescriptions of Insys Therapeutics’ fentanyl-based medication, Subsys. Often the painkiller was prescribed to patients who did not need it.

Over the next five years, the company has agreed to close federal monitoring and the federal government reserves the right to charge the company in the future if there’s a violation.

“For years, Insys engaged in prolonged, illegal conduct that prioritized its profits over the health of the thousands of patients who relied on it,” said United States Attorney Andrew Lelling in a statement. “Today, the company is being held responsible.”

This settlement, as well as the criminal prosecution of Insys executives, is part of the federal government’s efforts to punish pharmaceutical companies for their role in fueling the opioid epidemic.

“Today’s settlement sends a strong message to pharmaceutical manufacturers that the kinds of illegal conduct that we have alleged in this case will not be tolerated,” said Assistant Attorney General Jody Hunt in a statement. “I want to assure the families and communities ravaged by this epidemic that the Department of Justice will continue to act forcefully to hold opioid manufacturers accountable for their actions.”

The founder of Insys Therapeutics, John Kapoor, is among the highest ranking pharmaceutical executives to be convicted amidst the opioid epidemic. Sentencing of the former billionaire is scheduled for September.

A spokesperson for Insys Therapeutics did not respond to a request for comment regarding the settlement. However, in August 2018 the company announced the settlement-in-principle and a spokesperson said in a statement, “Insys Therapeutics in no way defends the past misconduct of former employees.”

The company has faced significant financial troubles that they attribute to legal costs. Earlier this year, an Insys spokesperson said the company may not survive.

Provided By NPR

IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed

admin No Comments

Issued by:

Guidance Issuing Office

Office of Good Clinical Practice

Center for Drug Evaluation and Research

Center for Devices and Radiological Health

Center for Biologics Evaluation and Research

Additional copies are available from:

Office of Communications
Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Silver Spring, MD 20993
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov

and/or

Office of Communication, Outreach and Development, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
(Tel) 800-835-4709 or 301-827-1800

and/or

Office of Communication, Education and Radiological Programs
Division of Small Manufacturers Assistance, WO66-4613
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., Silver Spring, MD 20993
Email: dsmica@cdrh.fda.gov; Fax: 301.847.8149
(Tel) Manufacturers Assistance: 800.638.2041 or 301.796.7100
(Tel) International Staff Phone: 301.827.3993

Procedural

TABLE OF CONTENTS

I. Introduction 1

II. Background

III. Discussion

1. Must an IRB review the qualifications of clinical investigators who conduct FDA-regulated research?

2. Is any information publicly available from FDA about a clinical investigator’s inspectional history?

3. Must an IRB review the adequacy of the research site?

4. What are the IRB’s responsibilities with respect to verifying the determination of whether an IND or IDE is required for an FDA-regulated investigation?
 

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

I. Introduction

All of the parties who conduct or have oversight responsibilities for biomedical research—sponsors, clinical investigators, and institutional review boards (IRBs)—have responsibility for ensuring that the research complies with applicable laws and regulations and that risks to subjects are minimized. Although selection of clinical investigators and research sites, and determining if an investigational new drug application (IND) or investigational device exemption (IDE) is required are viewed primarily as sponsor responsibilities, FDA is issuing this guidance to clarify IRBs’ responsibilities related to these activities and to encourage all parties to work together in order to protect the rights and welfare of study subjects.

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in agency guidances means that something is suggested or recommended, but not required.

To enhance protection of human subjects and reduce regulatory burden, the Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) and FDA have been actively working to harmonize the agencies’ regulatory requirements and guidance for human subject research. This guidance document was developed as a part of these efforts and in consultation with OHRP.

II. Background

Many of the recommendations in this guidance have appeared in other FDA guidance documents2 or have been communicated to IRBs who have contacted the agency directly about these issues. FDA has also provided instructions to its field investigators on the types of records that should be reviewed during an IRB inspection to determine whether the IRB performed an evaluation of an investigator’s qualifications, assessed the adequacy of a site, and questioned whether an IND or IDE is necessary. 3FDA has compiled the recommendations from these various sources into this guidance to ensure that all IRBs have access to it. In addition, FDA provides guidance on how IRBs may efficiently fulfill these important responsibilities.

The recommendations in this guidance are applicable to any IRB, independent or affiliated with an institution, whether serving as a local IRB or as the central IRB for other IRBs or institutions participating in a centralized review process for multi-site studies. The recommendations are general in order to provide IRBs with necessary flexibility in developing agreements for cooperative research as described in 21 CFR 56.114. As discussed in Guidance for Industry – Using a Centralized IRB Review Process in Multicenter Clinical Trials, 4FDA recommends that IRBs and institutions participating in a centralized review process agree on how to divide and carry out these responsibilities, and that such agreements be in writing to help ensure that the rights and welfare of study subjects are protected.

III. Discussion

1. Must an IRB review the qualifications of clinical investigators who conduct FDA-regulated research?

Yes. Although FDA’s regulations place responsibility on the sponsor to select clinical investigators who are “qualified by training and experience as appropriate experts” to investigate the test article, 5 IRBs also have a role in reviewing an investigator’s qualifications. 6 The regulations at 21 CFR 56.107(a) require that an IRB “…be able to ascertain the acceptability of the proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice…” In addition, the regulations at 21 CFR 56.111 require that an IRB determine that the proposed research satisfies the criteria for approval, including that “…risks to subjects are minimized…[and] reasonable in relation to anticipated benefits, if any, to subjects…” In order to fulfill these responsibilities, the IRB needs information about the qualifications of the investigator(s) to conduct and supervise the proposed research. Depending upon the nature and risks of the proposed research and the relationship between the IRB and the investigator or the institution where the proposed research is being conducted, this may be relatively simple and straightforward or it may entail a more involved assessment.

In many cases, the IRB may have previous experience with an investigator or institution that would allow the IRB to readily determine that the clinical investigator is appropriately qualified to conduct and supervise the proposed research. In other cases, the IRB may need additional information; however, the IRB should be able to obtain a statement confirming the investigator’s qualifications from an administrator of the institution. For example, for proposed research to be conducted at a hospital where only credentialed hospital staff may conduct research, the IRB may be able to rely on another office at the institution (e.g., the credentialing office, the clinical investigator’s medical department) for information about the clinical investigator’s qualifications. For proposed research to be conducted by a university faculty member (e.g., at an affiliated hospital or clinic), the IRB may be able to obtain a statement regarding the investigator’s qualifications from the chair of the investigator’s department.

On the other hand, if the reviewing IRB has no knowledge of either the clinical investigator or the institution (e.g., the IRB is not affiliated with the institution where the research will be conducted; the IRB has no previous experience with the investigator), the IRB would likely need to take additional steps to evaluate the investigator’s qualifications. Such steps may include, as appropriate, reviewing the curriculum vitae of the investigator, subinvestigators, and other necessary study staff, verifying professional associations and medical licensure, or reviewing relevant publications and the investigator’s training in good clinical practice.

The IRB may also need to assess the investigator’s training and experience specifically related to the proposed study, particularly if the proposed research involves higher risks, vulnerable subjects, or novel technologies. For such proposed research, the IRB’s determination that the investigator is qualified may need to include a review of the investigator’s previous specific experience as demonstrated by recent presentations or publications, and prior clinical experience with the test article or study-related procedures. In addition, the IRB should pay particular attention to an investigator’s qualifications to conduct a study submitted for approval to the IRB if the study involves one or more of the following:

  • a sponsor-investigator;7
  • a study that is outside of the investigator’s area of expertise; or
  • any study design features or other characteristic(s) that may significantly increase potential risks to subjects.

If any concerns remain, the IRB may also elect to observe, or have a third party observe, the consent process and the research (21 CFR 56.109(f)).

Appropriately trained IRB support staff may assist in obtaining and assessing information about an investigator’s qualifications. FDA recommends that the IRB’s written procedures describe the IRB’s process for evaluating the investigator’s qualifications to conduct and supervise the study.

2. Is any information publicly available from FDA about a clinical investigator’s inspectional history?

Yes. IRBs may check the lists posted on FDA’s website to determine whether a clinical investigator has been the subject of an inspection by the agency 8 and the results of such inspections (e.g.,Warning Letters). 9 FDA also posts on its website a listing of all investigators who have been notified of the initiation of a disqualification proceeding or have been disqualified. 10 FDA recommends that IRBs routinely check FDA’s Inspections, Compliance, Enforcement, and Criminal Investigations website11 for information related to clinical investigator inspections, Warning Letters, disqualification proceedings, and debarments.

3. Must an IRB review the adequacy of the research site?

Yes. FDA’s regulations require that before an IRB can approve research covered by the regulations, the IRB must “…be able to ascertain the acceptability of the proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice…” 12 The regulations also require that each IRB have sufficient information to determine that the proposed research satisfies the criteria for approval. 13

In the great majority of instances, an IRB will be familiar with the research site or institution at which the clinical investigator has proposed to conduct the research; in such cases, additional assessment of a site’s adequacy will probably not be necessary (for example, if the research is to be conducted at the IRB’s affiliated institution). In other cases, the IRB may need additional information to assess the site where the proposed research will take place to ensure it can adequately execute the protocol requirements. Depending upon the nature and risks of the proposed research and the IRB’s prior knowledge of or relationship to the institution or other site at which the research will take place, this may be relatively simple and straightforward or it may entail a more involved assessment.

For example, if a proposed clinical investigation involves administration of medical procedures by qualified healthcare providers using medical equipment, the IRB should be prepared to assess the adequacy of the facility’s staff and equipment, including the availability of emergency or specialized care, should the need arise. If the proposed research site is part of a major medical institution, the IRB may be able to simply note that fact. If, however, the IRB is unfamiliar with the proposed investigational site (e.g., research facility, hospital, physician’s office, dental clinic), the IRB may need to confirm whether the site is appropriately staffed and equipped to conduct the proposed research. The IRB should be able to obtain a statement from an appropriate person or persons at the research site or institution stating that the facilities are adequate. Alternatively, the IRB could ask that the investigator provide a description of the facility where the research will take place, including its staffing and resources relevant to the research under review.

Appropriately trained IRB support staff may assist in obtaining and assessing information about the adequacy of the research site. FDA recommends that the IRB’s written procedures describe the IRB’s process for carrying out these evaluations.

4. What are the IRB’s responsibilities with respect to verifying the determination of whether an IND or IDE is required for an FDA-regulated investigation?

In general, the IRB should ask the investigator if he/she considered whether an IND or IDE is required and the basis for that determination. The IRB’s specific responsibilities may vary, however, depending on the product that is the subject of the study, as discussed below.

Drug and Biologics Studies. FDA regulations require sponsors 14 and sponsor- investigators (of individual investigator-initiated studies) to determine whether an IND is required for a particular study. 15 The sponsor should be able to determine whether the IND regulations apply to a planned clinical investigation as required under 21 CFR 312.2(a). If a sponsor is uncertain whether an IND is required, we recommend that the sponsor contact the appropriate review division (i.e., for the therapeutic area being studied) in the appropriate FDA Center for advice (21 CFR 312.2(e)). FDA issued for public comment, Draft Guidance for Industry: Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND. 16When finalized, the guidance will represent FDA’s current thinking on this topic.

When reviewing a proposed study, IRBs should ask the clinical investigator whether the sponsor determined that an IND is or is not required and the basis for the determination. If the sponsor has determined that an IND is not required, the IRB may request that the investigator provide a copy of any available supporting documentation (e.g., letter from the sponsor or FDA, other basis for that determination). If during its initial review of a study, the IRB questions whether an IND is required, but is unable to resolve this issue, the IRB should follow its procedures for resolving controverted issues (e.g., notifying the clinical investigator in writing of the IRB’s concerns 17 and delaying approval of the study until the matter is resolved).

Organizational charts listing the review divisions for the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) and their phone numbers are available on FDA’s website. 18 If the relevant review division is not known, the sponsor may contact CDER or CBER directly:

CDER:

Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Avenue, 4th Floor
Silver Spring, MD 20993
(Tel) 301-796-3400

CBER:

Office of Communication, Outreach and Development 19
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1448
(Tel) 800-835-4709 or 301-827-1800

Device Studies. For studies involving an investigational device, the sponsor 20 is responsible for determining whether submission of an IDE application to FDA is required before a study may proceed. 21 The IDE regulations (21 CFR 812) describe three types of device stud ies: significant risk (SR), nonsignificant risk (NSR), and exempt studies. 22 SR device studies must have an IDE application approved by FDA and have IRB approval before they proceed, and they must follow all of the IDE requirements. 23 NSR device studies must follow the abbreviated IDE requirements at 21 CFR 812.2(b), including informed consent and IRB review, and do not require submission of an IDE application to FDA.

The sponsor is responsible for making the initial risk determination, SR or NSR, and presenting it to the IRB.24 If the sponsor has determined that a device study is NSR, the IRB must review the sponsor’s determination. 25 If the IRB disagrees with the sponsor’s NSR assessment and decides the study is SR, the IRB must inform the clinical investigator and, where appropriate, the sponsor. 26 The IRB should also document its SR/NSR determination in the IRB meeting minutes.

FDA is available to assist sponsors, investigators, and IRBs in making these determinations. For information on how to request such assistance, please see the guidance Procedures for Handling Inquiries Regarding the Need for an Investigational Device Exemptions Application for Research Involving Medical Devices. 27 Sponsors, clinical investigators, and IRBs who need assistance in making a risk determination for a medical device may also contact:

IDE Staff
Office of Device Evaluation
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
(Tel) 301-796-5640

Based on the information provided, FDA will determine if a device study is SR, NSR, or exempt from the IDE requirements found in 21 CFR Part 812. If FDA makes the SR, NSR, or exempt determination for a study, the agency’s determination is final. Additional information may be found in the Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors – Significant Risk and Nonsignificant Risk Medical Device Studies. 28

FDA recommends that the IRB have written procedures that explain how the IRB makes an SR/NSR determination.

Footnotes

1. This guidance was prepared by the Office of Good Clinical Practice (OGCP) in the Office of the Commissioner, with input from the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), and the Office of Regulatory Affairs (ORA).

5. 21 CFR 312.53(a); see also 21 CFR 812.43(a).

7. FDA’s regulations (21 CFR 312.53(a) and 21 CFR 812.43(a)) require that a sponsor select clinical investigators who are “qualified by training and experience” to investigate the test article. In a sponsor-investigator (S-I) clinical trial, the S-I assumes the responsibilities of both the sponsor and the investigator (see 21 CFR 312.3(b) and 21 CFR 812.3(o)); therefore, there is no independent assessment of the clinical investigator’s qualifications by the study sponsor. In this case, the IRB’s review of the investigator’s qualifications is particularly important to the determination that the risks to subjects are minimized and reasonable in relation to anticipated benefits, if any, to subjects.

12. 21 CFR 56.107(a).

13. 21 CFR 56.111(a).

14. See 21 CFR 312.3(b), definition of “sponsor-investigator.” In this section, when “sponsor” is used, the term includes “sponsor-investigator.”

15. See 21 CFR 312.2, 312.20, 312.50, and 320.31(c). Studies that are exempt from the IND requirements are required, however, to comply with 21 CFR Part 50 (Protection of Human Subjects) and Part 56 (Institutional Review Boards).

17. 21 CFR 56.109(e)

20. See 21 CFR 812.3(n) and 812.3(o); in this section, when “sponsor” is used, the term includes “sponsor-investigator.”

21. 21 CFR 812.2(b)(1)(ii).

22. With the exception of 21 CFR 812.119, exempt studies are not subject to the IDE regulations. 21 CFR 812.2(c). Exempt studies are required to comply with 21 CFR Part 50 (Protection of Human Subjects) and Part 56 (Institutional Review Boards).

23. 21 CFR 812.20(a)(1) and (2).

24. 21 CFR 812.2(b)(1)(ii).

26. 21 CFR 812.66.


Submit Comments

Submit comments on this guidance document electronically via docket ID: FDA-2013-S-0610 – Specific Electronic Submissions Intended For FDA’s Dockets Management Staff (i.e., Citizen Petitions, Draft Proposed Guidance Documents, Variances, and other administrative record submissions)

If unable to submit comments online, please mail written comments to:

Division of Dockets Management (HFA- 305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

All comments should be identified with the title of the guidance.

http://www.fda.gov/regulatory-information/search-fda-guidance-documents/irb-responsibilities-reviewing-qualifications-investigators-adequacy-research-sites-and

TeraPharm – 111111 – 10/09/2018

admin No Comments

TO: TeraPharm

FROM: The United States Food and Drug Administration

RE: Notice of Unlawful Sale of Unapproved and Misbranded Drugs to
United States Consumers Over the Internet

DATE: October 9, 2018

WARNING LETTER

The United States (U.S.) Food and Drug Administration (FDA) has determined that TeraPharm offers products for sale in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). More specifically, your network introduces into interstate commerce, misbranded and unapproved new drugs, including, but not limited to cancer drugs, in violation of sections 301(a), 301(d), 503(b), and 505(a) of the FD&C Act [21 U.S.C. §§ 331(a), 331(d), 353(b), and 355(a)].

In addition, the sale of unapproved and misbranded drugs poses an inherent risk to consumers who purchase those products, especially to those who suffer from serious conditions such as cancer. Unapproved new drugs do not have the same assurance of safety and effectiveness as those drugs subject to FDA oversight, and drugs that have circumvented regulatory safeguards may be contaminated, counterfeit, contain varying amounts of active ingredients, or contain different ingredients altogether.

FDA requests that you immediately cease offering violative drugs for sale to U.S. consumers.

Unapproved New Drugs

As labeled, certain products offered for sale by TeraPharm are drugs within the meaning of section 201(g) of the FD&C Act [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and/or because they are intended to affect the structure or function of the body. These drugs are also new drugs as defined by section 201(p) of the FD&C Act [21 U.S.C. § 321(p)], because they are not generally recognized as safe and effective for their labeled uses. New drugs may not be legally introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the FD&C Act [21 U.S.C. § 355(a)]. No approved applications pursuant to section 505 of the FD&C Act are in effect for these products. Accordingly, their introduction or delivery for introduction into interstate commerce violates sections 301(d) [21 U.S.C. § 331(d)] and 505(a) of the FD&C Act.

For example, TeraPharm offers letrozole, marketed as “Fempro” and described as being used “to treat breast cancer in women who are post‐menopausal.” While there are FDA‐approved versions of letrozole on the market in the U.S., there are no approved drug applications pursuant to section 505 of the FD&C Act in effect for the “Fempro” product offered by TeraPharm. FDA‐approved letrozole is associated with risks including increased incidence of bone fractures and osteoporosis. Furthermore, dosage modifications are required in patients with severe liver impairment.

Another example of an unapproved new drug offered by TeraPharm is acyclovir, marketed as “Aciclovir” and described as “an antiviral drug” that “slows the growth and spread of the herpes virus so that the body can fight off the infection.” While there are FDA‐approved versions of acyclovir on the market in the U.S., there are no approved drug applications pursuant to section 505 of the FD&C Act in effect for the “Aciclovir” product offered by TeraPharm. FDA‐approved acyclovir is associated with kidney failure, which in some cases has resulted in death. Furthermore, dosage modifications are required in patients with impaired kidney function.

Misbranded Drugs

A drug is misbranded under section 502(f)(1) of the FD&C Act [21 U.S.C. § 352(f)(1)] if it fails to bear adequate directions for its intended use(s). “Adequate directions for use” means directions under which a layperson can use a drug safely and for the purposes for which it is intended (21 CFR 201.5). Prescription drugs, as defined in section 503(b)(1) [21 U.S.C. § 353(b)(1)] of the FD&C Act include those that, because of their toxicity or other potentiality for harmful effect, and/or the method of their use, and/or the collateral measures necessary for their use, are not safe for use except under supervision of a practitioner licensed by law to administer them. Prescription drugs, as defined in section 503(b)(1)(A) of the FD&C Act, can only be used safely at the direction, and under the supervision, of a licensed practitioner.

Because the aforementioned drugs are prescription drugs intended for conditions that are not amenable to self-diagnosis and treatment by a layperson, adequate directions cannot be written such that a layperson can use the products safely for their intended uses. Consequently, the labeling for these drugs fails to bear adequate directions for their intended uses, causing them to be misbranded under section 502(f)(1) of the FD&C Act. In addition, because these drugs are not approved in the U.S., they are also not exempt under 21 CFR 201.115 from the requirements of section 502(f)(1) of the FD&C Act. By offering these drugs for sale to U.S. consumers, TeraPharm is causing the introduction of misbranded drugs into interstate commerce in violation of section 301(a) of the FD&C Act [21 U.S.C. § 331(a)].

* * *

FDA is taking this action against TeraPharm because of the inherent risk to consumers who purchase misbranded and unapproved new drugs. This letter is not intended to identify all the ways in which your activities might be in violation of law. Furthermore, included below is a list of websites identified as part of your network (this is not intended to be all‐inclusive). It is TeraPharm’s responsibility to ensure that all products you offer for sale are in compliance with the FD&C Act and its implementing regulations. You should take prompt action to correct the violations noted above as well as any other violations of the FD&C Act (which would include the offer for sale of all misbranded and/or unapproved new drugs, not just the drugs noted above). Failure to correct these violations may result in FDA regulatory action, including seizure or injunction, without further notice.

Please notify this office in writing within 10 working days of receipt of this letter of any steps you have taken or will take to correct the violations set forth above and to prevent their recurrence. If the corrective action(s) cannot be completed within 10 working days, state the reason for the delay and the time within which the correction(s) will be completed. If you believe that your products are not in violation of the FD&C Act, include
your reasoning and any supporting information for our consideration. Your response and any other inquiries
concerning this letter should be sent to FDA’s Internet Pharmacy Task Force at FDAInternetPharmacyTaskForce‐CDER@fda.hhs.gov.

Table of Websites:

Connecting URL
http://www.canadameds24h.com
http://www.infoaboutpills.com
http://www.cheamedspbuy.com
http://www.bestonlinepharmshop.com
http://www.noprescriptiontabs.com
http://www.fastxpills.com
http://www.medsatdiscountprices.com
http://www.new‐qualitypharm.com
http://www.edhelp24.com
http://www.24pills.org
http://www.about‐drugs.net
http://www.mypersonalpharmacy247.com
http://www.cheapmeds24.com
http://www.secure‐meds24.com
http://www.onlinepharmacynorx.com
http://www.rxlegal‐pharmacy.com
http://www.canadianrxpharma.com
http://www.discountrx24.com
http://www.bestonlinepharmshop.net
http://www.cheapmeds24.net
http://www.druggstorre.org
http://www.healmepills.net
http://www.online‐pharmacy‐market.net
http://www.secure‐meds24.nethttp://www.discountmeds.su
http://www.cheapmeds24.biz
http://www.hellpinmeds24x7.net
http://www.meds‐365.net
http://www.europharmapills.com
http://www.goodhealf.com
http://www.mdexpress.men
http://www.rxonline‐top.net

Sincerely,
/S/
Donald D. Ashley
Director
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration

http://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/terapharm-111111-10092018

Skip to toolbar