As 2020 comes to a close, drug development companies await the finalization and implementation of the ICH M10 guidance. The M10 guidance from the International Council for Harmonisation of Technical Requirements (ICH) focuses on the bioanalytical method development, validation, application and documentation of small and large molecular drugs.1 Regulators, laboratory testing partners, drug developers and consultants have been discussing the need for such guidance for years, intending to achieve global harmonization of bioanalytical method standard and requirements. This step forward makes the reporting and submission processes become less cumbersome in order to allow the drugs to reach the patients’ hands sooner.
With the ICH composed of almost 50 members and observers, the impacts of this regulation are far-reaching. While the industry widely anticipates these expectations, the actionable next steps will require drug developers to prepare for regulatory changes – specifically, in their reporting and documentation package. Companies ahead of the curve on these updates can reach non-clinical and clinical studies more quickly and cost-effectively by aiming to create a single global submission, without compromising quality or facing the threat of delays when reassessing information according to each intended health authority.
Harmonization on the Horizon
Over the past decade, many different regulatory agencies have issued bioanalytical method validation guidelines. Consequently, regional differences in regulatory expectations made global chemical and biological drug submissions more complex. ICH aims to play the role of harmonizing and standardizing regulatory requirements around the world to support effective and efficient drug evaluations and registrations.
Finding Common Ground
Drug developers can benefit from this guidance in many ways, but they need to know where these opportunities are. ICH M10 guidance for bioanalytical method validation will enhance clarity and consistency, support mutually acceptable data packages and lessen concerns about varying laboratory inspection expectations.
First, efficiency opportunities become available when submitting data to multiple regulatory bodies. Since bioanalytical standards are more aligned following this standard’s final publication, creating a single, mutually acceptable data package is easier and can contribute to submissions across various approval pathways.
As companies put this guidance to practice, regulators should have more consistent evaluation perspectives, ideally leading to a reduced need to issue requests for additional information. Reviewing data packages without as many setbacks helps speed up the overall filing process and tightens up timelines to market.
Additionally, working with a credible laboratory is pivotal in creating an acceptable submission, but drug developers can now look forward to more consistent inspection expectations that should reduce company or laboratory concerns from on-site audits. Companies should watch for opportunities to work with laboratories that are well prepared to adhere to ICH M10 standards. Overall, the registration processes, both on local and international levels, should significantly shorten the time for new drugs to reach patients and benefit all parties.
2021 will likely be a year of implementing these updates and understanding how they impact the testing and submission processes. The most distinct area expected to experience broad changes is in reporting requirements under the M10 guidance. Knowing what this looks like for the industry and for different types of molecules, as well as what potential pitfalls exist, are critical to drug development programs moving forward.
Changes to Reporting
Under the new guidance, regulators have provided detailed recommendations for bioanalytical reporting and submission formats. Putting these changes into practice means that companies will need to fine-tune the details with their internal teams and their laboratory testing partner. These documentation requirements will force some drug development companies to scrap their old templates and adjust to the new ones.
Many laboratories have opted to use reporting software to support each product’s approval pathway and to aid this submission transition. In any case, laboratories that offer services to deliver insights that plug right into the designated format provide a unique advantage. Also, partner organizations that utilize standard software tools can help harmonize reporting practices across the industry by creating alignment in what final results look like across laboratories.
While software solutions support measures to meet new requirements, efforts to implement reporting changes do not stop there. Drug developers must review report templates against thoroughly outlined ICH M10 guidelines. Then, because authorities such as the FDA and NMPA may not implement M10 in totality, parameters need to be set to specific formats to comply with the local health authority requirements, too.
The fact is for developers that lack global submission experience, adjusting current processes could require added efforts to prepare the data, format reports, and even review the quality assurance components of a submission. Still, for those already working under the U.S. FDA’s Bioanalytical Method Validation Guidance (BMV),2 past efforts to satisfy these standards will only need slight modifications to specific items.
Translating FDA BMV Experience
There is a significant overlap between the FDA BMV and ICH M10 guidance documents. Reflecting on these can reduce the learning curve as agencies implement updates. Some examples of these commonalities include:
ICH M10 guidance displays commonality with the FDA BMV guidance on reporting. It affirms requirements, “For comparative bioavailability (BA) and bioequivalence (BE) studies, internal standard (IS) response plots for each analytical run, including failed runs.” This is considered unique to M10, creating additional value when referencing BMV guidance.
The internal standard response (specific to LCMS technique) for a particular sample is an indication of how successful the sample is performing in the analysis, thus creating a benchmark for evaluators.
If the internal standard response of a sample, or samples from the same subject is considerably different from the rest, this result could impact the reliability of the data from these samples. For comparison, BA or BE reliability and consistency is the basis of the study endpoint, as the study design typically involves comparisons between different formulations (e.g., capsule versus tablet forms) with BA, or between the innovator and generic drugs with BE. The internal standard response plots provides the laboratories and the regulators an instantaneous insight on the quality and reliability of the batches of samples being analyzed. Any outliers or defective analytical batches can be visually identified earlier and necessary investigation and remedial actions can be taken to save on costs and time at early stages.
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ICH M10 asks for reporting of 100% of chromatograms (for comparative BA/BE studies) with bioanalytical reports where the FDA BMV looks for 20% in serial. Additionally, ICH requires bioanalytical reports to cover “100% of run summary sheets of accepted and failed runs, including calibration curve, regression, weighting function, analyte and IS responses and retention times, and dilution factor if applicable.” While these expectations are not entirely replicative, they give a sense of what regulators’ priorities will be when it comes to sharing data and results.
If drug developers lack the internal resources to produce adequate templates and formats, they will need to vet outside partners that offer services to automate report generation. This software should connect with corresponding lab systems that currently support data generation, analysis, standard operation procedures, etc. From there, reporting becomes a seamless workflow – exporting data, such as numerical and chromatograms, into a consistent format. Some laboratories also have templates in place for specific clients or health authorities.
While changes in reporting seem to have overlap with regulations that many developers have already been working under, it is still critical to understand how updates apply to each study program – and the potential challenges they present.
Impacts on Molecule Type
The differences seen in M10 expectations for chemical drugs (or small molecules) and biological drugs (or large molecules) primarily originate from the different experiments and evaluations they are subjected to. For example, ligand binding assays (LBAs) and chromatography assays will vary in reporting between small and large molecules, because each compound type is measured using different analytical theories and techniques.
One of the differences that stand out as the most influential is the Matrix Factor for chemical drugs. M10 does not mention the Matrix Factor, which authorities like the European Medicines Agency (EMA) use to study the analyte’s response when the matrix is present and when it is absent.
Rather than using the Matrix Factor, M10 updates should be alternatively satisfied using the quantification of the matrix spike. Using the alternative approach, laboratories can analyze the chemical drug with an essentially identical method in the accuracy and precision evaluation compared to the Matrix Factor, but with only low and high quality control concentration levels and three replicates each. This preference lends to the demonstration of method robustness across different test subjects, thus being more detailed to the overall submission. Then, teams can determine any bias on the particular matrix using the bioanalytical method.
Adhering to ICH M10 expectations can reveal a refreshed approach to the evaluation and analysis process. Take time to critically assess what this means based on a molecule’s data, and remain open to how it can improve current processes.
Potential Pitfalls
While ICH M10 is similar to other bioanalytical evaluation guidance, there are still gaps to be wary of during reporting and submissions. In China and the United States, regulators may not accept M10 in totality, leading to guidance having finite disparities in expectations.
One notable variance is the acceptability of biomarkers in bioanalysis. While the U.S. FDA BMV accepts biomarkers within the scope of bioanalysis, the same is not true in M10. Instead, the guidance notes, “The bioanalysis of biomarkers and bioanalytical methods used for the assessment of immunogenicity are not within the scope of this guideline.” When it comes down to designing a study program, this complicates study design and reporting when endogenous analytes are also biomarkers, such as the naturally occurring growth factor and hormone, testosterone. Such discrepancies between guidance need to be translated to submission documentation and reports.
While local authorities review and implement the standard, drug developers must follow conventional reporting and document practices. This precedent could prove to be a pitfall for companies that are not certain of a local authority’s implementation progress. It also complicates the reporting process and reveals gaps that developers could unknowingly overlook. It’s critical to consult with regulatory experts and consultants at this stage to ensure all reporting and documentation requirements are fulfilled.
Developers can overcome the challenge of variations in reporting requirements by comparing M10 and the local authority guidance item by item. Although this process may be time-consuming, it is the safest approach to please regulatory bodies during the implementation and acceptance phase. Partnering with an outsourced laboratory can grant access to regulatory specialists and the reporting software necessary to meet these requirements.
Though M10 provides recommendations for documentation and reporting, a perfect reporting template does not yet exist. The drug developers are trending to adopt some of the templates utilized by familiar laboratories across the globe. This trend may sync with ICH M10 in the years to come and push the industry towards report template harmonization.
In some ways, M10 is seen as a select compilation of guidance from numerous governing bodies. While M10 may not be fully compatible across the board, it can still support established guidance, such as 2012 European Medicines Agency (EMA) guidelines on bioanalytical method validation,3 by adding considerations that account for how methods are refined and evolved over time. In short, M10 can close the gaps while some areas of the industry determine what the future of bioanalytical testing looks like.
Remember that while ICH M10 may be prescriptive in creating reports for submission, there is not guidance for inspectors on interpreting M10 or the reporting techniques. If smaller drug developers are new to the bioanalysis, be sure to partner with a laboratory that has greater, ideally global exposure. This partnership can help predict how inspectors will approach new guidance, both now and moving forward.
What Next?
The future of ICH M10 is still uncertain, but there is great potential considering its aim for international harmonization. As the world becomes increasingly global, the way developers, laboratories and regulators work together to improve patient health and safety will continue to evolve. This regulation is just one component of that and drug developers are expecting the harmonized guidance for immunogenicity, biomarker and other assays.
If the insights discussed seem outside a company’s expertise, do not wait to engage experts with a wide range of experiences. While ICH M10 will not drastically overhaul bioanalytical evaluations, the details are critical to development programs and submissions. Companies should review their submissions for a successful report under the new guidance and reach out to a qualified partner.
References
- ICH M10, Step 2, Draft, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, 2019. https://database.ich.org/sites/default/files/M10_EWG_Draft_Guideline.pdf
- U.S Food and Drug Administration, Guidance for Industry: Bioanalytical Method Validation Guidance for Industry, 2018. https://www.fda.gov/regulatory-information/search-fdaguidance-documents/bioanalytical-method-validation-guidance-industry
- European Medicines Agency, Guideline on bioanalytical method validation, 2012. https://www.ema.europa.eu/en/bioanalytical-method-validation
Author Biographies
Dr. Xiaolong (Tom) Zhang joined WuXi AppTec in early 2020 as the Senior Director and U.S. head of Large Molecule Bioanalysis. He oversees operations and provides scientific and compliance supports to large molecule services including TK/PK, immunogenicity, biomarkers, PD, and cell assays. His team supports hundreds of studies covering a variety of drug modalities (e.g., fusion protein, antibody, bispecific, gene, and CAR-T therapeutics) from early discovery to late clinical phases and provides scientific and regulatory support for a wide range of biologics.
Dr. Zhang has over 10 years of experience in CROs, academia and pharmaceutical companies. He holds Ph.D. in Biomedical Engineering from Pennsylvania State University where he also serves on the Industrial and Professional Advisory Council. He has published over 20 manuscripts in refereed journals, as well as several book chapters, invited review articles, and patents.
Dr. Colton Wong joined WuXi AppTec in 2018 to lead the Shanghai Small Molecule Bioanalysis Method Development team. His extensive experience in the bioanalytical industry and strong leadership skills enabled Dr. Wong to build a highly efficient and professional team to enhance WuXi AppTec’s clinical bioanalytical capability towards oligonucleotides and small molecular biomarker panels.
Dr. Wong received his B.Sc. and Ph.D. in Chemistry from the University of Hong Kong. He worked in the Racing Laboratory at the Hong Kong Jockey Club in doping control before transitioning to the CRO industry for clinical studies in both the U.S. and Taiwan.
Since joining WuXi AppTec, Dr. Wong has co-led the International Project Management team to oversee global pharmaceutical companies to ensure on-time deliverables with high quality standard and regulatory compliance. During the rapid technical capability growth under Dr. Wong’s supervision, Small Molecule Bioanalysis has successfully delivered the first GLP compliant immunocapture LCMS method, several ADC Linker/Payload LCMS methods, and several ultra-sensitive methods.
In addition to his well-received presentations at both local and international conferences, Dr. Wong received the Young Scientist Award in the Chinese Bioanalytical Forum in 2019 and was the winner of the 2019 LTD Science Day Competition.