Susan Haigney

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On Dec. 19, 2023, FDA announced a joint Q&A document with the European Medicines Agency (EMA) that addresses questions about FDA’s breakthrough therapy (BT) designation and EMA’s priority medicines (PRIME) scheme. Specifically, the 

discusses expediting quality development for these therapies that treat unmet medical needs. It describes FDA’s policy on quality assessments for expedited products in the Center for Drug Evaluation and Research’s 

The document was developed after a 2018 workshop held by FDA and EMA where quality challenges and scientific approaches were discussed by regulators and members of industry to be sure robust quality and manufacturing data packages are submitted in a timely manner. Real case studies were explored at the workshop that showcased challenges with chemical molecules, biologicals, and advanced therapy medicinal products (ATMPs). Process validation, control strategy, compliance with current good manufacturing practice (GMP) requirements, comparability, stability, and regulatory tools were chosen as topics for discussion.

“These conversations focused on enabling timely access to medicines for patients while keeping in mind the importance of drug safety, efficacy, and quality and maintaining current regulatory standards of approval. FDA and EMA have engaged in further discussions on these topics, sharing their experiences and regulatory expectations in the context of PRIME/BT applications, and this new document is the result of these discussions,” the agency stated in a press release.

The document is broken down into questions on the following four sections:

Annex 1. Q&A on Control strategy considerations for PRIME/BT applications

Annex 2. Q&A on Process validation approaches for PRIME/BT applications

Annex 3. Q&A on Alternatives for determination of re-test period or shelf-life for PRIME/BT applications

Annex 4. Q&A on GMP considerations for PRIME/BT applications.

“These documents are only intended to provide general information and do not constitute regulatory guidance. Applicants interested in pursuing the approaches described in these Q&A documents should discuss the strategy required for their specific product with the relevant regulatory authority ahead of their marketing submission,” the Q&A document states.

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The agencies published a joint guidance document regarding quality development for breakthrough therapies and PRIME programs.

EMA and FDA Answer Questions About Breakthrough Therapies

The European Medicines Agency (EMA) announced on Dec. 18, 2023 that it has, along with the Heads of Medicines Agencies (HMAs), published a strategy for coordinating the use of artificial intelligence (AI) in medicines regulation. The Multi-annual AI Workplan 2023–2028 was developed by the HMA-EMA Big Data Steering Group (BDSG) to coordinate a strategy to best use the benefits of AI and minimize any risks associated with its use and help the European medicines regulatory network (EMRN) to utilize AI for the automation of processes and evaluating data.

“The increasingly sophisticated nature and the pace of change of AI bring opportunities but also challenges. The application of AI requires a collaborative, coordinated strategy to maximize the benefits from AI while ensuring that uncertainty is adequately explored, and risks are mitigated,” the 

The workplan focuses on four key elements:

Guidance, policy, and product support. The plan will give support for products in development and for guidance in development regarding the use of AI in a drug’s lifecycle. Preparations for the implementation of the EU AI Act will begin in 2024.

AI tools and technology. Frameworks will be identified and provided for the use of AI tools for data analysis and decision-making.

Collaboration and training. Initiatives will be created to develop capacity and capability of the EMRN, partners, and stakeholders.

Experimentation. Actions will ensure a structured approach to accelerated learning of AI.

“As AI technology is fast evolving, including the ethical and policy aspects related to it, the BDSG will regularly update the workplan. Regulators, medicine developers, academics, patient organizations, and other interested parties will be informed and engaged throughout the implementation of the plan,” EMA stated in a press release.

The Multi-annual AI Workplan creates a strategy to maximize the benefits and manage the risks of artificial intelligence.

EMA Publishes Guide for Use of AI in Medicine Regulation

FDA published draft guidance on Dec. 13, 2023 that provides recommendations for the development of peptide drug products submitted in a new drug application. The document describes the impact of clinical pharmacology considerations on a peptide drug’s pharmacokinetics (PK), safety, and efficacy.

The guidance defines a peptide as any polymer composed of 40 or fewer amino acids that can be isolated from animal tissue, produced synthetically, or produced through recombinant expression. According to FDA, there has been an effort to improve absorption, distribution, metabolism, and excretion (ADME) properties of native peptides. These efforts include increasing oral bioavailability, half-life, and conformational flexibility, as well as decreasing general hydrophobicity. Alterations (e.g., cyclization, pseudo-peptide bonds, unnatural 45 amino acids, and peptide conjugations) to the peptide structure have been included to gain more favorable ADME characteristics. Therefore, peptide drugs may exhibit distinct combinations of characteristics regarding their chemistry, pharmacology, PK disposition, and pharmacodynamics (PD), FDA said in the draft guidance document.

Topics discussed in the article include bioanalytical approaches, radiolabeled mass balance studies, and impaired renal function. Considerations for assessing immunogenicity include performing immunogenicity risk assessments, clinical immunogenicity assessments, and immunogenicity clinical impact analysis.

The guidance also addresses characterization of the impact of hepatic impairment, assessing drug interactions, and characterizing QT interval prolongation. Labeling considerations are also covered.

The guidance document discusses the impact of clinical pharmacology considerations on peptide drug development.

FDA Issues Guidance on Clinical Pharmacology for Peptide Drugs

FDA announced on Dec. 14, 2023 that the US District Court for the District of Massachusetts has entered a consent decree of permanent injunction against Pharmasol Corporation and its president, Marc L. Badia, for distributing adulterated drugs. The injunction orders the company to stop distributing products until it complies with requirements under the Federal Food, Drug, and Cosmetic (FD&C) Act. The complaint states the company violated the FD&C Act by distributing drugs through interstate commerce, which do not comply with current good manufacturing practices.

A 2022 inspection of the company’s facilities found repeated violations from a previous 2019 warning letter that include failures to investigate errors, follow written procedures, and adequately clean and maintain equipment. The 2019 warning letter stated customers complained of product leakage, which was not investigated properly by the company.

“When drug manufacturers violate the law and disregard safety standards, they put consumers at significant risk. In this case, the defendant’s company distributed adulterated, poor-quality drugs without regard for patients and consumers,” said Jill Furman, director of the Office of Compliance in FDA’s Center for Drug Evaluation and Research, in an agency press release. “[FDA] plays an important role in protecting consumers, and we will continue to work with our law enforcement partners to pursue and bring into compliance those who do not prioritize the health and safety of the American public.”

Pharmasol, which is under contract with several pharmaceutical companies, manufactures and distributes human and animal prescription drugs and over-the-counter drugs. Products include topical corticosteroids and inhaled anesthetics. Under the consent decree, the company is prohibited from directly or indirectly “manufacturing, preparing, processing, packing, repacking, receiving, labeling, holding and/or distributing any drug, at or from their facilities, unless and until defendants meet certain requirements.”

The US District Court for the District of Massachusetts entered a consent decree of permanent injunction against Pharmasol Corporation for distributing adulterated drugs.

Consent Decree Entered Against Pharmasol

FDA announced on Dec. 12, 2023 that the agency is creating the 

Genetic Metabolic Diseases Advisory Committee

, which will provide independent advice and recommendations on technical, scientific, and policy issues regarding treatments for genetic metabolic diseases. The committee will advise FDA on products used to diagnose, prevent, or treat metabolic diseases under the purview of the Division of Rare Diseases and Medical Genetics.

Committee members will include experts in metabolic genetics, management of inborn errors of metabolism, small population trial design, translational science, pediatrics, epidemiology or statistics, and related specialties. There will be nine voting members, and there will be a consumer representative and an industry representative. Members will serve overlapping terms of up to four years.

“Advisory committees allow [FDA] to receive invaluable input from clinicians, industry experts, academia, patients, caregivers, and other external stakeholders when evaluating the potential benefits and risks of a new therapy. They are an essential part of [FDA’s] work,” said Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research (CDER). “These expert panels support the agency by helping ensure [FDA’s] decisions on the safety and efficacy of drug products are informed and in line with our priorities and goals.”

Genetic metabolic diseases impact a person’s metabolism and develop when a genetic flaw causes a protein or enzyme to be faulty or non-existent. Most of these diseases are rare and can be life limiting, according to FDA.

“Genetic metabolic diseases include very rare diseases that individually affect a limited number of patients. Drug development for these conditions has unique and complex challenges, therefore few treatments are available to patients,” said Janet Maynard, director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine. “This new advisory committee will provide a forum for discussion of complicated issues with specialized and diverse technical and scientific experts in the field of metabolic genetics.”

The new advisory committee will provide the agency with technical and scientific advice and recommendations on potential treatments for genetic metabolic diseases.

FDA Announces Advisory Committee for Genetic Metabolic Disease Treatments

On Dec. 12, 2023, the European Medicines Agency (EMA) announced that the first version of the Union list of critical medicines was published by EMA, the European Commission (EC), and the Heads of Medicines Agencies (HMA) with the intention of preventing potential drug shortages in the European Union/European Economic Area (EEA). The list contains more than 200 APIs considered critical in the EU and, therefore, supply should be made a priority.

EMA stressed in a press release that medicines on the list are not necessarily in shortage, but the potential may be there in the future, and such a shortage could be harmful to the public. The agency considers medicines used to treat serious diseases and that may be hard to replace by other drugs as critical. Medicines must meet certain criteria and be critical in more than one third of the EU/EEA.

A review of 600 APIs from six national lists was conducted to create the list, which includes substances from a variety of therapeutic areas, vaccines, and treatments for rare diseases. EU Member States used an agreed upon methodology for the review that was designed in consultation with key stakeholder groups, such as patient organizations and industry associations. The list will be expanded in the coming year and updated every year after.

The Union list does not impact existing national lists of critical medicines or lists in development, but it may be used to support efforts to create national lists. The list will also support the EC’s supply chain analysis to determine possible vulnerabilities.

“Medicines on the list can continue to be prescribed and used as usual by patients and healthcare professionals. Additional reporting requirements for marketing authorization holders and national competent authorities will be established and become effective once the proposed pharmaceutical legislation becomes applicable,” EMA stated in the press release.

Regulators in the European Union have published the first version a list of critical medicines in the EU to avoid potential shortages.