The Multifaceted Future of Pharma – Chapter 8: Clinical Development
How has the process of clinical development in the pharma industry improved over the past decade? Experts discuss and look at what the future holds for the field.
From bottlenecks and barriers to regulations and resources, there is much that has improved in the clinical development sector over the past ten years, but the next ten will require further progress.
We asked: “What one thing could dramatically improve the pharma industry as we know it?”
“A shift that could significantly improve the pharma industry is the increased integration of genetic support into drug development. Evidence shows that drugs with strong genetic backing exhibit nearly a threefold higher probability of success in clinical trials compared to those without such support. This notable increase in success rates can be attributed to the better alignment between drug mechanisms and the genetic factors that influence disease progression and patient response.
“Advances in both imaging and sequencing techniques have profoundly enhanced our ability to understand genetic variation at the cellular level. Innovations in high-resolution microscopy methods allow for the detailed visualization of single cells within somatic tissues, enabling isolation of single cells for sequencing to identify genetic differences in cells with different phenotypes. Coupled with advancements in next-generation sequencing technologies, the industry has dramatically increased the speed, resolution, and accuracy of genetic analysis, enabling comprehensive mapping of somatic genomic diversity at the level of single cells from patients instead of the limited germline diversity from an individual patient that the field has been limited to for so long.
“The integration of advanced imaging and sequencing techniques provides a powerful toolkit for dissecting the complexity of genetic diversity, offering insights into how somatic genetic variations influence cellular processes and contribute to various diseases. This synergy is already paving the way for more precise and personalized approaches to understanding and treating genetic conditions.”
“A number of companies, particularly smaller biotechs, struggle to understand and make decisions around GMP requirements for key components versus active pharmaceutical ingredients (APIs). The confusion generally begins throughout the development process when drawing the line on what constitutes an API or a critical component and how to best approach GMP compliance – especially for manufacturing complex modalities like antibody-drug conjugates. Having clearer, more straightforward guidance on this distinction would be immensely valuable in helping smaller companies navigate the process in a costly, timely, and resource-efficient manner.
“There are many variables at play, and a clearer picture can help businesses make strategic decisions that are best for their company’s needs in the short- and long-term. Small biotechs may not have the same regulatory resources as biopharma to provide guidance on the matter, particularly for early development work, but these choices have major cost implications that can impact a company’s trajectory. Knowing exactly what components need to be manufactured in compliance with GMP and, importantly, when in the drug development process that needs to happen, is critical information that can help a small company make educated choices in light of their specific situation.
“Weighing the upfront costs associated with a GMP manufacturer during early-stage development against the time and resources needed to transfer to GMP later on can be difficult without a clear understanding of the guidelines for APIs versus critical components. Clearer FDA guidance on this topic, along with readily available support from expert suppliers to identify suitable solutions, could make a massive difference in facilitating efficient and successful drug development for companies of all sizes.”
“There is an opportunity to break down some of the barriers to increase diverse participation in clinical trials. One way we can address this challenge is through the clinical trial site selection process. For example, we’ve been able to increase representation in clinical trials by purposefully partnering with investigators and sites within diverse communities – providing resources and funding to ensure the sites are set up for success, so they can deliver optimal patient care in a clinical trial setting.
“We’ve already seen meaningful improvements. For example, in our completed phase II clinical trial for plantar fibromatosis, 20 percent of enrolled patients were black – a significant increase from historic participation rates of ~5 percent, and a potential challenge to conventional thinking that plantar fibromatosis primarily affects people of northern European descent.”
“Collaboration is the key to drug development. The earlier it starts, the better the outcome. In order to foster true collaboration, we need to involve a diverse set of cross-functional experts early and often.
“There are, of course, many factors and individuals driving early-stage drug research and development. Research priorities are often driven by exciting science and novel targets – which are needed to push our industry forward. But this process sometimes forgets to ask a key question: do patients need this drug?
“We are moving in the direction of asking questions like this earlier in the R&D process, which I believe will change how we fund drug development research, and improve our industry as we know it.
“This can only be done by engaging experts from departments beyond preclinical and clinical research, including commercial development, patient access, and patient advocacy, early in the process. These experts can provide guidance on where gaps in the patient experience exist and anticipate how to ensure patient access.
“One example specific to my area of expertise in commercial development, is the value of including commercial experts in clinical trial design. Input from commercial experts in these discussions can help ensure that trials are designed in line with what US and global payors will require to make reimbursement decisions – which, in turn, will determine if patients can have access to innovative medicines. This small investment for commercial input early can prevent a larger gap as drugs near approval and enable pharma to demonstrate the value their new medicines bring to patients.
“As an industry, we see the benefits of collaboration across our work, but if we bring more experts into the fold early, we can ensure more voices and perspectives shape our research in the interest of patients.”
“The last decade has seen an historic advance in therapeutic development and delivery, particularly in patient-centric precision medicines and cell and gene therapies. These therapeutic advances have resulted in “gold rush towns” of entire supply chains set up around them and have been realized through a considerable focus and dedication across the industry.
“However, whilst we are seeing new therapeutic modalities, there is still a considerably high failure rate of therapies in clinical development. For the last 20 years, there has been little improvement in a 93 percent failure rate in the clinic, and a 50 percent failure rate in phase III. A resignation no other industry would tolerate has emerged. This is just the way things are. We are seeing an investment drought, with investors reluctant to tolerate such high risks.
“There is also an assumption that the molecule is the problem. In many cases, however, the decisions taken have been the reason for therapeutic failures, but research evaluating over 1,200 clinical or commercial stage programs is available. 95 percent were not optimized for the target product profile, and 60 percent had no commercial utility and would never reach patients as a result.
“The drug development sector is blinkered in its mandate of reducing the costs of therapies that succeed, and under-focused on how to significantly improve clinical trial success rates. Clinical studies should be focused on the development of commercially impactful products at the time of launch.
“A new evolution in drug development is required to ensure development stage assets compete for capital in an increasingly competitive drug development and commercial landscape.”
“The life sciences industry is burdened by lengthy, complex, and costly clinical trials with 70 percent of phase II and III trials delayed by an average of 16 months. Overall Study startup (SSU) is one of the biggest barriers to speedy clinical trials with nearly 80 percent of trials experiencing startup delays. These delays have a ripple effect through the entire trial – and why I believe that accelerating SSU would dramatically improve the drug development industry.
“Key bottlenecks in study start-up include regulatory approvals, technology set-up, budget and contract negotiations, and clinical trial participant enrolment. Here are two examples - 90 percent of phase II/III trials undergo at least one significant protocol amendment and most large pharma company trials average 3-4 per trial; and 86 percent of trials experience enrolment delays of between 1 and 8 months.
“Regulatory approvals can vary significantly across different regions, adding layers of complexity and potential delays. Regulatory harmonization and standardization are crucial for improving SSU efficiency. Efforts to harmonize regulatory requirements, such as those by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, can simplify and expedite regulatory approvals, while not compromising participant safety. Standardized processes and documentation reduce redundancy and enhance collaboration between sponsors, sites, and regulators.
“Technology can streamline processes, but according to a 2023 Advarra Study Activation Trend Report, over 50 percent of trial sites indicated that technology set-up was their most burdensome activity. Trial sponsors can leverage advanced software solutions and platforms installed at many clinical trial sites to help automate and streamline many SSU tasks. For example, site-based clinical trial management systems can enhance document management, regulatory compliance, and site communication. AI and machine learning can be leveraged to identify optimal trial sites and predict patient recruitment success, reducing the time and cost associated with these activities.
“Budget and contract negotiations are right behind technology as the next two most burdensome activities for sites, according to the same report. Negotiating contracts between sponsors and sites can be lengthy and complex. Each party has its own interests, risk tolerances, and expectations, which can lead to protracted discussions (i.e., intellectual property rights, publication rights, and data ownership are often contentious issues that require detailed negotiation). Similarly, budget negotiations between sponsors and sites can be prolonged because of mismatches between each party’s expectations – sponsors typically seek to minimize costs by using more generalized fair market value calculators, while sites want to secure adequate funding to cover their costs, which vary dramatically by geography and institution. Reimagining this process through a more collaborative relationship between trial sponsors and sites will be critical.
“Improving site relationships and patient engagement requires a strong and trusting bond between sponsors and sites. Sponsors should invest in building and maintaining these relationships through transparent communication, fair contract terms, and ongoing support. Training and support for site staff can improve their readiness and efficiency in initiating trials. Patient engagement is another critical factor. Innovative patient engagement strategies, including the use of technology solutions that better connect sites and patients can dramatically improve patient retention and satisfaction.
“Transforming the SSU process is critical to driving impactful, long-term improvements into drug development. By leveraging existing site technology, harmonizing regulations, fostering site relationships, and enhancing patient engagement, we can achieve significant gains in efficiency, cost-effectiveness, and innovation while not compromising safety. These changes will not only benefit sponsors and sites but ultimately lead to better health outcomes for patients worldwide.”
“I would like to see the implementation of new, non-traditional approaches to drug development that could bring further innovation to patients more rapidly and, potentially, at drastically reduced development costs.
“One way this could be accomplished is by strengthening the utilization of ‘pragmatic’ clinical trials to inform drug development and support drug and biologics applications to health authorities. Pragmatic trials can be designed to evaluate the effectiveness of potential new medicines in real-world clinical settings, contrasting with traditional trials that focus on clinical efficacy under controlled conditions. These trials aim to provide insights that are directly applicable to everyday healthcare practice, thereby informing clinical and policy decisions more effectively.
“Pragmatic clinical trials can offer several advantages over traditional trials, including potentially reducing costs, producing results that are more generalizable to a broad spectrum of the population, providing valuable data that can help policymakers and healthcare providers make informed decisions about the adoption and reimbursement of new treatments, and improving ways to identify patient subgroups who could benefit most from a therapy.
“In addition, another pathway to support rapid development of novel interventions in infectious disease is the use of immunobridging. This concept is currently being evaluated by regulators for COVID-19 vaccines but could have broader application where immunogenicity data could be used to bridge to a previously approved vaccine where efficacy was previously demonstrated. A similar approach could be used for other modalities such as monoclonal antibodies for the same disease, utilizing the same target on the same backbone. Much progress is being made in this area, and there is opportunity to work closely with health authorities to move even faster.”
“In my opinion, new approach methodologies (NAMs) represent the biggest disruptor in our industry over the past 10 years. Roughly defined as any in vitro or computational (in silico) method that enables improved drug assessment through more relevant models, NAMs could potentially help reduce late-stage drug failure rates. Existing workflow challenges because of the simplicity of traditional in vitro tools and interspecies differences of animal models have been exacerbated by drugs with human specific modes of action where the use of animal models is less suited to determine drug efficacy and toxicity.
“The last decade has seen widespread development, commercialization, and validation of NAMs, and we are now at the point where mass adoption is a viable option. NAMs are already widely used for decision making in drug discovery and their impact will be seen ever more in the coming years as more drugs reach the clinic that have been developed using these, such as Inipharm’s INI-822, which was developed primarily using an in vitro organ-on-a-chip (OOC) model of metabolic liver disease.
“Ever increasing accessibility to advanced in vitro OOC technology has led to its adoption across a range of application areas (disease modelling, safety toxicology, and ADME profiling, for example), supported by the availability of primary human cells in larger batches with improved consistency and quality. In the future, we will see further advances to the human relevance of OOC models, with disease models developed that are challenging to recapitulate using animals, as well as toxicology assays that predict responses in specific patient cohorts rather than the general population.
“The data derived from predictive human OOC models enables better informed decisions about which drugs to take forward into in vivo studies so that only the most promising pass through, and de-risks ahead of first in human clinical studies to reduce late stage and costly drug attrition. Drug failure rates are already falling, and we haven’t yet truly observed the impact of NAMS, including OOC, so the future is looking bright.”
“In the next decade, I’d like to see advances in big data and AI to continue being a driving force for change in clinical development to get much needed drugs to patients faster. By harnessing next-generation clinical data science and predictive analytics to gather, tabulate, and analyze data effectively, sponsors can use real-world patient data to guide investigator site selection with improved precision, inform protocol design, simulate clinical trials, and construct digital twins. Digital twin technology transforms the planning and implementation of clinical trials, allowing sponsors to better align the trial design to the patient population, and identify and select investigator sites proven to be able to recruit targeted patients faster, helping eliminate costly protocol amendments and shorten cycle times.
“Digital twins will enhance the clinical trial toolkit and help the industry overcome long standing challenges faced in patient recruitment, as well as the ethical issues associated with placebo arms. By removing the need for a control arm, digital twins decrease the number of patients required for a trial, resulting in higher patient enrolment rates and more patient-centric trials. The next ten years should see greater application of data in clinical trial design and greater exploration of digital twin solutions to deliver smarter trials and faster cures.”
“Research from Deloitte shows that longer timelines caused the average cost of developing a new drug to increase by $298 million to $2.3 billion in 2022, so reducing drug delivery timelines should be a priority. One way the pharmaceutical sector can approach this is by removing time-intensive steps from the drug development process. For example, impurity profiling in raw materials is an essential but time-consuming step, and is often done through hyphenated chromatography techniques such as LC-MS, GC-MS, or LC-NMR. Harnessing new approaches, such as modern computational chemistry methods, and using these in tandem with proven technologies can help researchers completely avoid tasks such as developing reference standards (which can take weeks).
“The process analytical technology initiative also addresses this challenge because it aims to improve pharmaceutical processes by expediting the measurement of critical process parameters that affect drug quality. While optical spectral techniques such as Raman and IR can provide rapid in situ measurements, they display shortcomings when it comes to revealing information about compounds in mixtures. By leveraging technology that can identify and quantify compounds in mixtures, without the additional separation steps, researchers can save time and costs by automating real-time reaction monitoring. Researchers are already making huge progress in this field. This will continue as drug developers turn their attention towards other uses of existing instrumentation.”
“One of our goals at Regeneron is to find ways to advance investigational treatments through our pipeline as quickly as possible – and at an ever-growing scale. New modalities and new technologies bring new possibilities, but these require an industry-wide focus on modernizing current practices, systems, and infrastructure to enable trial execution.
“Clinical research has never been more complicated but has also never been more promising. Over the last several years, we’ve seen an explosion of potential therapies, providing a tremendous opportunity to offer new medicines to patients in need. With this opportunity, comes the challenge of how to get clinical trials done as efficiently as possible.
“One of the areas that could dramatically improve our industry as we know it is how we utilize the technology of today to build the clinical trials of tomorrow. These technologies include:
- The advent of digital health technologies and their associated digital biomarkers. These have the potential to allow for the continuous collection of objective data within the context of a clinical trial, allowing for an increase in reliability and reduction in variability possibly leading to better-quality data over longer periods.
- Advancements in health data interoperability, which have the ability to seamlessly translate EHR to EDC that can inform how we design studies, select sites, recruit patients, and gather clinical trial data during a trial based on real-world data.
- Applying AI and machine learning to bottlenecks, offering ways to improve our ability to process high volumes of data, and providing ways to accelerate the decision-making process.
“The potential impact of these technologies is immense. They provide the tools necessary for a deeper understanding of diseases, more precise measurement of treatment effects, a more inclusive approach to patient participation, and the ability to assess vast amounts of data.
“As we continue to explore and integrate these technologies into our clinical research, we stand on the brink of a new era of drug development – one that holds the promise to bring even more life-changing medicines to patients.”
