Regulatory News

The latest regulatory news, consultation documents, and adopted guidelines and legislation, mainly from the European Commission, the European Medicines Agency and the Food and Drug Administration.

ICH S5 (R3) guideline on reproductive toxicology
The European Medicines Agency have published: Scientific guideline: ICH S5 (R3) guideline on reproductive toxicology: Detection of toxicity to reproduction for human pharmaceuticals, Step 5, adopted.

This is a revision of the ICH guideline “S5 Detection of Toxicity to Reproduction for Medicinal Products” that was originally published in 1993. This revision brings the guideline into alignment with other ICH guidelines, elaborates on the use of exposure margins in dose level selection, incorporates a section on risk assessment, and expands the scope to include vaccines and biopharmaceuticals. It also describes qualification of alternative assays, potential scenarios of use, and provides options for deferral of developmental toxicity studies. More information is available on the EMA’s website.

Date for coming into effect: 30th July, 2020

ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials
The European Medicines Agency have published: Scientific guideline: ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials, Step 5, adopted.

To properly inform decision making by pharmaceutical companies, regulators, patients, physicians and other stakeholders, clear descriptions of the benefits and risks of a treatment (medicine) for a given medical condition should be made available. Without such clarity, there is a concern that the reported “treatment effect” will be misunderstood. This addendum presents a structured framework to strengthen the dialogue between disciplines involved in the formulation of clinical trial objectives, design, conduct, analysis and interpretation, as well as between sponsor and regulator regarding the treatment effect(s) of interest that a clinical trial should address. More information is available on the EMA’s website.

Date for coming into effect: 30th July, 2020

Revision of Annex 1, on manufacturing of sterile medicinal products
The European Commission has engaged a second targeted stakeholders’ consultation on the revision of Annex 1, on manufacturing of sterile medicinal products, of Eudralex volume 4.

Due to widespread interest from industry following the first targeted consultation, and because of substantial modifications introduced in several sections, it was agreed to engage with stakeholders a second targeted consultation on the updated draft guidance (version 12) focused on the sections and/or significantly modified paragraphs that raised most concerns by stakeholders. The second targeted consultation aims at collecting experience from the sectors on certain manufacturing steps. The European Commission therefore expect to receive contribution from the European associations representing the sectors. More information is available on the Commission’s website.

Consultation Deadline: 20th May, 2020

Evaluation of the immunotoxic potential of drugs and biologics
The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance entitled “Nonclinical Safety Evaluation of the Immunotoxic Potential of Drugs and Biologics.”

This guidance expands upon, consolidates, and supplements the recommendations on nonclinical immune system assessments provided across multiple guidance documents, most notably the International Conference on Harmonization (ICH) guidance for industry “S8 Immunotoxicity Studies for Human Pharmaceuticals.” The topics covered include various aspects of immune suppression, modulation, and stimulation. This guidance replaces the withdrawn guidance entitled “Immunotoxicology Evaluation of Investigational New Drugs.” More information is available on the Federal Register’s website.

Consultation Deadline: 20th April, 2020

Biosimilars and interchangeable biosimilars
The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed.”

When finalized, this draft guidance will provide recommendations to applicants seeking licensure under the Public Health Service Act (the PHS Act) of a proposed biosimilar or proposed interchangeable biosimilar for fewer than all of the reference product’s licensed conditions of use. Additionally, when finalized, this draft guidance will also provide recommendations on the submission of a supplement to a licensed biologics license application (BLA) seeking to add a condition of use that previously has been licensed for the reference product to the labeling of a licensed biosimilar or interchangeable product, including considerations related to the timing of such submissions. More information is available on the Federal Register’s website.

Consultation Deadline: 7th April, 2020

Developing drugs for treatment of mucopolysaccharidosis type III
The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “Mucopolysaccharidosis Type III (Sanfilippo Syndrome): Developing Drugs for Treatment.”

The purpose of this draft guidance is to foster greater efficiency in drug development in this rare disease with the goal of enhancing clinical trial data quality and supporting the development of treatments for mucopolysaccharidosis type III. Specifically, the draft guidance provides the Agency’s current recommendations regarding eligibility criteria, trial design considerations, and efficacy endpoints for use in clinical development programs of investigational drugs to treat mucopolysaccharidosis type III. More information is available on the Federal Register’s website.

Consultation Deadline: 5th May, 2020

Promotional labeling and advertising considerations for biological reference and biosimilar products
The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “Promotional Labeling and Advertising Considerations for Prescription Biological Reference and Biosimilar Products—Questions and Answers.”

FDA is issuing this guidance to provide manufacturers, packers, distributors, and their representatives (firms) with information to consider when developing FDA-regulated promotional labeling and advertisements (promotional materials) for prescription reference and biosimilar products licensed under the Public Health Service Act (PHS Act). Although the guidance covers promotional issues involving both reference and biosimilar products, some questions and answers are focused on only biosimilar product promotional materials. The guidance does not discuss considerations unique to promotional materials for interchangeable biosimilars. More information is available on the Federal Register’s website.

Consultation Deadline: 6th April, 2020

Good manufacturing practice and marketing authorisation holders
The European Medicines Agency have published: Scientific guideline: Reflection paper on good manufacturing practice and marketing authorisation holders, draft: consultation open.

This Reflection Paper is focussed on the GMP-related responsibilities that apply to Marketing Authorisation Holder (MAH) companies. While it is recognised that many MAH companies are not directly engaged in the manufacture of medicinal products themselves, the current European Commission (EC) guide to GMP (hereafter referred to as the ‘GMP guide’) refers, in several places, to MAHs and their responsibilities in relation to GMP. These responsibilities are spread over the various chapters and annexes of the GMP guide, and are quite numerous. This Reflection Paper seeks to provide clarity as to what the various responsibilities are and what they mean for MAHs at a practical level. In addition to the MAH responsibilities in the GMP guide, this paper also addresses the various legislative provisions (i.e. in European Directives and in other guidelines) which relate to GMP and which concern MAHs. Some of the responsibilities stated in the legislation (e.g. in Directives 2001/83/EC and 2001/82/EC) and in applicable guidelines are written in a way that they apply to marketing authorisation applicants, and they are included in this Reflection Paper because those provisions also convey responsibilities upon marketing authorisation holders in the post93 authorisation phase. More information is available on the EMA’s website.

Consultation Deadline: 17th April, 2020

Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management
The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has published on a draft basis a Recommendation on How to Evaluate / Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management (PI 054-1 (Draft 1)) developed by the PIC/S Expert Circle on Quality Risk Management (QRM).

This draft Recommendation will be applied on a 6-month trial basis by PIC/S Participating Authorities. The purpose of this draft document is to provide guidance on evaluating and demonstrating the effectiveness of a PQS in relation to risk-based change management. This is in recognition of the fact that the PIC/S GMP Guide requires companies to demonstrate the effectiveness of their PQS and to apply quality risk management (QRM) principles to change control activities. Further information on the background to this Recommendation and the anticipated benefits of this guidance are provided in PIC/S Concept Note (PS/INF 88/2019). This draft document is not open for comments by industry. Formal adoption of the guidance will proceed in accordance with PIC/S procedures on a revised version after completion of the trial-period. More information is available on the PIC/S’s website.

Establishing effectiveness of drugs for treatment of IC/BPS
The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS): Establishing Effectiveness of Drugs for Treatment.”

There is pharmaceutical and stakeholder interest in the development of new drugs for patients with IC/BPS. This draft guidance provides FDA’s recommendations for clinical trials intended to establish clinical effectiveness and safety for drugs intended to treat IC/BPS. More information is available on the Federal Register’s website.

Consultation Deadline: 2nd March, 2020

Adaptive designs for clinical trials of drugs and biologics
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “Adaptive Designs for Clinical Trials of Drugs and Biologics.”

This guidance provides guidance to sponsors and applicants submitting investigational new drug applications (INDs), new drug applications (NDAs), biologics license applications (BLAs), or supplemental applications on the appropriate use of adaptive designs for clinical trials to provide evidence of the effectiveness and safety of a drug or biological product. The guidance describes important principles for designing, conducting, and reporting the results from an adaptive clinical trial. This guidance finalizes the draft guidance entitled “Adaptive Designs for Clinical Trials of Drugs and Biologics” issued in October 2018. More information is available on the Federal Register’s website.

Falsified medicines GDP inspection aide memoire
The European Commission has published an aide memoire for GDP inspection of wholesalers’ compliance with Commission Delegated Regulation (EU) 2016/161 for safety features. More information is available on the Commission’s website.

Developing drugs for treatment or prevention of smallpox infection
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “Smallpox (Variola Virus) Infection: Developing Drugs for Treatment or Prevention.”

The purpose of this guidance is to assist sponsors in the clinical development of drugs for treatment or prevention of smallpox (variola virus) infection. Clinical efficacy trials of drugs for treating or preventing smallpox are not feasible and challenge studies in healthy subjects are unethical; therefore, drugs for these indications should be developed and approved under the regulations commonly referred to as the Animal Rule (21 CFR part 314, subpart I, for drugs and 21 CFR part 601, subpart H, for biologics). This guidance serves as a focus for continued discussions among the Division of Antiviral Products (DAVP), pharmaceutical sponsors, the academic community, and the public. More information is available on the Federal Register’s website.

Clinical investigation of medicinal products for the treatment of gout
The European Medicines Agency have published: Scientific guideline: Guideline on clinical investigation of medicinal products for the treatment of gout, adopted.

The main aim of the guideline is to address general guidance on the development of medicinal products for the treatment of gout. This guideline should be read in conjunction with other EMA and ICH guidelines, which may apply to these conditions and patient populations. In this document, guidance is provided on the clinical development of new ULT and anti-inflammatory treatment options. The study design, inclusion criteria, primary endpoints and trial duration largely depend on the treatment goal and mode of action of the new drug. More information is available on the EMA’s website.

Date for coming into effect: 1st June, 2020

Electronic submission of IND safety reports
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “Electronic Submission of IND Safety Reports Technical Conformance Guide.”

This Technical Conformance Guide (Guide) provides specifications, recommendations, and general considerations on how to submit electronic investigational new drug application (IND) safety reports to the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). The Guide supplements the draft guidance for industry Providing Regulatory Submissions in Electronic Format: IND Safety Reports (October 2019), which implements the electronic submission requirements of section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) with respect to electronic submissions for certain IND safety reports submitted to CDER or CBER. More information is available on the FDA’s website.

Identification of manufacturing establishments in applications submitted to CBER and CDER
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final question and answer document entitled “Identification of Manufacturing Establishments in Applications Submitted to CBER and CDER: Questions and Answers.”

This guidance is intended to clarify Agency expectations regarding facility information that should be included in original new drug application(s) (NDA); abbreviated new drug application(s) (ANDA); original biologics license application(s) (BLA); amendments; supplements; chemistry, manufacturing, and controls (CMC) supplements; and resubmissions to these submission types. Submission of Form FDA 356h fulfills the requirement for applicants to submit an application form (21 CFR 314.50(a) and 314.94(a)(1); 601.2(a)). Form FDA 356h serves as both a summary of administrative information, as well as a repository of complete information on the locations of all manufacturing, packaging, and control sites for both drug substance and drug product facilities associated with the application. This guidance addresses questions related to the inclusion and withdrawal of proposed commercial facilities and development facilities, the appropriate location within an application for facility information, and the type of facility information that should be included in applications. Applications that include appropriate and complete facility information in the establishment information section of Form FDA 356h will reduce the frequency of Information Request (IR), Refusal to File (RTF), and Refuse to Receive (RTR) actions and increase the efficiency of the application assessment process. This guidance describes the recommended placement of all facility information for both original and supplement applications. More information is available on the FDA’s website.

Good Clinical Practice specific to Advanced Therapy Medicinal Products
The European Commission has published: Guidelines on Good Clinical Practice specific to Advanced Therapy Medicinal Products.

Compliance with good clinical practice (“GCP”) is mandatory for clinical trials that are conducted in the EU. Article 4 of Regulation (EC) No 1394/20072 mandates the Commission to draw up guidelines on good clinical practice specific to advanced therapy medicinal products (“ATMPs”). These Guidelines develop the GCP requirements that are specific to clinical trials conducted with ATMPs. These Guidelines are to be read in conjunction with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines on good clinical practice,3 which are also applicable to ATMPs. To the extent that there is a difference in the requirements, the content of these Guidelines prevails. These Guidelines do not apply to clinical trials with medicinal products other than ATMPs. More information is available on the Commission’s website.

Promoting the authorisation of alternatives to antimicrobials in the EU
The European Medicines Agency have published: Scientific guideline: CVMP reflection paper on promoting the authorisation of alternatives to antimicrobials in the EU, draft: consultation open.

This reflection paper performs a gap analysis by reviewing the measures currently in place to support the authorisation of alternatives to antimicrobials (ATAm) in veterinary medicine, with particular emphasis given to alternatives to antibiotics, and identifying where and how these could be improved. More information is available on the EMA’s website.

Consultation Deadline: 30th April, 2020

Prescription drug user fee act waivers, reductions, and refunds for drug and biological products
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “Prescription Drug User Fee Act Waivers, Reductions, and Refunds for Drug and Biological Products.”

This guidance provides recommendations to applicants planning to request a waiver or reduction in user fees. This guidance finalizes the draft guidance for industry of the same title issued in June 2018. More information is available on the Federal Register’s website.

Nonclinical assessment of investigational enzyme replacement therapy products
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “Investigational Enzyme Replacement Therapy Products: Nonclinical Assessment.”

The purpose of this guidance is to help sponsors design and conduct nonclinical studies during development of investigational enzyme replacement therapy (ERT) products. Specifically, this guidance describes the Food and Drug Administration’s (FDA’s) current thinking about the substance and scope of nonclinical information needed to support initiation of clinical trials, ongoing clinical development, and marketing approval for investigational ERT products. More information is available on the Federal Register’s website.

European Commission Safety Features Q&A document updated
The European Commission has published an updated version, Version 16, of the Questions and Answers document on the Safety Features for Medicinal Products for Human Use.

Version 16 of the document, dated September 2019, supersedes Version 15. Q&As 2.23 and 7.20 were added, while Q&As 2.3, 2.12, 4.5 and 7.17 were revised.

More information is available on the Commission’s website.