2 FDA Draft Guidences Released for Public Comment

 The FDA has released two draft guidance for public comment:

It has taken the FDA 6 weeks to release this draft ICH guidance:

BIOEQUIVALENCE FOR IMMEDIATE-RELEASE SOLID ORAL DOSAGE FORMS

1.1 Objective

This guideline is intended to provide recommendations on conducting bioequivalence (BE) studies during both development and post approval phases for orally administered immediate-release (IR) solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension.

For my bioanalytical colleagues, it covers what should be measured (prodrug, drug, and or metabolite, as well as enantiomers vs racemates) and does point to ICH M10 Bioanalytical Method Validation and Study Sample Analysis for how the analyses should be conducted.

For my PK and statistical colleagues: Normally, excluding subject data for inconsistencies is difficult, but M13 allows their data to be excluded for subjects with low exposure (<5% geometric mean AUC of the product in question, which should be calculated without inclusion of data from the subject)

The second draft guidance covers

Considerationsfor the Design and Conduct of Externally Controlled Trials for Drug andBiological Products

This guidance deals with the use of data from subjects not enrolled within the trial in comparison to subjects enrolled in the trial and on trial therapy. From the Introduction:

The guidance addresses considerations for the design and analysis of externally controlled trials to study the effectiveness and safety of drugs, including discussion of threats to the validity of trial results from potential bias. Although various sources of data can serve as the control arm in an externally controlled trial, this guidance focuses on the use of patient-level data from other clinical trials or from real-world data (RWD) sources, such as registries as well as electronic health records (EHRs) and medical claims.

There may be a number of challenges to ensure reliable and unbiased data, but this guidance paves the way for reducing costs and potentially including larger control arm data sets.

Webinar notes: Revision of EU pharmaceutical legislation

Today, I listened to a webinar, "Even spaceships need a launchpad" presented by Reuters that focused on the ongoing revision of EU pharmaceutical legislation. That legislation is currently 20 years old.

 

There were for 4 panelists:

Emer Cooke, EMA

Nathalie Molle, EFPIA

Florian Schmidt, European Commission

Cristian-Silviu Busoi, European Parliament

 

The background to the discussion was that the EU has been falling behind in several fronts related to bringing new therapies to patients compared to other countries, including:

• Regulations do not support well the newer therapies (e.g., cell and gene therapies)
• Newer therapies include device combinations (~25%) that require bridging communications with the agency responsible for devices (delivery and companion diagnostics) and the two different regulatory frameworks
• A question remains is EMA staffed adequately to deal with the current science and the volume of work
• Fewer expedited pathways
• Practices need to be harmonized more across the countries

 

Once therapies are approved by the EU (EMA), taking on average 466 days, each of the 27 member countries has to approve. Subsequent to the individual country approvals, is the actual process (i.e., access) for getting new therapies to patients that include the payer approvals.

 

Emer Cooke refocused the discussion getting new therapies to patients.  She noted that a focus on unmet medical need therapies could be a more impactful approach vs therapies that provide only minor improvements over existing therapies. Additionally, an ongoing approach for multi-national review teams is aimed improving the post-EU approvals with the country approvals.

 

Florian Schmidt wants to improve the communications between the pharmaceutical sponsors and regulators to ensure more guidance is provided during the therapy development.  In the end, making sure that right research is completed so that the final submission is can undergo a smooth review.  He also wants to change the regulations to bring the drug and device regulators together to meet with the pharmaceutical sponsors during development so that the sponsors understand the expectations and have guidance from the regulators.

 

Overall, it was an interesting and insightful discussion on the challenges for obtaining new therapy approvals in the EU. Collaboration amongst the pharmaceutical therapy ecosystem is central to the future success. Worthwhile hearing for those who are supporting new therapy approvals for the EU.

American Society for Mass Spectrometry Course is Offering 15 Short Courses of Interest to Bioanalysts and Biomarker Scientists

ASMS will be offering the Two-Day Short Courses, Saturday and Sunday, June 3 and 4, 2023

 

All of the following two-day short courses will be in-person only at the George R. Brown (GRB) Convention Center in Houston, TX.  Several short courses will now be offered ONLINE, asynchronous to the annual conference.

 

Course offerings:

01 Bioinformatics for Protein Identification

 

02 Clinical Biomarkers: Development and Validation

03 DMPK: Experimentation and Data Interpretation

04 Glycans and Glycoproteins in Mass Spectrometry

05 LC-MS: Practical Maintenance and Troubleshooting

06 LC-MS/MS: Practical Method Development (Saturday one-day course)
            AND Bioanalytical Method Validation (Sunday one-day course)

07 LC-MS/MS: Understanding, Optimizing and Applying Techniques using Electrospray, APCI and APPI                 to Develop Successful Methods for Qualitative and Quantitative Analysis

08 Machine Learning for Mass Spectrometry Data Analysis

09 Native Mass Spectrometry

10 Peptides and Proteins in Mass Spectrometry

 

11 Protein Therapeutics: Practical Characterization and Quantitation by Mass Spectrometry

12 Quantitative Mass Spectrometry

 

13 Quantitative Proteomics: Case Studies

 

14 R for Mass Spectrometry Data Analysis: Getting Started

15 Top-Down Proteomics (Saturday one-day course) 

        AND Top-Down MS Data Analysis and Visualization (Sunday one-day course)

Article: Researchers predict Alzheimer's progression 3.5 years early with unique blood test

Published in Brain, "Predicting progression to Alzheimer’s disease with human hippocampal progenitors exposed to serum"

There is a long way to go before this cell-based is able to be used widely in assessing the general population, but further exploration of the factors that are affecting the hippocampal progenitors may produce a more simplified assay. My congratulations to the researchers who are furthering our understanding of this complex disease. 

 

Abstract:

Adult hippocampal neurogenesis is important for learning and memory and is altered early in Alzheimer’s disease. As hippocampal neurogenesis is modulated by the circulatory systemic environment, evaluating a proxy of how hippocampal neurogenesis is affected by the systemic milieu could serve as an early biomarker for Alzheimer’s disease progression. Here, we used an in vitroassay to model the impact of systemic environment on hippocampal neurogenesis. A human hippocampal progenitor cell line was treated with longitudinal serum samples from individuals with mild cognitive impairment, who either progressed to Alzheimer’s disease or remained cognitively stable. Mild cognitive impairment to Alzheimer’s disease progression was characterized most prominently with decreased proliferation, increased cell death and increased neurogenesis. A subset of ‘baseline’ cellular readouts together with education level were able to predict Alzheimer’s disease progression. The assay could provide a powerful platform for early prognosis, monitoring disease progression and further mechanistic studies.

Article: AI has designed bacteria-killing proteins from scratch – and they work

Unfortunately, the article is behind a pay wall, but what is visible is tantalizing:

An AI was tasked with creating proteins with anti-microbial properties. Researchers then created a subset of the proteins and found some did the job

An AI has designed anti-microbial proteins that were then tested in real life and shown to work. The same approach could eventually be used to make new medicines.

Proteins are made of chains of amino acids. The sequence of those acids determine the protein’s shape and function.

Ali Madani at Profluent, a biotechnology start-up in California, and his colleagues used an AI to design millions of new proteins, then created a small sample of those to test whether they worked.

The potential to use AI to target proteins and pathways in bacterial disease may keep us apace of the changes that nature builds continues to build into bacteria, and may ultimately produce new antibiotics. It will be interesting to see whom the company partners with to screen these compounds for safety and efficacy before entering animal and human trials.
 

 

First oral selective estrogen receptor degrader (SERD) approved by FDA

 From the article:

Italian drugmaker Menarini has succeeded where three European Big Pharmas have failed, pushing the first oral selective estrogen receptor degrader (SERD) to treat breast cancer across the FDA finish line.

The agency has signed off on Orserdu (elacestrant) for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

 AZ released an injectable SERD in 2002, and Roche, AZ and Sanofi had failed trials of their oral SERD.  The approval for Menarini also comes with an approval for a companion diagnostic. 

In an age where biologics, gene and cell therapies are growing, it is nice to see that oral drugs are still achieving approvals.  The companion diagnostic also shows the continued value of targeting the right patients to achieve success and not treat patient who will not respond.

Publication: Commutability assessment of human urine certified reference materials for albumin and creatinine on multiple clinical analyzers using different statistical models

 I first heard about "communtability" from Russ Grant (Labcorp) at either a CPSA or AAPS Crystal City conference during discussions of biomarkers.  The discussion furthered my enlightenment on the practices in clinical laboratories that support medical practice. These practices, while in some cases similar to the FDA Bioanalytical Method Validation guidance, are different; as would be expected for the differences in intended use of the data. John Allinson (Immunologix Laboratories), Steve Piccoli (SPARC) and Erica Troksa (Labcorp) subsequently challenged my notions on the application of BMV to biomarkers measured in clinical laboratories and helped me realize that clinical laboratory practices are many times superior to bioanalytical labs when it comes to measuring biomarkers; especially when considering the intended use of the data.

In this case, the authors of the article explore albumin and creatinine reference materials tested across several clinical analyzers to assess the comparability/comparability of the devices and their assays for these analytes (measurands) in urine.  There are numerous publications that discuss the challenges in achieving comparable (note not equivalent) results across clinical laboratories. This article explores one lab-based approach and 2 statistical approaches to demonstrate that the data from the different instruments and assays are similar enough to result in a common outcome (i.e., medical determination):

Abstract

Urine albumin concentration and albumin–creatinine ratio are important for the screening of early-stage kidney damage. Commutable urine certified reference materials (CRMs) for albumin and creatinine are necessary for standardization of urine albumin and accurate measurement of albumin–urine ratio. Two urine CRMs for albumin and creatinine with certified values determined using higher-order reference measurement procedures were evaluated for their commutability on five brands/models of clinical analyzers where different reagent kits were used, including Roche Cobas c702, Roche Cobas c311, Siemens Atellica CH, Beckman Coulter AU5800, and Abbott Architect c16000. The commutability study was conducted by measuring at least 26 authentic patient urine samples and the human urine CRMs using both reference measurement procedures and the routine methods. Both the linear regression model suggested by the Clinical and Laboratory Standard Institute (CLSI) guidelines and log-transformed model recommended by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Commutability Working Group were used to evaluate the commutability of the human urine CRMs. The commutability of the human urine CRMs was found to be generally satisfactory on all five clinical analyzers for both albumin and creatinine, suggesting that they are suitable to be used routinely by clinical laboratories as quality control or for method validation of urine albumin and creatinine measurements. [Analytical and Bioanalytical Chemistry volume 415, pages 787–800 (2023)]