As biopharmaceuticals aim to meet patient needs with deep scientific innovation in drug discovery and development like never before, clinical trial complexities are also growing considerably. The global research and development industry is heavily focused on the development and integration of purposeful technologies into clinical trials to create the efficiencies, quality and speed needed to ensure viable therapies have a higher probability of regulatory approval and reach patients sooner.

Looking closer at trial-related analytical laboratory needs, especially for complex cell and gene therapy and Antibody-Drug Conjugate development, there is a spectrum of tech-enabled approaches that can efficiently support clinical trials. However, there is more to these innovative techniques than the use of technology in silo.

Below, we dive into noteworthy advances in analytical lab service technologies making an impact throughout drug development and equally important core factors that underpin the use of these solutions to meet the demands of today’s R&D landscape.

1. Cutting-edge and end-to-end analytical lab technologies

Scientists use a broad range of in-silico tools and analytical lab technologies, some of which are needed for clinical trials. Whether it is high throughput via automation for large scale analysis with quicker turnaround times, multi-dimensional imaging and more, below are five examples of novel laboratory analytical technologies that are becoming widely introduced to enhance clinical trial sample testing:

• High resolution mass spectrometry applies to ADME (Absorption, Distribution, Metabolism, and Excretion), pharmacokinetics and biomarker analysis.
• Digital spatial pathology combines high-resolution imaging, molecular/immunoassays and sequencing technologies to determine the expression of genes and/or protein to map the spatial distribution of molecules within a micro-ultrastructure tissue environment. For example, this solution can help to determine if immune-check point inhibitors are expressed by the tumor itself or the tumor microenvironment to build a hypothesis on drug response.
• Single cell sequencing leverages next generation sequencing, which is used traditionally to analyze genome or gene expression at the level of an organism or a tissue, to go down to a single cell to evaluate genomic differences between cell types.
• Next generation flow cytometry is based on spectral signatures of fluorophore-conjugated antibodies to perform high-dimension/parameter immunophenotyping with unprecedented resolution.
• Digital pathology couples high resolution scanning of tissues following a conventional staining procedure (e.g., hematoxylin and eosin), immunohistochemistry or Fluorescence
• In Situ Hybridization with Artificial Intelligence image analysis to support the interpretation and quantification of biomarkers and specific physio-pathological changes in tissues. With three dimensionality capabilities, these digitized solutions allow for tissue views at 200X magnification to visualize molecular expression at a high resolution.

2. Matching technologies with skilled expertise

Advanced lab technologies can genuinely enhance how clinical trials are conducted. However, without a solid understanding of their use to support trial goals and improve patient outcomes, these technology solutions can only go so far. These solutions must be underpinned by deep and varying expertise to maximize usage with high focus on the quality of the lab results they generate.

Experts essential to effective oversight of analytical lab operations and outcomes analysis can include:

• ADME-Pharmacokinetics experts – Deploy solutions, including in-vitro and ligand-binding assays and high-resolution mass spectrometry to better predict and evaluate the ADME and the bioavailability of large and small molecule drugs and to assess drug-to-drug interactions.
• Immunogenicity experts – Predict a drug’s ability to induce an immune response by performing in silico and in vitro assessments. They also perform ligand-binding assays on plasma to detect anti-drug antibodies to evaluate the possibility of that the patient’s immune response might change the bioavailability of the drug.
• Cytometrists – Work across multiple instruments and technologies (e.g., spectral cytometry) to generate and oversee in-depth analysis of highly complex data available via new technologies’ increased panel dimensionality and resolution capabilities.
• Anatomic pathologists and Histotechnicians – Are vital to ensuring study-specific tissue assessment for specific cellular tissue content and anatomical structure and protein or molecular biomarker testing to confirm the original diagnosis and/or to better direct target patients needed for the study. They also help oversee companion diagnostic development specific to given therapeutic solutions.
• Genomics scientists – Extract comprehensive scientific insights from in-depth RNA/DNA sequencing analysis of tissue or liquid biopsies and single-cell sequencing to identify genetic and genomic variations potentially responsible for inherited diseases or associated with drug response.
• Proteomics experts – Oversee the development and validation of immunoassays relying on a broad spectrum of technologies, from basic enzyme-linked immunosorbent assay, molecular-assisted detection of proteins in multiplex formats to mass spectrometry to profile soluble proteins in several sample types, gauging their roles in cellular function to better understand molecular interactions and mechanisms.
• Bioinformatics and Data Analytics experts: Use innovative computer, statistical and AI tools to aggregate biological data obtained by various analyses to generate correlation and causal relationships to build-confirm hypothesis and discover-validate new biomarkers drug target and/or drug candidates.

3. Consistency in procedures for data comparability

Given the context of use and the value of the data produced during clinical trials, it is vital that such data can be compared across labs operating in various locations for global trials and over a long time. For instance, data generated in China this year must be comparable to that produced in China, the U.S. or any other regions in three years.

This can only be achieved through implementation of robust standardization, including:

1. Training.
2. Stringent assay validation/transfer plan and reports.
3. Processes.
4. Instruments/methodologies.
5. Reagent/quality control material.
6. Run acceptance criteria, reportable units, reference range, medical/decision cutoff values, proficiency testing.
7. Software and system interfaces.
8. Lab proficiency testing and certification programs (e.g., College of American Pathologist).

4. Centralized lab network versus local labs

In some instances, trial sponsors have elected to work with local labs for safety testing and for biomarker testing at times. However, for reasons explained above, it is very unlikely that using unrelated local labs can guarantee data comparability. Furthermore, local labs do not often perform advanced lab testing needed for today’s complex drug development. For example, high dimension flow cytometry, next generation DNA/RNA sequencing or the infrastructure to support the development of companion diagnostics are generally not available through local labs.

5. Regulatory monitoring and compliance

Labs generating tech-enabled testing results and outcomes need to meet varying and evolving regulations for all regions where testing is performed. Examples of lab testing-specific regulatory updates that sponsors need to understand and meet for current and future trials, include:

• Aiming to ensure safe and effective in vitro diagnostic tests, the European Union In Vitro Diagnostic Medical Devices Regulation has been in effect since May 2022. In January 2024, the European Commission announced it would allow some test developers to have more time to apply the IVDR to help make sure patients in need have access to these products, including high-risk IVDs needed for critical blood infections or organ donations. Based on the type of IVD, companies have an additional two years from the original date of required compliance to apply the IVDR. Of note, all tests considered “in-house” tests are not in scope for this extension and should comply with the IVDR guidelines (EUR-Lex – 02017R0746-20220128 – EN – EUR-Lex (europa.eu)).
• In April 2024, the U.S. Food and Drug Administration amended its regulations and announced a final new rule, ensuring more critical oversight of Lab Developed Tests for safety and effectiveness and accurate results. This final rule makes it clear that LDTs are designated as medical devices and will go through extensive pre- and post-market compliance requirements. Sponsors will need to monitor for updated requirements and the phase out policy for the previously set regulations.

Also, how the regulatory landscape is changing in various jurisdictions and the impact on lab testing, data compliance and acceptance will be necessary for sponsors to work within. For example, data generated in a China local lab may be compliant with the country’s regulatory authority but not for FDA regulatory approval.

Integrating regulatory lab expertise into the clinical study team and the clinical research organization, when applicable, can be beneficial to ensuring testing results data can be used for regulatory filings regardless of where the insights were collected by enhanced collection, analysis and reporting standardization. Alongside country or region-specific regulations, sponsors may rely on their lab analytical service provider to monitor regularly updated industry lab analytical guidelines, such as the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, Clinical and Laboratory Standards Institute and the College of American Pathologists.

6. Meeting intricate needs of therapeutic areas-indications, drug modalities and patients

Supporting the intricacies of numerous therapeutic areas and indications with specialized analytical expertise and tailored and comprehensive approaches to meet clinical trial protocol requirements can enhance drug development.

Because testing requirements are so diverse and specialized, sponsors will find it efficient to secure all required lab services for a trial under one roof to streamline communications regarding scientific objectives and testing requirements and facilitate data integration to improve the quality of deliverables. For example, a cell and gene therapy study for multiple myeloma can rely heavily on multiple technologies, such as:

• High dimension flow cytometry.
• Next generation sequencing.
• Fluorescence In Situ Hybridization.
• Immunohistochemistry.
• Anatomic pathology.
• Specialized chemistry/protein electrophoresis.
• IgG, kappa/lambda ratio measurement.
• Pharmacokinetics and immunogenicity assessment.

To confirm diagnosis, support a patient’s enrollment and properly monitor their response to treatment, seasoned hemato-pathologists, flow cytometrists, anatomic pathologists and clinical immunologists must interact to capture high quality data. These experts can also signal any analytical results requiring review when data is aggregated under a single lab organization.

Such analytical complexity applies to many other drug modalities (e.g., nucleic acids, bi-specific antibodies, ADCs and personalized neo-antigen therapeutic cancer vaccines).
With specific populations, such as pediatric trial participants, there are also pre-analytical and analytical considerations to ensure high quality data. For example, patients ages six and under suffering from a rare genetic disorder like spinal muscular atrophy can be debilitating and stressful for them and their caregivers. For these patients, blood collection should be as painless as possible, and the volume needed to draw and test should be minimized while also ensuring sample integrity and avoiding test cancellation.

7. Seamless connectivity between lab providers and CROs

In a competitive landscape when time and quality is of the essence, the interlock between CROs, who oversee all trial activities, and lab service providers, who manage patient lab data generation and analysis, must be effective and transparent.

With biotechs specifically, where there is a tremendous amount of innovation, seamless strategic planning and execution between CRO and lab partners is critical. These companies often play middleman between service vendors, overloading their in-house resources, delaying timelines and creating gaps in test requirement planning. Also, with pressure to ensure their limited assets “make it,” the need for strong connectivity between all stakeholders only intensifies.

For one, it is vital to keep communications open, inviting ideas from each’s respective areas of expertise, to better address the biotech sponsor’s nuanced challenges. In complex discovery and precision medicine, for example, it can be beneficial to draw upon each other’s diverse expertise in rare disease, cell and gene therapies, etc. to proactively provide sponsors with scalable yet realistic approaches and guidance on what solutions from each will help meet trial needs. Therapeutic strategy nuances may require pivots or specialized solutions (e.g., custom lab testing requirements or decentralized components). With the sponsor, CRO and lab provider working in unison, trial strategies can drive forward with cohesiveness and transparency to effectively take on evolving needs. As importantly, allowing biotechs to remove themselves as middlemen between service partners allows them to refocus on their long-term strategy and future development goals.

With early engagement, this tight collaboration can also keep all on the same page from the protocol design phase through enrollment of the first patient. With increasingly complex trial protocols and expanding analytical lab technologies and capabilities, trial sponsors, CROs and lab experts need earlier discussions to ensure alignment between lab technology offerings and expectations on the data to be delivered. They can dive into the following questions and more to optimize protocol design:

• What is the intended use/context of use of the assay result in the protocol (e.g., inclusion/exclusion criteria and primary, secondary, or exploratory endpoints)?
• Will the results be included in regulatory submission?
• Will the results go to sites?
• What sample type(s) will be collected and from which regions?
• Should the results be communicated with fast turn-around-time during or at the end of the study?
• How will the data be reported (e.g., qualitative, quantitative, units/cutoff, etc.)?

Bringing all puzzle pieces together by fine-tuning an integrated approach

As analytical lab technologies are continuously fine-tuned and expanding in capability, it is vital that drug developers recognize the value in a holistic approach to maximize their efforts and investments.

Early in trial design, it will be key to break down what tech-enabled lab solutions are most useful while also accounting for how these advancements fit together with the other core components discussed above for heightened efficiency and quality in continued and cohesive drug development. Essentially, it is paramount that innovative technologies are used within an integrated lab environment in close collaboration with the CRO and drug developers. Only then can lab-specific tech-enabled advances fulfill their potential. 

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Patrice Hugo, Ph.D., is Chief Scientific Officer at Q2 Solutions and R&DS Design and Delivery Innovation at IQVIA. Dr. Hugo has 30 years of senior scientific leadership experience with extensive management expertise in laboratory testing, drug target and biomarker discovery and assay validation as applied to drug development and diagnostics. In his current role with Q2 Solutions, Dr. Hugo leads scientific strategy and medical and scientific affairs for Central Laboratories and specialty testing to support clinical trials globally.