December 15, 2023 PAO-12-23-RT-02
First-in-human phase 0 imaging studies are also known as microdosing proof-of-concept studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of phase 0 studies include the administration of single subtherapeutic doses of the study drug to typically a small number of subjects to gather preliminary human in vivo data on pharmacokinetics, pharmacodynamics, and the target. They enable go/no-go decisions to be based on relevant human models instead of relying on animal data, which can be unpredictive and vary between species. A phase 0 study gives no data on safety or efficacy to cause any therapeutic effect and less risk to human toxicity (USFDA, CDER Guidance, August 2018).
The recent advancements and the great potential of Theranostics technology has allowed the utilization of radioimmune conjugates for diagnosis and treating various diseases in humans. To this end, the use of radiopharmaceutical drugs in phase 0 human studies and prior to early-phase human clinical trials are poised to become more mainstream and strategic regulatory guidance toward rapid, safer, cheaper, and more informed developmental decision in 2024 and beyond. GBI Biomanufacturing is a U.S.-based CDMO with about 20 years of experience and expertise in the radioimmune conjugate (and bioconjugation) arena.
The revision of EU GMP Annex 1, Manufacture of Sterile Medicinal Products, became effective in August 2023. This regulatory document provides general guidance for the manufacture of all sterile products using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate, and pyrogen contamination is prevented in the final product. Major elements of the existing quality management system (QMS) for sterile manufacturing are challenged with a general implementation period of 12 months. As a result, potential re-design of legacy installations has to be assessed and upgraded where needed.
Simultaneously, the FDA communicated an adjustment to their policy for inspections, mainly for Biologics License Applications (BLAs). Programs in established production facilities may not need to be inspected in person in the future, creating an opportunity for customers to benefit from faster approvals and potentially reducing the costs involved in gaining approvals.
The EU Green Deal includes several strategies and action plans which directly impact the pharma and biotech industry: Chemicals Strategy for Sustainability (CSS) was adopted in October 2020 to realize Europe’s zero-pollution ambition.
As it is translated to regulation in the coming years, it will change the available choices of reagents and raw materials for the pharma and biotech industry. Our customers might need to find substitutes for currently indispensable precursors, even if pharmaceutical regulations do not change.
While it is possible that exemptions for supplying the pharma industry will be granted in some cases, producing said product purely for the biotech and pharma industry might no longer be economically viable and therefore cease. With global, intertwined supply chains, U.S. companies are as much affected as the European ones.
Even more so, bans and restrictions will not only be introduced quicker and with a wider scope than ever before, but they will also be accompanied by comprehensive sustainability obligations and reporting, requiring contributions from the whole supply chain. Additionally, more regulations will follow for advanced materials, such as nanomaterials or biopolymers, which are widely used in pharma and biotech.
Within our organization, we have been diligently working to develop long-term viable solutions for our customers and will continue to invest in innovation for further yet unresolved challenges.
Achieving greater patient representation in clinical research has been a focus area of regulatory agencies for years. However, there is a lack of consistency across the industry in terms of readiness and proactive efforts to promote diversity throughout the drug development process. The U.S. Food and Drug Administration (FDA) is set to publish final guidance on diversity action plans in the coming year. This guidance will require clinical trial sponsors to establish benchmarks and tailored strategies for enrolling underrepresented populations in phase III clinical studies or other pivotal studies. The FDA also will release an annual report on these action plans, including explanations for any shortcomings in diverse enrollment.
During the FDA Virtual Public Workshop to Enhance Clinical Study Diversity in November 2023, it was emphasized that patient diversity is a top priority for the FDA. The FDA's mandates – including the Food and Drug Omnibus Reform Act (FDORA), Patient Diversity Plan Guidance and Decentralized Clinical Trials Guidance –– are crucial steps toward improving health equity and encouraging change in clinical research practices. The guidance on diversity plans is expected to foster greater transparency and dialogue among regulators, sponsors, clinical research organizations, research sites, community partners, and other stakeholders. This collaborative effort will help identify what strategies are effective and what areas need improvement. The insights gained from these experiences will be invaluable and will be the responsibility of the clinical research community to integrate into standard operating procedures, ensuring that patient diversity becomes a fundamental aspect of the research process.
Moving into 2024 amid the never-stagnant regulatory landscape, the biologics industry may face mounting difficulties in sufficiently supplying high-demand drugs to where they are needed the most on time. Affected by the stringent health authority oversights, the COVID-19 pandemic hangover, wars in Ukraine and Israel, and the ongoing power game between the United States and China, the need for regulatory expertise and operational flexibility in coping with rigorous regulatory guidance would likely grow among drug developers across the world.
In tandem with the growing regulatory challenges, drug developers may need to seek help from a competitive contract development and manufacturing organization (CDMO) offering a depth of regulatory expertise and experience, along with its one-stop development/manufacturing service. CDMOs adept at processing the realm of regulations varying by each country in a fast but reliable manner can help drug developers in bringing early access to their drugs to patients.
Additionally, the emergence of personalized medicines, increased demand for biosimilars, the rapid approval of orphan drugs, and the growing industry’s emphasis on ESG compliance will further encourage more drug developers to seek help from CDMOs offering sustainable business strategies and execution optimized for minimizing risk while maximizing quality. Therefore, the role of CDMO is projected to take a larger pie in the biologics industry as the global regulatory atmosphere continues to evolve.
Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)
In 2024, the most significant regulatory decisions will be centered around the implementation of the Inflation Reduction Act (IRA) and the Centers for Medicare & Medicaid Services (CMS) negotiations with drug manufacturers on September 1, when Maximum Fair Prices (MFPs) are set to be published. Patient assistance programs face scrutiny, and potential policy changes could impact affordability. The pharmaceutical industry anticipates budget constraints, leading to a reevaluation of investments and a shift in research and development (R&D) focus. New and emergent biopharma is expected to collaborate through joint ventures. Regulatory changes are foreseen in AI and precision medicine, while cell and gene therapy (CGT) discussions extend beyond therapy to broader patient experiences. Clinical trials prioritize decentralization, and therapeutic advances include GLP-1s achieving widespread prescription status
Generative AI Regulation. As we look towards 2024 and beyond, the most significant regulatory guidance in the pharma/biopharma industry is expected to revolve around the regulation of GAI technologies. With GAI becoming increasingly integral to various pharmaceutical processes, regulatory bodies are poised to play a crucial role in shaping how these technologies are managed. The focus of upcoming regulatory guidance will likely be on ensuring that GAI is used responsibly and ethically in the industry. This includes addressing concerns related to data privacy, as GAI systems often require access to sensitive patient and research data. Regulators will aim to establish frameworks to safeguard these data against misuse or breaches. Another area of focus will be on addressing the potential for biased outputs from GAI systems. As these technologies rely on data for learning and decision-making, there is a risk that potentially biases in the data could lead to skewed or unethical outcomes. Regulatory bodies will seek to ensure that GAI systems are designed and operated in a manner that minimizes such biases, promoting fair and unbiased outcomes. Industry regulators are also likely to emphasize the importance of establishing strong governance policies within pharma/biopharma companies. These policies will be crucial in managing the risks associated with GAI use, ensuring accountability, and maintaining the integrity of pharmaceutical processes.
On October 1, 2023, India brought in a mandatory requirement to provide an IUPAC name and CAS number for bulk and basic chemicals, and on October 17, 2023, the EC dropped the chemicals (REACH) reform.
Meanwhile, the UK charts its post-Brexit regulatory path, and the Rolling Action Plan (RAP) for UK REACH promises to shape the future landscape for pharma and biotech companies in the UK. This roadmap emphasizes key objectives, including regulatory clarity, risk assessment and management, innovation support, and international collaboration.
The UK REACH Alternative Transitional Registration model’s (ATRm) aim is to reduce the cost to business whilst maintaining health and the environment; consultation on this policy starts in early 2024.
RAP introduces a new era of regulatory expectations. Compliance will demand a heightened focus on data integrity, safety assessments, and adherence to evolving guidelines. The RAP aims to foster innovation by supporting research and development in biotechnological and pharma ecosystems.
RAP’s emphasis on aligning with global standards and sharing best practices ensures smoother cross-border commerce, with the intent to form a cohesive global biotech pharma community.
Navigating the RAP will necessitate strategic resource allocation, but companies that embrace this dynamic regulatory landscape and get involved in the ATRm consultation can not only ensure compliance but also ensure their voice is heard.
In summary, RAP for UK REACH alongside the changes that could come out of ATRm represents both a challenge and an opportunity. Adapting to these changes will require a forward-thinking approach and the ability to keep up.
Now that we’ve witnessed the power of CRISPR for diseases like transfusion-dependent beta thalassemia (TDT) and sickle cell disease (SCD), in the next few years I believe we will see additional approvals using CRISPR to treat a wide range of diseases. I also believe that CAR-T cell therapies will continue to provide significant benefits to patients and will gain additional regulatory decisions in the next few years. The recent news surrounding CAR-T sheds light on the need to continue monitoring patients for safety, but it is clear that the benefits of the approach significantly outweigh the risk.
With medicines like CRISPR and CAR-T, the field is moving toward novel modalities and therapeutic approaches beyond small molecules and antibody-based therapies. While there is still a significant need for small molecules and antibodies, newer medicines are now proving their value. This was apparent during the COVID-19 pandemic, which realized the transformative potential of RNA-based therapeutics.
As a life sciences community, we need to continue pushing for novel methods to treat diseases because the status quo is not adequately addressing patient needs and improving outcomes. To achieve this, and before we bring new drugs into patients, we need to tap into advanced technologies like artificial intelligence (AI) and machine learning to ensure that the next generation of medicines are rationally designed for long-term safety and efficacy.
The cell and gene therapy space is hindered by a lack of standardization in several key areas. In particular, regulators in the United States and Europe can play a pivotal role in guiding the development of standards for starting materials to support the growing numbers of clinical trials. Ideally, this should start with guidance that clearly defines the specification or qualification of the starting materials. This is especially needed for allogeneic cell therapies, and we hope to see new rules implemented in the coming years. We hope regulators will also support standardization of other key aspects of the starting material collections and logistics process, including characterization criteria for cell collections and cryopreservation.
As an industry, we remain focused on the quality of the end product cellular therapy that is to reach patients. To ensure this, it is equally important to invest significant attention in the starting materials used to manufacture potent batches of cell and gene therapies. Given the rapid growth of this space and the tendency of biopharma companies to withhold data that might otherwise support the development of standards, it's imperative for regulators to push forward with guidance in this sector.
The regulatory landscape for the pharma and life sciences industry will heat up in 2024. One area of regulation, specifically related to both clinical and in vitro drug–drug interaction studies, that I am keeping my eye on is what’s coming out of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The committee is working on a final “Drug Interaction Studies” guideline (M12) –– which should be released in April 2024. We saw the initial draft come out July 2022, which combines insight from multiple entities –– the FDA, EMA, and PMDA, for example. However, when we see the guidance finalized next year, it will allow all pharma companies to take a single approach to running in vitro drug interaction studies. So, instead of going through several different study designs (which is the current process) from the key entities, pharma companies will eventually have one standard design that will be consistent across the board and submittable to all the different regulatory agencies. I expect this to have a positive impact on the industry at large. The result of the “all in one” method will streamline the approach experimentally for in vitro drug interaction studies and will expedite the timeline to get drugs approved on multiple markets and available to patients that need them most and quicker –– which is something I am excited about and look forward to seeing come to fruition in the coming year.
The role of decentralized clinical trials (DCTs) in the clinical trial industry has changed in recent years, and the COVID-19 pandemic further impacted the way they can be conducted. The next evolution of DCTs will include self-service tools that allow sponsors and sites to set up and run global trials on a common platform using standardized processes. These DCTs, whether fully or partially decentralized, include artificial intelligence/machine learning, augmented reality, virtual reality, digital therapeutics, wearables, remote patient monitoring, and software. Some trial activities will involve in-person visits by trial participants, and other activities will be conducted at locations other than traditional clinical trial sites, such as participants’ homes.
Next year, the FDA’s new Digital Health Advisory Committee will explore the complex scientific and technical issues relating to DCTs and provide recommendations to sponsors, investigators, and other stakeholders regarding drugs, biologics, and devices. The committee demonstrates the agency’s strong interest in finding more efficient ways to bring innovative medicines to patients as quickly as possible.
In 2024, we will also see major regulatory decisions and guidance on the use of AI and digital tools for therapeutics and health monitoring, with significant implications for clinical trials and healthcare management. Biopharmaceutical companies, such as BioSenic, have groundbreaking products in their pipelines that could save many lives or significantly improve patients' quality of life. It is heartening to see regulators committed to overcoming hurdles that can delay development and impede patient access. Ensuring that innovative medicines get into the hands of patients quickly and easily should be the number one priority of every regulatory system.
Regulations around synthetic therapeutic peptides and oligonucleotides are –– and will be –– of vital importance to improve product knowledge and hence product risk assurance. The use of state-of-the-art analytical technologies, such as nuclear magnetic resonance (NMR) and mass spectrometry (MS), is highly recommended. What is not measured or controlled may lead to unintended consequences, such as loss of potency or efficacy or even undesired pathological effects. NMR is highly sensitive to changes in the primary, secondary, and tertiary structure of active pharmaceutical ingredients (APIs) and drug products [1,2]. It is also able to differentiate diastereomers, such as those arising from non-stereospecific P=0 P=S substitutions in phosphorothioate oligonucleotides [3,4,5].
Following the increased interest in peptide therapeutics, such as synthetic human glucagon and glucagon-like peptide-1 (GLP-1), the European Medicine Agency (EMA) has announced a new draft guidance on the development and manufacture of synthetic peptides. According to the draft guidance, NMR experiments are recommended to be part of the characterization studies, and their use is encouraged to give details about possible (or absence of) 3D structure and as an orthogonal method for the identification of the peptide as part of the specifications and release.
Guidance has also been provided on the use of oligonucleotide therapeutics. For example, recent draft guidance from the United States Food and Drug Administration (FDA) on givosiran sodium recommends testing with orthogonal analytical methods with sufficient sensitivity, discriminating, and resolving power, such as NMR.
Building upon an FDA public workshop entitled “Advancing the Utilization and Supporting the Implementation of Innovative Manufacturing,” one of the most significant regulatory programs on the horizon in 2024 and beyond will be the rollout of the Advanced Manufacturing Technologies Designation Program (AMTDP). The AMTDP stems from the Prescription Drug User Fee Act (PDUFA) VII commitment letter and the Federal Food, Drug, and Cosmetic Act and is designed to support the implementation and use of innovative platform technologies to manufacture drug products that are of equivalent or superior drug quality. The AMTDP will outline the regulatory strategies and science and risk-based approaches for the development and adoption of innovative manufacturing technologies across multiple drug products and manufacturing sites. Specifically, this program will play a critical role in allowing cell and gene therapy (CGT) developers to drive towards industry standardization and streamline the chemistry, manufacturing, and controls (CMC) strategy for CGTs where CMC remains the bottleneck in getting these lifesaving therapies to patients. The CGT industry needs to move away from complex and bespoke manufacturing processes where processes are changed throughout the drug development life cycle. Instead, the industry needs to move toward the implementation of platform technologies that will enable CGT developers to reliably deliver safe, efficacious, high-quality, and cost-effective drug products for all patients in need. The AMTDP will undoubtedly be an important program in supporting CGT developers in the translation of their CGT product portfolio to patients and accelerate access to these life-saving therapeutics.
The most significant regulatory topic on the horizon appears to be the FDA’s renewed vigor on pharmacovigilance. The agency appears to have adopted a persistent strategy to highlight safety concerns and absence of long-term survival benefit with approved medicines.
This is not contradictory as it may seem to the cursory reader. In fact, it is entirely within the agency's mandate to protect public health while still allowing for early access mechanisms to bring innovation to patients in need. This strategy underscores a delicate balance between innovation and risk mitigation, reaffirming the FDA's dedication to fostering a robust and safe pharmaceutical landscape for patients in need.
This includes for example:
I expect there will be continued emphasis on data privacy and security in 2024 and beyond. Life sciences organizations continue to enable their digital transformation efforts, and this will likely be accelerated by the intent to adopt AI/ML, in addition to cloud and digital data approaches. Success with AI depends on access to quality data and relies upon an infrastructure that supports data access for a regulated environment. We know from our clients that these areas are top of mind and, as such, we have successfully maintained SOC 2 Type II certification for several years, continuing to evolve our posture with the addition of two recent ISO certifications. As more organizations in life sciences contend with these challenges, there will likely be additional guidance from regulatory authorities informing approaches for protecting and securing valuable data in the context of digital trials.
Pharma 4.0 has been a buzzword in the industry for some time, but it is only recently that it has gained more attention and urgency. One of the reasons for this is the rapid increase of general awareness driven by generative artificial intelligence (AI), such as ChatGPT. Additionally, we have seen advancement of AI and its applications in various aspects of pharmaceutical manufacturing and quality.
AI has the potential to transform the way we design, develop, produce, monitor, and control our products, as well as how we interact with regulators and customers. AI can also enable us to leverage the vast amount of data that we generate and collect and turn them into actionable insights and value. However, AI also poses new challenges and risks, such as ethical, legal, and technical issues, that need to be addressed by appropriate regulatory frameworks and guidance.
The development and implementation of such frameworks and guidance is anticipated to be the most significant regulatory decision or guidance on the horizon for 2024 and beyond. It will have a profound impact on how we operate and innovate in the pharma industry, and how we ensure the quality, safety, and efficacy of our products.
In the biopharma industry, there is a need for quality and regulatory standards to be harmonized for bioprocess ingredients used in cell culture media and upstream and downstream processes. Using low-quality ingredients with unclear or flexible standards in the bioprocesses that create important biologic drugs, such as monoclonal antibodies, antibody–drug conjugates, and other therapeutic proteins is still a cause for concern. Evonik is doing its part by strictly adhering to quality and regulatory standards, producing ingredients in regularly audited cGMP facilities, following a global pharma-grade quality system, and controlling impurities including endotoxins and heavy metals. However, there is a need for regulatory guidelines to ensure that all bioprocess ingredients meet the same high standards.
In 2024 and beyond, it will also be interesting to see the impact of the U.S. Inflation reduction Act (IRA) on the pharmaceutical industry. The implementation of the IRA in the industry remains uncertain, and patents on many of the first 10 drugs will expire by the time negotiated prices become effective. This means that market prices will reduce due to competition from generic drugs. If further drugs are included on Medicare's list for price negotiation, the global pharmaceutical sector may start shifting its R&D focus toward complex biologic products with longer periods before price negotiation is required. As a result, small molecule drugs may receive less attention and investment as they often experience significant sales revenue loss in the 12 months following patent expiration. This shift in focus could lead to an even greater focus on biologics in pipelines.
AI's foray into healthcare predominantly concentrated on chemistry. This focus was logical, given the tangible, quantifiable nature of chemical interactions. However, as we enter 2024, I anticipate a significant shift towards biology. This pivot represents a shift in how we approach healthcare and drug development. Biology, with its complex systems and intricate processes, offers a fertile ground for AI to unearth insights that were previously unattainable. In this context, AI becomes a tool for understanding biological mechanisms at a molecular level and integrating these insights into a broader, system-wide context. By harnessing AI in biology, we are poised to discover new therapeutic targets, which are the starting points for drug discovery. These targets, often hidden in the vast complexity of biological systems, can now be identified with greater precision and speed. AI's role in understanding patient biology allows for more personalized treatment approaches. This personalization is not just about selecting the right drug for the right patient but also involves tailoring treatment regimens and combinations to individual patient needs. While the incremental gains from AI applications in chemistry were noteworthy, the shift to biology is where I believe the monumental breakthroughs will occur. These breakthroughs will not only redefine drug discovery but also fundamentally change how we understand and treat diseases. As a leader in this space, Faeth Therapeutics is committed to being at the forefront of this exciting transition, driving innovation and improving patient outcomes through the power of AI in biology.
It’s speculative, but I hope to see regulators to move forward on expanded use of strain change exemptions. Currently recognized for vaccines preventing influenza and COVID, accelerated vaccine development in other areas could be enabled by adoption of a prescription platform product policy. Once a vaccine platform like HDT Bio’s repRNA/LION is established as safe and immunogenic, then pathways to additional vaccine product testing should be streamlined.
The Inflation Reduction Act (IRA) will change the pricing strategy for pharma and biotech, as it introduces limits on price increases that are relative to the rate of inflation. As this applies not only to Medicare but also to private health insurance, and manufacturers who do not comply will face severe penalties, there are likely to be reverberations for years.
In addition, implementation of telemedicine regulations will define how we utilize this technological advancement to provide care. The regulatory environment is far from certain and will continue to evolve in 2024 and beyond. The COVID-related public health emergency resulted in a temporary lifting of certain regulations. However, it appears that telemedicine in the post-COVID world is here to stay and will thus need to be appropriately regulated.
Next year, the Centers for Medicare & Medicaid Services (CMS) will start to reimburse physicians for telehealth services at a higher non-facility physician fee schedule rate. CMS is also adding flexibility for telehealth providers, allowing them to use their practice address on Medicare forms rather than their home address.
As for the future, the Drug Enforcement Administration is considering a telemedicine registry that will have implications for the kinds of treatments that can safely be delivered using tech-enabled services. In addition, incorporation of artificial intelligence into the telemedicine milieu will likely lead to new regulations about disclosing the nature and source of the care dispensed via phone/computer.
I perceive the implementation of the DSCSA (Drug Supply Chain Security Act) as one of the most substantial regulatory challenges our industry will face in 2024 and beyond. This goes beyond a mere regulatory hurdle; it’s a paradigm shift toward supply chain accountability, extending from the macro level down to the minutiae of individual pills, encompassing everything from the API to the final packaged products. Simultaneously, delving into the intricacies of supply chain pricing, especially scrutinizing pharmacy benefit managers (PBMs) and assessing the value they contribute, represents the second significant factor.
While the latter isn’t strictly a regulatory mandate, it is integral, as understanding pricing dynamics will inevitably influence the regulatory landscape in the future. These dual focus points –– DSCSA implementation and comprehensive pricing evaluation –– are the linchpins that will shape the industry’s trajectory. They transcend mere regulatory decisions; they are pivotal guidelines that will redefine how we conduct business, sell pharmaceuticals, and introduce products to the market. In essence, they are key forces steering the pharmaceutical landscape into a new era.
The recently announced FDA pilot, Support for clinical Trials Advancing Rare disease Therapeutics (START) is a largely significant regulatory initiative on the horizon for 2024. The program aims to accelerate and improve the development of treatments for rare diseases.
Medicus Pharma, particularly through its subsidiary Skinject, is hoping to be part of this program. Skinject has developed a novel, minimally invasive treatment for basal cell and squamous cell skin cancer that utilizes a patented dissolvable microneedle patch. This treatment has the potential to offer several advantages, including being easier and less painful than traditional treatments and potentially lowering the chance of disease recurrence. There is a significant gap in skin cancer care, given that basal and squamous cell carcinomas are the most prevalent forms of skin cancer, with around 5.4 million diagnosed in the United States annually. Furthermore, Skinject is a potential candidate for treating other rare skin cancers, such as xeroderma pigmentosum, metastatic cutaneous melanoma, or metastatic Merkel cell carcinoma.
The START pilot will catalyze the development of rare disease treatments and offer hope for patients. Medicus is looking to leverage this program to foster innovations that potentially provide less invasive and more effective treatment alternatives for those with rare skin cancers.
The additional regulatory decision expected from the U.S. FDA in December for sickle-cell disease (SCD) will forever enshrine 2023 as the turning point in medicine when humanity successfully and safely altered the human genome to cure genetic diseases. This first approval and the lessons learned throughout the drug development process will pave the way for future therapies utilizing ever more complex and powerful genome engineering approaches to directly replace or correct mutated genes.
What has become clear throughout the process leading up to this groundbreaking advancement, as was acutely raised by an expert advisory committee in October, is that ultra-deep characterization of both intended and aberrant editing outcomes throughout drug development, product manufacture, and in patients well beyond the course treatment is critical to ensure efficacy and safety. As we accelerate this new era of medicine, drug developers and tools providers like Mission Bio will need to continue to partner, pushing the boundaries of molecular and cellular analytics necessary for continued success.
Ongoing efforts to limit the risks associated with per-and polyfluoroalkyl substances (PFAS) highlight the growing recognition of their toxicological impacts. The proposed restriction on PFAS across the European Economic Area (EEA) outlines a critical crossroads in environmental policy and public health, as the implications for the pharmaceutical sector, particularly the potential shutdown of manufacturing, cannot be overlooked.
A ban on all PFAS, as currently proposed by 2027, risks disrupting the production of essential health products and technologies. Forensic fingerprinting of PFAS will transform toxicological studies through precise identification of these compounds. This specificity is fundamental, as not all PFAS are equally hazardous.
The European Federation of Pharmaceutical Industries and Associations’ (EFPIA) response to the European Chemicals Agency (ECHA) highlights the need for nuanced characterization of PFAS. It is imperative to distinguish between PFAS types –– separating those of high environmental and health risk from those deemed low risk and essential for critical applications.
Minimizing PFAS emissions is crucial, as is the equally important need for a balanced approach. This involves rigorous analytical analyses and studies to ensure that the right compounds are restricted, thereby safeguarding public health and the environment without unnecessarily hampering vital sectors. The challenge lies in striking an equilibrium between environmental protection and the practical necessities of applications where PFAS play a pivotal role.
The regulation of AI is still in the very early stages in the United States, but given the rapid adoption we saw over the last year across all industries, we can anticipate seeing more significant regulation around the use of AI next year. Cybersecurity appears to be one of the most important areas of concern, particularly concerning data privacy management, as we’ve seen a significant rise in cyber breaches over the past year due to AI. Cybersecurity concerns are a major issue in the pharmaceutical industry, considering these companies hold highly sensitive data. Ransomware attacks could lead to the stealing, modifying, or destroying of valuable data for strategic or financial gain, and with the rise in deepfakes, this issue could worsen. These issues are too significant not to regulate. While the scope of what that law might look like for the United States is unclear, investments in responsible AI will need to be top of mind.
I believe increased focus and pressure to ensure diversity and inclusiveness in clinical trials will be a key mechanism to drive multiple areas of important advancements. Improved diversity in trials has been a topic for decades but until fairly recently addressed on a voluntary basis by pharma and device companies. It is understood that a clinical trial should accurately reflect that population affected by the condition being investigated and should match the real-world population for interpretable results across race, ethnicity, gender and geography. Diversity and inclusion should be considered throughout the planning and execution phases of the trial, as participant attrition may affect overall representation. While the medical research needs to accurately reflect the diverse population it aims to serve, patient inclusion has not achieved demographic levels in the United States, and improvement is needed.
In April 2022, draft guidance was published, with the FDA announcing significant changes in how clinical trials are conducted; focused on trial design that supports broad participation and limits unnecessary exclusions, improvements around patient recruitment and minimization of barriers, and application across all trials, including rare disease. Earlier this year, an omnibus spending bill was enacted that requires diversity action plans for the clinical trials used by the FDA with the goal to encourage investigators to develop a strategy for reaching a broad study population on the front end, instead of failing to do so or acting later and increasing an already costly trial process (Public Law 117-328). Furthermore, FDA Commissioner Robert Califf has stated that diversity must be a more prominent priority. Additional updates of the Diversity and Inclusion guidelines are expected to be published by the end of this year, with enforcement targeted to begin in 2024 that will include mandatory aggregate reports of action plans and details of where falling short.
The continued focus on representativeness in research will drive meaningful changes in how we plan and operationalize trials. One area I am eager to see evolve is the utility of leveraging RWD more readily to meet these objectives: from optimized protocol design to targeted patient recruitment efforts in a manner to circumvent burden, to the conduct of active data collection only where needed –– as a supplement only to passive data collection. I believe utilization of RWD to design robust, inclusive protocols, coupled with pragmatic active and passive data collection, will drive more efficient trials that represent more accurately the patient population under investigation, getting medical products to the right patients faster.
The recent approval of a commercial CRISPR gene therapy in the UK –– likely to be echoed by FDA, as of this writing –– marks a watershed moment in the history of medicine, heralding a new era of transformative precision medicine. Cell and gene therapies have already shown remarkable success in treating –– even curing –– certain diseases that had been untreatable, especially refractory, late-stage blood cancers. But as this regulatory success shows, gene editing technologies like CRISPR are opening new doors.
As we approach the end of 2023 and step into 2024, this groundbreaking decision will not only revolutionize the treatment of severe genetic diseases but also pave the way for a future where CRISPR and other gene-editing technology revolutionizes healthcare across a broad spectrum of medical conditions. The same drug may also receive approval for another rare blood disorder, beta thalassemia, in May.
With these supportive signals from regulators, it is likely that many of the dozens of ongoing clinical trials for CRISPR and other gene editing–based therapies will progress. These hold promise for diseases ranging from solid tumors to inherited hypercholesterolemia, and rare diseases like Duchenne muscular dystrophy and Leber congenital amaurosis.
Labeling for biosimilars in the United States currently states whether the product “is biosimilar to” or “is interchangeable to” the reference biologic, and this verbiage in prescribing information has led to confusion among healthcare professionals, as it only has relevance at the pharmacy level. Following guidance put forth in September, the FDA has firmly recommended that all products state which reference product they are “biosimilar” to, doing away with the interchangeability statement. I believe this guidance will help reduce confusion among the HCP community, furthering adoption of these more affordable alternatives to some of the world’s most expensive medicines.
To meet patient demand, the cell and gene therapy (CGT) industry must focus resources in 2024 and establish a landscape to develop actionable solutions to commercial challenges that have contributed to commercial, not regulatory, removal of 28% of approved gene therapies in Europe. Today, issues like manufacturing, market access, and reimbursement stand in the way of many patients accessing these therapies.
CGTs are clearly the next frontier in medicine, confirming their promise of hope for people living with incurable and fatal conditions. Several are up for regulatory approval next year or soon thereafter, and we expect advancements to continue to shape the next phase of the industry.
We also expect to see continued progress in clinical trials for earlier-line treatment with existing cell therapies, as well as expanding into indications across autoimmune diseases and solid tumors. The FDA’s ongoing safety investigations for approved CAR-T cell treatments will be an industry concern, although the agency has made clear that it does not believe the acceptable risk-to-reward is unbalanced –– rather, it is reviewing post-marketing data now that a more significant number of patients have been treated.
The rapid growth of approved CGTs will continue to be outpaced by patient demand, leaving manufacturers racing to increase their output. Only a small fraction of eligible patients receives currently approved commercial cell therapies. Commercial challenges should be addressed right from the beginning of development to enable scalable commercial production. We expect solutions to this challenge will continue to evolve and advance the industrialization of precision medicine to meet demand for these life-changing treatments.
The Montreal Protocol resulted in a ban on substances that deplete the ozone layer and as a result, regulations on fluorinated gases (F-gases) came into force stipulating the phase-down of use by 2047 (The Kigali Amendment). This change in F-gas regulation has a significant impact on the market for inhalation products: switching to inhalers with propellants with a lower GWP (global warming potential) is a commercial imperative for pharma manufacturers.
Pharmaceutical propellants are expected to become more scarce, which is creating pressure on the industry to develop viable alternatives, which need to be trialed in new formulations and new devices to comply with the phase-down. A significant amount of R&D is needed to support the transition to next-generation propellants for pMDIs (pressurized meter dose inhalers). Currently, R&D is focusing on moving away from HFA 134a and 227 MDI propellants toward low-GWP HFA and HFO propellants, such as 152a and 1234ze.
This pressure also provides opportunities for the industry to explore better dosage delivery for inhaled drugs and minimize dose wastage, reducing greenhouse gas usage but also improving inhaled product performance. Successful development of new devices depends on combinations of formulation, valves, canisters and actuators and a specialized understanding of product formulation in a pressurized environment.
There is no question in my mind that the most significant guidance the industry is seeking is related to AI and modeling. The agency issued several white papers in 2023, which highlighted both concerns and challenges in utilizing AI and machine learning. The agency is looking to the industry to innovate and propose the best approaches to these questions. The FDA themselves are embarking upon AI adoption utilizing large language models to drive both efficiency and uniformity across all their divisions for the submission review process. The FDA Modernization Act advocated that animal testing is no longer required for drug submission. However, the requirements for utilizing surrogates, such as organ-on-a-chip, have not been articulated. As the industry rapidly integrates AI across the drug development value chain, there is a growing expectation for the establishment of standardized approaches for training, verification, and validation of AI models. This standardization could significantly shrink the time to market through better molecule selection, faster and more representative safety testing, and accelerated patient recruitment for clinical trials.
Legislation continues to be a linchpin in achieving inclusivity in research and clinical trials. The most pivotal regulatory decision of 2023 was Public Law 117-328, which requires diversity action plans for the clinical trials used by the FDA to decide whether drugs are safe and effective. The need for diverse representation in research and development has been a recent focal point, starting with the passage of the Race and Ethnicity Diversity Plan in 2022. To ensure comprehensive understanding of a medication's efficacy and safety, it is crucial for clinical trials to include diverse participants. This allows healthcare providers to make more informed decisions.
Achieving inclusivity has presented challenges, transcending beyond a checkbox exercise and necessitating a fundamental shift in mindset. Barriers such as accessibility to clinical trials do exist, but this legislation emphasizes the need for decentralized trials to include populations with limited resources, which includes seniors, who are often marginalized and overlooked. The only way we’ll move the needle in 2024 is through better collaboration –– not just within the pharmaceutical industry but also across the care continuum to break down silos and attempt to fix the disjointed nature of healthcare delivery for the aging population. Utilizing real-world data can shed light on trial design, outcomes, and patient experience, facilitating data-driven decisions and expediting initiatives, particularly in the realm of diversity, equity, and inclusion in research and development. Looking ahead, having legislation that supports inclusivity –– and more importantly, penalizes exclusivity –– is the only way to move forward.
We expect a regulatory decision next year on the first tumor-infiltrating lymphocyte (TIL) therapy to reach regulatory submission. A commercial approval would represent a significant milestone in the progress of cell and gene therapies (CGTs) for the treatment of solid tumors, the cause of most cancer deaths. The decision will have widespread implications for the rest of the CGT field and will likely increase confidence in developing advanced CGTs targeting solid tumors.
As more of these are brought to the clinic because of the wide-scale adoption of standardized manufacturing with the G-Rex integrated cell manufacturing platform, regulatory agencies like the FDA and EMA are expected to focus on creating more adaptive and streamlined regulatory frameworks that will enable accelerated reviews and approvals of lifesaving treatments.
The key development will be establishing more comprehensive and flexible guidelines for CGTs that will provide the clarity needed to enable creative, high-throughput manufacturing strategies to be employed safely and without regulatory risk or uncertainty. These guidelines, in turn, will facilitate the adoption of standardized manufacturing strategies that reduce costs, reduce risks, and accelerate clinical timelines. Agencies will welcome adopting a standardized process because it will streamline regulatory review.
Finally, regulatory guidance on bespoke cell therapies, where treatments are tailored to individual patients, is expected as personalized medicine grows. This will be a work in progress, and close collaboration between cell therapy developers and regulatory agencies will be paramount for ensuring these therapies reach patients sooner rather than later.
Of the regulatory changes in the pipeline, the European Chemicals Agency's (ECHA) proposed ban on per- and polyfluoroalkyl substances (PFAS), also known as "forever chemicals," is the most significant and has far-reaching implications. PFAS are extensively used in various aspects of drug production and packaging due to their unique properties, such as their ability to repel moisture and prevent contamination.
The ban's impact on drug manufacturing would be multifaceted. PFAS lubricants are employed in powder handling to prevent adhesion, while PFAS coatings are used on tablet surfaces to improve flowability and prevent sticking. Blister packaging, which protects medications from moisture, light, and contamination during storage and transportation, relies heavily on PFAS. Similarly, injectable drugs utilize PFAS in elastomeric stoppers and seals to prevent leakage and maintain sterile conditions.
The proposed PFAS ban could lead to supply chain disruptions as the industry seeks suitable alternatives. Replacing PFAS with alternative materials and technologies will require significant development and adoption efforts, which would add to the inflationary pressure already felt. Moreover, the availability of suitable substitutes may be limited, causing drug shortages if the transition to alternative materials is delayed or proves to be challenging.
The pharmaceutical industry is actively exploring alternatives, including biopolymers derived from natural sources and surface modifications that enhance hydrophobicity without the need for PFAS. Process optimization, such as reducing moisture exposure or using different granulation techniques, can further minimize the need for PFAS lubricants or coatings. Combined with proactive investment in alternative technologies, these strategies can help mitigate potential disruptions and strengthen the industry's long-term sustainability.
The proposed EU PFAS ban presents a significant transition for pharmaceutical manufacturing. While it necessitates a shift toward more environmentally sustainable practices, it also offers an opportunity for innovation and improvement. By proactively adopting alternative solutions and optimizing processes, the industry can ensure the continued production of safe and effective medications while minimizing the environmental impact of its operations.
The proposed regulation on the standards of quality and safety for substances of human origin (SoHo) will impact the cell and gene therapy field in 2024. The starting material for both allogeneic and autologous manufacturing still remains the critical aspect of whether the product is eligible for treating patients and currently, the legal framework for blood, cells, and tissues varies, not only globally, but also within the European Union (EU). For example, monocyte concentrate from leukapheresis can be regulated by the blood directive in one country and cell and tissues directive in other countries. The SoHO regulation will help clarify the categorization meaning it will not be necessary to implement it into the local EU countries' legislation.
Additionally, the implementation of long-expected EU good manufacturing practice (GMP) Annex 1, which was heavily commented on in the pharmaceutical industry, is not fully applicable in the advanced therapy medicinal product (ATMP) world, as the relevant section of GMP for ATMP (EU GMP Part IV) remained unchanged. But in the coming year, this will definitely trigger a discussion of the possible changes in this area in cell and gene therapy manufacturing.
Despite the authorities' activity in the regulatory field, not all challenges of ATMP manufacturing can be covered in guidelines, such as GMP certification of small startup laboratories, variability of the biological materials, raw materials available on the market in “for research” quality only, necessary flexibility during the manufacturing process, or designing product potency testing that would be acceptable for the regulators.
Artificial Intelligence (AI) continues to be at the forefront of the conversation around technological innovation. With the emergence of OpenAI’s ChatGPT and other AI platforms, people around the world across all industries now have a greater interest in how AI will affect the future of how we work. To many, AI has limitless potential to impact our lives in both positive and negative ways. This potential has many leaders around the world and across industries wondering how AI will be regulated.
As the CEO of a publicly traded, clinical-stage biotech company that is advancing a novel cell therapy platform for chronic diseases, I am most interested in how the U.S. FDA will begin regulating the use of AI in the life sciences industry. Many biopharma companies are already looking to AI to find ways to be more efficient; this includes identifying new biological targets faster, speeding up drug development, increasing clinical trial recruitment, improving operational excellence, maximizing commercial opportunity, and much more. This year, we have seen an increase in collaboration and partnership from big pharma and firms that are advancing new AI technologies that are specifically designed to improve the drug development process. I anticipate we will see a continued increase in these types of deals throughout the new year. In 2024, I look forward to seeing more guidance from the U.S. FDA on how AI technologies will be regulated in the life sciences industry.
The upcoming Draft Packaging and Packaging Waste Regulation represents a pivotal stride in sustainable practices within the pharmaceutical industry.[i] Expected to be adopted in 2024, this EU-wide regulation is set to be directly applicable across member states and highlights the growing emphasis on extended producer responsibility (EPR) and packaging sustainability. Pharmaceutical companies operating within the EU will need to consider how the new packaging regulations impact their company at a compliance and strategic level.
The regulation serves as a call for change, urging pharmaceutical companies to innovate and adopt eco-conscious packaging solutions. As sustainability takes center stage, pharma companies will need to reevaluate their packaging strategies, seeking materials that prioritize recyclability, biodegradability, or circularity. Embracing this shift not only ensures regulatory compliance but also aligns businesses with consumer expectations for environmentally responsible practices.
The inherent properties of glass offer a multitude of benefits for companies looking for a sustainable packaging option for their pharmaceutical products. Firstly, glass is infinitely recyclable without compromising its quality –– significantly reducing its environmental footprint and mitigating the need for new raw materials. Moreover, its inert nature ensures that pharmaceutical products remain uncontaminated throughout storage and transport in the supply chain. Beyond its recyclability and preservation qualities, glass packaging excludes durability, often outlasting its contents and thereby reducing waste generation. The pharmaceutical industry is already contributing towards sustainable sourcing through industry-led, collaborative initiatives that are working to build responsible supply chains and this new regulation in 2024 will reinforce the need for more eco-friendly packaging options.
As more than 100,000 Americans are impacted by sickle cell disease, the November 7 FDA panel recommendation that the gene-editing technique CRISPR be approved for its treatment will not only have a major impact on those patients but also for the millions of patients with other diseases across the world.
CRISPR gene therapy applications have the ability to revolutionize medicine and the potential to transform disease treatment and prevention. In addition to sickle cell disease, other genetic diseases like cystic fibrosis and muscular dystrophy could someday be treatable. It also shows promise in enhancing cancer treatments, making cells more susceptible to existing therapies, and can be employed to prevent diseases by correcting mutations that elevate the risk of conditions like heart disease and Alzheimer's disease.
While CRISPR gene therapy is at an early stage, and precautions need to be taken to mitigate risks, such as precise delivery to target cells and avoiding unintended consequences in gene edits, its potential to revolutionize disease treatment and prevention is evident.
On September 22, 2023, the FDA issued a new draft guidance titled “Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications Guidance for Industry.” Although the draft is still out for comments, it gives a behind-the-scenes look at the FDA’s use of proposed “alternative tools” in conducting remote-based inspections. The draft guidance documents reflect the FDA’s intention to make permanent the use of certain inspectional assessment tools, which the FDA applied broadly in response to the COVID-19 pandemic.
A Remote Regulatory Assessment (RRA) is an examination of the establishment and/or its records, conducted remotely by the FDA to evaluate a firm’s compliance with cGMPs.
An RRA can take different forms. A Remote Interactive Evaluation (RIE), a category of RRA, for example, typically involves remote visual observation of a product, facility, manufacturing operations, and records, whether through livestreaming of video or screen sharing. The agency may make informal requests to view or receive records as part of an RIE. Generally, any interaction between facility staff and the FDA will be virtual, through video or telephone conferencing.
Industry should carefully consider all risks that may arise due to use of alternative tools, including those that go beyond potential snafus with technology. For example, an FDA subject matter expert participating remotely might not get a full or clear picture of a process of interest or part of the site, causing the expert’s assessment to be less favorable than it would be if the expert had been on-site.
Facilities should update their inspection readiness training programs to account for these new tools, technologies, and procedures. Ensuring information security is also critical. Careless use of technology in remote evaluations could lead to leaks of confidential or privileged information.
The most impactful regulatory decision next year may be the one that doesn’t happen. The FDA has long predicted it will approve between 10–20 cell and gene therapies (CGTs) a year by 2025. But it will have approved no more than seven by the end of 2023, with at least two decisions coming in after their initial deadlines. And Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), acknowledged that it may not hit the benchmark.
The danger is the impact regulatory delays could have on the momentum of a field that is making curative therapies but struggles to reach patients. We work with developers to optimize the early stage of CGT manufacturing –– cell collections –– and we share their dedication to improving efficiency and expanding access.
Recruiting and retaining sufficient talent may be the most significant regulatory challenge, although recent legislation has improved the traditional pay disparity between regulators and the private sector. CBER has reorganized CGT oversight in a new Office of Therapeutic Products –– with 500 vacancies to fill in the coming years.
There is a deluge of cell and gene therapy clinical trials being conducted. And the current lack of standardization for cell and gene therapy manufacturing means that each clinical trial must be assessed on a case-by-case basis to determine whether it poses any significant risks to patients. We remain hopeful that the FDA will hit its goals, but the agency has an uphill climb.
The biopharmaceutical industry will see a number of exciting trends and innovations in 2024, such as more focus on gene editing, precision medicine, tissue engineering, artificial intelligence, and synthetic biology. Several of these opportunities may also impact regulatory authorities around the world, including the Food and Drug Administration (FDA). However, next to these exciting opportunities and developments, the FDA’s biggest challenge will be how to deal with the rise in counterfeit drugs, with thousands of new pharmaceutical crimes reported year over year. For example, according to the WHO, roughly 10% of medicinal products circulating in low- and middle-income countries are substandard or falsified. The United States is not that far behind. To combat this alarming increase, both governments and regulatory bodies worldwide will likely have to provide guidance to companies emphasizing data transparency, quality assurance, and the need for greater traceability of pharmaceutical products throughout the supply chain in 2024.
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