Despite more than 200 companies worldwide actively developing microbiome-based therapeutics, both the pre-clinical and clinical development of these drug products is fraught with uncertainty. Data generated from R&D activities on a microbiome-related drug product are particularly problematic because no standards exist for processing and analysing microbiome samples. Nor are there clear guidelines on the types of OMICS data that shouldcomplement this microbiome data. As a result, microbiotic medicinal product developers are left to guess what data will pass muster with the regulatory agencies.
Regulators, too, struggle with ambiguity in this early era of ‘living medicines’: as more and more microbiome-focused companies submit applications with pre-clinical data generated using various specialised methods, interpreting and comparing them becomes extremely difficult. It’s not unlike a group of chefs who must judge and compare a number of meals– basedon the recipesalone, not the final products –and moreover, the recipes are for different types of meals, written in different languages, using different units of measurement.
To date, neither the drug developers nor European drug regulatory agencies have put a framework around microbiome-related data, leaving all parties questioning which studies warrant regulatory approval. But in an attempt to improve this situation, stakeholders came together in early 2020 to form a task group that will devise guidelines for accurate, reproducible OMICS datain studies for microbiome-based drug products—taking the form of good practices and harmonised minimum requirements. The efforts are led by the Pharmabiotic Research Institute (PRI) (www.pharmabiotic.org), a non-profit industry group with a mission to clarify the regulatory and scientific requirements for microbiome-based drug products in the European Union.
Guidelines for microbiome-related data
Warren Flood, Chief Operating Officer at the Norway-based microbiome discovery company Bio-Me, chairs the PRI’s OMICS data task group. He says,
“Alot of live biotherapeutic product (LBP)developers are uncertain, asking: what type of data do we need to present for our pre-clinicalstudies, and how do we show that our LBP does what we believe it does?”
Furthermore, developers can leverage many different OMICS techniques in a study—among them, genomics, transcriptomics, metabolomics, and proteomics—but Flood says they remain unsure about which dataset will give them the most informative results.
“We’re trying to formulate clearer structure around which OMICS are relevant in which situations,”
The task group is working to identify good practices and harmonised minimum requirements formicrobiome analysis, all in the service of regulatory clarity. Flood says,
“We’re looking to create a framework for developers to go through in a decision-tree process and,based on the question they want to answer, find the ‘quality by design’ principles that they can apply to get solid data.”
In other words, the group aims to give companies a tool for helping them better understand what constitutes quality during microbiome-related drug development, in order to increase the likelihood of ending up with safe, effective products.
Reducing biases in metagenomics datasets
Arne Materna, Vice President of Productat CosmosID, a US-based microbiome service provider, says the task group’s efforts are important because metagenomics work is uniquely vulnerable to the introduction of biases.
“If you consider that in every step up to sequencing you can introduce problems, it becomes immediately clear why there is a need for caution and for measures that allow you to detect whether you’re introducing contamination or bias. And ideally, to quantify that event.”
The group will underline the necessity of introducing different kinds of controls throughout the end-to-end process of microbiome analysis in order to generate data that’s both accurate and reproducible at every stage.
“These can be a series of negative controls that control the introduction of contamination, as well as positive controls that confirm the validity of the run and assess sample-to-sample bias and variability,” says Materna.
He notes that such practices also allow continuous tracking and assessment of the microbes attributable to lab contamination—a recurrent issue in the field, pertaining to both human and non-human samples.
“Using these, you end up with higher accuracy, and ultimately, precision.”
Guidelines with built-in flexibility
Flood acknowledges that others have made previous attempts to rally around standardization of OMICS data, but says these attempts have not ultimately led to clarity within the field.
“Possibly where they’ve fallen down is they’ve had a more prescriptive procedural approach. But the technology is moving too fast for that,” he says.
It was thus clear to members of the task group that an approach with built-in flexibility was necessary in this relatively young field. Materna explains,
“It is probably far more realistic, and also beneficial, to not lock down and standardize the methods in themselves, but rather to focus on how you validate those methods.”
“While there are minimal requirements, like the ability to resolve microbiomes to strain level, or to flag a likely false positive call, it would be wrong to block continuous technology evolution. We therefore need to allow for different sequencing platforms, reagents, and bioinformatic tools to mature and improve—but define instead how to validate and verify that this end-to-end workflow performs and does what it should be doing.”
According to the PRI’s Scientific and Regulatory Affairs Director Magali Cordaillat-Simmons, the intent is to mirror the type of good manufacturing practices (GMPs) and good laboratory practices (GLPs) that regulators already know well.
“Since GMPs and GLPs are indeed sets of ‘good practices’, the work of this task group fits into the landscape of potential regulatory texts,” she says. “The regulatory authorities may not incorporate these good practices right away, but the important thing is that the industry shows their practices lead to better quality of the studies.”
Flood says the good practices developed by the group will remain robust over time, even in a field known for rapidly-advancing technologies.
“There are physiological principles to take into account when you’re handling microbiome samples: degradation of DNA, degradation of metabolites. Those principles won’t change but there may be new methods that emerge. For each of these considerations we want to have standards or references that people can measure their new method up against.”
Toward greater certainty for study design
The OMICS standardization task group convened by the PRI includes approximately 20 organisations with broad areas of expertise: contract research, microbiome-focused drug development,andbasic academic research. Flood says, “Each type of stakeholder hasimportant insights but also important constraints that need to be factored in.”
The PRI-led group is also communicating and collaborating with other organisations leading microbiome standardization initiatives—for instance, in the UK and Japan.
“The time is right, because we see a lot of developers getting very close to Phase3,” says Flood. “Some have struggled in that journey, and others are unwilling to pursue a therapy because of the difficulties surrounding it.”
He sees the task group’s efforts as forging a new path for microbiome-focused drug developers, giving them greater confidence in the design of their studies for regulatory success.
The PRI welcomes organisations to learn more about European regulatory discussions on microbiome-related drug products: [email protected]g