MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY (MHRA)
Update on MHRA Regulatory Flexibilities Resulting from Coronavirus (COVID-19) Guidance
The update on the Guidance was published on 4th August 2020. The MHRA has identified areas of flexibility which differ from the EU. These are indicated by an asterisk (*) in the Guidance (please follow a link below). It is stated in the update to be aware that some UK flexibilities, while aligned with those of the EU, are not limited to treatments for COVID-19 products, but cover the supply of other essential products that have been affected by the outbreak by factors such as travel and transportation restrictions or shortages of starting materials. These are indicated by two asterisks (**).
Update on Guidance Good Clinical Practice for Clinical Trials
On 31st July 2020 MHRA updated ‘Good Clinical Practice for Clinical Trials’ Guidance*. New versions of the ‘Guidance for the notification of serious breaches of GCP or the trial protocol’**, and the ‘notification of serious breaches of GCP or the trial protocol form’ were uploaded.
New Publications by the MHRA Inspectorate Blog
On 18th August 2020 Graeme McKilligan published the article ‘Cross Contamination Control in Shared Facilities and Equipment. Reflection on common deficiencies and expectations as seen in recent PIC/S guidance’ in Good Manufacturing Practice (GMP). The MHRA has been conducting predominantly remote inspections and has reflected on some of the common factors in critical deficiencies the Agency has been seeing in control strategies for cross contamination between products in shared facilities. In the publication the MHRA highlights some elements of the Industry’s control strategy that they should ensure they are addressing:
- Health Based Exposure Limits (HBELs) completed for all products by experienced professional Toxicologists;
- The HBEL value and hazard knowledge should be used to set the context and the reference for conducting Quality Risk Management development of Organisational and Technical controls;
- Sole reliance on visual inspection for cleanliness at changeover between products following cleaning validation should only be made when there is clear and safe evidence that residues can be consistently and readily seen at the acceptance criteria level.
Links to the full publication, to the PIC/S Q&A document and to the PIC/S’s Aide-Memoire ‘Inspection of health based exposure limit (HBEL) assessments and use in quality risk management’ document published in June 2020 are available below.
On 3rd August 2020 the MHRA issued a post to outline that annual metrix report for GCP referrals was published for 2019 and to remind of the updated Guidance on serious breaches reporting.
In 2019, MHRA received a total of 112 serious breach notifications, of which 75 were deemed to be a serious breach, 36 deemed not to be a serious breach and one awaiting further information to enable final determination. Patient safety was the main reason for reporting of serious breaches in 2019 (56/112), with the sponsor being the primary reporter of breaches (83/112); 57% of breaches were on commercial trials; 43% on non-commercial. One serious breach of the 112 prompted a triggered inspection, with the majority (66%) requiring in-house follow-up with the organisation.
ADMINISTRATION OF RADIOACTIVE SUBSTANCES ADVISORY COMMITTEE (ARSAC)
Changes to Research Application Process by the ARSAC
It was announced on 14th August 2020 that a new online portal to apply for the ARSAC approval of research studies will launch in September 2020. The new system will enable applicants to monitor the progress of their applications and will allow applicants to share access to their submissions.
Public Health England will manage the new research applications through the ARSAC online portal.
EUROPEAN MEDICINES AGENCY (EMA)
COVID-19 Updates by the EMA*
Update on 20th August 2020:
– The EMA decided to continue holding its committee and working-party meetings and its stakeholder events virtually until the end of 2020. Read more
Updates on 31st July 2020:
– The EMA had finalised 17 scientific advice procedures for potential medicines to treat COVID-19, with a further 15 ongoing. It had also been in contact with the developers of 154 potential COVID-19 treatments and 38 potential COVID-19 vaccines. Read more
– Progress is being made on developing a pharmacovigilance network for vaccines, carrying out research in pregnant women and the establishment of international patient cohorts. Read more
– Regulatory authorities are receiving numerous proposals for phase 3 clinical trials from developers of COVID-19 treatments. Regulators have agreed on acceptable clinical-trial endpoints to facilitate rapid and consistent clinical trials for COVID-19 treatments. Read more
Update to Joint Audit Programme for EEA GMP inspectorates
Updated ‘Joint Audit Programme for EEA GMP inspectorates*’ and ‘Joint Audit Programme for EEA GMP inspectorates**’ documents were issued on 31st July 2020.
FOOD AND DRUG ADMINISTRATION (FDA)
Publishes revised MAPP, Consolidation of ANDAs by the Office of Generic Drugs (MAPP 5241.2)
On 19th August 2020, the FDA published a revision to the Manual of Policies and Procedures (MAPP 5241.2), “Consolidation of ANDAs by the Office of Generic Drugs.” This MAPP describes the process for reviewing and approving or denying requests to consolidate previously approved abbreviated new drug applications (ANDAs) submitted by an ANDA applicant.
Issued Guidance for Industry on ‘Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers’
The Guidance was issued on 19th August 2020 and is aimed to address the Coronavirus Disease 2019 (COVID-19) public health emergency. The purpose of the Guidance is to provide answers to frequently asked questions about regulatory and policy issues related to inspections, pending drug applications, and changes in manufacturing facilities for approved pharmaceutical products.
Updates to the Purple Book: Database of FDA-Licensed Biological Products
The update to the ‘Purple Book’ was issued by the FDA on 3rd August 2020. The FDA has transitioned the ‘Purple Book’ to a searchable, online database that contains information about biological products, including biosimilar and interchangeable biological products, licensed (approved) by the FDA under the Public Health Service (PHS) Act.
Currently, the searchable database contains information about all FDA-licensed biological products regulated by the Center for Drug Evaluation and Research (CDER), including licensed biosimilar and interchangeable products, and their reference products, and FDA-licensed allergenic, cellular and gene therapy, hematologic, and vaccine products regulated by the Center for Biologics Evaluation and Research (CBER).
FDA finalises Guidance, ‘Limited Population Pathway for Antibacterial and Antifungal Drugs’
On 5th August 2020, the FDA announced the finalisation of a Guidance ‘Limited Population Pathway for Antibacterial and Antifungal Drugs.” This guidance provides information on the implementation of section 506(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), added by section 3042 of the 21st Century Cures Act, which established the limited population pathway for antibacterial and antifungal drugs (LPAD pathway).
Section 506(h)(5) of the FD&C Act requires FDA to issue guidance “describing criteria, processes, and other general considerations for demonstrating the safety and effectiveness of limited population antibacterial and antifungal drugs.” This guidance provides this information and is intended to assist sponsors in the development of certain new antibacterial and antifungal drugs for approval under the LPAD pathway.
The FDA published the Guidance for Industry on ‘Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act; Content and Format’.
The ‘Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act; Content and Forma’ Guidance was issued on 10th August 2020 and it is intended to assist holders of new drug applications (NDAs) and ANDAs approved under section 505(c) and 505(j) of the FD&C Act (21 U.S.C. 355(c) and (j)), respectively, with submission of marketing status notifications required under section 506I of the FD&C Act (21 U.S.C. 356i). This guidance identifies the required content for these marketing status notifications and the format by which these notifications should be submitted to the Agency.
FDA issues Final Guidance on “Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank”
On 12th August 2020, the FDA issued a final Guidance on ‘Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank’. This guidance document is intended to describe the current thinking of the FDA’s CDER, CBER, and Center for Devices and Radiological Health (CDRH) regarding civil money penalties under section 303(f)(3) of the FD&C Act. That section authorises the FDA to assess civil money penalties against responsible parties and/or submitters of certain applications and submissions to FDA regarding drug products, biological products, and device products who violate applicable FD&C Act prohibitions relating to requirements under section 402(j) of the PHS Act, including its implementing regulations in 42 CFR part 11, to submit clinical trial registration and/or results information to the ClinicalTrials.gov data bank and/or certain certifications to FDA.
The guidance document addresses the following questions:
− How do the Centers intend to identify whether responsible parties have failed to submit required clinical trial registration and/or results information to the ClinicalTrials.gov data bank or submitted false or misleading information to the data bank, or whether submitters have failed to submit to FDA the certification required by section 402(j)(5)(B) of the PHS Act or knowingly submitted a false certification to FDA?
− Under what circumstances may a Center decide to seek civil money penalties against a responsible party or submitter?
− What procedures apply when a Center seeks civil money penalties?
− What civil money penalty amounts may be assessed for (1) failing to submit required clinical trial registration and/or results information to the ClinicalTrials.gov data bank, (2) submitting false or misleading information to the data bank, (3) failing to submit the required certification to FDA, or (4) knowingly submitting a false certification to FDA?
FDA publishes guidance for industry: Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 320.38(c)
On 18th August 2020, the FDA published the guidance for industry entitled ‘Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 320.38(c)’. This guidance describes FDA’s compliance policy related to the retention of reserve samples of the test article and reference standard used in an in vivo bioavailability and in vivo or in vitro bioequivalence study. Specifically, this guidance:
Addresses the requirement at 21 CFR 320.38(c) to retain reserve samples of sufficient quantity to permit FDA to perform five times all the release tests required in an application or supplemental application
Describes the conditions under which the Agency does not generally intend to take enforcement action against an applicant or contract research organization for retaining less than the quantity of reserve samples of the test article and reference standard that were used in the BA or BE study as specified in 21 CFR 320.38(c).
FDA Issues Draft Guidance for Industry, ‘Drug-Drug Interaction Assessment for Therapeutic Proteins’
A draft guidance for industry entitled, ‘Drug-Drug Interaction Assessment for Therapeutic Proteins Draft Guidance for Industry’ was issued for the public comments on 12th August 2020. The purpose of this guidance is to help sponsors of investigational new drug applications (INDs) and applicants of biologic license applications (BLAs) determine the need for drug-drug interaction (DDI) studies for a therapeutic protein by providing a systematic, risk-based approach. Although this guidance applies to therapeutic proteins, the general concepts could be applicable to other biological products, including biological products regulated by CBER such as cellular and gene therapies.
The comments are expected by 9th November 2020.
Other recent issued final Guidance by the FDA:
‘Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 320.38(c): Guidance for Industry’ was issued on 18th August 2020.
‘Male Breast Cancer: Developing Drugs for Treatment: Guidance for Industry’ was issued by the FDA on 12th August 2020.
On 5th August 2020, the FDA issued a Guidance on ‘Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act’.
For the full list on the issued documents by the FDA please follow this link.
THE INTERNATIONAL COUNCIL FOR HARMONISATION (ICH)
The E6(R3) Expert Working Group (EWG) is working on the revision of the E6(R2) Guideline “Good Clinical Practice” (GCP) with a view to addressing the application of GCP principles to the increasingly diverse trial types and data sources being employed to support regulatory and healthcare related decision-making on drugs, and provide flexibility whenever appropriate to facilitate the use of technological innovations in clinical trials.
ORGANIZATION FOR ECONOMIC COOPERATION AND DEVELOPMENT (OECD)
Published Draft Guidance Document on Good Laboratory Practice (GLP)
OECD Draft Advisory Document of the Working Group on Good Laboratory Practice on GLP Data Integrity has been made available at the beginning of August 2020 for public comment. Deadline for comments is 18th September 2020.
INTERNATIONAL ORGANIZATION FOR STANDARDIZATION (ISO)
International Standard for Medical Device Testing Updated
New version (Edition 3) of ISO 14155 ‘Clinical investigation of medical devices for human subjects — Good clinical practice’ was issued in July 2020.
ISO 14155 has been revised to align with recent regulatory changes and amendments to other relevant standards. Additional details and information designed to help protect participants in clinical trials and medical device users and to achieve sound results were also added.
Danielle Giroud, Convenor of the ISO working group of experts who developed the standard, said “We have included significantly more guidance in areas such as risk-based monitoring, quality management, study design, auditing and ethics committees,”
“This means greater detail about aspects such as informed consent, vulnerable populations, data protection and statistical considerations, all of which result in a safer clinical investigation with more solid evidence.
ISO 14155 has also been aligned with changes to other standards in the sector as well as regulations such as the European Medical Devices Regulation, the European Commission Guidelines on Good Clinical Practice and other similar guidance from the US Food and Drug Administration.”
EUROPEAN COMMISSION (EC)
Published Draft – Questions and Answers Document – Regulation (EU) 536/2014 – Version 2.4
Draft Questions and Answers document Version 2.4 for Clinical Trials Regulation (EU) no 536/2014 was published in July 2020:
The EC Published a Summary of Stakeholders Workshop of 14/15 July 2020
On 04th August 2020, the EC published a summary of Pharmaceutical Strategy for Europe Workshop held on 14-15 July 2020. To see the full document please follow a link below *.
Evaluation of the Medicines for Rare Diseases and Children Legislation
On 11th August 2020, the EC published its evaluation on the legislation for medicines for rare diseases and for children.
This is the first comprehensive evaluation of the two regulations since their adoption in 2000 and 2006 respectively. They are evaluated together, given that the majority of rare diseases may appear already in children and many children’s diseases are also rare.
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