Susan Haigney

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - © Artur - stock.adobe.com

FDA announced on April 15, 2024 that it has established the Center for Clinical Trial Innovation (C3TI) in the Center for Drug Evaluation and Research (CDER). 

 was created in response to the need to enhance the implementation of CDER’s efforts to innovate and maximize drug development. The new center will promote activities CDER is doing to create innovation in clinical trials. These activities will include internal and external communications and collaboration.

Created as a central hub within CDER, C3TI will support approaches to clinical trials that will make drug development more efficient by sharing lessons learned across CDER’s existing initiatives in clinical trial innovation. C3TI will manage a demonstration program to expand opportunities for sponsors of trials to collaborate with CDER and spur additional implementation. This demonstration program will include point-of-care or pragmatic trials, Bayesian analyses, and trials that use selective safety data collection.

C3TI will allow internal and external parties to access information about innovation efforts, collaborate with CDER, identify resources, and identify development programs. The center will help those involved with clinical research stay current with innovations and improve the effectiveness of trials. It will also help to increase participation in clinical trials from diverse populations.

“For years, CDER has championed innovation, and our activities to foster and support innovation span drug development programs, therapeutic areas, and disciplines. These CDER efforts have led to improvements in the design and conduct of clinical trials that are intended to efficiently generate evidence on the safety and effectiveness of new therapies in ways that meet the growing demands of drug development,” the agency stated in a press release.

A public docket was opened by CDER in 2023, and a two-day public workshop was held in March 2024,in collaboration with the Duke-Margolis Institute for Health Policy, to address how drug development could be improved by innovations in clinical trial approaches. According to Kevin Bugin, PhD, lead for C3TI and deputy director of operations in the Office of New Drugs (OND), “CDER staff noted they would benefit from greater exposure to or experience with the use of innovations in their regular review work. There is a desire across the drug development ‘ecosystem’ to integrate innovation, but there is a need for more direction on how to better bridge the gap between policy and implementation” (1).

“Based on this insight, C3TI will aspire to create more opportunities for staff to participate in development programs planning to implement novel trial approaches to gain experience with a given innovation, via a C3TI Demonstration Program. C3TI will also explore how to create new opportunities for CDER staff to receive training and exposure to new clinical trial methods, technologies, and tools. Lastly, C3TI intends to better capture and disseminate lessons learned from implementing a given clinical trial innovation through improved communication and coordination with colleagues (e.g., dedicated rounds to discuss clinical trial innovation) and with external parties (e.g., public meetings or webinars),” said Bugin.

“CDER’s long-standing efforts to embed innovation in clinical trial design and conduct into our regulatory work have been crucial in bringing new therapies to areas of unmet medical need,” said Patrizia Cavazzoni, MD, director of CDER, in the press release. “We are eager to build on this foundation by launching C3TI to further spur the adoption of clinical trial innovation across industry and within CDER.”

Bugin stated that he plans for the center to accelerate innovation through collaboration and promotion of these initiatives. More information about C3TI can be found on 

FDA. CDER Launches a Center for Clinical Trial Innovation. 

https://www.fda.gov/drugs/cder-conversations/cder-launches-center-clinical-trial-innovation

FDA. CDER Center for Clinical Trial Innovation (C3TI). 

 (accessed April 15, 2024). https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/cder-center-clinical-trial-innovation-c3ti

Articles

C3TI will promote CDER’s clinical trial innovation activities both internally and externally.

FDA Establishes Center for Clinical Trial Innovation

On April 12, 2024, the European Medicines Agency announced that its Pharmacovigilance Risk Assessment Committee (PRAC) has concluded that there is no link between glucagon-like peptide-1 (GLP-1) receptor agonists and suicidal or self-harming thoughts or actions. GLP-1 receptor agonists (e.g., dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide) are used to treat type 2 diabetes; some of these medications are also authorized for weight management.

 after reports of users of liraglutide and semaglutide having thoughts of suicide and self-harm (1). PRAC requested additional data from marketing authorization holders of these types of drugs in November 2023. Results from a study published in 2024 were also analyzed by PRAC (2). The study examined the risk of suicide and self-harm in patients with type 2 diabetes. The study results did not show there to be a link between GLP-1 receptor agonists and a risk of suicide/self-harm thoughts or actions.

“After reviewing the available evidence from non-clinical studies, clinical trials, post-marketing surveillance data and the available studies the PRAC considers that no update to the product information is warranted. The marketing authorization holders for these medicines will continue to monitor these events closely, including any new publications, as part of their pharmacovigilance activities and report any new evidence on this issue in their Periodic Safety Update Reports (PSURs),” EMA stated in a press release.

between the drugs and thoughts of suicide after a preliminary evaluation. “Because the information provided was often limited and because these events can be influenced by other potential factors, we determined that the information in these reports did not demonstrate a clear relationship with the use of GLP-1 RAs. Similarly, our reviews of the clinical trials, including large outcome studies and observational studies, did not find an association between use of GLP-1 RAs and the occurrence of suicidal thoughts or actions. However, because of the small number of suicidal thoughts or actions observed in both people using GLP-1 RAs and in the comparative control groups, we cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue,” FDA stated (3).

EMA’s PRAC also provided safety information to healthcare professionals regarding new Rybelsus tablets (oral semaglutide) on April 12. PRAC was asked to consult on a proposed direct healthcare professional communication (DHPC) as part of an ongoing application for new strengths of Rybelsus tablets. PRAC agreed to the content in the DHPC, and it will be forwarded to the Committee for Medicinal products for Human Use for adoption. Once finalized, the DHPC will be provided to healthcare professionals by marketing authorization holders. Rybelsus is used control blood glucose levels in adults with type 2 diabetes.

EMA Statement on Ongoing Review of GLP-1 Receptor Agonists

 Association of Semaglutide with Risk of Suicidal Ideation in a Real-World Cohort. 

FDA. Update on FDA’s Ongoing Evaluation of Reports of Suicidal Thoughts or Actions in Patients Taking a Certain Type of Medicines Approved for Type 2 Diabetes and Obesity. 

The agency’s risk assessment committee has concluded that available evidence has not been found that supports a causal association between glucagon-like peptide-1 receptor agonists and self-harming thoughts and actions.

EMA Says No Evidence for Link between Type 2 Diabetes Drugs and Suicidal Tendencies

On April 1, 2024, FDA issued a draft guidance document, 

Data Integrity for In Vivo Bioavailability and Bioequivalence Studies

, which provides recommendation for data integrity for clinical and bioanalytical portions of bioavailability (BA) and bioequivalence (BE) studies submitted with investigational new drug applications (INDs), new drug applications (NDAs), and abbreviated new drug applications (ANDAs). The guidance also applies to the bioanalytical portion of clinical pharmacologic studies supporting biologic license applications (BLAs) regulated by the Center for Drug Evaluation and Research (CDER) and the bioanalytical portion of nonclinical studies. Applicants and testing sites are also encouraged by the agency to use these recommendations when conducting other studies, including 

 and pharmacology and toxicology studies.

All data submitted to FDA must be accurate, complete, and reliable, FDA states in the document. Applicants and testing sites must achieve and maintain data integrity throughout a product’s data lifecycle. To assist applicants in doing this, the guidance document outlines ways to achieve and maintain data integrity for applicants, testing site management, and quality management systems. However, the document does not list all best practices that should be used for data integrity.

Data integrity has been on the agency’s radar for a while. “In recent years, FDA has observed data integrity concerns during the inspection of testing sites, clinical testing sites, and analytical testing sites, and during the assessment of the BA and BE study data submitted in support of applications. Data integrity concerns can impact application acceptance for filing, assessment, regulatory actions, and approval as well as post-approval actions, such as therapeutic equivalence ratings,” the document states (1).

“It is each applicant’s responsibility to achieve and maintain data integrity for their studies, which includes identifying and implementing the most effective and efficient risk-based controls. FDA encourages applicants and testing site management to review FDA regulations and all applicable guidance for industry to understand FDA’s current thinking on a topic,” the agency states in the guidance.

FDA defines data integrity in the document as “the accuracy, completeness, and reliability of data. Accurate, complete, and reliable data should be attributable to the person generating the data, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA). These characteristics of the data should be maintained throughout the data lifecycle.” The document emphasizes that data integrity and data quality are different, with data quality providing the assurance that data are generated “in compliance with applicable standards and can be used for its intended purpose.”

Guidance provided in the guidance document include recommendations for testing site selection, monitoring and oversight, testing site management, quality management systems, data storage and backup, and quality assurance. Training of personnel who interact with BA and BE study data is also addressed.

With data integrity being such a priority for both regulators and industry, advances in artificial intelligence (AI) and machine learning (ML) have helped drug companies manage and utilize the wealth of data that is available from clinical studies, manufacturing, post-marketing studies, and real-world experiences. But the pharma industry may need to take steps to fully accept and implement these tools.

“Unlike oil or precious gems, data are abundant. However, as with precious gems, quality is paramount. High-quality data can improve efficiency and unlock insights that lead to new discoveries and support better manufacturing processes, especially with the help of [ML and AI]. Relying on bad data, however, can lead to wrong conclusions and have significant cost implications,” 

according to Natalie Batoux and Dan Rayner.

 “The biopharmaceutical industry is lagging behind other industries in terms of digital transformation. To catch up, companies will need to treat their data as one of their most valuable assets, prioritize the capture of high-quality data at every level of the business going forward, and check the integrity of their historical data” (2).

Data Integrity for In Vivo Bioavailability and Bioequivalence Studies 

https://www.fda.gov/media/177404/download

Batoux, N. and Rayner, D. In a Digital Goald Rush, Data Integrity is Priceless. 

Pharmaceutical Technology In the Lab eNewsletter

https://www.pharmtech.com/view/in-a-digital-gold-rush-data-integrity-is-priceless

The draft guidance provides recommendations for data integrity for clinical and bioanalytical portions of bioavailability and bioequivalence studies submitted with drug applications.

FDA Releases Guidance on Data Integrity for In Vivo Bioavailability and Bioequivalence Studies

On April 3, 2024, FDA’s Center for Drug Evaluation and Research (CDER) announced the release of the 

2023 annual report of the Office of Pharmaceutical Quality (OPQ)

. The report provides a look back at the office’s accomplishments in quality assessments, inspections, surveillance, research, and policy making (1). OPQ performed quality assessments on more than 1100 approved drug applications in 2023 and conducted more than 60 pre-license inspections in 18 countries and 10 states. The office also participated in the release of 10 guidance documents and authored 90 articles promoting best practices and science-based improvement.

The office uses four priorities for assuring drug quality: collaboration, communication, engagement, and innovation. OPQ’s collaboration efforts included supporting 55 novel drug approvals that included 17 biotechnology products. The office helped expedite 359 quality assessments in order to address drug shortages and performed 28 priority assessments for orphan disease treatments.

Communication efforts including publishing seven Manuals of Policy and Procedures and two compliance programs. Staff also participated in public workshops, conferences, and webinars more than 350 times in 2023. Furthermore, a report on pharma quality was published in June of 2023.

OPQ forged partnerships and connections in 2023 that included developing 12 CDER workshops and events and hosting the biennial Pharmaceutical Quality Symposium. The office also participated in the development of seven international quality guidelines, participated in 119 US Pharmacopeia expert bodies, and evaluated two submissions with other global regulators in international pilot programs.

Innovation efforts included the acceptance of 15 proposals to the Emerging Technology Program, hosting workshops on artificial intelligence and advanced technologies, and the use of the Knowledge-aided Assessment and Structured Application to assess approximately 1400 applications.

CDER’s OPQ office oversees the assurance that medicines in the US market meeting quality requirements. It reviews both domestic and foreign drug manufacturing for new and generic drugs, biologics, and over-the-counter products. OPQ operates as the lead for pre-license inspections of manufacturing facilities and acts as subject matter experts on preapproval inspections. The office uses surveillance to continuously monitor the quality of products and alert consumers to potential risks.

“The strategic pillars of collaboration, communication, engagement, and innovation support OPQ’s core functions. Collaboration strengthens OPQ’s culture and relationships with FDA business partners. Communication allows OPQ to elevate awareness and commitment to the importance of pharmaceutical quality. Innovation works to promote the availability of better medicines for the American public, while engagement forges partnerships and connections with public stakeholders,” the report states.

In 2024, OPQ has reorganized to “adapt to the changing pharmaceutical landscape by being more agile and efficient.” The office has consolidated research functions into a single office to improve coordination and manage lab-based resources. A new Office of Quality Assurance has been created to foster improvement and staff development. Existing assessment functions have been placed in new Offices of Product Quality Assessment I, II, and III to “encourage a lifecycle focus and agility in responding to an evolving workload.”

Office of Pharmaceutical Quality, 2023 Annual Report 

The annual report details OPQ’s quality assurance work for 2023 including its support for the creation of guidance documents.

FDA’s Office of Pharmaceutical Quality Reports on 2023 Quality Assessments

Amneal Pharmaceuticals announced on March 27, 2024 that it was voluntarily recalling four lots of Vancomycin Hydrochloride for Oral Solution, USP, 250 mg/5mL packaged in 80 mL, 150 mL, or 300 mL pack sizes. The recall was issued because some bottles may have been overfilled, resulting in over potency. Vancomycin Hydrochloride for Oral Solution, USP, 250mg/5mL, is used to treat enterocolitis caused by 

 (including methicillin-resistant strains) and antibiotic- associated pseudomembranous colitis caused by 

The company stated in a press release that the error occurred during the manual filling of the bottles at the manufacturing stage. The recommended maximum daily dose allowance is 2 gm per day. If patients were prescribed 500 mg/10 mL, the maximum dosage would be exceeded, which could be harmful to patients with renal insufficiency, according to the company.

“Adult patients who are prescribed the maximum daily dose of up to 2 grams per day of Vancomycin Hydrochloride for oral solution, USP 250 mg/5mL, may receive up to 4 grams of oral vancomycin per day because of the overfilled bottle. Some patients with inflammatory disorders of the intestinal mucosa also may have significant systemic absorption of vancomycin. These patients may be at risk for the development of adverse reactions associated with higher doses of vancomycin oral solution. Worsening renal function could be associated with electrolyte abnormalities such as high potassium leading to cardiac arrest,” the company states in the press release.

The recalled lots were distributed nationwide in the United States to wholesalers and distributors between Nov. 9, 2023 and Feb. 20, 2024. Lot information is as follows:

NDC No. 69238-2261-3; Lot 22613003A; Expiration Date 09/2025; Pack size 80 mL

NDC No. 69238-2261-7; Lot 22613004A; Expiration Date 09/2025; Pack size 150 mL

NDC No. 69238-2261-7; Lot 22613005A; Expiration Date 09/2025; Pack size 150 mL

NDC No. 69238-2261-5; Lot 22613005B; Expiration Date 09/2025; Pack size 300 mL.

The company is advising retailers to examine inventory and cease dispensing recalled lots. Amneal states it has not received any confirmed reports of adverse events related to the recall. Adverse events may be reported to FDA via its MedWatch program.

In other company news, FDA approved Amneal’s abbreviated new drug application for ciprofloxacin and dexamethasone otic suspension on March 25, 2024 (1). Ciprofloxacin and dexamethasone otic suspension combines a fluoroquinolone antibacterial, ciprofloxacin, and a corticosteroid, dexamethasone. It is used to treat infections caused by susceptible isolates of the designated microorganisms in acute otitis externa children age six months and older, adults, and elderly patients due to 

“This approval represents the addition of another complex, high value medicine,” said Andy Boyer, executive vice president, chief commercial officer–Generics, in a press release. “It reflects the ongoing shift of our leading affordable medicines portfolio towards complex products and the continued successful diversification of our business.”

Amneal is headquartered in Bridgewater, NJ, and develops, manufactures, and distributes more than 270 pharmaceutical products, mostly within the United States. The company produces generic drugs across a variety of therapeutic areas, including injectables and biosimilars, as well as specialty branded pharmaceuticals for central nervous system and endocrine disorders.

Amneal Receives U.S. FDA Approval for Ciprofloxacin and Dexamethasone Otic Suspension

The company is voluntarily recalling the product for potential super potent bottles due to overfilling.

Amneal Pharmaceuticals Recalls Vancomycin Hydrochloride for Oral Solution USP, 250 mg/5 mL

Science laboratory test tubes, laboratory equipment | Image Credit: © BillionPhotos.com - © BillionPhotos.com - stock.adobe.com

Dr. Reddy’s Laboratories, a pharmaceutical company located in Hyderabad, India, announced on March 27, 2024 that it has entered into a partnership with Sanofi Healthcare India Private Limited to exclusively distribute Sanofi’s vaccine brands in India, including its pediatric and adult brands Hexaxim, Pentaxim, Tetraxim, Menactra, FluQuadri, Adacel, and Avaxim 80U. Sanofi retains ownership and will manufacture and import the vaccines into India.

“Vaccine confidence has reached its highest in India in the last few years. Yet, there is much to be done for the rest of the country’s large unvaccinated cohort. To fulfill our long-term commitment to India and expand our geographic reach, we’re pleased to partner with Dr. Reddy’s Laboratories (Dr. Reddy’s) for exclusive distribution and promotion. We’re confident this partnership will further bolster our promise of saving millions of lives against vaccines preventable diseases with improved vaccination coverage,” said Preeti Futnani, general manager India for Vaccines, Sanofi, in a press release.

“We are happy to have the opportunity to leverage our strengths in promotion and distribution to considerably expand engagement with healthcare professionals and help widen access of Sanofi’s well-established and trusted vaccine brands in India,” said M.V. Ramana, chief executive officer, Branded Markets (India and Emerging Markets), Dr. Reddy’s, in the press release. “We continue our efforts to become the partner of choice in bringing novel, innovative and trusted drugs to patients in India through strategic collaborations. The portfolio now gives Dr. Reddy’s a strong presence in the vaccine segment, propelling us to the second position among vaccines players in India. Through each product and partnership, our aim is to serve over 1.5 billion patients by 2030.”

In addition to the Sanofi partnership, on March 22, 2024, Dr. Reddy’s announced it has entered into a licensing agreement with United States biopharmaceutical company, Pharmazz, for the commercialization of the company’s first-in-class innovative drug, Centhaquine, in India. Centhaquine is a resuscitative agent that treats hypovolemic shock. Dr. Reddy’s will have exclusive rights to market and distribute the drug, under the brand name Lyfaquin, in India. Pharmazz will receive upfront payments and royalties (1).

“The partnership with Pharmazz and launch of this first-in-class drug marks the latest in our effort to enter into strategic collaborations to bring novel molecules to India to meet genuine unmet patient needs,” said Ramana in a press release. “The clinical studies for Lyfaquin have demonstrated significantly better and promising outcomes, making it as a potential add-on drug in the management of hypovolemic shock and enhancing the current standard of care for its treatment in India.”

Anil Gulati, inventor, CEO, and chairman of the Board of Directors of Pharmazz, said in the release, “India's emergence as a hub for developing and introducing innovative medicines is a remarkable achievement. It reflects the country's growing capabilities in research and development within the pharmaceutical sector. It is a large step for Pharmazz to partner with Dr. Reddy's, a leading global pharmaceutical company from India. For patients with hypovolemic shock, I believe Dr. Reddy's is the best partner for Pharmazz to market Centhaquine, an innovative, first-in-class novel resuscitative agent, in India."

Dr. Reddy's and Pharmazz, Inc. Enter into Licensing Agreement to Market First-in-Class Centhaquine (Lyfaquin®) for Hypovolemic Shock in India. 

Dr. Reddy’s has gained exclusive rights to promote and distribute Sanofi’s vaccines in India.