Susan Haigney

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FDA announced a draft guidance on Dec. 5, 2024 that explains the procedures and criteria for the agency’s accelerated drug approval for serious conditions.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

Articles

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.

No Causal Link Between Doxycycline and Suicide, Says EMA Safety Committee 

The European Medicines Agency (EMA) reported on Nov. 28, 2024 that the European Shortages Monitoring Platform (ESMP) is now live with core functionalities. ESMP enables marketing authorization holders (MAHs) to submit data to report shortages of centrally authorized medicines in the European Union on a routine basis. Use of ESMP will become mandatory on Feb. 2, 2025, per Regulation 2022/123, which facilitates the exchange of information to prevent drug shortages in the EU.

A second version of the ESMP will be released in February 2025 and will include full functionality for MAHs and national competent authorities to submit data on supply, demand, and availability of centrally and nationally authorized drugs during crises actions set forth by EMA’s Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG). These types of actions are taken by MSSG to monitor and mitigate potential shortages of important medicines.

“The release of the ESMP is a major milestone in the effort to tackle medicine shortages and ensure that medicines are available to patients when and where they need them most,” the agency stated in a press release (1). “It will centralize and automate data collection on medicine shortages, giving regulatory authorities access to real-time, comprehensive information to improve the prevention, monitoring, and management of medicine shortages across the EU and the European Economic Area (EEA).”

MAHs are encouraged to become familiar with the ESMP before it becomes mandatory. EMA is offering training, webinars, and information material on its website. The agency will also be providing updates on timelines and developments on its website at 

https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/medicine-shortages-availability-issues/european-shortages-monitoring-platform

More information about drug shortages in the EU can be found on EMA’s Medicine Shortages Single Point of Contact (SPOC) Working Party webpage (2). SPOC monitors and reports on events that may impact the drug supply in the EU. Information on ongoing and resolved shortages can be found on the webpage as well as registries of shortages by EU Member State. The agency lists 30 drugs as currently short in supply.

Drug shortages can be caused by a variety of problems, including quality control issues at manufacturing plants, high product demand, and natural disasters across the world. In June 2024, EMA and the Heads of Medicines Agencies issued recommendations to address the shortage of glucagon-like peptide-1 (GLP-1) receptor agonists due to a surge in demand (3).

“Member States should consider, jointly with marketing authorization holders, measures to control and optimize the distribution of these medicines. Member States’ continuous collaboration and cooperation through the [SPOC] will allow the MSSG to gain a comprehensive overview of the situation and assess the impact of the measures taken. Member States are also encouraged (together with experts and learned societies) to develop guidelines to facilitate prioritization of patients who have the greatest need for the medicines,” the agency stated in the release (3).

In late 2024, a series of intense storms hit the United States, causing damage to manufacturing facilities (4). Baxter had to close its facility in North Carolina, which is the largest manufacturing site for intravenous and peritoneal dialysis solutions in the US (5,6).

EMA. European Shortages Monitoring Platform Enables Better Monitoring of Shortages in the EU. Press Release. Nov. 28, 2024.

EMA. Medicine Shortages Single Point of Contact (SPOC) Working Party. 

https://www.ema.europa.eu/en/committees/working-parties-other-groups/medicines-shortages-single-point-contact-spoc-working-party

Baxter. Baxter Provides Update on North Cove, N.C., Facility and Hurricane Helene Relief Plans for Community. Press Release, Sep. 29, 2024.

Baxter. Hurricane Helene Updates. Press Release, Oct. 21, 2024.

A new platform allowing market authorization holders to report drug shortages has gone live. 

EMA Announces Drug Monitoring Platform

Ask the Expert Episode 6: Non-Animal Derived Reagents

In this episode of the Ask the Expert video series, 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, published by the 

United States Pharmacopeia–National Formulary 

November 2024. 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).

“Twenty years ago, the predominant test procedure for determining endotoxin level, or pyrogen level, as we called it, was the rabbit test. And we used to actually inject rabbits, which was a very subjective because you'd measure their temperature,” says Schniepp. And then we evolved to using the limulus amoebocyte lysate or LAL test, and there was the chromogenic [test] but they were all predicated off the horseshoe crab. So now we're moving forward to reagents for this test, which is critical to the release of sterile injectables that does not involve animals. So absolutely, we should consider this.”

“I think it is also worthwhile mentioning that what is happening in the US is mirrored in other jurisdictions, for example, when you look at the European Medicines Agency [EMA], they support the use of animal free cell culture reagents as part of its efforts to reduce animal use in medicine testing,” adds Schmitt. “We don't want to use rabbits. We don't want to use horseshoe crabs, and it's EMA’s innovation task force that encourages that use of alternative methods to animal models, and that, what they say is, will improve the scientific quality and also, of course, animal welfare.”

Click the video above to watch Sue and Siegfried answer the following question:

"USP just published a new chapter on the use of non-animal derived reagents. We are not currently using non-animal derived reagents. Is this something we should consider changing?"

Chapter for Endotoxin Testing Using Non-Animal Derived Reagents Published for Early Adoption

Welcome to the Ask the Expert video series. This series is an extension of the PharmTech Group’s long-running print column in which industry experts answer common quality and regulatory questions from the industry. This new video series will expand on topic areas to include development and manufacturing concerns to help those working in the industry better understand bio/pharmaceutical requirements. Have a question you would like answered? Send it to PTProjects@mmhgroup.com, and it may appear in a future episode or print column.

Videos

In this episode of the Ask the Expert video series, 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

Non-Animal-Derived Reagents for Endotoxin Testing

Ascend Advanced Therapies announced on Nov. 12, 2024 that it is partnering with EW Healthcare Partners to expand capabilities and invest in infrastructure in the United States. As part of the agreement, EW Healthcare’s Advanced BioScience Laboratories (ABL), a biotherapy, oncolytic and viral vector contract development, and manufacturing organization (CDMO) located in Rockville, Md., will become part of Ascend. EW Healthcare will also make capital investment in Ascend.

ABL’s Rockville facility and team will provide development and manufacturing experience, virus modalities, and good manufacturing practice (GMP) capacity for adeno-associated virus (AAV) production. Ascend’s fill/finish capacity in the US will also be expanded.

“We founded Ascend with a vision to quilt together the best operators and technologies within the advanced manufacturing field. The complementary services at ABL and Ascend will further strengthen our service offering to customers,” Fred Cohen, chairman of Ascend and Founding investor at Monograph Capital, said in the press release (1). “We look forward to working with our new colleagues at the Rockville facility and our partners at EW.”

“We have known Ascend and followed its progress in creating effective and high-quality gene therapies, and have been impressed with how the management team, which we also backed at Cognate BioServices, has expanded the business,” said Evis Hursever, PhD, managing director of EW Healthcare Partners. “We are excited about merging ABL with Ascend to create a scalable CDMO that will serve as a global platform for the manufacturing of advanced therapies. We have considerable experience and expertise in this space and the combined company’s strategic plans are very well aligned with our long-term vision. We look forward to working with the Ascend and ABL teams to further growth.”

This isn’t the first investment Ascend has made in 2024. In April, the company acquired Beacon Therapeutics GMP facility in Alachua, Fl. to obtain Beacon’s chemistry, manufacturing, and controls team; process and analytical development capabilities; and three ocular gene therapy products utilizing AAV to deliver gene constructs that address retinal disorders.

“Ascend was founded with a unique science and technology-driven strategy. As we continue building the most flexible [AAV] platform across serotypes on the market, we also understand the critical value of our experienced employees,” Mike Stella, CEO at Ascend, said in a press release (2). “This acquisition allows us to now support customers from research through to commercialization and adds to one of the most experienced gene therapy teams in the market. Every day we are working together to grow the company with a long-term mindset of quality first to appropriately balance quality and yield for the life of each product.”

“We are excited to enter this strategic arrangement with Ascend to advance our sight saving therapies toward approval. This alignment is critical to securing GMP drug product supply for our late-stage clinical asset AGTC-501 for the treatment of X-[l]inked [r]etinitis [p]igmentosa,” David Fellows, CEO at Beacon Therapeutics, said in the release. “The Ascend team brings significant experience in gene therapy manufacturing and a strong commitment to building capabilities to support future Beacon pipeline programs.”

1. Ascend. Ascend Advanced Therapies Partners with EW Healthcare Partners to Expand United States Capacity and Capabilities. Press Release. Nov. 12, 2024.
2. Ascend. Ascend Acquires GMP Manufacturing Capacity in Alachua, Florida from Beacon Therapeutics. Press Release. April 9, 2024.

Ascend is partnering with EW Healthcare Partners to expand capabilities in the United States.

Ascend Advanced Therapies Expands US Footprint in New Partnership

AAPS PharmSci360 Challenges in Peptide-Based Drugs

The development of oral peptide-based drugs presents unique challenges, specifies Brittany Hayes, PhD, Highly Potent & Oncology Platform Director at CordenPharma, due to the harsh environment of the gastrointestinal tract, highly acidic stomach, and enzymes that degrade peptides. “New manufacturing technologies and formulation techniques have shown to increase bioavailability by a few percentage points,” says Hayes. “But there's a lot of variability here, including variability from one patient to the next and also in the same patient from one day to the next day. One of the big ones that's been out there is permeation enhancers.”

Analytics is an important factor for the development of peptide-based drugs, highlights Hayes, because degradation products may be difficult to detect and quantify. “And then, with the use of these permeation enhancers, there needs to be simultaneous dissolution of the permeation enhancer and the peptide,” she says. “So, there may be some challenges here with analytical methods.” She also points out these novel excipients may require more regulatory qualifications and could be treated differently than conventional excipients.

Click the video above to watch the full interview.

Pharmaceutical Technology® caught up with Brittany Hayes, PhD, Highly Potent & Oncology Platform Director at CordenPharma, after AAPS PharmSci 360 to talk about the challenges and quality requirements involved in the development and manufacture of peptide-based oral dosage forms. 