Susan Haigney

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FDA has chosen seven companies to participate in its Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program. START was created to advance development of novel drugs and biologics for rare diseases. The pilot will gather information on how to best facilitate efficient development of therapies for rare diseases and assist sponsors to generate high-quality data to support new drug or biologics license applications.

The Center for Drug Evaluation and Research (CDER) chose the following companies to participate in START for the development of rare neurodegenerative conditions:

Larimar Therapeutics to treat Friedreich’s ataxia through its Nomlabofusp product

Calico Life Sciences to treat vanishing white matter disease with its ABBV-CLS-7262 product

Denali Therapeutics for its DNL 126 product to treat Mucopolysaccharidosis Type IIIA (Sanfilippo syndrome).

The Center for Biologics Evaluation and Research (CBER) chose the following companies for their gene or cellular therapies to treat rare diseases:

Grace Science for their GS-100 (AAV0-rhNGLY1) product to treat NGLY1 deficiency

Moderna TX for their mRNA-3705 product to treat isolated methylmalonic acidemia due to complete or partial methylmalonyl-coenzyme A mutase deficiency

Myrtelle to treat Canavan disease with their product, rAAV-Olig001-ASPA

Neurogene for the treatment of Rett syndrome with NGN-401.

“Although there were a number of excellent and qualified applicants, there was only availability for a limited number of programs within the START Pilot Program. In making these selections, we considered the strength of the development programs, and the unmet medical need represented by the indicated conditions. To help aid our evaluation of the program, we also attempted to include a spectrum of entities in the pilot ranging from companies initially established to produce a single product to established biotechnology companies,” CDER Director, Patrizia Cavazzoni and CBER Director, Peter Marks stated (1).

Participants in START will receive advice from FDA regarding product-specific development issues such as clinical study design, control groups, and patient populations. Early development problems will be addressed to avoid potential delays or prevention of trial progression. Access to FDA programs, such as the Advancing Real-World Evidence Program, Complex Innovative Trial Design program, Translational Science Team, and Rare Disease Endpoint Advancement Pilot, will be given to those participating in START.

Eligibility requirements to participate in START per FDA include (2):

“For both CBER and CDER, the program is open to sponsors of products currently in clinical trials under an active investigational new drug application (IND) and IND has been submitted in or converted to Electronic Common Technical Document (eCTD) format, unless the IND is of a type granted a waiver from eCTD format.”

“For both CBER and CDER, the program is open to sponsors who have demonstrated substantial effort to ensure that Chemistry, Manufacturing, and Controls (CMC) development aligns with clinical development.”

“For CBER, eligible products must be a gene or cellular therapy intended to address an unmet medical need as a treatment for a serious rare disease or condition, which is likely to lead to significant disability or death within the first decade of life.”

“For CDER, products must be intended to treat rare neurodegenerative conditions, including those of rare genetic metabolic etiology.”

“CBER and CDER look forward to actively working together to fulfill our shared vision of bringing better treatment options to patients and their families. Through the START Pilot Program, the opportunity for increased engagement with the selected sponsors should facilitate more rapid achievement of regulatory milestones, if supported by the data and the science,” Cavazzoni and Marks stated (1).

FDA. FDA Opens Doors for More Treatments for Rare Diseases through the New START Pilot Program. 

https://www.fda.gov/drugs/our-perspective/fda-opens-doors-more-treatments-rare-diseases-through-new-start-pilot-program

FDA. Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program. 

https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/support-clinical-trials-advancing-rare-disease-therapeutics-start-pilot-program

Articles

The seven chosen sponsors will help accelerate development of novel drugs and biologics for rare diseases.

Participants for START Pilot Program Selected by FDA

On June 24, 2024, FDA posted a conversation on its website with Yoni Tyberg, associate director of the Special Program Staff in the Office of New Drugs, regarding the progress of the modernization of the New Drug Regulatory Program (NDRP). NDRP’s modernization goal, which began in 2017, is to increase the efficiency and effectiveness of the processes of the Center for Drug Evaluation and Research (CDER). This initiative was spurred by the ever-increasing growth of genetic science, personalized medicine, and treatments for rare diseases.

According to Tyberg, NDRP began with a diagnostic phase to assess areas in need of improvement. A plan was then developed with six core objectives: scientific leadership; integrated assessment; operational excellence; benefit-risk monitoring; managing talent; and knowledge management. Seven task clusters were also created for achieving the objectives. The plan then moved into the implementation phase.

Accomplishments of the NDRP so far include improvement of advisory committee structure and improved committee tools and processes through the work of the advisory committee workstream.

The workstream enhanced areas of the advisory committee planningprocess such as clarifying when a committee meeting is appropriate, streamlining the process for recruiting and retaining experts for the committees, and developing accessible resources for FDA review teams,” Tyberg said (1). “These new resources included a tool to help review teams determine whether an advisory committee meeting is appropriate, an educational reference guide, technology/knowledge management platforms for CDER staff, learning modules for advisory committee experts, and a template to help staff efficiently produce streamlined advisory committee briefing documents. These changes helped promote more efficient advisory committee meetings that were better able to provide well-informed, clear, and consistent expert advice.”

The Investigational New Drug (IND) Review Management helped streamline the IND review process and implemented new review templates for IND 30-day safety and protocol and amendment reviews.

“It also transitioned the IND 30-day safety reviews into an automated workflow system to enhance efficiency, collaboration, knowledge management, and process standardization. This workstream collected multiple rounds of feedback from reviewers and regulatory program managers to ensure the templates and processes were designed for a specific purpose and implemented successfully,” said Tyberg.

Additional pathways for the CDER office to work together were created under the NDRP modernization’s scientific leadership objective, so partners within and outside of FDA can share information to develop ways to treat and prevent COVID-19. NDRP also impacted public health by identifying risks across the lifecycle of a drug through its Benefit-Risk Monitoring objective.

“We have several short-term goals and next steps we hope to accomplish in the coming year, along with a number of endeavors planned for the future,” Tyberg said. “We plan to add improvements based on user input for the dashboards we’ve developed, such as integrating them into the review workflows for easier access to important product lifecycle information. Another planned improvement is for the Information Request focused dashboard, which provides the ability to search and filter information requests. It will receive additional improvements to help its integration with the review workflows and enable better lifecycle tracking and search capabilities.”

More information on the program’s achievements can be found in the 

NDRP Modernization–Impact Narrative 2023

1. FDA. Modernizing the New Drugs Regulatory Program. FDA.gov. June 24, 2024.

Yoni Tyberg, associate director of the Special Program Staff in the Office of New Drugs, provided an update on efforts to modernize CDER processes.

CDER Gives Update on New Drugs Regulatory Program

Quality Considerations in Changing Excipient Providers

Ask the Expert June 2024

Changing excipient providers is not as simple as it may seem. The surge of complex therapeutics makes it even more complicated, according to Susan J. Schneipp, distinguished fellow at Regulatory Compliance Associates. “I would go visit them and look at their culture and what they're doing in the way of change control and how their QMS is handled, because that is going to be critical to securing your supply chain with this new excipient provider,” Schniepp says.

According to Siegfried Schmitt, vice president, Technical at Parexel, excipient providers are inspected by regulators and require audits to be performed by the company purchasing the ingredients. “And there are various ways of performing an audit. Of course, it doesn't always have to be on site, in person. It can also be, for example, [a] questionnaire [sent to the supplier], and you hope you get something filled in truthfully. You can perform online searches. Many excipient providers have very good reputations and standings in industry, and some also provide audit reports or certifications from independent companies like EXCiPACT,” Schmitt adds.

Click the video above to watch Sue and Siegfried answer the question: “My company is looking at changing our excipient provider for our therapeutic pipeline, what quality issues should we consider when choosing the grade of our excipients and what should we ask of our new provider?”

 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. 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. We hope you enjoy the discussion!

Susan J. Schneipp is distinguished fellow at Regulatory Compliance Associates and a member of 

Siegfried Schmitt is vice president, Technical at Parexel and a member of 

Videos

In the premiere episode of the Ask the Expert video series, Susan J. Schneipp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice president, Technical at Parexel, discuss the challenges involved in changing an excipient supplier. 

The United States Pharmacopeia (USP) announced on June 13, 2024 that it is collaborating with the African Union Development Agency (AUDA –NEPAD), the Africa Centres for Disease Control and Prevention (Africa CDC), the Association of African Universities (AAU), and the Federation of African Pharmaceutical Manufacturers Associations (FAPMA) to advance access to medicines and vaccines. USP grant-free access to the 

United States Pharmacopeia–National Formulary

) and USP’s education training library to all stakeholders in Africa, including regulatory authorities, laboratories, academic institutions, and manufacturers.

The new initiative will support African-led efforts, such as CDC’s New Public Health Order and AUDA-NEPAD's Pharmaceutical Manufacturing Plan for Africa, to increase the production of medical products. The initiative also builds on USP’s efforts to expand access to medicines in Africa through the organization’s direct investment, along with donors such as the US Agency for International Development. These efforts have included capacity building with 39 African manufacturers and 33 African regional and national regulatory authorities.

“Africa’s over-reliance on pharmaceutical imports created unacceptable supply chain vulnerabilities and delays during the COVID-19 pandemic,” said Jean Kaseya, MD, director-general of Africa CDC, in a USP press release (1). “We are committed to working with partners [such as] USP to build African manufacturing capacity to ensure that never happens again.”

“Development and growth of the pharmaceutical and vaccine manufacturing sector in Africa is critical to building sustainable and equitable access to health products in Africa,” said Symerre Grey Johnson, director for Human Capital and Institutional Development of AUDA-NEPAD, in the release. “With the actualization of the African Medicines Agency coupled with the African Free Trade Agreement and high-level commitments made by the African Union and numerous heads of states, the enabling conditions are primed for this sector to grow.”

“The growth of pharmaceutical manufacturing in Africa hinges on a dynamic and robust workforce,” said Olusola Oyewole, PhD, secretary-general of the Association of African Universities (AAU), in the release. “The development of a well-trained human resource pool with access to essential resources, such as those provided by USP, is crucial for educating tomorrow’s workforce, and transforming the continent’s pharmaceutical ecosystem.”

“Quality, including the adoption and scale up of accepted quality standards, must be at the heart of Africa’s expanding pharmaceutical sector,” said Emmanuel Mujuru, chairperson of FAPMA, in the release. “These resources will help African manufacturers move ever closer toward a thriving, quality-focused African pharmaceutical industry.”

The collaboration was announced at the inaugural meeting of USP’s Africa Regional Chapter. The Africa Regional Chapter brings together perspectives and expertise to identify priority issues. USP’s regional chapters will provide a forum for stakeholders to collaborate to advance pharmaceutical manufacturing and other priorities. There are more than 5000 quality standards in the 

for both chemical and biologic drugs, APIs, and excipients, therefore providing a comprehensive source for quality standards.

USP. African Institutions and USP Announce Free Access to Resources to Support Production of Quality Medical Products in Africa. Press Release. June 13, 2024.

A new initiative will advance access to quality medicines and vaccines in Africa.

USP and African Institutions Provide Free Access to Pharma Production Resources

The German government, in 2022, awarded a contract to WACKER, a contract manufacturer, and CordenPharma, a contract development and manufacturing organization, to produce and supply vaccines to prepare for potential future pandemics (1, 2). On June 19, 2024, WACKER and CordenPharma announced that their joint consortium entered the pandemic-readiness state on June 1, 2024 after the expansion and qualification phase. The consortium now enters the stand-by phase for a minimum of five years.

The two companies have taken measures to be able to produce 80 million vaccine doses a year under a short timeframe. A fee will be paid to the two companies to keep their capacity and expertise available for at least five years; the German government will request specific messenger RNA (mRNA) vaccines should a need develop.

Vaccines will be jointly produced by WACKER and CordenPharma with production occurring mostly in Germany. WACKER will produce plasmid DNA (pDNA), active pDNA, and lipid nanoparticles at its site in Halle, Germany, which was expanded to accommodate production over the past two years to include a new mRNA Competence Center.

CordenPharma will manufacture custom and standard lipids for the consortium at their Frankfurt, Germany and Chenôve, France sites. Aseptic fill/finish and packaging will be done at CordenPharma’s Caponago, Italy facility. To meet demand, the company invested in expansions in new lipid purification capacity and capabilities using supercritical fluid chromatography (SFC) and new compounding and freezing equipment. Both companies have also strengthened production security and supplier networks.

“We have expanded our Halle site into a Competence Center for mRNA production,” said WACKER CEO Christian Hartel, in a press release (3). “WACKER has invested over 100 million Euros in this expansion and created over 100 highly qualified jobs. Our expertise in making mRNA and LNPs [lipid nanoparticles] will contribute to the fight against future pandemics. Together with CordenPharma, we are proud to serve the German government in its pandemic preparedness plans.”

“Obtaining the official confirmation of pandemic readiness by the German government is a major milestone for CordenPharma,” said Michael Quirmbach, CEO of CordenPharma Group, in the release. “I am extremely proud of our teams across the CordenPharma sites involved in establishing and delivering our pandemic readiness plan on schedule. We are now ready, together with our partner WACKER, to manufacture end-to-end mRNA-based vaccines for the German government and other customers.”

At the time the contract was awarded, Hartel commented in a press release (1), “We are happy that our expertise in making mRNA vaccines will contribute to the fight against future pandemics. Together with CordenPharma, our partner, we will produce vaccines for Germany should the need arise.”

“WACKER and CordenPharma jointly cover the entire manufacturing chain for mRNA vaccines, which we will supply to the German government if needed. We are proud to contribute to supply security in Germany,” Quirmbach added (1).

CordenPharma. CordenPharma and WACKER to Produce mRNA Vaccines for Germany When Needed. Press Release. April 11, 2022.

CordenPharma. CordenPharma & WACKER Prepare for mRNA Vaccine Production. Press Release. June 14, 2022.

WACKER. WACKER & CordenPharma Enter Pandemic Readiness on 1 June 2024 After Successful Expansion & Qualification. Press Release. June 19, 2024.

The companies have completed the expansion and qualification phase and now enter a stand-by phase for five years.

CordenPharma and WACKER Consortium Enters Pandemic Readiness

The European Medicines Agency (EMA) announced on June 14, 2024 that the agency’s Pharmacovigilance Risk Assessment Committee (PRAC) is evaluating potential risks associated with the painkiller metamizole. PRAC is also researching the possible risk of secondary cancers developing in patients who are treated with chimeric antigen receptor (CAR) T-cell medicines.

According to EMA, concerns that measures put in place to minimize the risk of agranulocytosis in the painkiller metamizole might not be adequate. Drugs containing metamizole are authorized in the European Union, varying from country to country, for treating moderate to severe pain and fever. These medicines have a known side effect, agranulocytosis, where a sudden drop in white blood cells occurs. Agranulocytosis is a rare or very rare side effect that may lead to serious, and possibly fatal, infections. There are measures set by EU countries to minimize the risk; however, PRAC is looking into the effectiveness of these measures.

Regarding CAR T-cell medicines, PRAC states that patients receiving these treatments should be monitored for the rest of their lives for secondary cancers. New cancers, different from the original malignancy, may develop after treatment with CAR T-cell medicines.

PRAC came to this conclusion after reviewing data from 38 cases of secondary malignancies of T-cell origin in approximately 42,500 patients. “Tissue samples were tested in half of the cases, revealing the presence of the CAR construct in 7 cases. This suggests that the CAR T-cell medicine was involved in disease development. The secondary malignancies of T-cell origin have been reported within weeks and up to several years following administration of CAR T-cell medicines. Patients treated with these medicines should be monitored life-long for new malignancies,” EMA stated in a press release (1).

Product information, which has advisory information about secondary malignancies, will be updated to include new information about T-cells. PRAC is discussing direct healthcare professional communication about CAR T-cell medicines and will inform professionals about its new conclusion.

There are six approved CAR T-cell treatments in the EU: Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, and Yescarta. They treat a range of blood cancers.

In November 2023, FDA in the United States announced it was investigating the risk of T-cell malignancy following CAR T-cell immunotherapies (2). “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action,” FDA states on its website. “The initial approvals of these products included postmarketing requirements (PMRs) under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) to conduct 15-year long term follow-up observational safety studies to assess the long-term safety and the risk of secondary malignancies occurring after treatment.” The agency also said that patients of these treatments should be monitored for life for new malignancies.

EMA. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 10-13 June 2024. Press Release. June 14, 2024.

FDA. FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T Cell Immunotherapies. Nov. 28, 2024. 

https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous

PRAC is reviewing the risk of secondary malignancies in patients treated with CAR T-cell medicines. 