The drug development landscape is constantly evolving, with science and technology advancing hand-in-hand to improve the essential steps of determining drug concentration profiles and the characterization of drug transformation products. The ultimate goal is to better understand drug distribution, metabolism, and pharmacokinetic characteristics, and to present regulatory bodies with a complete and comprehensive submission package driven by current guidelines.

To this end, liquid chromatography (LC) coupled with mass spectrometry (MS) via an atmospheric pressure ionization (API) interface is a well-established analytical approach to support each phase of drug development, from early discovery through to clinical studies.

In Issue 30 of The Altascientist, we explore the numerous benefits of incorporating a stable isotope labelled internal standard for quantitative LC-MS, and detail recent advances in MS technology, including: 
•    stable isotope labelled internal standards (SLIS) for LC-MS quantitation
•    Dried blood microsampling
•    anti-epileptic drug panel
•    COVID-19 neutralizing monoclonal antibodies
•    differential mobility spectrometry
•    bioequivalence 
•    large molecule bioanalysis
•    oligonucleotides

Also included are several case studies, which exemplify novel bioanalytical workflows that are required to meet the challenges faced in both nonclinical and clinical development, across a variety of drug classes.

What is Liquid Chromatography-Mass Spectrometry?

The mainstream adoption of the LC-MS approach for the support of drug development initiatives originated in the early 1990s, pioneered by the triple-stage quadrupole (QqQ) platform. To this day, the QqQ architecture remains the gold standard for drug quantitation in biological fluids due to the unique nature by which MS/MS is performed.

Specifically, ionized precursor ions with a targeted mass-to-charge ratio (m/z) are transmitted through the first resolving quadrupole (Q1) and axially accelerated into a collision cell (q) containing an inert gas (N2 or Ar). The resulting collision-induced fragmentation leads to the production of progeny ions whose profile represents a fingerprint unique to that of the selected precursor. Progeny ions of a specific m/z can then be transmitted from the collision cell through the third resolving quadrupole (Q3) for detection. The scan function representing precursor ion selection with subsequent collision-induced dissociation and detection of a specific progeny ion is often referred to as multiple (or selected) reaction monitoring (MRM or SRM, respectively), and is single-handedly responsible for the mainstream adoption of the QqQ platform for quantitative mass spectrometry.

Over the years, advancements in LC-MS technology have been required to meet the ever-increasing complexities of assay demands. And the ubiquitous leveraging of LC-MS may largely be attributed to the following characteristics:
•    high sensitivity with broad dynamic range and selectivity from interferences, particularly when incorporating a tandem mass spectrometric (i.e., MS/MS) approach;
•    a near-universal and thermodynamically favorable electrospray ionization process that facilitates the transport of analyte ions from the condensed state of LC into the gas phase for MS detection; and
•    the ability to support multiplexing capabilities due to rapid MS/MS scanning and chromatographic separation. 

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Quality, reliable data is the key to successful drug development. From the initial preclinical data, the plan to bring a drug to market is built upon the foundation of solid, reliable data that demonstrates safety in a human patient population.

In this journal, we lead you on the complex, multi-step data journey for Phase I clinical trials, from conceptualization and initial protocol development, collection and analysis, through final regulatory submission. We highlight best practices and approaches to mitigate challenges, and show how integration and collaboration build the strongest datasets for your drug development program.

In Issue 29 of The Altascientist: 
•    Protocol development
•    Data management
•    Statistical support
•    Analysis and reporting

Clinical Trial Protocol Development—The First Important Step

Developing a protocol is the first step in making your study design a concrete, actionable plan to generate data for regulatory submission. Meticulously documented and validated, a well-designed protocol provides the structure for the trial activities that will generate the data to support the study objectives; it is integral to the success of any drug development program.

The credibility of the data from the clinical trial is mainly dependent on the trial design. The trial design in the protocol defines the endpoints and study type (double-masked, placebo-controlled, parallel design), and includes detailed information about the investigational product (IP), the anticipated duration of subject participation, and the sequence and duration of all trial periods, including follow-up. Discontinuation criteria are also key elements for data-driven decision-making during study conduct.

In addition, the protocol includes the description of the analysis and statistical methods to be employed, including timing of any planned interim analyses and quantification of the approach, such as selection criteria for analysis populations (all randomized, all dosed, all eligible, etc.), sample size, calculation of power of the trial, and clinical justification. Finally, the protocol details procedures for reporting any deviations from the original statistical plan, and the use of any excess, missing, or spurious data. 

Once the study protocol is final, it becomes the foundation for additional and more detailed study documents, including the Data Management Plan (DMP) and Statistical Analysis Plan (SAP). Here, the first steps of the data journey truly begin.

How Altasciences Will Support Your Clinical Trial Data

At Altasciences, we take pride in the way we handle your data and facilitate your journey. We have a talented, experienced, and integrated team, whose collaborative efforts ensure that your data is collected and managed with the utmost speed, efficiency, and respect for quality.

Following rigorous processes and standard operating procedures and leveraging a deep and broad knowledge of CDASH and CDISC guidelines, we ensure that your critical trial data is delivered in a regulatory-compliant format. Our PK and PD experts ensure that all analyses are carried out with rigor in a timely fashion so that the data is thorough, accurate, and actionable. When you partner with us, you need never be concerned about the quality, security, or accuracy of the data you present in support of your drug development program.
 

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