GDUFA (GENERIC DRUG USER FEE ACT): Q&A TELECONFERENCE 26 TH JUNE 2012

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1 The US-FDA pending Generic Drug User Fees Act (GDUFA) is expected to come into force on 1 st October, A slide set was provided to participants as a comprehensive brief to stimulate questions. Those questions received before the teleconference are answered below. The number in the left hand column of the table indicates which cluster the question was assigned to. Q&A CLUSTERS 1 Implementation timelines 2 Benefit to industry 3 Fee amount - DMF and facility 4 DMF fee one time fee when new LoA is issued 5 Facility fee 6 Facility registration process 7 Intermediates, are they covered? 8 ectd is it mandatory? 9 Deficiency letter improved process 10 Payment process Carla 11 Available for reference status - Carla 1

2 Cluster Question Answer 1 Confirmation of GDUFA implementation date: October 2012? The Congress has passed GDUFA and its implementation date is October However the due dates for payment depend on the Appropriation Act, which is when FDA receives authorization to collect the money. It is recommendable to follow Federal Register closely during the 1 st year of GDUFA. 8 Is GDUFA expected to have any implications concerning the format (paper/electronic) in which DMFs are submitted? The goals as defined in the goals letter 2B (DMF Review Efficiency Enhancements), apply to edmfs submissions. It is not mandatory filing in ectd. 7 Could you confirm that sites producing intermediates prior to API molecule obtaining do not have to pay a facility fee? Do analytical testing sites have to pay a facility fee? API as defined in GDUFA includes a substance intended for final crystallization, purification or salt formation or any combination of these activities to become the final API. Manufacturers of late stage intermediates under this definition will have to pay a facility fee for the intermediate and for the DMF type II as well if it exists. 4 - Will only PAS in relation to the qualification of a new API supplier/reference to a new DMF be subject to the payment of the fee by Analytical sites or bioequivalent sites don t have to pay a facility fee. The DMF fee is only paid for the initial Letter of Authorization. Therefore only when a new LoA is part of a PAS it will trigger the 2

3 the new API supplier (no impact for the approved API suppliers/old DMF holder already part of the corresponding ANDA)? DMF fee. 4 - Can the submission by the ANDA applicant of a PAS (to an approved ANDA referring to an old DMF) not linked to the old/approved drug substance/dmf (e.g. change in the process of the drug product) result in a request from FDA for the payment of the DMF fee by the holder of the old DMF (since the old DMF is part of the corresponding approved ANDA and even if it is not the reason of the PAS)? 4 Will the kind of changes described below (i.e. changes to drug substance manufacture or control reported in relevant FDA guideline as major changes and consequently subject to PAS) in an old DMF (already part of the approved ANDA) trigger a request from FDA for the payment of the DMF fee? The following changes for drug substance Any process change made after the final intermediate processing step in drug substance manufacture. Changes in the synthesis or manufacture of the drug substance that may affect its impurity profile and/or the physical, chemical, or biological properties. This was discussed at length during negotiations and it resulted in the statutory language proposed as initial Letter of Authorization. This means that only 1 st time Letter of Authorizations will trigger DMF fee. As indicated above only initial Letters of Authorization have to pay the fee. According to GDUFA legislative language, the DMF pays one-time-fee the first time the LoA is issued. The DMF fee is not associated to changes made in the drug substance, unless they are associated with a new LoA. 3

4 6 Are there any actions to perform vs FDA before October 31 st 2012 for APIs manufacturers? (e.g. Registration of API facilities) All sites need to be registered electronically according to current procedure using the Drug Establishments Current Registration Site. If an API manufacturer listed in an ANDA is not register it should do it. FDA is updating the databases for information needed for GDUFA. Before/by October 1 st 2012 a Federal Register will be published indicating deadlines and details about facility registration. Once notification is published companies have 60 days to register. 6 Under which process/format the annual reconfirmation of data will have to be done? The manufacturer is responsible to keep the information updated in the API registration database. Annual payment is due at the 1 st October for the first year, and June 1 st thereafter. 4/5 Is GDUFA involving payment of fees only or also any regulatory submission on existing DMFs and registered sites? Need to understand this question??? 9 Teleconference for deficiency letter: can we have more details about the practical conditions? Is it applicable to deficiencies resulting from DMF amendments? 4/5 Sharing of fees between APIs manufacturers, DMF holders, ANDAs holders (e.g when a new API customer cross-refers a DMF in his new ANDA) The goal metrics only apply for DMFs submitted after the program s implementation date. DMF amendments will not be subject to these efficiency enhancements listed in 2.B of the Goals Letter. Need to understand this question??? 4

5 8 It seems that electronic format of dossiers (e-ctd) will be requested after GDUFA implementation: does it apply also to US DMF? Nees format accepted? Electronic DMFs will need to follow the ectd format in effect at date of submission, only if the DMF holders want to take advantage of the efficiency metrics. GDUFA doesn t making mandatory the electronic submissions of DMF. 5 Please confirm a site will only pay once in a year for annual facility fee irrespective of number of DMFs filed and/or named as DP manufacturer in number of ANDAs. (If we are listed as DS and DP manufacturer, does annual facility establishment fees covers all activities irrespective of number of DMFs/ANDS listed that as manufacturing site. Correct. Each establishment DS and DP will have to pay one annual facility fee, independent of the number of DMFs or ANDAs it supports. 7 If a Type-II DMF for a drug substance refers a Type-II DMF for an intermediate/starting material, does GDUFA apply to the intermediate/starting material in the same way as drug substance DMF or DS manufacturer also charged for facility establishment fee as like ANDA holder due to end user of that intermediate/starting material. 5 Even though our site has been inspected & approved for products (NDAs) previously, will FDA charge again annual site establishment fee for APIs. An intermediate that under GDUFA is defined as an API will have to pay for the facility fee and DMF fee as well (in case there is a separate DMF and respective LoA in the DMF of the DS. This is correct, as long as the APIs produced in that site are exported to the USA and used to manufacture a generic product used in the USA Please confirm that sites will need to self-identify for GDUFA. 2. Does the "new database" already exist and is there a link to it? Yes, by October 1 st 2012 Federal Register will publish a notice requiring each facility to register. Each facility must comply within 60 days. Even if registered before you have to do that 5

6 Where is the "i-store" located and will instructions be published for the required GDUFA site invoicing steps? Related to slides and 14: Please confirm that DMF holders will have to create their own invoice at the "i-store" for their DMFs; i.e., the FDA will not send an invoice. again. The database will be an improvement from the existing Drug Establishments Current Registration Site, which is being updated to include the information needed for GDUFA. It is the same systems as PDUFA, once FDA advises how this will be done EFCG will disseminate it to its membership. All user fees will share the same FDA user fee portal For new DMFs, please confirm that the invoice is created after the DMF is listed. (Please review these steps and how the DMF holder can check the status to know when to create their own invoice in order to move to the next stage to have the FDA perform a "document check".) For DMFs already filed with the FDA, (and after Oct 1, 2012/official GDUFA implementation date,) please confirm that the invoice is created after the DMF holder issues an Initial Letter of Authorization but prior to the FDA document check YES each Fee paying companies needs to go to i-store and self-generate After October 1 st 2012 and as soon as the Appropriation Act is enacted, a company submitting a new DMF with the objective to make it available for reference should create an invoice at istore and pay. It doesn t have to check anything else. For those already filed and already reviewed prior to 1Oct2012, if another ANDA is to refer then the DMF holder has to generate an invoice and pay before the ANDA referencing the DMF is filed if filed after 1Oct2012. Correct. The DMF fee is due when the ANDA is submitted (with a new LoA). This means that payment is due before the DMF is 6

7 10 checked ) How sure are we that GDUFA will be implemented in October 2012? 2) The presentation states that will move from pre-approval inspection approach to a continuous surveillance approach. Does this mean that pre-approval inspections will be no longer carried out in future? 3) Annual site fee: maybe under $60000 per site per year. How sure are we about this amount? Does a site that only manufactures 1 API pay the same amount compared to a site which makes many more APIs? 4) The one time DMF fee may be about $35000 per DMF for the first review? How sure is this amount? You say first review Do we have to pay later again when there is a second review? Are DMFs for intermediates excluded? 1) The timelines defined by FDA have been met, the legislation was passed by Congress in June. 2) I think you will always have pre approval inspections 3) Yes, it is one annual facility fee independent of the number of APIs listed in ANDAs 4) No, only one-time-fee is applied to DMFs ) If we have an already active DMF (already referenced by a customers ANDA) do we still have to pay? When do these fees need to be payed? 6) What will exactly change compared to the current DMF data base? Do we have to do something with the current DMFs to 5) If you have a new customer for which you issue a new LoA, triggering a new review, you will have to pay at that point. 6) To make a DMF available for reference you have to pay 7

8 11 6 come in this new database? 7) The new database for sites, when does this come available and is this linked to the current establishment registration? What do we need to do to come in this database? 8) We are manufacturing APIs for USA in several sites and we have many DMFs referenced in multiple ANDAs. What are subsequent actions we do need to take from now on till the end of the year? the fee. If a fee is not paid it will not be listed in the new database of the available for reference 7) Yes, it is an update of the current Establishment Registration site. Once Federal Register is published on/before October 1 st notifying companies to register, you need to go to this updated database and make the registration again, create an invoice in istore and pay the facility fee. 1/4/5 2 4/5 4 1) what will be the expected benefits for API and ANDA holders of the payment system? is there any chance that the system will be not active on October 1 st? 2) it is confirmed that there will be 3 fees ( DMF, annual registration for the plant, FDA inspection)? estimated amount? Payment will be requested in advance? 3) I understand that this is no a retrospective rule and this fees is linked to the revision process so is it known if the API DMF already active and 8) Follow federal register and take the actions that are there determined. You will have to register all these sites in the update database, pay for each facility, and in case you have a new customer with a new LoA, you need to pay the DMF fee. 1) Benefits: parity of inspections, level playing field, faster ANDA approvals, direct contact with FDA to handle DMF deficiency letters, science plan. Nothing was announced differently by FDA or congress, implementation date is October 1 st ) There are only 2 fees for the API: one time DMF fee and facility fee. DMF fee at the time LoA is issued (ANDA submitted) and facility fee annually as defined in GDUFA legislation 3) Only is a new LoA is issued it needs to pay. 8

9 4 10 reviewed will be requested to pay anyhow case of new LoA? 4)is it confirmed if the ANDA should pay for the changes and if so starting from which category PAS and or CBE? 5) is there any indication about how the payment system will work? 6) what will be the consequences in case you do not pay in advance? is the system reversible after the payment? 4) ANDA holders will have to pay for PAS. 5) Yes. Each company creates an invoice in a User fee portal (the same PDUFA is using but updated to GDUFA). Invoice is created and payment made in istore. 6) The ANDA holder receives a notification that payment is missing and the API company has then 20 days to remedy the situation. 9