Bioanalytical reports
A bioanalytical report gives the concentrations of a drug measured in biological samples, together with the evidence that the measurements can be trusted, and supplies the primary data for toxicokinetic and pharmacokinetic evaluations. Laboratories issue it as a method validation report and a sample analysis report, and the bioanalytical part of the Common Technical Document summarises it. Bioanalysts usually write these reports, and medical writers rarely contribute to them.
What depends on bioanalytical reports
Bioanalysis determines drug concentrations in biological samples and so provides the primary data for toxicokinetic and pharmacokinetic evaluations. The validity of those evaluations depends directly on the validity of the bioanalytical measurements beneath them. So bioanalytical studies should be properly documented and reported, and a bioanalytical report should present evidence of the quality of the data. The reports should also be closely aligned with the nonclinical study or clinical trial they belong to and be read in the context of the regulatory submission as a whole. These demands are a great challenge to bioanalytical laboratories, which usually produce their study reports on their own.
The three key documents of regulated bioanalysis are the method validation report, the sample analysis, or analytical, report and the bioanalytical part of the Common Technical Document.
The medical writer's contribution
Bioanalytical reports are usually, if not exclusively, written by bioanalysts, and medical writers rarely contribute to them. Getting started with bioanalytical reports can be difficult. A medical writer can greatly assist in preparing them, bringing expertise in presenting data and in managing complex documents. That contribution makes document development more efficient and improves the quality of data presentation. With a good overview of the drug development process, a writer can place the reports in the perspective of a clinical trial or a submission package.
A good insight into bioanalysis lets a writer consider bioanalytical issues while developing a clinical trial protocol and coordinate clinical and bioanalytical reporting at the end of the trial. This integrative approach is especially beneficial for trials that depend heavily on bioanalysis, such as bioequivalence trials.
One experienced writer is convinced that the quality of bioanalytical reporting improves considerably when medical writers are involved. Medical writers preparing bioanalytical reports may seem unorthodox at first, but hardly anyone in the industry would insist that clinical reports be written by investigators. Medical writers provide valuable contributions to clinical reports, and in this view they can surely do the same for bioanalytical reporting.
The quality of concentration data
The task of a bioanalytical investigation is to provide concentration data, but much of the scientific effort goes into ensuring the quality of those data. Before sample analysis, validation experiments need to demonstrate that the bioanalytical method is valid. During sample analysis, the performance of the method needs to be monitored constantly to confirm that the concentration results are acceptable. Regulatory guidelines describe systematically which parameters of a method need to be validated and monitored.
Accuracy and precision
Accuracy and precision are the key parameters of a bioanalytical method, and both are assessed by measuring quality control samples, which hold known concentrations of the analyte. Accuracy, the closeness of the determined value to the accepted true value, is calculated by comparing a quality control sample's measured concentration with its nominal concentration. Precision, the degree of scatter between measurements, is evaluated from repeated measurements of the same quality control sample. Together they determine whether a single analytical run is acceptable and whether the study results are valid overall.
Incurred sample reanalysis
The performance of the method during sample analysis is also controlled by reanalysing incurred samples, the study samples from dosed animals or subjects. The deviations between the original concentrations and those found in the reanalysis are evaluated against predefined criteria. A failure of incurred sample reanalysis implies that the data are not reliable and requires a laboratory investigation. Incurred sample reanalysis should not be confused with study sample reanalysis, because its results are not used to generate concentration data, only to control the reproducibility of the results obtained.
The validated range and the lower limit of quantitation
The accuracy and precision of a method refer to the range of concentrations for which they were established. A concentration outside this range can still be determined, but its accuracy and precision are uncertain. High concentrations pose no significant problem, because such samples can be diluted down to the validated range before analysis, but low concentrations cannot be brought up to it. So bioanalytical laboratories do not report quantitative data for concentrations below the lower end of the validated range, the lower limit of quantitation, and set such values to missing, to zero or, in pharmacokinetic models, to half the lower limit of quantitation. The lower limit of quantitation therefore directly influences the validity of pharmacokinetic evaluations, and it should be stated clearly in both the bioanalytical and the clinical reports.
Bioanalytical guidelines
Intensive dialogue between industry and regulators has produced clearly written and widely accepted guidelines on regulated bioanalysis and a high degree of harmonisation between regulatory requirements. The harmonisation of method validation began in 1990 at the first bioanalytical method validation workshop, co-sponsored by the American Association of Pharmaceutical Scientists, the FDA and others, and continued at a second workshop in 2000. The results of both workshops were implemented in the FDA guidance published in 2001, the first regulatory guideline on bioanalysis, which the Brazilian Health Surveillance Agency followed in 2003 with a detailed guide.
The rapid advance of bioanalytical methods in the 2000s called for further regulation, and workshops in 2006 and 2008 prepared the ground for the EMA guideline on bioanalytical method validation. Issued in 2011 and well accepted by the bioanalytical community, the EMA guideline introduced new developments such as incurred sample reanalysis and an elaborated description of ligand-binding assays, and was otherwise considered in line with the FDA regulations. In May 2012 the Brazilian agency updated its guide, and the FDA then published a draft revision of its guidance, which mostly implemented methodological advances but also covered new topics, including the analysis of biomarkers and examples of report tables.
These guidelines define the regulatory framework for bioanalytical method validation and sample analysis in nonclinical studies and clinical trials. They are largely compatible, and their differences reflect technical advances rather than differing regulatory views. Most of their content describes experimental conduct, but they also set requirements for bioanalytical documentation and for the content of final reports. Any writer preparing bioanalytical reports should be familiar with them and know the definitions they give.
Other regulations
Regulated bioanalysis can also fall under many other regulations, some covering trial-specific requirements and others, most notably good laboratory practice, applying at least partly to most bioanalytical studies. Bioequivalence guidelines are commonly encountered trial-specific regulations, and they set additional, stricter requirements on conducting and reporting bioanalytical studies that support bioequivalence claims. The bioanalytical specifications for therapeutic proteins are another example. The general principles to consider include good laboratory practice and good clinical practice, although applying them to bioanalysis, and deciding whether they apply, is not always straightforward.
Good laboratory practice and good clinical practice
Good laboratory practice is a quality system designed for nonclinical studies, and although most bioanalytical laboratories run under its conditions, it remains somewhat uncertain how far it applies to bioanalysis. Sample analysis in nonclinical studies clearly requires compliance with good laboratory practice, but method validation experiments and clinical sample analysis may fall outside its scope. Its principles may also be difficult to apply fully to clinical bioanalysis, even where the regulator clearly requires that they be followed, as for bioequivalence trials. The European Bioanalysis Forum therefore recommends using good laboratory practice for all bioanalytical studies and claiming compliance with it for nonclinical sample analysis. Claiming compliance presumes verification, or monitoring, by the good laboratory practice authority, which under European Union legislation does not cover clinical sample analysis.
As a nonclinical standard, good laboratory practice does not address the safety and rights of trial subjects. The bioanalysis of human samples is subject to the same ethical provisions as the clinical part of a trial, but good clinical practice lacks clear guidelines for the processes at bioanalytical laboratories and so cannot easily be applied to bioanalysis. Good clinical laboratory practice guidelines have therefore been issued, which combine the principles of good laboratory practice and good clinical practice and so provide a framework for analysing clinical trial samples under good laboratory practice conditions. Some regulators' positions can be found in the good clinical practice inspection procedures for the bioanalytical part of bioequivalence trials.
Report content and format
The bioanalytical guidelines set regulatory standards for the content of the final report but give no guidance on its structure. The lack of a dedicated guideline leads to a wide variety of report formats, which makes many stages inefficient, including report writing, the preparation of submission summaries and regulatory review. To standardise the presentation of bioanalytical reports, the Global Bioanalysis Consortium has been developing a high-level report structure and has published its first recommendations.
The method validation report and the analytical report
Bioanalytical laboratories issue two types of report, the method validation report and the analytical report. The two can be prepared separately or combined, for example by appending a method validation report to an analytical report, especially where a per-study validation was performed. In any case, the analytical report must reference the applicable validation report or reports.
Title page
It is advisable to give on the title page the identifier of the nonclinical study or clinical trial whose samples were analysed, as bioanalytical studies often have different identifiers. This eases attribution of the report and the creation of summary tables for regulatory submissions. Under good laboratory practice, regulators sometimes require more than one signed report, and the identification of each, original 1 or 2, must be present and can be placed on the title page.
Compliance and quality assurance statements
A good laboratory practice compliance statement must be included in the final report of a study performed under good laboratory practice, but this may not apply to the bioanalysis of clinical samples. For such studies, the bioanalytical community proposed a more general regulatory statement that avoids claiming compliance and should refer to the good clinical laboratory practice guidelines. The final report of a compliant study must also be inspected by quality assurance and include a quality assurance statement.
Study summary table
A summary table of the study's key parameters can substantially ease the preparation and review of higher-level summaries, submission packages and clinical trial reports. It can be designed from the templates in the guidelines and may be aligned further to a specific regulatory requirement, such as the bioequivalence summary for Health Canada.
Method description
The validation report should give detailed information on the bioanalytical method, whereas the sample analysis report may give a short description of the assay procedure with a reference to the validation reports. The Global Bioanalysis Consortium suggests a brief method description in the text, with the detailed information in the appendices.
Compounds, calibration standards and quality control samples
Reference items and internal standards should be listed in the report with the data the regulators require, such as origin and purity, and certificates of analysis can be included in the appendices where available. The report should describe the preparation of calibration standards and quality control samples, including storage conditions. Regulatory requirements differ in the level of detail this section needs, and the bioanalytical community favours a very general description, with the specific information kept in the raw data.
Sample receipt and storage
The sample receipt and storage section is by definition present only in the analytical report, except for some validation experiments that also need subject samples. Its goal is to show that the storage conditions and period are fully covered by the validation stability experiments. At minimum it should contain a table with the longest storage period and the conditions, although the extent of the required information varies between guidelines and even between the recommendations of bioanalytical societies. It can also briefly state that the laboratory was informed in a timely manner if a subject withdrew informed consent, as the good clinical laboratory practice guidelines require.
Experimental phase
The analytical experiments should be sufficiently described in the report, in particular the acceptance criteria for an analytical run. Criteria for sample reanalysis should be predefined, for example in a standard operating procedure, and clearly stated in the report, and regulators are very sensitive to this issue. As with the method description, the text can be brief, with the detailed information in the appendices. Studies under good laboratory practice must give the experimental start and completion dates.
Results
The results section describes the study results, with references to the data tables in the tables section at the end of the report. Both types of report present the number of analytical runs, all and valid, the experimental dates, the precision and accuracy of calibration standards and quality control samples and, where applicable, assay linearity, and validation reports present them in more detail. The analytical report should include a summary of the sample analysis, giving the number of samples analysed and reanalysed, the reasons for reanalysis and the number of samples with valid results, and, where applicable, a summary of the incurred sample reanalysis.
Appendices
The appendices can include the study plan, standard operating procedures, representative chromatograms in a validation report or serial chromatograms of the sample analysis in an analytical report, certificates of analysis, method validation reports where they are not standalone, and any other supporting documents, such as laboratory investigation reports.
Bioanalysis in the Common Technical Document
The Global Bioanalysis Consortium has criticised the presentation of bioanalysis in the Common Technical Document for a lack of standardisation and uniformity that hinders efficient review. Summaries of bioanalytical methods are contained in Sections 2.6.4.2 and 2.6.5 for nonclinical studies and in Section 2.7.1 for clinical studies. Section 2.7.1, however, covers bioanalysis performed in biopharmaceutical trials, such as bioequivalence trials, and so may not suit bioanalytical information from other pharmacokinetic trials. The consortium therefore proposes a separate section, a summary of bioanalytical methods, with tables showing method validation parameters and the links between clinical trials and their bioanalytical validation and sample analysis studies. The EMA and, more recently, the FDA have provided templates for such summary tables, which should be considered when preparing bioanalytical study reports.