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Review of Developments in GMP and the Regulation of Medicines December 2020

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Volume 25-4 C December-2020
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During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry. This month reported issues have come from the Australian, EU, PIC/s and USA regulatory authorities.

[Understandably there are few items this month from the USA as they will have been busy with their presidential election and the Thanksgiving holiday. Globally much focus has been on COVID 19 vaccines with early approvals looking likely for at least 3 candidates – Well done everyone involved in this. There will be many logistics challenges to ensure a smooth roll out and supply of the vaccines once they are approved but the Pharma industry, academia and the regulatory bodies involved have done a fantastic job so far in such a short timescale. MBH]

The topics covered in this edition of the “Update” include:

  • HMA/EMA statement on approval of vaccines

  • Continuation of COVID-19 vaccine trials for longer-term safety and efficacy follow-up

  • EMA organises public meeting on COVID-19 vaccines

  • Q&A on labelling flexibilities for COVID-19 vaccines

  • Workshop on regulatory support for development of orphan medicines

  • Frequently asked questions about parallel distribution

  • Brexit-related guidance for companies

  • Notification on arrangements for requesting EMA certificates through urgent and standard procedure for December 2020

  • Cross Labeling Oncology Drugs in Combination Regimens Guidance for Industry

  • Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act

  • Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA Guidance for Industry

  • COVID-19 vaccine provisional determinations

  • Manufacturing Quality Branch annual reports

  • Brazil / ANVISA joins PIC/S

  • Update on remdesivir - EMA will evaluate new data from Solidarity trial

  • Metformin- (Australian TGA) Low levels of contamination with N-nitrosodimethylamine (NDMA)




HMA/EMA statement on approval of vaccines

Development and deployment of safe and effective vaccines is seen as an essential element in the management and solution of the COVID-19 pandemic. There are no COVID-19 vaccines approved yet in the European Union, but due to the urgency posed by this health crisis, different mechanisms are in place to expedite the development of such vaccines in order to make them available as soon as possible while safeguarding the mandatory requirements of quality, safety and efficacy.

According to EU legislation (Regulation 726/2004) most COVID-19 vaccines fall under the scope of the centralised procedure since they are produced by biotechnological processes for which the centralised procedure is mandatory (as listed in Annex 1 to the Regulation). For other types of vaccines currently under development, such as those composed of whole-inactivated virus or live attenuated virus, the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) network encourage marketing authorisation holders to submit their applications through the centralised procedure in order to ensure that those vaccines reach all Member States at the same time, with no unfair access in the Union. This is possible according to Article 3.2 of the above-mentioned Regulation:

In accordance with predefined standards for quality, safety and effectiveness that adequately protect EU patients and all people who receive medicines or vaccines, EMA in close cooperation with NCA experts in scientific committees, uses accelerated procedures to speed up the process. The goal is to deliver assessments of high-quality applications in the shortest possible timeframes while ensuring robust scientific opinions. Therefore, COVID-19 vaccine applications should be assessed via the centralised procedure and, in addition to the centralised procedure itself, EMA’s scientific advice mechanism should be used whenever necessary, to advise developers on the quality, safety and efficacy requirements that must be met to enter the European market.

Continuation of COVID-19 vaccine trials for longer-term safety and efficacy follow-up

EMA has endorsed a statement by the International Coalition of Medicines Regulatory Authorities (ICMRA) that urges all stakeholders, including vaccines researchers and investigators, academia, regulators and the pharmaceutical industry, to continue COVID-19 vaccine trials beyond the time when the pre-defined cases of COVID-19 disease for final analysis in a trial have been reached. This can provide important additional and more precise information on longer-term safety and efficacy of a vaccine against COVID-19

EMA organises public meeting on COVID-19 vaccines

EMA will organise a public meeting on 11 December 2020 to inform European citizens about the EU regulatory processes for the approval of COVID-19 vaccines and the Agency’s role in their development, evaluation, approval and safety monitoring. The public meeting will inform citizens about EMA’s role in the pandemic and of EU regulatory procedures. It will also give the opportunity to the public and stakeholder groups to speak and share their needs, expectations and any concerns, that will be considered by EMA and the European medicines regulatory network in the decision-making process.

Those interested in making an intervention during the public meeting should do so no later than 27 November 2020. EMA will look at all requests and, in view of the available time, will select a group of people to speak at the meeting. EMA will publish the list of speakers who will make an intervention in advance of the event.

The public meeting will be broadcast live and will be open to all citizens.

Q&A on labelling flexibilities for COVID-19 vaccines

EMA together with the Member States, have developed this Q&A document with the aim to provide operational guidance on labelling flexibilities for COVID-19 vaccines. The topics addressed in the present document are primarily based on the European Commission’s Memorandum of Understanding (MoU) with Member States on regulatory flexibility for COVID-19 vaccines; in addition, a number of these topics are stemming from numerous questions received from COVID-19 vaccine developers in the course of the last few months. The flexibilities discussed in this document take into account the preparedness work of COVID-19 vaccine developers and the associated logistics of early printing packaging activities. The ultimate goal is to facilitate the large scale and rapid deployment of COVID-19 vaccines for EU citizens within the existing legal framework. It is important to note that any exemption described in this document, is of a temporary nature. Marketing Authorisation Holders (MAHs) will ultimately have to comply with the full labelling requirements. MAHs shall provide information on the length of time such exemptions will be needed, including an indicative end to any derogations granted from labelling requirements. The duration of the exemptions may be limited to certain time period, number of batches in the context of the pandemic, and will be determined on a case by case basis. All labelling exemptions will be reflected in the Committee for Human Medicinal Products (CHMP)assessment report and will be published on the EMA website.

Workshop on regulatory support for development of orphan medicines

On Monday, 30 November, EMA is hosting a workshop to discuss the benefits and impact of early regulatory interactions and incentives for the development of medicines for rare diseases.

The purpose of the workshop is to encourage early dialogue between developers and regulators in order to facilitate the development of innovative medicines in neglected disease areas. The workshop is targeted at small and medium-sized enterprises (SMEs), academia, patients, healthcare professionals and European Reference Networks (ERNs) who are often at the forefront of medicine development in rare and neglected diseases.

EMA offers incentives to encourage companies to research and develop medicines for rare diseases that otherwise would not be developed.

Early interaction with regulators also helps medicine developers understand regulatory requirements and generate the robust data needed to draw conclusions on the medicines’ benefits and risks.

The outcomes of the workshop and presentations will be published on the event page after the meeting.

Frequently asked questions about parallel distribution

EMA has recently updated this FAQ. The update includes new Q&As on:-

  • What are the procedures of parallel distribution?

  • Can the parallel distribution notice be transferred?

  • What is a safety update?

  • How to submit safety update.

  • What is the scope of a bulk change?

  • How to submit a bulk change.

Brexit-related guidance for companies

The EMA has updated its BREXIT guidance in relation to Ireland / Northern Ireland. The protocol on Ireland / Northern Ireland forms an integral part of the withdrawal agreement concluded by the EU and the UK. It will become fully applicable at the end of the transition period.

The protocol is subject to periodic consent of the Northern Ireland Legislative Assembly. It’s initial period of application extends to four years after the end of the transition period.

It provides that EU pharmaceutical law as laid out in the ‘acquis communautaire' applies to and in the UK in respect of Northern Ireland.

This means that medicinal products placed on the market in Northern Ireland have to comply with EU pharmaceutical law, meaning that the European Commission or the UK must issue Marketing Authorisations for such medicinal products in accordance with EU pharmaceutical law.

The Marketing Authorisation Holders and the QPPV for such a medicinal product may not be established in Northern Ireland, with the exception of authorisations issued by the UK in respect of Northern Ireland.

However, the manufacturer responsible for importation, finished product batch-control testing or batch release may be located in Northern Ireland.

Notification on arrangements for requesting EMA certificates through urgent and standard procedure for December 2020

Urgent Requests submitted to EMA by 15 December 2020 will be processed before the end of 2020. For requests submitted to EMA on or after 15 December 2020 it cannot be guaranteed they will be processed before the end of 2020. Where a request made using the urgent procedure will not be processed within 2 working days, the fees applicable to the standard procedure shall be payable.

Standard Requests submitted to EMA by 30 November 2020 will be processed before the end of 2020. Requests submitted to EMA on or after 30 November 2020 may not be processed before the end of 2020 and will be undertaken after 4 January 2021.

United States of America

The US Food and Drug Administration (USFDA)

Cross Labeling Oncology Drugs in Combination Regimens Guidance for Industry

Drug approvals in oncology often build on treatment effects by adding drugs to current regimens or by combining investigational drug products in a combination regimen, creating new regimens with greater efficacy. Traditionally, applicants have not requested changes to the labeling of a previously approved drug to describe how to use that drug in a new regimen (cross labeling). However, there has recently been an increasing number of applications that have proposed cross labeling for oncology drug combination regimens. The purpose of this guidance is to describe FDA’s current recommendations about including relevant information in labeling for oncology drugs approved for use in a combination regimen, including important considerations for cross labeling of these drugs. This guidance does not address all issues that might arise relating to labeling for oncology drugs for use in a combination regimen. Applicants proposing cross labeling for oncology drug combination regimens should contact the review division for information on cross labeling of their individual products.

Comments should be submitted by 19 Jan 2021

Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act

This draft guidance document provides answers to common questions from prospective applicants and other interested parties regarding the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). The question and answer (Q&A) format is intended to inform prospective applicants and facilitate the development of proposed biosimilar products and proposed interchangeable products, as well as describe FDA’s interpretation of certain statutory requirements added by the BPCI Act.

Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA

This guidance describes an enhanced pathway for discussions between FDA and a prospective applicant preparing to submit to FDA or an applicant that has submitted to FDA an abbreviated new drug application (ANDA) for a complex product, as defined in this guidance. Specifically, this guidance provides information on requesting and conducting product development meetings, pre-submission meetings, and mid-review-cycle meetings with FDA.


Australia (TGA)

COVID-19 vaccine provisional determinations

TGA has granted a number of provisional determinations in relation to COVID-19 vaccines.

The granting of a provisional determination means that the TGA has made a decision that relevant sponsors are now eligible to apply for provisional registration for the vaccine in the Australian Register of Therapeutic Goods (ARTG).

Provisional determination is the first step in the process and does not mean that an application has or will be made, or that the vaccine will be provisionally approved for inclusion in the ARTG. Provisional determinations are effective for 6 months.

Normally for a vaccine to be registered in Australia, a sponsor (usually a pharmaceutical company) is required to submit a complete and comprehensive package of data to the TGA. A formal evaluation is then carried out in multiple stages by technical experts, prior to a decision being made.

The provisional pathway provides a formal and transparent mechanism for speeding up the registration of promising new medicines with preliminary clinical data. In order to apply for provisional registration, the sponsor must first apply for a provisional determination.

Manufacturing Quality Branch annual reports

The annual reports for GMP regulation and Recalls provide an overview of key statistics, stakeholder engagement, regulatory activity and operational changes.

The GMP annual report highlights regulatory activities, stakeholder engagement, international regulatory engagement, compliance, and improvements to Australia’s regulatory requirements to meet TGA’s objectives under the TGA Business Plan for 2019-20.

TGA’s team is focused on making sure therapeutic goods supplied in Australia from domestic and international manufacturers meet specified standards and manufacturing principles. This is done through risk-based inspection and desk-top assessment programs.

During the 2019–20 financial year, the TGA:

  • Received 778 applications for the GMP licences and certificates

  • Conducted a total of 214 GMP inspections

  • Completed 7051 GMP clearance desktop inspections

The Recalls Annual Report provides an understanding of our regulatory activities, stakeholder engagement and improvements made to our regulatory requirements to meet our objectives achievements required to meet our objectives under the TGA's Business Plan for 2019-20, in regard to the removal of products from the market that pose an unacceptable risk to consumers.

During the 2019-20 financial year, the TGA:

  • Coordinated 790 recalls for medicines, medical devices, blood products and biological products.

A high number of recalls were due to labelling and packaging and impurity and degradation issues.

[For as long as I can remember (and that is a very long time) labelling and packaging issues have been a significant factor in recalls. – Isn’t it time that industry got its act in order in this respect?

Degradation issues have been a significant issue this year (e,g NMDA / nitrosamines) and work in this respect is still ongoing world-wide. MBH.]


Brazil / ANVISA joins PIC/S

The PIC/S Committee has invited Brazil’s Agência Nacional de Vigilância Sanitária (ANVISA) to join the PIC Scheme.Brazil / ANVISA will become PIC/S’ 54th Participating Authority as from 1 January 2021.


Update on remdesivir - EMA will evaluate new data from Solidarity trial

EMA is aware that the WHO has updated its guidelines advising against the use of remdesivir in hospitalised patients with COVID-19, regardless of disease severity based on a recent meta-analysis. Remdesivir was authorised in the EU in July 2020 as Veklury for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen. EMA has requested the full Solidarity data from WHO and the marketing authorisation holder. Once the data are available, EMA will assess the evidence, together with other relevant data, to see if any changes are needed to the marketing authorisation of Veklury (remdesivir) in the EU.

Metformin- (Australian TGA) Low levels of contamination with N-nitrosodimethylamine (NDMA)

Recently, TGA's laboratories completed testing a selection of immediate- and extended-release metformin medicines for the presence of NDMA. This found that approximately 30% of batches contained levels of NDMA that modestly exceed the acceptable limit (less than twice the limit). One batch was found to have higher levels (4.4 times the limit). Only limited stock of this batch has been supplied, and it has now been recalled from wholesalers.

Metformin is an important treatment for diabetes. The risks from not treating diabetes are far greater than the risks posed by the levels of NDMA seen to date.

The TGA has carefully considered the risk for patients from batches that modestly exceed the limit. This included an analysis of the commonly prescribed doses of metformin using data from the general practice program. Overall, the risk is considered to be very low for patients on both immediate- and extended-release products. The TGA investigation indicates that the majority of patients would not be exposed to levels of NDMA that exceed the acceptable intake limit.

The limits set by the TGA for NDMA are very conservative. They are calculated to ensure that an individuals' excess cancer risk would not exceed 1:100,000 if that individual was on the maximum daily dose of the medicine for 70 years. As most individuals do not take the maximum daily dose, and are not using metformin for this long, the risks are very low.

And finally…

Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website (members area) by utilising the hyperlink within that particular Update.

We hope that our readers find our reviews to be both informative and helpful in keeping up to date with pharmaceutical legislation and regulatory guidance.


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