Aligning mRNA Progress with Regulatory Streamlining

BioPharm Peer Exchange

Dosage Forms: Roundtable on Oral Solid Dosage Trends

Drug Solutions Podcast: 

Pharmaceutical packaging must advance to adapt to new, complex modalities

Out-of-the-Box Packaging Advancements

From Theory to Reality: Automating Process Development

Drug Digest: 

The Importance of Appropriate Supplier Oversight

Ask the Expert

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

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On July 2, 2024, Eli Lilly and Company announced that FDA had approved Lilly’s Kisunla (donanemab-azbt), a once-monthly monoclonal antibody injection for IV infusion, indicated for treatment of adults with early symptomatic Alzheimer’s disease, including those with mild cognitive impairment or who are in the mild dementia stage of the disease with confirmed amyloid pathology (1).

The therapy is the first which targets amyloid plaques, excessive buildup of which in the brain can result in thinking or memory issues consistent with Alzheimer’s disease, to be approved in the United States, according to a Lilly press release (1).

A Phase III study showed that people who were least advanced in their disease progression had the strongest responses to Kisunla, but overall, the treatment reduced amyloid plaques in participants by 61% from six months after the start of the study, 80% after 12 months, and 84% after 18 months (1). Cognitive and functional decline was reduced by up to 35%, compared to placebo, at 18 months, with participants’ risk of progressing to the next clinical stage of disease reduced by 39%.

"Kisunla demonstrated very meaningful results for people with early symptomatic Alzheimer's disease, who urgently need effective treatment options. We know these medicines have the greatest potential benefit when people are treated earlier in their disease, and we are working hard in partnership with others to improve detection and diagnosis,” Anne White, executive vice president and president of Lilly Neuroscience, Eli Lilly and Company, said in the press release. “Each year, more and more people are at risk for this disease, and we are determined to make life better for them."

According to the Alzheimer’s Drug Discovery Foundation (ADDF), anti-amyloid drugs have the potential to become the standard of care in fighting Alzheimer’s disease, but there remains a need to develop multiple novel drugs even after FDA gave the green light to Kisunla (2).

“This approval is emblematic of the new era of Alzheimer's research where we now have the first class of disease-modifying drugs that will eventually be used in combination with novel therapies—based on the biology of aging—that target all the underlying complexities of this disease,” said Howard Fillit, MD, ADDF co-founder and chief science officer (2). “This milestone will not only catalyze the next generation of therapies, but also reframe how we deliver treatments. It’s promising to see that some patients essentially enter remission, where they achieve full amyloid clearance with no resurgence in substantial plaque buildup for several years to follow.”

In discussing side effects, Lilly said its therapy can cause amyloid-related imaging abnormalities, which do not usually result in symptoms and can be detected via MRI (1). This condition can present as temporary swelling in different areas of the brain that resolves over time, or as small spots of bleeding in or on the brain’s surface; in rare cases, larger areas of bleeding in the brain are possible and can be serious or life-threatening.

1. Eli Lilly and Company. Lilly's Kisunla (donanemab-azbt) Approved by the FDA for the Treatment of Early Symptomatic Alzheimer's Disease. Press Release. July 2, 2024.
2. ADDF. ADDF Statement on FDA’s Traditional Approval of Kinsunla (Donanemab). Press Release. Comment received via email correspondence on July 2, 2024.

Articles

Kisunla (donanemab-azbt) reduced amyloid plaques in Phase III study participants by 84% after 18 months.

FDA Approves Lilly Treatment for Early Symptomatic Alzheimer’s Disease

Mike Hennessy Jr. is the President and CEO of 

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On June 20, 2024, FDA announced that it had expanded its approval of delandistrogene moxeparvovec-rokl (Elevidys), a gene therapy for the treatment of Duchenne muscular dystrophy (DMD), to cover both ambulatory and non-ambulatory DMD patients of four years and older with a confirmed mutation in the DMD gene (1). This expanded approval will allow for a greater number of patients suffering from DMD, which is a rare and serious genetic condition that progresses over time, to be treated. In addition, the expanded approval will help to meet the urgent unmet medical need of this patient population.

The area of rare, difficult-to-treat diseases is where cell and gene therapies truly shine, offering treatment options where there have previously been none and in some cases, even the potential to eliminate the disease altogether. Given the promise of these advanced therapies, it is no wonder that the global market is expected to witness significant double-digit growth over the next few years (2).

However, as the cell and gene therapy sector continues to mature, greater attention is being paid to increasing therapeutic efficacy while also improving patient safety. This particular topic has been explored in this issue’s cover story on pages 10–12 (3), where experts reveal some of the strategic approaches being used to overcome constraints and challenges related to emerging therapies, such as reducing vector tropism to reduce liver damage or regulating the immunoreceptor complex with a dimerizing agent.

As researchers from all over the industry and regulatory bodies continue to focus on their investigations into approaches and strategies to improve not only the therapies themselves, but also methods to test these novel drugs, their efficacy and safety for patients will be optimized, and more unmet medical needs will be fulfilled.

1. FDA. FDA Expands Approval of Gene Therapy for Patients with Duchenne Muscular Dystrophy. Press Release, June 20, 2024.
2. Research and Markets. 

Cell and Gene Therapy Global Market Report 2024

. Market Report, February 2024.
3. Mirasol, F. Taking Stock of a Maturing CGT Sector. 

Mike Hennessy Jr is president and CEO of MJH Life Sciences®

When referring to this article, please cite it as Hennessy, M. With Age Comes Wisdom. 

A greater number of patients with Duchenne muscular dystrophy will be able to be treated after FDA's approval of a gene therapy.

Publisher's Note: With Age Comes Wisdom

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Angelini Pharma, a part of Angelini Industries in Rome, has announced the “New Drug Delivery Systems and Treatments for Improved Adherence and Better Management of Epilepsy” challenge, its second partnership with Wazoku, an innovation scale-up that boasts a network of more than 700,000 experts in problem solving from scientists and pharmacists to CEOs, engineers, and PhD students (1).

The first pairing between Angelini and Wazoku, which launched a series that Angelini is calling the “Open Innovation Challenge,” sought solutions for new, digital approaches to target discovery in epilepsy (1). Angelini Pharma’s focus in research, development, and commercialization is primarily in the area of brain health—epilepsy included. One of the most prevalent worldwide neurological diseases, epilepsy affects approximately 50 million people and carries risks that include premature mortality at a rate nearly double the general population.

However, given that approximately 70% of people with epilepsy respond to treatments that reduce seizures and improve quality of life, new improvements for existing, available anti-seizure medications (of which there are currently around 30), drug delivery systems (DDS), and treatments are needed to increase adherence (1).

“Approximately one-third of people living with epilepsy face difficulties with anti-seizure medicine adherence, and this is particularly challenging for elderly and pediatric populations,” Rafal Kaminski, Angelini Pharma chief scientific officer, said. “Non-adherence can result in several serious consequences, including breakthrough seizures. This low adherence underscores the urgent need for more effective treatments that can better address the diverse needs of patients with epilepsy.”

“Open innovation is being used more and more in the pharmaceutical sector and its potential to deliver solutions to challenges is vast,” said Dino Ribic, an innovation consultant for Wazoku. “We have already completed one successful campaign with Angelini Pharma, and I await eagerly to see what is delivered this time.”

According to the submission page for the challenge, not only is Angelini seeking solutions that increase adherence from those who choose to participate, but also attention to factors such as age, genetics, and any potential side effects or drug-related aspects like safety, efficacy, pharmaceutical forms, and the optimal dosage (2).

At least one cash prize of $25,000 is guaranteed for the winning submission, with smaller prizes not less than $5000 potentially available for proposed solutions that partially meet the requirements set forth.

The “New Digital Approaches to Target Discovery in Epilepsy” challenge, the maiden partnership between Angelini and Wazoku, received 28 solution submissions, from which the two companies jointly selected four entries for awards. Wazoku said it has handled more than 2500 challenges previously, receiving more than 200,000 ideas for innovation (1).

The “New Drug Delivery Systems and Treatments for Improved Adherence and Better Management of Epilepsy” challenge closes on Aug. 26, 2024. Submissions can be made at 

1. Angelini Industries. Angelini Pharma Launches New Crowd-Sourcing Challenge to Fund Innovative Solutions to Drug Adherence and Management of Epilepsy. Press Release. June 28, 2024.
2. Wazoku Crowd—Challenge Center. New Drug Delivery Systems and Treatments for Improved Adherence and Better Management of Epilepsy. 

The company is referring to its search for innovative approaches as crowdsourcing and will award at least one cash prize.

Angelini Pharma Seeks Solutions for New Drug Delivery Systems and Treatments

Siegfried Schmitt, PhD, is Vice President Technical at Parexel International, Siegfried.Schmitt@parexel.com.

Question mark background | Image Credit: © Leigh-Prather - © Leigh Prather - stock.adobe.com

Q: We received a warning letter (WL) from FDA, to which we provided a written response. Although we are confident that our reply is comprehensive, we would like to get confirmation from FDA. Is there a way to ask FDA to give us this feedback?

A: It is understandable that you want to be certain that your response to FDA is complete and acceptable. You should stay in contact with the person(s) mentioned in your WL and to who you addressed your response letter. In addition, under the Generic Drug User Fee Amendments (GDUFA or GDUFA III Commitment Letter) (1), your facility may be eligible for a Post-Warning Letter Meeting, as described in section VII(D)(1) of the GDUFA III commitment letter (2).

You can only be granted such a meeting if you have “submitted to FDA a thorough and complete corrective action and preventive action (CAPA) plan that addresses all items cited in the warning letter, and reasonable progress has been made toward remediation” (2). As mentioned above, your facility needs to keep FDA informed regularly about progress with the remediation effort as detailed in the CAPA plan. As FDA must see what progress you made, they cannot grant a meeting earlier than six months from the date of a company’s initial response to a WL. In fact, you should be certain that you have reached significant milestones in your remediation program before applying for a Post-Warning Letter Meeting, or FDA may deny you such a meeting.

What can you expect from such a meeting with FDA? The meeting will allow you to present the remediation progress to date and the projected completion dates for any remaining CAPA activities. FDA will voice any concerns they may have regarding your roadmap back into compliance. The agency will tell you if you are on the right track or if additional efforts are needed. It will give you assurance that your planning schedule is appropriate. It should be noted that FDA’s advice is not binding. Furthermore, agreeing to a Post-Warning Letter Meeting “does not preclude FDA from taking any regulatory actions necessary, including a follow-up inspection at any time” (2). You can request a maximum of two Post-Warning Letter Meetings.

Success depends very much on good preparation. You should, therefore, study the FDA’s draft guidance (3) that provides information on how to prepare the Meeting Package and the Meeting Package Content. Should you be eligible for such a meeting, it is recommended that you include this in your overall communication plan with FDA. Returning to a compliant state of operations at your facility has highest priority. Leveraging all available tools to inform and convince the agency of your sincere intentions, actual progress, and estimated fulfillment dates of all commitments is a sensible and logical approach.

FDA. Post-Warning Letter Meetings Under GDUFA. September 2023, 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/post-warning-letter-meetings-under-gdufa

GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027

. https://www.fda.gov/media/153631/download

Post-Warning Letter Meetings Under GDUFA Guidance for Industry

https://www.fda.gov/media/171785/download

Siegfried Schmitt is vice president, Technical at Parexel.

When referring to this article, please cite it as Schmitt, S. Post-Warning Letter Interaction with FDA. 

Communication and meetings with FDA after receiving a warning letter 
demonstrates a serious response, says Siegfried Schmitt, vice president, Technical at Parexel.


Post-Warning Letter Interaction with FDA

Communication between the manufacturing plant and retail stores. | Image Credit: © Cagkan - stock.adobe.com

Aurigene Pharmaceutical Services, an India-based contract research, development, and manufacturing organization (CRO/CDMO), said on July 1, 2024 that it would be providing discovery services in the area of cell therapy to Edity Therapeutics, headquartered in Israel (1).

The partnership, both companies announced in a press release, intends to not only support but also accelerate clinical development of both advanced and novel technologies, and builds on Aurigene’s track record of discovery and development services for advanced therapies, including but not limited to antibodies, antibody-drug conjugates (ADCs), cell therapeutics, and viral vectors (1). The agreement follows an initial strategic collaboration started between Edity and Aurigene’s parent company, Dr. Reddy’s Laboratories, in January 2024 (2).

“We are delighted to add Edity to the growing list of global companies recognizing Aurigene as a valued partner in the biologics and advanced therapies space,” said Roger Lias, PhD, global commercial head of biologics for Aurigene, in the press release. “Our true end-to-end service offering from discovery through large-scale CGMP [current good manufacturing practice] manufacture allows us to efficiently deliver speed, unwavering quality and economically viable solutions to our customers as they bring much-needed therapeutics to patients.”

In the press release, Edity detailed its development of a first-of-its-kind immune cell delivery platform, which the company says allows for selective delivery intracellular therapeutic proteins—with the end result of targeting cells at a high level of specificity (1). Currently, Edity says it has product candidates across the fields of oncology, gene therapy, autoimmune disorders, and regenerative medicine.

Regarding oncology, Edity said it has been focusing on meeting the challenges of cell therapies for solid tumors, including antigen heterogeneity, the immunosuppressive tumor microenvironment, and tumor resistance to death (2).

"We are excited about the collaboration and look forward to working with Edity in building novel technologies,” Aurigene CEO Akhil Ravi said in the release. “Edity’s cellular reprogramming technology to deliver therapeutic payloads, specifically to target cells, adds a new mechanism to CAR [chimeric antigen receptor]-T based cell therapeutics with the potential to significantly increase the efficacy."

In January 2024, Edity announced the beginning of a strategic collaboration with Dr. Reddy’s Laboratories, the parent company of Aurigene, to create novel cell therapy medicines using Edity’s proprietary delivery platform. That announcement followed the acquisition of an equity stake in Edity by Dr. Reddy’s (2). The new pairing of Edity with Aurigene aligns with the latter company’s goal of providing cost-effective manufacturing of small molecules and biologics (1).

“We are thrilled to be working with Aurigene's world-class team,” Edity CEO Michal Golan Mashiach said in the release. “Their experience and breadth of technology offerings will help Edity to advance our pipeline and help patients with severe diseases. This collaboration will support our growth as we seek to create best-in-class medicines.”

1. Aurigene Pharmaceutical Services. Aurigene Pharmaceutical Services Limited, a Global CRDMO, and Edity Announce a Strategic Collaboration in Cell Therapy. Press Release. July 1, 2024.
2. Edity Therapeutics. Edity Therapeutics Enters Into a Strategic Collaboration with Dr. Reddy’s Laboratories to Advance Novel Cell Therapy Approach Using Edity’s Proprietary Delivery Platform. Press Release. Jan. 16, 2024.

This collaboration aims to support and accelerate clinical development of advanced and novel technologies.

Aurigene to Provide Cell Therapy Discovery Services to Edity to Support Clinical Development

Feliza Mirasol is the science editor for 

GSK's application for expanding the use of Jemperli (dostarlimab) in combination with standard-of-care chemotherapy (carboplatin and paclitaxel) has been accepted by the European Medicines Agency (EMA). GSK is seeking approval for the combination therapy for treating all adult patients with primary advanced or recurrent endometrial cancer. The EMA’s Committee for Medicinal Products for Human Use is expected to begin formal review process to make a recommendation to the European Commission, with approval expected in the first half of 2025, according to a June 24, 2024 GSK company press release.

In the European Union (EU), Jemperli in combination with carboplatin and paclitaxel is currently approved for treating adult patients who are candidates for systemic therapy with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H). If approved under the new application, dostarlimab would be expanded to treating all patients with primary advanced or recurrent endometrial cancer. Treatment would be administered regardless of the patients’ biomarker type, including those with mismatch repair proficient (MMRp)/microsatellite stable (MSS) tumors, where currently no approved frontline immuno-therapy-based treatments are available in the EU, according to GSK in the press release.

GSK’s application is based on results from Part 1 of a Phase III trial (RUBY), in which the primary endpoint was met—investigator-assessed progression-free survival and overall survival (OS), which demonstrated a statistically significant and clinically meaningful benefit in the overall patient population treated with dostarlimab plus carboplatin-paclitaxel compared to chemotherapy alone. According to the company press release, this trial is the only clinical trial that has shown a statistically significant OS benefit in this patient population. “The safety and tolerability analyses from RUBY showed a safety profile for dostarlimab plus carboplatin-paclitaxel that was generally consistent with the known safety profiles of the individual agents,” GSK stated in the release.

Endometrial cancer is found in the endometrium (inner lining of the uterus) and is the most common gynecologic cancer in developed countries. Approximately 417,000 new cases are reported each year worldwide (1) with incidence rates expected to increase by almost 40% between 2020 and 2040 (2,3). Approximately 121,000 people are estimated to be diagnosed with primary advanced or recurrent endometrial cancer yearly in Europe (4).

Jemperli, which was discovered by AnaptysBio, was licensed to TESARO in March 2014 (5); in December 2018, GSK announced its acquisition of TESARO in 

 (6). Therefore, under the agreement with AnaptysBio, GSK is responsible for the ongoing research, development, commercialization, and manufacturing of Jemperli as well as another monoclonal antibody, cobolimab (GSK4069889), a T-cell immunoglobulin and mucin domain-containing protein 3 antagonist.

Jemperli is a programmed cell death receptor-1-blocking antibody; it forms the backbone of GSK’s immuno-oncology-based R&D program, according to the company press release. The company is carrying out a robust clinical trial program for Jemperli, including studies of Jemperli alone and in combination with other therapies in gynecologic, colorectal, and lung cancers. In the United States, Jemperli is approved in combination with carboplatin and paclitaxel, followed by Jemperli as a single agent, for treating adult patients with primary advanced or recurrent endometrial cancer that is dMMR, as determined by a FDA-approved test, or MSI-H. Separately, it is approved as a single agent to treat adult patients with dMMR-recurrent or advanced endometrial cancer, as determined by a FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and who are not candidates for curative surgery or radiation. Jemperli is also indicated in the US for treating patients with dMMR recurrent or advanced solid tumors, as determined by a FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

Meanwile in the EU, Jemperli is indicated in combination with carboplatin-paclitaxel for treating adult patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer and who are candidates for systemic therapy, and as monotherapy for treating adult patients with dMMR/MSI-H recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.

1. Faizan, U.; Muppidi, V. Uterine Cancer (Archived) [Updated Sep 4, 2023]. In 

; StatPearls Publishing, 2024.
2. Braun M. M.; Overbeek-Wager, E. A.; Grumbo, R. J. Diagnosis and Management of Endometrial Cancer. 

 (6), 468–474.
3. International Research on Cancer. Global Cancer Observatory. 

 gco.iarc.who.int/tomorrow/en (accessed July 1, 2024).
4. Concin, N.; Matias-Guiu, X.; Vergote, I.; et al. ESGO/ESTRO/ESP Guidelines for the Management of Patients with Endometrial Carcinoma. 

International Journal of Gynecologic Cancer

, 12–39.
5. AnaptysBio. Anaptysbio and Tesaro Announce Strategic Immuno-Oncology Antibody Collaboration. Press Release, March 13, 2024.
6. GSK. GSK Reaches Agreement to Acquire TESARO, an Oncology Focused Biopharmaceutical Company. Press Release, Dec. 3, 2018.

GSK’s application for using Jemperli (dostarlimab) plus chemotherapy for all adult patients with primary advanced or recurrent endometrial cancer has been accepted by the EMA.

GSK’s Application for Jemperli Plus Chemotherapy for Use in All Patients with Endometrial Cancer Accepted by EMA

ROSS Model HSM-405SC-25 Inline High Shear Mixer | Image Credit: © Charles Ross & Son Company

The ROSS Model HSM-405SC-25 Inline High Shear Mixer with solids/liquid injection manifold (SLIM) Technology is designed for production floors that require flexibility. The stainless-steel portable skid features a built-in workbench that helps save time and money. It allows the mixer to be used anywhere in a plant, eliminating the need for separate mixers for each vessel or product.

As an external mixer, the Inline SLIM can be piped to the recirculation loop of virtually any size vessel. Featuring sanitary tri-clamp connections, this 3A-compliant machine can be cleaned in place or quickly disassembled for deep cleaning and sanitation. Using the tabletop workbench, operators can open bags and load powders into the hopper that sits on top of the mixer, ensuring a consistent feed and minimizing aeration.

The SLIM is a unique rotor/stator device capable of injecting powders directly into a fast-moving liquid stream without the use of an eductor or pump. Engineered for high-speed and high-volume mixing requirements, this device can wet out powders and create a fine immediate dispersion, greatly reducing the occurrence of floating powders, lumps, and agglomerates.

The ROSS Model HSM-405SC-25 Inline High Shear Mixer features a built-in workbench and is designed for production floors that require flexibility.

Flexible Inline High Shear Mixer with Built-in Workbench

Thermo Fisher Scientific has introduced the Thermo Scientific Heracell VIOS 250i AxD CO2 Incubators, first-of-their-kind CO2 incubators designed for integration into automated and modular laboratories to support future implementation of automated cell therapy workflows. The VIOS family of incubators are known for optimal cell growth conditions and minimal contamination risk. The new Heracell VIOS 250i AxD incubators have the added innovation of a patent-pending automated door control, allowing them to open automatically when integrated into a centralized lab automation platform. The added innovation allows for vessel loading and unloading through robotic control and supports continuous cell therapy production processes. Other important features include in-chamber high efficiency particulate air filtration; Thermo Scientific THRIVE active airflow for homogeneous culturing conditions throughout the incubator chamber; and the Thermo Scientific Steri-Run Cycle, which is capable of a 12-log sterility assurance level, eliminating more than one million biological indicators for both dry heat sterilization and autoclave sterilization in half the lethal time used in production models.

The VIOS family of incubators are known for optimal cell growth conditions and minimal contamination risk.

CO2 Incubators

Big data technology and data science illustration. Data flow concept. Querying, analysing, visualizing complex information. Neural network for artificial intelligence. Data mining. Business analytics. | Image Credit: © NicoElNino - stock.adobe.com

Wherever there are large volumes of complex data to be processed and understood, especially where information exists in an unstructured form (in a Word document or some other note form, perhaps mentioned in an email), there is considerable administrative overhead involved in rendering the pertinent content useable and meaningful. And it is here that the latest advances in artificial intelligence (AI) and machine learning (ML) offer substantial process transformation potential, not only process efficiency, but also significantly improved accuracy—once the software knows what it is looking for.

Generative AI (GenAI) technology, using large language models (LLMs), has shown a new path forward by quickly understanding what to look out for and ably summarizing key findings for the user—and, crucially, without the need for painstaking “training” by overstretched teams, or validation of each configuration (required to cope with each different content format).

In a drug development context, safety and regulatory requirements present an enormous data burden that consumes vast resources and usually carries a time-based penalty (e.g., linked to prompt adverse event notification or safety reporting, or affecting speed to market). While process automation solutions have existed for some time to lighten the manual load and enhance efficiency, there have been two main sticking points up to now: how to swiftly train modern AI algorithms so that they pick up on only what’s significant, and how to satisfy regulators’ need for accuracy and transparency (so that any findings can be fully trusted).

LLMs (the vast data banks referred to by GenAI tools), and advanced natural language processing (NLP) techniques like retrieval-augmented generation (RAG), are now being applied to fill these gaps and make advanced automation a safe and reliable reality in key life sciences R&D processes, and crucially without the need for continuous, painstaking oversight. In simple terms, RAG simplifies the process of fine-tuning AI models by allowing LLMs to integrate proprietary data with publicly available information, giving them a bigger pool of knowledge, and context, to draw from.

Learning on the fly, without risk to data

The biggest breakthrough with all of this is that specialized applications can now be developed that can apply GenAI-type techniques, contextually, to data they haven’t seen before—learning from and processing the contents on the fly.

For drug developers, this has the potential to transform numerous labor-intensive processes ranging from dynamic data extraction associated with adverse event (AE) intake, to safety case narrative generation, to narrative theme analysis in safety signal detection, to the drafting of safety reports. And solutions for all of these use cases are coming down the line.

Importantly, carefully combined LLM and RAG capabilities are sufficiently transparent and explainable to regulators for the technology to be acceptable as safe and reliable. Responsible AI and AI compliance are particularly critical in life sciences-use cases, so it is essential that companies deploy solutions that are proven and transparent. The LLM/RAG approach addresses potential concerns about data security and privacy, too, as it does not require the use of potentially sensitive patient data for algorithm training and ML. It also stands up to validation by way of periodic sampling by human team members, sampling which can be calibrated as confidence grows in the technology’s performance, ensuring that efforts to monitor its integrity do not undermine the significant efficiency gains that are possible.

The trouble with ML solutions up to now has been the training burden. For instance, in the case of AE recording, systems would need to be shown what to look for in the information provided via a range of different channels and formats, before extracting and processing it. For each different source type, a new configuration of the software would be needed too, pushing up the training overhead and overall expense, including the maintenance burden each time the technology was updated.

LLMs make it possible to bypass the need to train AI models or algorithms on what to look out for and/or what something means, so that a single technology solution can handle all variations of incoming data. RAG patterns can play an important role here, in explaining a standard operation procedure to an LLM using natural language, so that the system knows what to do with each of many thousands of forms—without the need for special configuration for each relative format.

The potential impact is impressive. Application of LLM/RAG technology to transform AE case intake has been shown to deliver upwards of 65% efficiency gains, with 90% or better data extraction accuracy and quality in early pilots of our Advanced Intake solution this year (1). In the case of safety case narrative generation, the same technology is already demonstrating 80–85% consistency in the summaries it creates. And that’s from a standing start, without prior exposure.

The ability to retrieve data in context, rather than via a “Ctrl-F” (find all) command (e.g., everything among a content set that mentions headaches) could transform a range of processes linked to safety and AE discovery and reporting.

Certainly, it lays the foundation for drug developers to substantially streamline some of their most demanding data-based processes. In due course, these will also include the drafting of hefty regulatory safety reports, with advanced automation generating the preliminary narrative, and narrative theme analysis in safety signal detection. Here, there is vast scope for the technology to help in distilling trends that have not been captured in the structured data. These could include a history of drug abuse, or of people living with obesity, across 500 patient narratives that are potentially of interest. The potential is extremely exciting.

It is this kind of development that is now being avidly discussed at meetings of the industry’s new global GenAI Council, a powerful peer group that is pushing the boundaries of what’s possible with Generative AI across the life sciences R&D lifecycle. Any hesitation about adopting smarter automation out of reliability or compliance fears has now been superseded by a hunger to embrace new iterations of the technology which directly address those concerns and deliver demonstrable step changes in productivity and efficiency. That 2024–2025 will be a defining period for GenAI and surrounding innovation in this industry seems certain.

1. Aris Global. Early customer pilots of ArisGlobal Advanced Intake, 2024.

 is vice president of technology at ArisGlobal, with a special interest in the application of AI and ML to transform life sciences R&D regulatory and safety use cases. He is based in Bengaluru, Karnataka, India. 

 is vice president of product development at ArisGlobal, and a specialist in digital transformation in life sciences R&D. He is based in Charlotte, North Carolina, USA. 

linkedin.com/in/ravikanth-valigari-93311520/

Both Ramesh and Ravi have deep expertise in applying AI, NLP, and other smart automation technologies to life sciences R&D regulatory and safety use cases via powerful, targeted and quick-to-deploy cloud/multi-tenant software as a service (SaaS) applications.

Life sciences data sets can be vast and complex to process, but up to now bringing intelligent automation systems up to speed and validating them has felt debilitatingly onerous. Large language models tackle these barriers head on. Ramesh Ramani and RaviKanth Valigari, technology innovators at ArisGlobal, explain.

Beyond GenAI: The Training-Free Discovery Potential of LLMs in a Drug Safety and Regulatory Context

The National Institute for Pharmaceutical Technology and Education (NIPTE), a nonprofit organization that partners with 17 universities in the United States along with other institutions in and outside of academia, has released a strategy to reduce risks to the US pharmaceutical supply chain, in a white paper and press release issued June 18, 2024 (1–3).

The white paper, “Overcoming Global Risk to the Pharmaceutical Supply Chain for the United States: Achieving Pharmaceutical Independence by Reshoring Manufacturing Capacity and Capability,” was co-authored by Vadim J. Gurvich, NIPTE executive director and a professor at the University of Minnesota, and professors Fernando J. Muzzio of Rutgers University and B. Frank Gupton and James K. Ferri of Virginia Commonwealth University (2).

"We are issuing a call to action to refine the identified priorities and begin to work towards implementation," Gurvich said in the press release. "The time to act is now."

In summary, the authors say that because the United States relies on imports from overseas, primarily China, for the majority of APIs for the manufacture of drug products of crucial importance to US patients, there is a need to find new “synthetic pathways” for APIs as well as excipients, using “chemical building blocks” manufactured in the US or countries which are close allies (1).

"If a major disruption of international commerce prevented the US from importing APIs and finished pharmaceutical products, the impact could be catastrophic," Gurvich said. "We currently lack much of the industrial capacity needed to replace API imports. We need to find consensus and begin to implement a plan."

The strategy would identify the 50 most crucial medicines for life-saving treatment in the US, building on other, existing critical medicine lists. Furthermore, NIPTE intends to use artificial intelligence (AI) tools to optimize manufacturing routes for these drugs.

"AI-assisted retrosynthetic analysis and reaction databases can be used to create potential routes to each regulatory starting material (RSM),” Gurvich said. “Other tools will be expanded to predict impurities and identify separation procedures. In developing updated, advanced manufacturing processes, we can also build in efficiency and environmental and economic sustainability."

Making manufacturing more efficient in this way, NIPTE said, could lower processing costs for generic drugs, which would play a central role in alleviating drug shortages (1).

With regard to a timeframe for implementing this strategy, the white paper said that development, scaling up, and transfer of each new formulation of each API and excipient of interest would take approximately six months, but that bioequivalence studies and stability testing would require additional time (2). The creation of a nonprofit corporation has been proposed to be the main program management entity that reports to the government, and a board created by the government and participating organizations.

1. NIPTE. NIPTE Announces Call to Achieve US Pharmaceutical Independence by Building On-Shore Capacity and Capabilities. Press Release. June 18, 2024.
2. Muzzio, F.J.; Gupton, B.F.; Ferri, J.K.; and Gurvich, V.J., “Overcoming Global Risk to the Pharmaceutical Supply Chain for the United States: Achieving Pharmaceutical Independence by Reshoring Manufacturing Capacity and Capability,” Whitepaper, June 18, 2024.
3. NIPTE. About—The National Institute for Pharmaceutical Technology and Education. 

The US currently relies heavily on imports from China and other overseas nations for APIs needed to manufacture drug products of critical importance to US patients.

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