Bioequivalence and Bioavailability Forum

Dear all,

if found an interesting Q&A-document “FDA response for questions raised during Post office trips in the MENA region“ at Turkey’s Clinical Research Association. Since it might not stay online forever, below its entire content:

1. Can one ANDA application have two strengths or sizes?
   Yes.
   Guidance for Industry, “Submitting Separate Marketing Applications & Clinical Data for Purposes of Assessing User Fees”, details the cases where one application could be accepted for multiple strengths or packagings. The guidance is available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079320.pdf.
   
   
2. Do companies have to submit data on failed BE studies (as part of their application to FDA) if they were conducted for a comparison with a European reference drug?
   Yes.
   Data from failed BE studies should be submitted (as a part of an ANDA to FDA) if the studies were conducted for the same test product (definition of similar product is present in the BE data submission guidance) that is the subject of the ANDA, regardless of whether the studies compared the test product with a U.S. or non-U.S.- reference product.
   
   
3. Are bioequivalence studies unblinded?
   Yes.
   BE studies are conducted unblinded; it is a common practice, though, to have the analytical part blinded.
   
   
4. Is it correct that BE acceptance parameters can be widened for narrow therapeutic drugs (NTI drugs)?
   No.
   BE acceptance criteria are not widened for NTI drugs. However, currently, the U.S. FDA adopts reference-scaled average BE approach for NTI drugs, such as warfarin. For more details on this approach, please see the product-specific guidance at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM201283.pdf.
   
   
5. What happens if the BE data are acceptable but the dissolution comparison does not pass the f₂? If in vitro fails, is BE accepted?
   The f₂ similarity factor is not used for comparison of dissolution data between the test and reference products to determine the acceptability of the dissolution data of the test product. f₂ is used for comparison between strengths of the test product to confirm the proportionality between the bio-study test strength and other test strengths, in determining the eligibility for waiver requests of non-bio-study test strengths (together with proportional similarity of test formulations and acceptability of the BE studies).
   
   
6. Can an originator drug manufactured and registered in Puerto Rico be considered as RLD in the USA?
   The ANDA applicant must use the reference listed drug that is identified in Approved Drug Products with Therapeutic Equivalence Evaluations. This is the only drug product that the FDA will accept as a Reference Listed Drug.
   
   
7. Do additional post market warnings and side effects have to be approved by FDA?[list=a]
8. The labeling of the generic drug in an ANDA would need to be the same as the RLD labeling. If the RLD holder submits changes to their label, including post market warnings and side effects, the ANDA holder must submit the same changes to their label to get them approved by the FDA. These could be submitted as a “Changes Being Affected Supplement”.
   
9. If the ANDA holder determines that there are warnings, precautions, or side effects that warrant a change in their label, the information may be submitted with documentation in a supplement to this ANDA and it will be reviewed.

For more details about Supplements and other changes to an approved application, see 21 CFR 314.70.

[*]Does citizen petition delay the review/approval of an ANDA? Would the review stop while FDA is looking into the citizen petition? e.g., the citizen petition could be asking that FDA should request the BE studies to be repeated.
No.
The review of the ANDA would continue while the FDA reviews the citizen petition. If the citizen petition raises scientific issues that the FDA determines need to be addressed, the ANDA holder will be asked to address those issues.

[*]If a DMF was registered prior to GDUFA, should it be reviewed again to be listed in the DMF list under GDUFA? How long would it take to review?
GDUFA established a requirement for a Completeness Assessments (CA) for all DMFs that pay the GDUFA DMF fee. The owner of a DMF incurs the fee the first time that a generic drug submission references that DMF by an initial letter of authorization on or after October 1, 2012 (more details are available at:
http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm319567.htm).
Once the DMF holder files a Type II API DMF7 with the generic drug user fee cover sheet (Form FDA 3794) and the fee payment has been verified FDA will perform the initial the CA. This process is different from the full scientific review, which is performed to determine the adequacy or inadequacy of the information contained in the DMF to support an ANDA review decision. For clarity “CA” refers to this new type of evaluation and “review” refers to the full scientific review.
All DMFs which pay the fee get a CA, this holds whether they have been reviewed previously or not. The guidance “Initial Completeness Assessments for Type II API DMFs Under GDUFA” provides additional detail on the kinds of information FDA will confirm when performing an initial CA on a DMF. As stated in this guidance (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM321884.pdf), DMFs which have a review on file after November 30, 2007 are eligible for an administrative CA. The administrative CA is an abbreviated process and usually takes about two weeks to complete after payment for the DMF is received after which the DMF will appear on the “Available for Reference” list. Those DMFs not eligible for the administrative CA will receive a full CA, the timing of which depends on the priority and current workload. Currently the full CAs take 12 to 16 weeks to complete after payment is received.

[*]What does the company do if it observes a side effect that is in the originator drug? Do they need to report it?
Yes.
See 21 CFR 314.80 for Postmarketing Reporting of Adverse Drug Experiences. In case of adverse drug experience that is both serious and unexpected, the company should submit a report as soon as possible but in no case later than 15 calendar days from initial receipt of the information by the applicant. Otherwise, the company can submit these side effects in the periodic adverse drug experience reports.

[*]Are facility registration fees applicable to contract manufacturer/packager or contract test lab under GDUFA?
The following types of generic industry facilities, sites, and organizations are required to self-identify with FDA:

1. Facilities that manufacture or intend to manufacture human generic drug APIs, finished dosage forms (FDFs), or both.
   
2. Sites and organizations that package the FDFs of a human generic drug into the primary container/closure system and label the primary container/closure system.
   
3. Sites that are identified in a generic drug submission and pursuant to a contract with the applicant remove the drug from a primary container/closure system and subdivide the contents into a different primary container/closure system.
   
4. Bioequivalence (BE)/bioavailability (BA) sites that are identified in a generic drug submission and conduct clinical BE/BA testing, bioanalytical testing of samples collected from clinical BE/BA testing, and/or in vitro BE testing.
   
5. Sites that are identified in a generic drug submission and perform testing of one or more attributes or characteristics of the FDF or the API pursuant to a contract with the applicant to satisfy a current good manufacturing practice (CGMP) testing requirement (excludes sites that are testing for research purposes only).

However, only facilities that manufacture or intend to manufacture generic drug APIs or FDFs, or both, are required to pay facility fees. Sites and organizations that only perform testing, repackaging, or relabeling are not required to pay a user fee. The agency is considering clarifying the guidance document as to whether facilities that package generic drugs are required to pay annual facility fees. FDA intends to address this issue more fully in future guidance.
Facilities that package the FDF of a human generic drug into the primary container/closure system and/or label the primary container/closure system are considered to be manufacturers and are, therefore, required to pay an annual FDF fee. This is true for packaging done pursuant to a contract or by the applicant himself. Once applicants determine the type of facility, site or organization is applicable in their specific situations, they can review fee related information at: http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm316678.htm.
It may be helpful for applicants to review the information available in the Questions & Answers Guidance available via the GDUFA website at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM316672.pdf.

[*]How does FDA collect Pharmacovigilance reports? How is the information collected and what means does the FDA use to collect such information and data?
The data are collected from the 15-day reports and the periodic adverse drug experience reports submitted in the drug application as well as MedWatch reports from the public. The Office of Safety Evaluation compiles the data in a database and continuously identifies the trends.

[*]Is there a way to accelerate an inspection for an API manufacturer?
The only way an inspection for an API manufacturer may be expedited is if the application itself falls into one of the expedited review categories established by FDA. More information is available at FDA webpage at: http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm. Moreover, FDA has issued new draft guidance for such expedited programs available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf.

[*]For the first three production batches submitted into the market, is it required to submit dissolution comparison versus RLD or the bio-batch on which BE was performed?
Comparison with the RLD or bio-batch is not required. Batch data should meet the release and stability specifications as agreed upon at the time of approval.

[*]A drug regulatory authority had a case where the biobatch submitted to FDA was R and D batch, is that acceptable?
In some cases the R and D batch may be manufactured in the plant itself where some manufacturer has a pilot unit in the plant with very similar equipment to the production scale units. In such case where the R and D fulfill the pilot batch requirements it might be accepted if manufactured under cGMP.

[*]In cases a product is not stable at 30 °C is 25 °C stability data acceptable even if it is manufactured in Zone IV with clearly labeling the storage conditions not to exceed 25 °C?
This can be accepted but manufacturer has to clearly label the storage conditions on the product to be stored below 25 °C. Kindly refer to ICH Q1A. If the product is not stable at 30 °C, product or container closure remediation due to intermediate condition failure should be considered (i.e., reformulation, protective packaging, labeling). Moreover, it may be required to ensure that temperature did not exceed these conditions during shipping to the US by temperature data logger (supply chain of the product).

[*]Does the manufacturing site have to be registered at FDA prior ANDA submission?
Site information should be provided within the submission (parallel to the file submission) where firm is inspected as part of compliance program (pre approval inspection). This is different in most of MENA countries where firm is resisted first and file cannot be submitted before the whole process of inspection and site registration is completed. There is GDUFA related guidance for facilities that should be consulted.

[*]We are generic manufacturer and has developed a combination product of amoxicillin and floxacillin tablets, there is no available brand combination for such product in the market. Can we perform comparative dissolution versus the individual products amoxicillin and floxacillin?
This depends on the reason why the product is not available. First and foremost, in order to qualify as a generic in the US, there must be a comparison with a previously approved product. After this, was it withdrawn from the market, withdrawn from the orange book, withdrawn for safety reasons; is there another generic on the market? There are ways to manage this but it depends on why the product is not on the market. If such a drug product never was approved or it was withdrawn for safety reasons, there cannot be an ANDA submitted for the product.[/list]