Statement from FDA Commissioner Scott Gottlieb, M.D., on newsteps to advance medical device innovation and help patients gain faster access to beneficial technologies
Statement from FDA Commissioner Scott Gottlieb, M.D., on newsteps to advance medical device innovation and help patients gain faster access to beneficial technologies
Enabling patients and providers to have efficient access to new and innovative medical products that meet the FDA’s gold standard for safety and effectiveness is a core part of our mission. We’re advancing these goals as part of the Medical Innovation Access Plan that I announced earlier this year. While we’ve unveiled parts of that plan already, we’ll be releasing its full detail shortly. As one part of that effort, we’re announcing some additional steps we’re taking right now to promote beneficial medical device innovation. Continue reading.
In March 2011, the European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA) launched, under US-EU Confidentiality Arrangements, a joint pilot program for the parallel assessment of applications containing Quality by Design (QbD) elements.
The aim of this program was to facilitate the consistent implementation of QbD concepts introduced through International Council for Harmonisation (ICH) Q8, Q9 and Q10 documents and harmonize regulatory decisions to the greatest extent possible across the two regions.
To facilitate this, assessors/reviewers from US and EU exchanged their views on the implementation of ICH concepts and relevant regulatory requirements using actual applications that requested participation into the program. The program was initially launched for three years. Following its first phase, both agencies agreed to extend it for two more years to facilitate further harmonization of pertinent QbD-related topics.
The program officially concluded in April 2016. During this period, the agencies received 16 requests to participate. One submission was rejected because the approach presented was not limited to QbD applications, and another application was not reviewed because it was never filed by the applicant.
In total, two Marketing Authorisation Applications (MAA)/New Drug Applications (NDA), three variation/supplements and nine scientific advice applications were evaluated under this program. One MAA/NDA was assessed under the parallel assessment pathway, with the rest following the consultative advice route. Based on the learnings during the pilot, FDA and EMA jointly developed and published three sets of Question and Answer (Q&A) documents.
These documents also addressed comments from the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), which participated as an observer, offering input to further facilitate harmonization. The objective of these Q&A documents was to generate review guides for the assessors/reviewers and to communicate pilot outcomes to academia and industry.
Additionally, these documents captured any differences in regulatory expectations due to regional requirements, e.g. inclusion of process validation information in the dossier. The following topics were covered in each of the three Q&A documents: –
Q&A (1) published on Aug 20, 2013 included the following topics: (a) Quality target product profile (QTPP) and critical quality attributes (CQA), (b) Criticality, (c) Level of detail in manufacturing process descriptions, and (d) QbD for analytical methods1 –
Q&A (2) published on Nov 1, 2013 on Design Space Verification, that included definition, presentation, justification (including potential scale-up effects) and verification of design spaces both for active substances and finished products2 –
Q&A (3) published on Dec 19, 2014 included the following topics: (a) Level of detail in the dossier regarding Risk Assessment (RA), (b) Level of detail in the dossier regarding Design of Experiments (DOE) and Design Space3 R
Additionally, the FDA-EMA pilot provided the agencies an opportunity to harmonize regulatory expectations for the following precedent-setting applications that were reviewed under the consultative advice pathway: – The first continuous manufacturing (CM) based application submitted to both agencies.
Based on the learnings from this application, the following areas related to CM were harmonized: batch definition; control of excipients; material traceability; strategy for segregation of nonconforming material; real-time release testing (RTRT) methods and prediction models; and good manufacturing practice (GMP) considerations for RTRT, validation strategy, models, and control strategy. – A post approval supplement that included a broad based post-approval change management plan/comparability protocol.
Both agencies were harmonized on the expected level of detail in the protocol and considerations for implementation of a risk based approach to evaluate the changes proposed in the protocol. In line with the scope of the QbD pilot program, joint presentations of key findings were publically presented and discussed with stakeholders at different conferences.
These included the Joint EMAParenteral Drug Association QbD workshop4 organized in 2014 which also included participation from FDA and PMDA.
Overall, it is concluded that, on the basis of the applications submitted for the pilot, there is solid alignment between both Agencies regarding the implementation of multiple ICH Q8, Q9 and Q10 concepts. The FDA/EMA QbD pilot program opened up a platform for continuous dialogue which may lead to further communication on areas of mutual interest to continue the Agencies’ support for innovation and global development of medicines of high quality for the benefit of patients.
Both agencies are currently exploring potential joint activities with specific focus on continuous manufacturing, additional emerging technologies, and expedited/accelerated assessments (e.g. PRIME, Breakthrough). Additionally, EMA and FDA are hosting experts from each other’s organisations to facilitate dialog and explore further opportunities.
References: 1. EMA-FDA pilot program for parallel assessment of Quality-by-Design applications: lessons learnt and Q&A resulting from the first parallel assessment http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/08/WC500148215.pdf
2. FDA-EMA Questions and Answers on Design Space Verification http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/11/WC500153784.pdf
3. FDA-EMA Questions and answers on level of detail in the regulatory submissions http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/12/WC500179391.pdf
4. Joint European Medicines Agency/Parenteral Drug Association quality-by-design workshop http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2013/12/event_detai l_000808.jsp&mid=WC0b01ac058004d5c3
|EMA/ FDA Mutual Recognition Agreement moving forward|
|A possible agreement between the EMA and the US FDA on mutual recognition agreement on drug facility inspections could already be signed in January 2017.|
A possible agreement between the European Medicines Agency EMA and the US Food and Drug Administration FDA on mutual recognition of drug facility inspections could already be signed in January 2017. This is noted in a report of the EU Commission: “The state-of-play and the organisation of the evaluation of the US and the EU GMP inspectorates were discussed. In light of the progress achieved, the conclusion of a mutual recognition agreement of Good Manufacturing Practices (GMPs) inspections by January 2017 is under consideration.”
But, according to the Commission, some issues are still not resolved – like, for example, the exchange of confidential information and the inclusion of veterinary products in the scope of the text.
The “Report of the 15th Round of Negotations for the Transatlantic Trade and Invesment Partnership” summaries the 15th round of negotiations for the Transatlantic Trade and Investment Partnership (TTIP) from 3rd to 7th October 2016 in New York.
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At the Particles in Parenterals Conference Dr Stephen Langille from the US FDA gave a talk on the FDA’s current thinking with regard to the visual inspection of medicinal products for parenteral use.
Dr Stephen Langille from the US FDA gave a talk on the FDA’s current thinking with regard to the visual inspection of medicinal products for parenteral use. In his presentation he showed the number of recalls caused by visible particulate matter over the last 11 years. For him, most of the recalls were justified when the types of particles found were taken into consideration. He also emphasized that something is possibly wrong in the visual inspection process if particles found in the market are bigger than 1000 µm.
The prevention of particles is very important to him. From his perspective the best particle is one which is not in the product. Also important to him are threshold studies, meaning to show the minimum particle size which can still be detected (dependent of product and type of container). These threshold studies are crucial for the setup of the test sets and the qualification of the inspectors of the manual inspection. He also mentioned the semi-automated inspection process. For him semi-automated inspection is good for detecting container-closure issues, like missing stoppers. But he also questioned whether an inspection time of about one second is suitable to detect particles with a size of 200µm for example. In the discussion he was asked about FDA’s opinion on the USP chapter <790>. In his opinion, USP chapter <790> can be an effective tool for ensuring that the manufacturing process and 100% inspection process are adequate to limit visible particle contamination. However, cGMPs must be followed during the manufacturing and visual inspection process. Meeting the requirements of USP <790> should not be used to excuse not meeting cGMPs.
You will find the complete presentation in the members area of the ECA webpage.
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ANDA Submissions – Prior Approval Supplements Under GDUFA, FDA Guidance document, oct 2016, Generics
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GDUFA: FDA’s new Guidance on Self-Identification of Generic Drug Manufacturers
FDA’s new Guidance requesting generic drug manufacturers who want to export to the USA to self-identify has recently been published in a finalised form. Read more here about what types of generic drug manufacturers are affected and which company data are required by the FDA.
The GDUFA (Generic Drug User Fee Amendments) is a legislative package which came into force in 2012 and entitles the US-American FDA to collect fees from generic drug manufacturers, who strive for a marketing authorisation for the American market. An annual fee has to be paid after the successful registration.
The core of the document is the obligation to “Self-Identify” for those companies that have to submit essential site-related information to the FDA. The details of this self-identification are set in a Guidance for Industry entitled “Self-Identification of Generic Drug Facilities, Sites, and Organizations” published on 22 September 2016 by the FDA in the finalised form.
The Guidance describes the following elements:
1. Which types of generic facilities, sites, and organizations are required to self-identify?
2. What information is requested?
3. What technical standards are to be used for electronically submitting the requested information?
4. What is the penalty for failing to self-identify?
Hereinafter, you will find a short summary of these four topics:
1. Companies that manufacture finished generic medicinal products for human use or the APIs for them, or both are required to self-identify as well as companies that package the finished generic drug into the primary container and label it. Besides, sites that – pursuant to a contract with the applicant (generic drug manufacturer) – repack/redistribute the finished drug from a primary container into a different primary container are also required to submit a self-identification as well as sites that perform bioequivalence/bioavailability studies. Last but not least, the obligation to self-identify also concerns sites that are listed in the application dossier as contract laboratories for the sampling and performing of analytical testing.
2. Essential data are: the D-U-N-S number (a unique nine-digit sequence specific for each site / each distinct physical location of an entity), the “Facility Establishment Identifier, FEI” (an identifier used by the FDA for the planning and tracking of inspections) and general information with regard to the facility (company owner, type of business operation, contact data, information about the manufacture of non generic drugs).
3. The HLS standard (Health Level Seven Structured Product Labeling) requested for generic applications (ANDAs) has to be also used for the submission of self-identification information. A detailed description of this standard can be found in the Guidance “Providing Regulatory Submissions in Electronic Format – Drug Establishment Registration and Drug Listing“.
4. Companies that fail to self-identify do not have to expect an explicit penalty. However, such a failure leads to two drawbacks: first, the likelihood of a site inspection by the FDA prior to approval is higher. The second drawback which is much more serious is that all the APIs or finished drugs from a manufacturer who hasn’t self-identified are deemed misbranded. For the FDA, such products are not allowed for importation in the USA.
To the satisfaction of the FDA, the regulations set in the GDUFA and the provisions laid down in the new Guidance represent a major contribution to an enhanced transparency in particular of complex supply chains.
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Generic drugmakers submitting abbreviated new drug applications (ANDAs) and prior approval supplements (PAS) will see their US Food and Drug Administration (FDA) fee rates drop in 2017, though all other rates, including those for drug master files (DMF) and facility fees will increase when compared to 2016.
For FY 2017, the generic drug fee rates are: ANDA ($70,480, down from $76,030 in 2016), PAS ($35,240, down from $38,020 in 2016), DMF ($51,140, up from $42,170 in 2016), domestic active pharmaceutical ingredient (API) facility ($44,234, up from $40,867 in 2016), foreign API facility ($59,234, up from $55,867 in 2016), domestic finished dose formulation (FDF) facility ($258,646, up from $243,905), and foreign FDF facility ($273,646, up from $258,905 in 2016).
The new fees are effective 1 October 2016 and will remain in effect through 30 September 2017.
FDA explained the increases and decreases in fees, noting that for ANDA and PAS fees, the agency is expecting an increase in the number of submissions estimated to be submitted in FY 2017 when compared to 2016. For 2017, the agency estimates that approximately 891 new original ANDAs and 439 PASs will be submitted and incur filing fees.
Fees for DMFs will increase, meanwhile, because of an expected decrease in the number of submissions estimated to be submitted in 2017 (FDA is estimating 379 fee-paying DMFs for 2017), when compared to the estimated submissions from 2016.
And all facility fees will increase in 2017 when compared to the previous year because of a decrease in the number of facilities that self-identified (the total number of FDF facilities identified through self-identification was 675, of which 255 were domestic facilities and 420 foreign facilities; while the total number of API facilities self-identified was 789, of which 101 were domestic facilities and 688 were foreign facilities), FDA said.
How FDA Calculates the Fees
In order to calculate the ANDA fee, FDA estimated the number of full application equivalents (FAEs) that will be submitted in FY 2017, which is done by assuming ANDAs count as one FAE and PASs (supplements) count as one-half of an FAE, since the fee for a PAS is one half of the fee for an ANDA.
The Generic Drug User Fee Act (GDUFA) also requires that 75% of the fee paid for an ANDA or PAS filing be refunded if either application is refused due to issues other than a failure to pay the fees.
And since this is the last year of this iteration of GDUFA (the next version is still in the works), the agency is allowed to further increase the fee revenues and fees established if such an adjustment is necessary to provide for not more than three months of operating reserves for the first three months of FY 2018, though FDA estimates that the GDUFA program will have carryover balances for such activities in excess of three months of such operating reserves, so FDA will not be performing a final year adjustment.
To pay the fees, companies must complete a Generic Drug User Fee Cover Sheet, available at http://www.fda.gov/gdufa and generate a user fee identification (ID) number. Payment must be made in US currency drawn on a US bank by electronic check, check, bank draft, US postal money order or wire transfer.
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