Susan Haigney

The Impact of USP Chapter <86> on Endotoxin Testing

The US Pharmacopeia (USP) published Chapter <86> Bacterial Endotoxins Test Using Recombinant Reagents into the

 United States Pharmacopeia–National Formulary (USP–NF) 

The chapter permits the use of non-animal-derived reagents for endotoxin testing and is part of USP’s commitment to expanding the use of animal-free methods and materials (1).

Endotoxins, which are present in the environment, can have dangerous effects if they are contained in pharmaceutical products. Gram-negative bacterial endotoxins are difficult to destroy, according to Nicola Reid, Associate Director Product Management, Endotoxin Products at Charles River Laboratories. “When [endotoxins] do end up in a final product, [and] when that [product] is injected or implanted into a patient, it can lead to what we call a pyrogenic response. What that means is the human body is reacting to this contaminant, and it can cause anything from a mild fever all the way through to death. That's the ultimate circumstance of too much endotoxin. So, therefore, most pharmaceutical products that are tested for endotoxin are those that are injectable or implantable and come into contact with the bloodstream, and therefore have to have low levels of endotoxin.”

 in which Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice president, Technical at Parexel, discuss the new chapter, Chapter <86> Bacterial Endotoxins Test Using Recombinant Reagents. 

https://www.pharmtech.com/view/non-animal-derived-reagents-for-endotoxin-testing

Currently, most manufacturers use the limulus amebocyte lysate (LAL) test to perform endotoxin testing. The LAL test is an animal-derived test, and though the animal itself is not tested upon, there is still concern about the use of animals in testing. Therefore, USP has introduced this new chapter to the 

® spoke with Reid to get her perspective on endotoxin testing and how the new USP chapter might impact the pharmaceutical industry.

Click on the video above the watch the interview.

1. USP. Expert Committee Approves Endotoxin Testing Using Non-animal Derived Reagents. Press Release. July 26, 2024.

Videos

Pharmaceutical Technology® spoke with Nicola Reid, Associate Director Product Management, Endotoxin Products at Charles River Laboratories, to get her perspective on endotoxin testing and USP’s new Chapter <86> Bacterial Endotoxins Test Using Recombinant Reagents.

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AbbVie announced on Dec. 11, 2024 that its acquisition of Aliada Therapeutics,a biotechnology company working to solve challenges in central nervous system (CNS) drug development, has been completed. Announced in October 2024, the acquisition strengthens AbbVie’s neuroscience pipeline and includes Aliada’s anti-pyroglutamate amyloid beta (3pE-Aβ) antibody, ALIA-1758, for the treatment of Alzheimer’s disease.

"Alzheimer's disease poses a significant public health challenge, impacting millions worldwide and is becoming more prevalent as populations age," said Dawn Carlson, MD, vice-president, neuroscience development at AbbVie, in a press release (1). "With the acquisition now complete, we look forward to advancing potentially disease-modifying therapies such as ALIA-1758 for Alzheimer's disease and bolstering our neuroscience discovery and development efforts by leveraging Aliada's novel CNS drug delivery platform."

ALIA-1758, which is currently in a Phase I clinical trial, uses a novel blood-brain barrier (BBB)-crossing technology, Modular Delivery (MODEL) platform, that enhances delivery of targeted drugs into the CNS. MODEL targets transferrin (TfR) and CD98 receptors to deliver different types of biological cargoes into the brain. ALIA-1758 uses TfR to transport a 3pE-Aβ antibody across the BBB. This enables the degradation and elimination of amyloid beta plaques, according to the company.

"Neuroscience is one of our key growth areas and we are committed to driving innovation in this field to address critical unmet needs for patients living with seriously debilitating neurological diseases such as Alzheimer's disease," said Roopal Thakkar, MD, executive vice-president, research and development, and chief scientific officer, AbbVie, in the October 2024 press release (2). "This acquisition immediately positions us to advance ALIA-1758, a potentially best-in-class disease-modifying therapy for Alzheimer's disease. In addition, Aliada's novel BBB-crossing technology strengthens our R&D capabilities to accelerate the development of next-generation therapies for neurological disorders and other diseases where enhanced delivery of therapeutics into the CNS is beneficial."

"We are pleased to announce the acquisition of Aliada by AbbVie and are excited about AbbVie's commitment to bringing ALIA-1758 to patients with Alzheimer's disease. Our proprietary MODEL platform has enabled the development of ALIA-1758, a promising step forward in brain delivery of an anti-amyloid antibody therapy," said Michael Ryan, MD, chief medical officer at Aliada Therapeutics, in the October release. "Many promising CNS-targeted therapies fail to reach late-stage trials due to their inability to cross the blood-brain barrier. Our MODEL platform addresses this challenge directly, efficiently delivering targeted drugs and potentially transforming how we treat neurological diseases."

According to the October press release, the agreement hasAbbVie gaining all outstanding Aliada equity for $1.4 billion in cash.

This isn’t the only acquisition this year for AbbVie. The company also added to its neurological pipeline in August 2024 with 

the acquisition of Cerevel Therapeutics, a clinical-stage biopharmaceutical company specializing in neuroscience diseases 

(3). The company also expanded its anti-inflammatory disease pipeline with the 

acquisition of Celsius Therapeutics in June of 2024 

AbbVie. AbbVie Completes Acquisition of Aliada Therapeutics. Press Release. Dec. 11, 2024.

AbbVie. AbbVie to Acquire Aliada Therapeutics, Strengthening Focus in Alzheimer's Disease and Neuroscience Pipeline. Press Release. Oct. 28, 2024.

AbbVie. AbbVie Completes Acquisition of Cerevel Therapeutics. Press Release. Aug. 1, 2024.

AbbVie. AbbVie Acquires Celsius Therapeutics. Press Release. June 27, 2024.

Articles

AbbVie has completed its acquisition of Aliada Therapeutics which includes Aliada’s disease-modifying therapy for Alzheimer’s disease.

AbbVie Acquires Aliada Therapeutics, Gains Neuroscience Pipeline

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People around the world rely on medicines to improve—and often save—their lives. These therapies must not only be effective, but also safe for people to use. Regulatory bodies offer guidelines and regulations to ensure medicines are properly developed and manufactured. These guidelines are commonly referred to as good manufacturing practices (GMPs), among other ‘good practices’, in the United States and are outlined in the 

) and ensured by FDA (1). In Europe, GMPs are coordinated by the European Medicines Agency (EMA) and compiled in the 

 (2,3). Knowledge and proper implementation of these guidelines is key to the production of safe and effective medicines.

For patients, a lack of quality in a therapeutic product can have a dire impact. From a business perspective, a lack of training can result in delays getting product to market, product recalls, and regulatory scrutiny. Regulators want the assurance that a company’s training is adequate. “Regulators consistently review training programs during quality inspections,” says Peter Phillips, vice president, Quality Operations, BioVectra (a part of Agilent). “This is typically examined in two contexts: either as part of an investigation into specific incidents or as a standalone area of focus. Inspectors also assess how well the training aligns with employees’ job descriptions and actual responsibilities, ensuring that staff are properly trained to perform their tasks in compliance with regulatory requirements.”

The development and manufacture of medicines, however, is a complex process that involves early development scientists, pre-marketing analysts, manufacturing engineers, quality control personnel, contract organizations, and a variety of other personnel. If these many and varied individuals are not properly trained in their individual tasks, there may be a negative impact on the final drug product.

In an example of poor training impacting drug quality, Lara Ionescu Silverman, principal consultant at LIS BioConsulting, shares the story of a company’s quality department tracking results from a new analytical method that showed a decreasing trend in one value across all evaluated materials. “After an investigation, it was determined that the operator was slowly morphing the method and did not recognize the change, which resulted in the shift in values. Due to the criticality of the test, many contract projects had to be notified and retested at great expense. This could have been avoided through more frequent retraining, operator observation, and the use of multiple operators (to more quickly reveal any issues from a single operator),” says Silverman.

Training should be a constant, living element in a bio/pharmaceutical organization to prevent these kinds of problems. “Consistent, repeatable processes are critical to ensuring a robust product and process, and these processes rely on thorough and appropriate training. This includes not only technical and equipment operation training, but also safety protocol training and regulatory requirements,” says Phillips. “If personnel are not adequately trained … and a well-structured training program put in place, it can lead to process variability, safety risks, and non-compliance,” he warns.

Development of a drug is the first step in getting a therapy into the hands of patients. This step involves choosing the building blocks of the drug, from ingredients to delivery method to process development.

“It is critical to ensure that the research and development staff understand the future activities required to get a novel biologic or small-molecule drug approved,” says Silverman. “These scientists are doing incredible work to uncover novel mechanisms, drugs, and treatments. But, if they don’t keep the end in mind, issues can arise down the road. Providing basic training on the regulatory, manufacturing, and commercialization requirements can help scientists understand future activities and drive their present-day work.”

A lack of training in those individuals involved in the development of a drug can impact the quality of that drug in a variety of ways, according to Tony Cucinella, vice president, head of Quality and Regulatory Affairs at Selkirk Pharma. He points to poor aseptic techniques as a risk factor for contamination. “This [factor] is particularly critical for biologics, which are highly sensitive to microbial contamination,” says Cucinella. Improper training of processes can lead to variability, which can lead to inconsistencies in batches of product, he reports. Proper handling and storage of materials and the final product is also essential. “Improper training can result in mishandling, degrading the drug’s efficacy and safety,” Cucinella says. Lastly, he stresses that accurate documentation is key to drug quality. “Poor training can lead to errors in data recording, which can compromise the integrity of the development process and regulatory submissions.”

Utilizing reagents and equipment properly in a GMP setting with good controls and consistency is essential, specifies Silverman. “These materials and equipment should come from reputable manufacturers and allow for large-scale production, enabling the company to meet their market size goals to achieve ultimate commercial success. Also, it is important to gather (and organize!) analytical data from the ancillary materials, the process, and the final drug substances/products to allow for future comparability as well as the development of suitable control strategies to enable efficient GMP manufacturing,” she stresses.

Errors such as choice of delivery technology can happen when a development scientist is not properly trained, according to Chris Moreton of FinnBrit Consulting. “From my own experience, such a failure can cause a delay of about two years in the time to get to a reliable Phase I clinical trial result. This would be a fatal delay for many biotech start-up companies,” Moreton says.

Cucinella stresses that a comprehensive and ongoing training program for all those involved in drug development is essential for quality. “Trained personnel are better equipped to identify and troubleshoot issues during development. Without proper training, problems may go unnoticed or unresolved, affecting the drug’s quality,” he states.

A variety of unexpected events can happen during drug manufacturing, warns Michael Pinaud, senior vice president of Operations at Ascend Advanced Therapies, that can result in a final product that is unsuitable for use. “Without proper training on how to deal with the unexpected, the result can have detrimental impact on the quality and the ability to release drug product, says Pinaud. “Training operators to follow the appropriate procedures and keep good batch records should be considered the bare minimum expectation. Capturing all the relevant information and keeping a thorough timeline of events (through investigations and real time interviews) also helps to ensure that if/when something happens, it is clear if/how the quality of final drug product might be impacted because you have a detailed record of what actually occurred to refer to.”

Drug products are manufactured under strict quality requirements, especially biologics, according to Phillip Hernandez, head of Quality, Andelyn Biosciences; therefore, personnel working in these areas must be thoroughly trained in processes, gowning, the flow of the facility, aseptic techniques, contamination control, and documentation. “Improper training can lead to breaches in contamination control, introducing harmful microorganisms or particles into the drug product, which can have serious implications for patient safety. Proper training in documentation practices is crucial for maintaining compliance and traceability,” Hernandez stresses. “Manufacturing processes require precise execution of protocols and batch records. Variability in execution can result in batches that do not meet established quality standards, affecting efficacy and safety.”

Hernandez points to the example of a vaccine manufacturing facility that received an FDA Form 483 for multiple quality control deficiencies that resulted from poor training. “As a result of these findings, the company faced regulatory action and had to implement multiple corrective actions, including enhancing their training programs and reinforcing SOP [standard operating procedure] compliance among all personnel,” Hernandez warns. “This incident highlights the critical importance of effective training in ensuring product quality and regulatory compliance, particularly in high-stakes environments like vaccine manufacturing.”

While training is obviously not new in the pharma industry, Pinaud stresses that teaching the ‘how’ of an operation isn’t the only thing that matters. Personnel should also be taught the ‘why’ of what they are doing. “Training has been a focus for years now, so the actual execution of manufacturing is covered for the manufacturing operators. What we can tend to see is a focus on how to perform each operation and less of a focus on why each unit operation matters and what each step is accomplishing. Understanding the why is just as important as the how when taking a holistic approach to quality training,” he says.

Often, it’s the method of training that is lacking and/or how the training is conducted, according to Siegfried Schmitt, vice president, Technical at Parexel, often relying on great amounts of SOPs to be read and remembered. “If the training of the SOP were conducted in conjunction with performing the tasks, then this is much more efficient as visual experience is much better remembered than pure text, especially when unrelated to practical experience,” says Schmitt. “Training on the job beats mere theoretical training hands down.”

When training lapses or fails, it’s often up to training programs that have not been updated to include new technologies and changing regulatory expectations, according to Phillips. Management skills, especially, can be undervalued. “This area of training is critical, as poor management can lead to issues such as employee retention problems, insufficient follow-up on corrective actions, and decreased overall team performance,” says Phillips.

“I think the biggest area lacking training is around regulatory requirements,” says Silverman. “This area is particularly important because so much of the activities that occur at GMP facilities are a direct result of FDA requirements. Implementing such training is challenging because FDA regularly releases updated guidance documents and information; however, ensuring that staff are aware of regulatory topics can lead to smoother operations overall.”

Cucinella agrees that rapid advancements in technology are a challenge, with automation, artificial intelligence, and machine learning requiring continuous learning. In addition, Cucinella says, “With the increasing reliance on digital systems, ensuring data integrity and cybersecurity is paramount. Training on how to handle, store, and protect data is often lacking.”

“Pharmaceutical companies and contract manufacturers often lack robust and continuous training programs in GMP compliance and in the nuances of understanding analytical testing methods and interpreting data,” says Shailesh Vengurlekar, senior vice president Quality and Regulatory Affairs, LGM Pharma. “Personnel may lack training in data integrity and the importance of accurate and traceable data in manufacturing, especially with electronic record-keeping systems. Many contract manufacturers ignore the importance of instrument maintenance programs, which could lead to several product quality issues including contamination.”

Lee McKinley, director, Organizational Development, BioVectra (a part of Agilent) points to personnel not being able to fully observe processes and often not having full access to equipment for training. “Providing a safe environment for hands-on training, where employees can practice without disrupting ongoing operations, is crucial. Without this, ramp-up times can be significantly delayed, affecting overall efficiency and performance.”

How can training be conducted to ensure the quality of bio/pharmaceuticals? Moreton suggests the appointment of a ‘training officer’ who’s job and authority is to ensure proper training is taking place for both new and existing staff. “The training officer must also monitor the quality of training and keep records of attendees and also monitor individual training records. In the event of an error or incident that compromises quality, the training officer should be part of the investigation team,” says Moreton.

A comprehensive onboarding program that focuses on GMP training is essential, remarks Cucinella, as are detailed SOPs. Training for the role is also important, he says, to be sure the employee is trained on their specific roles and responsibilities. Creating a quality culture that fosters continuous improvement is also key, notes Cucinella.

Cyrill Kellerhals, COO at Andelyn Biosciences takes onboarding of personnel seriously by going “well above-and-beyond” when it comes to minimum requirements. The company also has a partnership with a university for new staff training and incorporates on-site training before a new operator begins. “[We also have] on the job training to ensure more experienced operators are working with new staff members while they build up their comfort level and ability to execute,” says Kellerhals.

After onboarding, Diem Hoang, director of Quality, LGM Pharma recommends that a training timeline be established to set training expectations going forward, then follow up with documentation to track the employee’s progress. Recertification should be scheduled if needed.

McKinley stresses that training should incorporate diverse learning styles and backgrounds, with clear lay-person language, in-person sessions, e-learning, hands-on practice, interactive elements, and feedback.

An electronic data management system (eDMS) should be implemented, according to Hernandez. “An effective eDMS provides up-to-date, dynamic reporting on the training records of every staff member and serves as a repository for the version history and current revisions of all SOPs and quality documentation,” he says.

The effectiveness of training should be measured with pre- and post-assessments, according to McKinley. Assessments enable one to identify where improvements in the training program are needed. “Additionally, incorporating refresher training later in the onboarding process helps reinforce key concepts. Repetition is vital to ensure that staff internalize GMP standards and consistently follow quality procedures. All of this contributes to a successful training program,” says McKinley.

Industry groups offer expert training. Utilizing industry groups is a tool bio/pharmaceutical companies can use to ensure a robust training program, specifically for GMPs, according to Phillips. These groups are usually knowledgeable of current regulations and often offer their own training programs that can be tailored to group members. “In addition, participating in these networks creates opportunities for knowledge sharing, adding insights to courses, and accessing further training resources,” says Phillips. “However, it’s equally important to have an effective mechanism for integrating this training into the organization. Often, employees attend external training sessions but fail to share their learnings with the broader team, which represents a missed opportunity for company-wide improvement. Establishing a system for disseminating and reinforcing acquired knowledge can enhance the overall impact of training,” he stresses.

“Such [professional] training can be used to augment any in-house training. They can also be used to audit company in-house training and overall training. In-house trainers must also be properly trained in training techniques and methods of instruction,” agrees Moreton. “Not everyone can train, but even good trainers can improve their effectiveness with proper training.”

With the global biologics market expected to reach US$1,374.51 billion by 2033 (4), it would suggest that this growth would create a demand for experience in the development and manufacture of these products. But how can bio/pharma companies and contract organizations keep up with the training their employees will need to meet this demand?

Moreton suggests that training in new modalities not be left to non-technical staff and that information available in the scientific literature be reviewed. “This can be achieved in several ways; one of the most effective is to engage the scientific and technical staff and ask them to review literature sources and add any noteworthy information to a central repository that is reviewed and discussed at regular meetings of the technical and scientific staff for relevance and importance,” he says.

“Maintaining effective training in the evolving field of biologics requires active engagement with industry groups and networking with other companies, as mentioned above,” says Phillips. “By staying connected to what is currently happening in the industry and understanding emerging standards, companies can continuously adapt their training programs to meet new challenges and requirements.”

The trainer also needs training to keep up with these new modalities, explains McKinley. “It is crucial to ensure that trainers possess the necessary expertise to effectively deliver training. This includes staying up to date on best practices by regularly participating in ‘train the trainer’ programs and professional development sessions,” he says. “These sessions should focus on emerging training technologies, innovative learning modalities, and adult learning principles, which are essential for adapting to the rapidly changing environment of biologics manufacturing.”

Quality in the bio/pharmaceutical is the responsibility of everyone involved in the development and manufacture of drugs. But if those individuals are not properly trained, mistakes can happen, resulting in either unsafe and/or ineffective drugs. Therefore, training should be an important part of a pharmaceutical company’s and/or contract organization’s procedures.

“While the quality department is ultimately responsible, it is critical for individuals in manufacturing, supply chain, and other functions to also understand what might impact quality, so that investigations can be initiated if concerns arise,” stresses Silverman. “Such inquiries can be especially important in highly complex drug products such cell and gene therapies, where the product characteristics can be hard to understand.”

FDA. Current Good Manufacturing Practice (CGMP) Regulations. 

https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations (accessed, Nov. 1, 2024).

 https://www.ema.europa.eu/en/human-regulatory-overview/research-development/compliance-research-development/good-manufacturing-practice (accessed, Nov. 1, 2024).

. https://health.ec.europa.eu/medicinal-products/eudralex_en (accessed, Nov. 1, 2024).

Biologics Market Size, Share & Trends Analysis Report by Source (Microbial, Mammalian), By Product (MABs, Recombinant Proteins, Antisense & RNAi), By Disease Category, By Manufacturing, By Region, And Segment)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2024–2033.

®
Vol. 48, No. 12
December 2024
Pages: 10–15

When referring to this article, please cite it has Haigney, S. Enhancing Quality Through Training. 

With so many personnel involved in the development and manufacture of pharmaceuticals, proper training of all staff is key to ensuring a quality product.

Enhancing Quality Through Training

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The first CPHI Middle East event, to be held Dec. 10–12, 2024 at the Riyadh Front Exhibition & Convention Center Riyadh in Saudi Arabia, is expected to be host to 30,000 pharma professionals, according to the event’s planners. According to CPHI, the region is planning to expand its domestic manufacturing capabilities as new technology investments are poured into the market.

Indian contract development and manufacturing organizations are expected to invest in the region as they support emerging biotechs that have product development in India, according to CPHI, with more than 80 Indian companies exhibiting at the event. There are a total of 400 companies exhibiting, with more than 65 from Europe and 90 from China.

“The event is held under the patronage of the Saudi Ministry of Health, who will be among more than 160 experts presenting at the event,” CPHI stated in a press release (1). “A Ministerial Panel on 10 December will outline the Kingdom’s strategy to develop a biopharma ecosystem, in alignment with the Kingdom’s vision to be the leading biotech hub in MENA [Middle East and Northern Africa] by 2030 and globally by 2040. The Kingdom has ambitious plans to reduce its reliance on imported drugs. In fact, currently, Saudi Arabia imports over 81% of its generic medicines and 94% of its medical devices, however, by 2030, the Kingdom aims to produce 40% of its drug needs domestically.”

Hala Audi, CEO of UNIZIMA—which specializes in partnerships for bioproduction facilities in emerging market—is a keynote speaker at the event and will discuss building biologics capabilities in emerging markets.

“The event’s success is just another indicator of the significant investment underway in the region,” said Audi in the press release (1). “The rate of change is only accelerating, and the Kingdom is building pharma infrastructure at pace. The [g]overnment is rightly driving the momentum, by focusing on its strengths—a sizeable domestic market, growing scientific and medical talent, and financing power. I believe that with the right technology partnerships, the region is poised to build a biotech ecosystem that will compete with the best globally. Next generation technologies for vaccines and therapeutics including, for instance, RNA based treatments offer an opportunity for KSA [Kingdom of Saudi Arabia] and the region to leapfrog and lead the way in biotech.”

The conference agenda will include a variety of topics related to the future of pharmaceutical development in the Middle East and will span four show-floor theaters. Panel discussions will include talks on the expansion of Saudi Arabia’s domestic manufacturing hub.

“CPHI Middle East is set to be the portfolio’s most successful launch to date – with incredibly impressive attendee and exhibitor numbers,” April Hung, brand manager for CPHI Middle East, stated in the release. “This level of interest reflects the region’s ambitions and strong demand for partnerships. The public–private collaboration here is impressive, and by bringing CPHI to Saudi Arabia, we’re helping accelerate the development of partnerships and supply ecosystems that will fuel growth over the next five years. We’re thrilled to launch the show and play a role in building a new ‘heart of pharma’ in the Middle East.”

1.	CPHI. Saudi Arabia Poised to Expand Domestic Manufacturing Eco-system as 30,000 Attendees join Inaugural CPHI Middle East. Press Release. Dec. 9, 2024.

The first CPHI Middle East event will be held Dec. 10–12, 2024 at the Riyadh Front Exhibition & Convention Center Riyadh in Saudi Arabia and is expected to be host to 30,000 pharma professionals.

CPHI Middle East Sees Domestic Manufacturing Expansion in Saudi Arabia

FDA announced a draft guidance on Dec. 5, 2024 that explains the procedures and criteria for the agency’s accelerated drug approval for serious conditions. The guidance, 

Expedited Program for Serious Conditions–Accelerated Approval of Drugs and Biologics, 

also explains procedures for expedited withdrawal of approval (1). Revisions made by Congress through the Consolidated Appropriations Act, 2023 (Public Law 117-328) are also discussed.

FDA’s accelerated approval pathway is one of the agency’s expedited programs for the development and review of new drugs to meet unmet medical needs for serious or life-threatening conditions in a timely manner. Sponsors whose product is granted accelerated approval conduct confirmatory trials that are completed postapproval to verify and describe the anticipated effects and benefits of the drug. If these trials confirm the clinical benefit, FDA will then count the confirmatory requirement as met. However, if the sponsor fails to conduct the trial with due diligence or the trial fails to verify effects and benefits, FDA may withdraw approval.

Per the guidance document, conditions and requirements associated with accelerated approval include:

The conducting of postapproval studies to verify and describe the anticipated clinical benefit of the drug.

FDA must specify the conditions for postapproval studies, by the date of approval. These may include a deadline to submit the final study protocol, targets for enrollment progress, and other milestones such as the target date for study completion.

The agency may require postapproval studies prior to the accelerated approval.

A succinct description of limitations of usefulness and anticipated benefits must be included in the drug label’s Indications and Usage section with a reference to the Clinical Trials section.

Copies of sponsor’s promotional materials must be submitted to FDA with specified time frames.

Progress reports on the postapproval studies must be submitted to FDA approximately every 180 days.

“Accelerated approval should not be considered if the completion of an adequate and well-controlled clinical trial to verify and describe clinical benefit will be infeasible,” the agency states in the document (1).

The guidance document specifically provides considerations for the use of surrogate and intermediate clinical endpoints, evidentiary criteria for accelerated approval; requirements for confirmatory studies; and labeling, promotional materials, postmarketing recordkeeping, and safety reporting considerations. In regard to evidentiary criteria, the document states, “Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval. For effectiveness, the standard is substantial evidence based on adequate and well-controlled clinical investigations. For safety, the standard is having sufficient information to determine that the drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling. An application for accelerated approval should also include adequate evidence that a proposed surrogate endpoint or an intermediate clinical endpoint is reasonably likely to predict the intended clinical benefit of a drug.”

The document’s section on withdrawal of accelerated approval states, “The Agency generally expects that any proposal to withdraw approval of a drug that has been granted accelerated approval will be issued by the center or centers (hereafter, Center) that approved the drug. When the data or other information received by the Agency raises concerns that one or more of the criteria for withdrawing approval may have been met, responsible officials within the Center should discuss their concerns with the sponsor and seek an appropriate resolution. Such discussions may result in the sponsor’s voluntary request for withdrawal of approval under 21 

 601.5(a) or other regulatory actions, as appropriate, 552 depending on the circumstances” (1).

Expedited Program for Serious Conditions–Accelerated Approval of Drugs and Biologics, Guidance for Industry, Draft Guidance

The draft guidance provides information on the agency’s accelerated approval process and criteria for approval.

FDA Releases Guidance on Accelerated Approvals

The European Medicines Agency (EMA) announced on Nov. 29, 2024 that its Pharmacovigilance Risk Assessment Committee (PRAC) has found no causal link between doxycycline, a broad-spectrum antibiotic, and the risk of suicide or suicidal thoughts.

PRAC began a review of the safety of doxycycline in November 2023 after reports of a possible risk of suicidal thoughts or actions with the use of doxycycline from the Finnish national competent authority, as well as other cases reported to the European database of suspected side effects, EudraVigilance. The PRAC review included a cumulative data review from all relevant sources by the marketing authorization holders. There was also a study based on real-world evidence that included data from electronic health records and disease registries.

“After reviewing all available evidence from spontaneous reports, the literature, the discussion on possible mechanisms and the study performed via DARWIN EU [the Data Analysis and Real World Interrogation Network], the PRAC considered that the evidence is not sufficient to establish a causal relationship and that no update to the product information of doxycycline is warranted.

Suicide-related events in relation to doxycycline will be closely monitored and any new evidence will be discussed in the Periodic Safety Update Reports (PSURs),” EMA stated in a press release (1).

During the November meeting, PRAC also agreed to provide a direct healthcare professional communication (DHPC) on the liver injury risks associated with Veoza (fezolinetant). Veoza is used to treat moderate-to-severe vasomotor symptoms (i.e., hot flashes) that occur with menopause. PRAC is recommending that liver function be monitored in patients before and during treatment with fezolinetant. The recommendations are a result of a review of fezolinetant that included information from reports of suspected side effects and published scientific studies. The review showed a potential risk of drug-induced liver injury.

“Severe elevations of the liver enzymes alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (>10x upper limit of normal) with concurrent elevations in bilirubin and/or alkaline phosphatase (ALP) have been reported post marketing in women taking Veoza. In some cases, elevated liver function tests (LFTs) were associated with signs or symptoms suggestive of liver injury such as fatigue, pruritus, jaundice, dark urine, decreased appetite, or abdominal pain.”

Therefore, PRAC is recommending LFTs be performed before treatment is started and monthly tests during the first three months of treatment, with testing conducted thereafter based on symptoms of livery injury. Product information and packaging is being updated with the new safety information.

“Once adopted, the DHPC for Veoza will be disseminated to healthcare professionals by the marketing authorisation holders, according to an agreed communication plan, and published on the 

Direct healthcare professional communications

 in EU Member States,” the agency stated in the release.

1. EMA. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 25-28 November 2024. Press Release. Nov. 29, 2024.

The agency’s safety committee found no sufficient evidence of causal relationship between the antibiotic doxycycline and the risk of suicide or suicidal thoughts.