Daria G. Husni

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On July 28, 2023, FDA approved RiVive, 3 mg naloxone hydrochloride nasal spray for over-the-counter (OTC), nonprescription use as emergency treatment of confirmed or suspected opioid overdose. This product is the second nonprescription naloxone FDA has approved, increasing consumer non-prescriptive access to naloxone. The manufacturer will determine the timeline for availability and the price of this product. 

A study from the manufacturer showed comparable levels of RiVive reach the bloodstream as an approved prescription naloxone product. The drug showed it was safe and effective for use as outlined in its labeling. The manufacturer submitted data exhibiting consumers can comprehend how to safely and effectively use RiVive without a healthcare professional’s supervision.

“We know naloxone is a powerful tool to help quickly reverse the effects of opioids during an overdose. Ensuring naloxone is widely available, especially as an approved OTC product, makes a critical tool available to help protect public health,” said FDA Commissioner Robert M. Califf, M.D in an FDA press release. “The agency has long prioritized access to naloxone products, and we welcome manufacturers of other naloxone products to discuss potential nonprescription development programs with the FDA.”

Drug overdose continues to be a major public health concern in the United States. Over 105,000 fatal overdoses were reported in the 12-month period ending in February 2023, most of which were driven by synthetic opioids such as illicit fentanyl. Naloxone, which quickly reverses the effects of opioid overdose, is the standard treatment for opioid overdose.

Individuals who are dependent on opioids may experience severe opioid withdrawal while using RiVise, whose symptoms include the following: body aches, increased heart rate (tachycardia), diarrhea, runny nose, fever, sneezing, goose bumps, yawning, sweating, nervousness, restlessness or irritability, nausea or vomiting, shivering or trembling, abdominal cramps, weakness, and increased blood pressure.

This approval is part of a series of steps FDA has taken to enable better access to products that treat opioid overdose, while reducing opioid exposure and curbing new cases of addiction. Other products approved by the agency include 

the first generic nonprescription naloxone nasal spray product in March 2023

the first generic nonprescription naloxone nasal spray product in July 2023

. Over the last year, the FDA endeavored to decrease the non-medical use, accidental exposure, and overdose of opioids, with new programs such as the 

. FDA wrote that it “remains focused on responding to all facets of substance use, misuse, substance use disorders, overdose and death in the U.S.”

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The nasal-spray drug can be used to reverse the effects of opioid overdose.

FDA Approves OTC Opioid Overdose Treatment

On July 26, 2023, FDA released a guidance document on a program at FDA’s Center for Drug Evaluation and Research (CDER) to publicize a listing of accepted voluntary consensus standards that related to pharmaceutical quality. FDA wrote that its involvement in the development and use of technical consensus standards has been crucial to its mission. FDA has used its standards to “develop and/or evaluate performance characteristics of dosage forms, testing methodologies, manufacturing practices, product standards, scientific protocols, ingredient specifications, labeling of drug products, and other technical or policy criteria.”

The guidance document highlights the scope and purpose of the program, before going through the specific elements of the program, including openness, balance, due process, appeals process, and consensus. The document then addresses CDER’s policies and procedures for evaluating voluntary consensus standards, which are recognition request submission and communication with requestors, recognition request evaluation, and updating the CDER program’s recognized standards database. The document ends with a Q&A section, addressing queries such as where recognized standards are posted and how the CDER program will affect other FDA centers.

The CDER program aids submissions by external stakeholders and FDA staff who are proposing voluntary consensus standards that relate to pharmaceutical quality for recognition. In the document, FDA wrote, “CDER believes that this program will help promote beneficial innovation in pharmaceutical development and manufacturing and streamline the preparation and assessment of marketing applications for products regulated by CDER.”

If an industry stakeholder references one of CDER’s accepted voluntary consensus standards with a product regulated by CDER, FDA may still request additional information to show that the standard was observed and is correct for the intended purpose. FDA wrote that the stakeholder’s use of a recognized standard is strictly voluntary.

The program aims to aid submissions from external stakeholders and FDA staff.

FDA Releases Guidance on Standards Related to Pharmaceutical Quality

FDA announced a final guidance for industry on July 25, 2023, 

titled M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk

 (M7(R2) Guidance). Two additional documents, 

M7(R2) Addendum: Application of the Principles of the ICH M7 Guidance to Calculation of Compound-Specific Acceptable Intakes

M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Questions and Answers,

The M7 (R2) guidance emphasizes the importance of safety and risk management in creating levels of mutagenic impurities that are anticipated to not pose significant carcinogenic risk. It outlines recommendations for assessment and control of mutagenic impurities that live in (or are anticipated to live in) final drug substance or product, with consideration for the planned conditions of human use.

The guidance highlights considerations for marketed products, including post-approval changes to the drug substance chemistry, manufacturing, and controls, and changes to the clinical use of marketed products. It also contains a drug substance and drug product impurity assessment, touching on synthetic impurities, degradation products, and considerations for clinical development. Then it goes over hazard assessment elements and risk characterization, with sections for threshold of toxicological concern (TTC)-based acceptable intakes and acceptable intakes based on compound-specific risk assessments, less-than-lifetime (LTL) exposure, and multiple mutagenic impurities. Finally, the document outlines control of process-related impurities and degradation products, lifecycle management, and considerations for control approaches, periodic testing, and clinical development.

FDA stated, “This document is intended to provide guidance for new drug substances and new drug products during their clinical development and subsequent applications for marketing.” The focus of the guidance is on DNA-reactive substances that could cause direct DNA damage when present at low levels, which could lead to mutations and potentially cause cancer. The agency clarified that assessment is not intended for these drug substances and drug products: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin. It is also not intended to be used with certain advanced cancer indications, excipients used in existing marketed products, perfumes, colorants, or flavoring agents. A more detailed description of applications for this guidance can be found under section II: Scope of Guidance.

The guidance document outlines recommendations to limit potential carcinogenic risk.

FDA Guidance on Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals

FDA released a press statement on July 21, 2023, to update the public on the damage to Pfizer’s facility at Rocky Mount, NC. “Importantly,” FDA wrote, “we do not expect there to be any immediate significant impacts on supply given the products are currently at hospitals and in the distribution system, but this is a dynamic situation and FDA staff are in frequent communication with Pfizer and other manufacturers.” FDA wrote it will work with its partners in government, industry, and the broader health care system to minimize impact on patient care.

As Pfizer has one third of the total sterile injectable drug market for US hospitals, and this facility produces 25% of Pfizer’s total product for this market, 8% of US consumption is supplied by this site. FDA’s analysis identified fewer than 10 drugs for which this plant is the sole source for the US market, but many of these are specific formulations that have substitutes available or where many weeks’ worth of stock should be housed in Pfizer’s other warehouses. For products produced at this facility that are in or may be at risk of shortage, FDA has started mitigating the impact on the market, through steps such as finding additional sources and asking other manufacturers to prepare to increase production.

To keep fair product distribution and maintain availability to those in most need, as well as to avoid hoarding, Pfizer has put strict allocation on the inventory of many of their products. This could impact localized suppliers depending on contractual relationships for supplies. FDA advised health care systems struggling to obtain specific drugs to contact their distributor or Pfizer directly.

“More broadly, this incident underscores that a robust, resilient, and safe drug supply chain is essential for public health and national security,” FDA wrote. The redundancy of manufacturing locations and suppliers is crucial to alleviate risks to supply that can occur from less predictable events such as natural disasters or geopolitical conflicts.

The damage to the facility, which produces 8% of US injectable drug consumption, should not significantly affect the current supply.

Update on Storm Damage to Pfizer Facility in North Carolina

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On July 20, 2023, the European Medicines Agency (EMA) announced their expansion of the OPEN initiative from COVID-19 vaccines and treatments to a wider range of medicines. These medicines can potentially address respiratory syncytial virus (RSV) infections, antimicrobial resistance (AMR), or newly diagnosed myelodysplastic syndromes (and other hereditary diseases). The new extended scope includes marketing authorization applications for medicines targeting AMR, medicines through EMA’s PRIority MEdicines scheme (not including advanced therapy medicinal products), medicines for RSV infections or newly diagnosed myelodysplastic syndromes and other hereditary diseases, and medicines responding to health threats or public health emergencies.

The first product under OPEN assessment is an messenger RNA (mRNA) vaccine against RSV, which is being assessed alongside Swissmedic. To be eligible for OPEN assessment, medicines require EMA’s human medicines committee (CHMP) and at least one OPEN partner to agree to conduct parallel assessments. Discussions will continue with OPEN partners to select other products for the OPEN framework, and the agency will continue engagement with stakeholders as more experience is gained.

OPEN was created by EMA in December of 2020 initially as a pilot, meant to provide a framework for international collaboration on the evaluation of COVID-19 vaccines and therapeutics. It is used by regulators from Australia, Brazil, Canada, Japan, Switzerland, and the World Health Organization (WHO) to conduct near-concurrent reviews of new medicines and exchange views and reports on product assessments. This collaboration both accelerates and aligns regulatory decisions, leading to more clarity in the industry and more unity on product labeling while keeping regulator’s decision-making independence. “The collaboration with WHO means that OPEN can accelerate regulatory decisions and availability of medicines in low- and middle-income countries,” the agency states in a press release.

The extension of the OPEN framework is based on the positive findings and recommendations, which can be found in a report on the OPEN pilot. EMA wrote that it “has bilateral agreements with all regulatory authorities involved in OPEN. Standard EMA requirements for EU experts participating in the assessment of medicines (e.g., confidentiality and absence of conflicts of interest) also apply to OPEN experts.” Medicines assessed under OPEN will be labeled in publicly available CHMP agendas and minutes, and on EMA’s website.

The framework is now expanded beyond COVID-19 vaccines and treatments.

EMA Extends OPEN Framework to More Medicines

The European Medicines Agency (EMA) published a draft reflecting paper on July 19, 2023 detailing the agency’s current outlook on the use of artificial intelligence (AI) “to support the safe and effective development, regulation and use of human and veterinary medicines.” The paper, now open for public discussion, outlines recommendations for the use of AI and machine learning (ML) during any step of a medicines’ lifestyle, from drug discovery to the post-authorization setting.

“AI and ML tools have the potential to effectively support the acquisition, transformation, analysis, and interpretation of data across the medicinal product lifecycle,” wrote EMA in a press release. “Their application can include, for example, AI/ML modelling approaches to replace, reduce, and refine the use of animal models during the preclinical development.”

During clinical trials, AI/ML systems may also assist with data recording and analyses that can be submitted to regulators in marketing-authorization procedures. During the marketing-authorization stage, AI has tools to draft, compile, translate, or review data that are used in the product information of a medicine. During the post-authorization stage, these tools could potentially support pharmacovigilance activities.

The reflection paper emphasizes that a human-centric approach should be at the forefront of all development and deployment of AI and ML. All use of AI should comply with existing legal requirements and take ethics and the respect of fundamental rights into consideration.

“The use of artificial intelligence is rapidly developing in society, and as regulators, we see more and more applications in the field of medicines. AI brings exciting opportunities to generate new insights and improve processes. To embrace them fully, we will need to be prepared for the regulatory challenges presented by this quickly evolving ecosystem” said Jesper Kjær, director of the Data Analytics Centre at the Danish Medicines Agency and co-chair of the joint HMA-EMA Big Data Steering Group (BDSG), in an EMA press release.

EMA recommends that developers seek early regulatory support for AI/ML systems expected to impact the benefit-risk balance of a medicine. “With this paper, we are opening a dialogue with developers, academics, and other regulators, to discuss ways forward, ensuring that the full potential of these innovations can be realized for the benefit of patients’ and animal health,” said Peter Arlett, EMA’s head of Data Analytics and Methods, co-chair of the BDSG, in an EMA press release.

The paper is part of BDSG initiatives to “to develop the European Medicines Regulatory Network’s capability in data-driven regulation.” It was creative collaboratively by the BDSG, EMA’s Committee for Medicinal Products for Human Use and its Committee for Veterinary Medicinal Products.

All stakeholders are invited to comment on the draft reflection paper. The public consultation will be open until Dec. 31, 2023. The HMA and EMA will hold a joint workshop on Nov. 20–21, 2023 to discuss the topic further.

The paper highlights the potential of AI in the medicinal product lifecycle and the approach that developers should take with it. 