The US FDA has found the carcinogenic nitrosamine impurity NDMA in several batches of extended-release (ER) formulations of metformin, which is used to treat patients with type 2 diabetes. The impurity was found to be above the acceptable limit in these products.
The agency has, therefore, called upon the five pharmaceutical companies involved to voluntarily recall these ER metformin products. Other metformin manufacturers which supply a large portion of the US market have not been affected by the recall. However, the FDA is collaborating closely with manufacturers to ensure appropriate testing for NDMA levels in these products. The agency is also conducting assessments to determine whether any shortages in metformin may arise due to the recalls, and it intends to help prevent or reduce the impact of any such shortages.
The EMA has issued a Q&A document (June 2020) highlighting some key points for successful qualification of digital technology-based methodologies used in medicines development, for example as part of the conduct of a clinical trial. The Q&A reflects the EMA’s current experience, and notes that if a digital technology is used in the context of product development, evaluation or monitoring, and could impact the benefit-risk assessment, then relevant aspects will be discussed at product assessment (such as reliability versus established data capture methods), and so qualification should be considered during development. Examples are given of technologies falling within the scope of the qualification programme, and the process for requesting advice or an opinion is outlined. The Q&A ends with five overarching guiding principles for a qualification submission, and in particular the importance of early and focused interactions with the agency.
The document is available here: https://lnkd.in/d9u3iEH
MHRA “Guidance Good clinical practice for clinical trials” gives guidance on how to show MHRA you’re meeting GCP standards and what to expect from an inspection. MHRA requests pre-inspection documentation information in the form of a GCP inspection dossier & a clinical trials spreadsheet within 30 days of notification of an inspection. The GCP dossier clinical trials spreadsheet which is used to prepare the GCP dossier and is part of the requested pre-inspection documentation was updated on the 22nd May 2020.
The updated GCP inspection dossier clinical trial spreadsheet can be viewed via this link https://bit.ly/3gs2BPB
What are the key pharmacokinetic considerations in the assessment of biosimilarity?
The EMA has updated question 7.1 of its Clinical Pharmacology and Pharmacokinetics Q&A, which tackles the above issue. The related response clarifies the differences between requirements for biosimilar products and small molecule generics. It provides further detail on the following issues that need to be considered in assessment of biosimilarity: linear clearance, nonlinear clearance, anti-drug antibodies, batch selection and protein content correction, study population, dose level, sampling times, and statistical comparison: https://bit.ly/RealCMC-2Aa1OCk
Mexico has been welcomed as an observer state by the European Pharmacopoeia Commission.
Mexican authorities can now participate in the scientific work of the European Pharmacopoeia Commission and other activities of the European Directorate for the Quality of Medicines (EDQM). This brings the European Pharmacopoeia’s total observer countries to 30, together with the 39 European countries and European Union as signatory parties: https://bit.ly/RealCMC-2yzsTyv
The WHO has released a new digital version of its Model list of Essential Medicines (EML).
This WHO reference tool is currently used by over 150 countries to compile their national essential medicines lists to ensure that these essential medicines are always available in their health care system in the appropriate dosage forms and quality, and at affordable prices.
Users will now be able to freely access the EML online database on smartphones and computers. The system also allows users to create their own customized lists by exporting the list (or part thereof) into an Excel or Word version.
The EMA has released several updates to its pre-authorisation and post-authorisation procedural advice for users of the centralised procedure. Some of the updates include:
The EMA now aims to respond to queries within 10 days instead of 5. Other changes as can be seen in the tracked documents linked here: https://lnkd.in/dpW7TF7
The International Council for Harmonisation (ICH) Management Committee and Assembly has indicated that it intends to collaborate more closely with the Pharmaceutical Inspection Co-Operation Scheme (PIC/S) and that new topics and reflection papers are currently under development.
ICH Management Committee has proposed that the PIC/S would be involved in ICH guideline work relevant to regulatory assessor [MG1] and inspector disciplines, during the public consultation following Step 2b. Additionally as an ICH Observer, the PIC/S may also request to be part of Plenary Working Parties which would allow its involvement prior to Step 1.
A revised draft reflection paper on model-informed drug development and an update on a draft reflection paper on patient-focused drug development are also in the pipeline. The Biotechnology Innovation Organization has also proposed to develop a reflection paper on gene therapy harmonization. https://bit.ly/RealCMC-3eagyQe
Pharmeuropa has released new supporting information on the new draft Ph. Eur. Chapter 2.4.35 ‘Extractable elements in plastic materials for pharmaceutical use’, which is open for consultation until the end of June 2020. The document proposes that the long‑established individual tests for specific elements are maintained in the Ph. Eur. general chapters on plastic materials, since the quality of plastic materials influences that of the containers manufactured from them.
In future, cross‑reference to this new general chapter will also be made in each existing Ph. Eur. text on plastic materials. The supporting information also indicates that all the existing Ph. Eur. general chapters on plastic materials should be revised to delete the heavy metals test and to perform the tests on target elements according to the new general chapter. https://bit.ly/RealCMC-3bUORJM
“Field Safety Notices (FSNs) are a key part of the medical device vigilance system. Manufacturers are required to inform users about corrective actions involving their device as soon as possible using a Field Safety Notice (FSN). Published on the 20th May by the MHRA to advise manufacturers on how to write clear FSNs to maximise response rates the guidance provides supplementary information to MEDDEV 2.12/1 rev 8 (how to write and distribute effective FSNs) and covers such topics as good traceability, content, effective targeting of FSNs and Field Safety Corrective Action (FSCA) strategy. Manufacturers are advised to read the document via the following link: https://bit.ly/36hrYiH.
We’re proud to have our Real expert, Dorothée Fouchier, attending the virtual 2nd Joint DIA-EUCOPE Workshop on ATMPs, Innovative Gene and Cell Therapies, next week alongside our industry peers to discuss the challenges, opportunities and political implications of advanced therapies. If you’re also attending, get in touch! To arrange a meeting visit: https://lnkd.in/dc_SDsr
The European Medicines Agency (EMA) has reduced the fee for on-site GMP inspections by 100%. This fee reduction is only applicable in cases where the GMP compliance of a manufacturing site with restricted access due to the COVID-19 pandemic, could not be confirmed via a distant assessment and an on-site inspection is, therefore, required. Fees for Plasma Master Files inspections will also be similarly reduced.
The EMA has also advised that during this initiative, remuneration to national competent authorities (NCA) will not be reduced, if the NCA provides a comprehensive inspection report for the distant assessment and a subsequent independent report for the on-site inspection. Further information is available here: https://bit.ly/RealCMC-2XbhKMr
The scope of EMAs ITF covers regulatory, technical and scientific issues arising from innovative medicines development, new technologies and borderline products. The objective of the interactions with the ITF is to facilitate informal exchange of information and guidance during the product development process. Interactions take the form of informal brainstorming discussions are led by experts from the Agency network, working parties and committees. These meetings are free of charge and 1.5 hours long. ITF has just issued a new briefing meeting request form in order to standardise company initial dialogue. The form can be found here: https://lnkd.in/dTK2axt
The MHRA inspectorate posted ‘How to manage temporary GDP process changes and risks through the COVID-19 pandemic’ on their blog on the 13th May to advise companies on how to manage changes to GDP processes to address exceptional circumstances that have arisen due to Covid-19. Such changes should be documented either as deviations, change controls or similar and incorporate quality risk management principles. Changes may be documented either as single reports or an over-arching one specific to COVID-19. The post has a link to GDP flexibilities introduced by the MHRA to assist with distribution of medicines during COVID-19 pandemic documented in ‘Guidance Exceptional GDP flexibilities for medicines during COVID-19’. The GDP flexibilities introduced cover Supply Chain, Transportation, RP, Facilities & Equipment and Reporting.
Companies applying these flexibilities need to report to Covid19.GMDP@ mhra.gov.uk as outlined in the guidance, however you only need to report once for each flexibility and reports don’t require approval to implement. The post can be accessed via this link: https://bit.ly/2LIjR5g
The 505(b)(2) route to marketing authorisation in the United States has become very popular. Companies owning a product registered (or eligible to be registered) via this pathway might also wish to submit their product in Europe. Real Regulatory can help companies navigate the significant complexities involved in choosing an appropriate legal basis for submission, setting regulatory strategy and dealing with scientific advice and marketing authorisation procedures.
Read the linked article for an overview of the intricacies and the ways in which we can assist. https://lnkd.in/dzjU_Jj
The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has released a new version of its ‘Application for new Manufacturer’s “Specials” Licence (MS) (Human Use).
To access the new version of the application form please see the following link: https://bit.ly/RealCMC-2ThytN4
The GCP IWP has published its meeting dates and a list of its priorities for 2020. The priorities of the group will continue with an EU focus and maintaining international relationships. However, of particular interest is the upcoming work to create and finalise a series of Q&As on the following noteworthy topics Q&A on inspectors’ access to patients’ medical records/data when the access of EEA inspectors to medical information is not clearly stated in the Informed Consent Form (ICF). Q&A on sponsor oversight of activities subcontracted to third parties. Q&A on expectations for provision of written information to clinical trial subjects in relation to new information requiring re-consent. Q&A on confidentiality undertaking of EU/EEA inspectors.
The full entirety of the work plan can be found under this link: https://lnkd.in/djgDh2T
The EMA’s Dasatinib product-specific bioequivalence guidance is currently under revision. A revised draft guideline has been released for public consultation and comments will be received until 31st August 2020. The current adopted guidance concerns bioequivalence testing requirements for Dasatinib 20, 50, 70, 80, 100 and 140 mg film-coated tablets. The draft revised document also includes requirements for Dasatinib 10 mg/ml suspension and the additional requirement for a fed study for both dosage forms.
CMDh has updated the following guidance: – RMS validation checklist for human medicinal products in DCP – Data requested for New Applications in the MRP/DCP which are not stated in the current EU legislation and/or in Volume 2B, Presentation and format of the dossier Common Technical Document (CTD) and/or in the EEA approved Guidelines/Recommendation papers – Data requested for Variations and/or Renewal Applications in the MRP/DCP which are not stated in the current EU legislation and/or in Volume 2B, Presentation and format of the dossier Common Technical Document (CTD) and/or in the EEA approved Guidelines/ Recommendation papers – CMDh Best Practice Guide on the use of the electronic Common Technical Document (eCTD) in the Mutual Recognition and Decentralised Procedures – CMDh Questions & Answers on implementation of outcome of Art. 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group – Practical guidance for procedures related to Brexit for medicinal products for human use approved via MRP/DCP.
The updated documents (most with tracked changes) may be viewed here: https://bit.ly/RealCMC-2T4PycX
The MHRA has recently adopted a flexible and pragmatic approach to regulatory requirements for medical device clinical investigations during the COVID-19 pandemic. This is documented in Guidance “Medical devices clinical investigations (CIs) during the coronavirus (COVID-19) outbreak”. The updated guidance, which now includes a new section relating to COVID 19, details regulatory flexibilities introduced for ongoing and new submissions for CIs.
There is an expedited process in place for CIs directly relating to COVID-19. However, it states that if MHRA is unable to reach a decision by the new internal deadline, the 60-day assessment period still applies, and the applicant cannot start the study until they have received a final decision from the MHRA or until 60-days after the notification. The update also states that the MHRA is working on a process for studies where there is both a medicine and a medical device to allow for a single application via the Clinical Trials Unit to ensure a smooth and fast assessment of both elements.
The guidance document which can be accessed via this link: https://bit.ly/2zymV0Y
The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended the precautionary suspension of all ranitidine medicines in the EU due to the presence of low levels of the potentially carcinogenic impurity, N-nitrosodimethylamine (NDMA).
Many European national authorities had already recalled ranitidine medicines as a precautionary measure during the EMA’s review. There is some evidence which shows that NDMA may form from the degradation of ranitidine itself over the course of its shelf-life, however, it is still unclear whether the impurity can also be formed from ranitidine inside the human body.
The CHMP recommendation will be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.
The 166th European Pharmacopoeia (Ph.Eur.) Commission session was still held electronically despite the restrictions and lockdowns brought on by the COVID-19 pandemic. During the Ph.Eur. Commission session, 91 texts, including 11 new texts, were adopted and will be published in the Ph. Eur. Supplement 10.4 and effective from 1st April 2021.
The new texts include general chapter 5.28 on Multivariate Statistical Process Control and monographs for Regorafenib Tablets, Riociguat Tablets, Rivaroxaban Tablets and Sorafenib Tablets. A list of the adopted texts will soon be available on the EDQM website. Monographs for sartan drug substances have also been revised to add a requirement for risk assessment of the manufacturing process and to replace interim limits for NDMA and NDEA with a 0.03 ppm limit. The next Ph. Eur. Commission session is due to take place on 23rd June 2020.
MHRA has updated its guidance on the GMP flexibilities it is allowing on an exceptional basis during the current pandemic. The flexibilities cover two main areas relate to manufacture and importation, and pharmaceutical quality system topics. However, it is stressed that implementation of any described flexibilities is contingent on Qualified Person input to that decision. The guidance also requests companies to speak with MHRA where these flexibilities are not sufficient to overcome current challenges. The full text detailing the specifics can be found here https://lnkd.in/da22tgr
EMA has just updated the deadlines for submission of applications for orphan medicinal product designation to the EMA and corresponding COMP timetable for valid applications, full tabulated details can be found at this link https://lnkd.in/dhRqpEh
The European Medicines Agency (EMA) has issued a privacy statement regarding the EU PAS Register®. The latter is a publicly available database to provide a register of non-interventional post-authorisation studies (PAS). The Privacy Statement explains the most essential details of the processing of personal data by the EMA in the context of the European Union electronic Register of Post-Authorisation Studies (EU PAS Register), the full statement can be found under the following link; https://lnkd.in/dxK4TAG
MHRA published ‘Collection MHRA guidance on coronavirus (COVID-19)’ on the 19th March 2020 providing guidance to industry during the COVID-19 pandemic, this document is continually under review and is updated as required. One specific area covered within guidance is Regulatory Flexibilities, MHRA is meeting weekly to address implications of COVID 19 pandemic as they arise for medicines and medical device sectors. MHRA has already published a number of GDP and GMP flexibilities and continues to add additional flexibilities as and when needed. Keep up to date on all COVID-19 regulatory flexibilities by checking the published guidance collection linked here https://bit.ly/39HWh1P on the MHRA website.
The UKs NICE has posted feedback on a joint Scientific Advice process conducted with MHRA and a team from the University of Birmingham. The applicant was trying to establish what evidence would be needed in order to licence the product and ensure future reimbursement of the product. Full details of their experience is detailed under this link https://lnkd.in/dABayiQ
Real Regulatory has long since had the systems in place to support our clients on a remote basis while our staff too have always had the flexibility to work remotely. At this time, our priority is the safety of our team and the continuation of our high quality services for our customers. In order to protect our fantastic staff and to ensure business continuity, all of our consultants are working from home. We are, as ever, always available if you need support during these times and available to help on an interim or ongoing basis. If you have any queries related to your projects, please don’t hesitate to chat to us: https://lnkd.in/eFeHweG
The UKs MHRA has a published a case study detailing how the agency approved a flu vaccine within 7 months rather than the usual 12 month turnaround. Since the 2018 to 2019 flu season, a vaccine specially designed to have optimal efficacy in the elderly has been available for preferential use in the over-65s. More details of the specific case can be found here https://lnkd.in/dkJSuNx The agency is very keen to demonstrate their agility, flexibility and willingness to collaborate with industry. If you need any help with the agency dialogue or need a UK/EU based company entity to become temporary licence holder for your product application. Please contact RRL https://lnkd.in/daQjxxj
MHRA has issued comprehensive advice on managing clinical trials during the period of restrictions imposed as a result of COVID19. Importantly, MHRA has clarified that ‘An increase in protocol deviations in relation to Coronavirus will not constitute a serious breach, therefore there is no need to report this to us (unless of course patients are being put at risk).’ MHRA has specified that prospective protocol waivers remain unacceptable, they would not expect companies to bypass the eligibility process due to difficulties in assessing subjects and carrying out tests. Safety of patients remains a priority and they should not be included into a trial unless they meet the inclusion and exclusion criteria. If the safety of a trial subject is at risk because they cannot complete key evaluations or adhere to critical mitigation steps, then consideration to discontinuing that subject must be discussed, which may also extend to the whole trial in some cases. Urgent Safety Measures may be used to halt, or even temporarily halt a trial, or halt recruitment. A temporary halt, including for logistical reasons such as trial team unavailability, should be submitted as a substantial amendment. http://bit.ly/2Wq7LEg
Inspections are an opportunity to demonstrate your organisations compliance to GCP. Inspectors will always be open and honest, and likewise is expected from the organisations. Inspections and how they are conducted has evolved over the years and has had to, due to the increased complexity of trials, organisations, implementation of electronic clinical trial systems and the development of technology. No longer are trial teams based in one office with a single paper trial master file (TMF). Issues are often encountered during the inspection with TMF access and navigation, document request provision and sometimes simply finding the right person to answer a particular question. This can be frustrating for both parties and may even lead to the extension of the inspection. MHRA has issued a of the dos and don’ts and questions to raise through each phase of the process of conducting a GCP inspection. Full details of the recommendations can be found under this link https://lnkd.in/dX-fast
All stakeholders can keep up to date on implementation of technical aspects of Regulation EU 2016/161 via Q&A Document Safety Features for Medicinal Products Human Use updated on the 9th March 2020 to v17 and linked here https://bit.ly/2U6kKIj.
Wholesalers are referred to Section 5 of the Q&A document which addresses VERIFICATION OF THE SAFETY FEATURES AND DECOMMISSIONING OF THE UNIQUE IDENTIFIER BY WHOLESALERS, in particular newly added Q&A 5.11 below 5.11. Question: Should wholesalers be connected to the national repositories or can they be connected to the European hub? A wholesaler physically holding products and performing activities related to wholesale outlined in Articles 20-23 Commission Delegated Regulation (EU) 2016/161 (such as the verification of returns or decommissioning for export) should be connected to and perform operations in the national repository where the activities take place.
A connection to the national system is necessary to ensure that the audit trail is accurate and complete. Stakeholders all have an important role to play in implementation of Regulation EU 2016/161 to ensure that public health is safeguarded by protecting the pharmaceutical supply chain from infiltration by falsified (or counterfeit) medicines.
The EMA recognises the importance of the European Commission recommendations to improve the EU product information. EMA see this as a unique opportunity to improve the information EU patients receive on their medicines, within the boundaries of the current legislation. The plan envisages;
The action plans in full can be found under this link; https://lnkd.in/ekzb6Ye
We’re proud to have our Real Expert, Dorothée Fouchier, on site at the Good Clinical Practice Symposium 2020 in London next week alongside our industry peers to discuss the integrity of data generated in clinical trials and to ensure that clinical trials are conducted according to regulations. If you’re also attending, get in touch! Dorothée would be pleased to see you there.
To arrange a meeting visit: https://lnkd.in/drv5fsr
MHRA has issued a request to MAHs to review their manufacturing processes to identify and, if found, to mitigate risk of presence of nitrosamine impurities. The risk evaluation should be done per the CMDh guidance for MAHs of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines and needs to be completed by March 2020. Further information can be found under this link https://lnkd.in/dXkpA5p
EMA has published a new interactive timeline here https://lnkd.in/dxnrRy3 to demonstrate the journey of a medicine assessed by EMA from laboratory to patient. It includes nice visuals and links to click for further information at each step of the way.
CHMP scientific advice questions are often related to the suitability of comparability proposals following changes to ATMP manufacturing details. Manufacturing process changes may encompass improvements/change in equipment, raw materials and critical starting materials such as the cells or the vector or their suppliers, manufacturing process scale or product stability. Oftentimes these changes are frequent, particularly in the early stages of development. Thus, EMA has just issued at Q&A to consider when compiling comparability proposals. Full details can be found under the link https://lnkd.in/dBqFCeD
We’re proud to have our Real Expert, Niamh Miller, on site at the MHRA GMP & GDP Symposium in London next week to discuss the latest updates on guidance and increasing complexity in the manufacturing and distribution chain requirements with our industry peers. If you’re also attending, get in touch! Niamh would love to see you there! Contact us to arrange a meeting: https://lnkd.in/daQjxxj
Will you be at the American College of Toxicology 40th Annual Meeting 17-20 November 2019 in Phoenix, Arizona? Our Real expert, Leslie Dowling, will be giving the EU presentation in the Continuing Education session CE08: Regulatory Meeting Preparation and Conduct: US, EU, and China on 17 November, with Q&A at the panel discussion at the end of the session. For more info or to arrange a one-on-one, email firstname.lastname@example.org
Good Clinical Practice (GCP) is an international ethical and scientific standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. All clinical trials must comply with GCP regulations with compliance assessed via audit by a regulatory body. MHRA is a regulatory body with vast experience in conducting GCP audits and has documented that knowledge and experience in MHRA guidance document ‘GCP for clinical trials’ and GCP Inspection Metrics Report. Real Regulatory article ‘Good Clinical Practice for Clinical Trials’ provides a succinct summary of the MHRA intelligence addressing assessment of GCP compliance via the MHRA GCP inspection process, MHRA GCP inspection findings for 99 GCP audits conducted between April 2016 and March 2017 and available GCP compliance tools to help relevant parties comply with GCP regulations. If you are involved in any aspect of clinical trials, then this article is of interest to you and can be found on the RRL website. https://lnkd.in/dEDcnk3
The EC has designated a 2nd IVDR Notified Body (NB), namely BSI Assurance UK Ltd (BSI) https://bit.ly/36xrAMu. German NB DEKRA Certification GmbH was the first NB to be designated (Oct 10th). BSI is the first notified body to achieve full scope designation, which covers all devices specified under the Implementing Regulation (EU) 2017/2185. Both NB ‘s are listed in the EC NANDO database linked here https://bit.ly/2qucB5m. It’s probably a good idea to regularly check this link for further designations to both the Medical Device Regulation (MDR) and IVDR. It is a constantly evolving list.
In late September, EMA,FDA and PDMA further discussed alignment on clinical trial designs for key indications for antibacterial drugs. Notably, they also expanded the discussions to include antifungal agents, an area which is also affected by growing antimicrobial resistance and where clinical development programs can be challenging. Further information can be found under the link below; https://lnkd.in/dPDnAJF
We’re excited to be discussing the latest updates on guidance and increasing complexity in the manufacturing and distribution chain requirements with our peers at the MHRA GMP & GDP Symposium in London, 11-12 Nov. If you’re also attending, get in touch! Our QMS and regulatory affairs compliance expert Niamh Miller would love to see you there! Contact us to arrange a meeting: https://lnkd.in/daQjxxj
HMA-CMDh has just issued their annual recommendation on submissions dates for DCP and MRP for 2020. Check out the individual links below for details ⬇️⬇️
Recommendations on submission dates in 2020 for applicants of the DCP: https://www.hma.eu/92.html
Recommendations on submission dates in 2020 for applicants of the MRP: https://www.hma.eu/93.html
EMA has issued an overview to advise companies on steps to take to avoid nitrosamines in human medicines. This includes templates, published 28th Oct 2019, for responses to EMA following Step 1: Risk evaluation and Step 2: Perform further confirmatory testing. Further details can be found on the EMA website here: https://lnkd.in/d9T22zp
A Good Practice document on the assessment of GMO related aspects in clinical trials with AAV clinical vectors has been developed by the national competent authorities & the Commission services. It builds on possibilities under the existing legislation to facilitate the conduct of clinical trials with ATMPS and has been endorsed by Austria, Belgium, Croatia, Czechia, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Latvia, Luxembourg, Netherlands, Portugal, Romania & Spain.
Developers that intend to conduct a trial in these countries can follow the approach laid down here: https://lnkd.in/ey2NfV9
In addition, a common application form for investigational medicinal products for human use that contain or consist of AAV vectors has been endorsed by the above Member States: https://lnkd.in/eCmCCEE
The Deputy Commissioner of the Chinese National Medical Product Administration (NMPA) visited EMA on 25 October together with a delegation. The visit took place in the context of the ongoing EU-China regulatory dialogue on pharmaceuticals. Topics for discussion included GMP standards for active pharmaceutical ingredients, GCP standards, and the Commission’s strategic approach to pharmaceuticals in the environment. Further discussion can be found here https://lnkd.in/eYr5dBK