Effective clinical trial programs have become an important differentiator for developers of probiotics. Faced with evolving regulatory requirements and consumer demands, forward-thinking companies are running clinical trials to validate the efficacy of products and secure a competitive edge for years to come. This is easier said than done, though. To thrive, companies must design and run high-quality trials that balance marketing and scientific goals and consider the entire product lifecycle.
A look at the North American regulatory and commercial landscape shows the importance of clinical data to the prospects of probiotics. In Canada, probiotics require pre-market approval. If the product is novel, regulators want to see high-quality research showing it works as claimed. The amount of research companies must present rises in line with the risks associated with the desired health claim.
Across the border in the US, probiotics come to market without undergoing pre-market assessment but increasingly need the validation of clinical trial data nonetheless. The Federal Trade Commission is investigating whether companies can substantiate advertising claims, and plaintiffs in class action lawsuits are accusing manufacturers of making false statements. In this environment, companies see it as prudent to generate supporting data before making label claims.
The upshot is probiotics manufacturers need clinical trial data to access the North American market. Small, uncontrolled or poorly designed trials are not good enough, though. Only well-designed, high-quality trials can satisfy regulatory data demands. Generating this data is a significant challenge, particularly for organizations with minimal experience of designing and running pharmaceutical-style clinical trials in the West.
In trying to meet this challenge, businesses can draw on the experience of companies that have pioneered the clinical development of probiotics. These companies have seen what works, giving them insights into the best practices for probiotics clinical trials. This feature will discuss these best practices and how companies can use them to unlock Western markets.
Laying the groundwork for success
Preparations for probiotics trials start long before investigators begin enrolling participants. To start human testing and prevent avoidable failures, companies must characterize their strains and assess how they interact with antibiotics and the gastrointestinal tract. If a probiotic is affected by an antibiotic, people taking that medication must be excluded from clinical tests of its efficacy. Similarly, if a probiotic is destroyed during digestion its developer needs to rethink the whole project.
When a company decides to move a probiotic into clinical development, it then considers the current operating environment and how it is changing. The probiotic and wider dietary supplement sectors have been through major changes since the 1994 passage of DSHEA in the US. In the years following that landmark legislation, regulatory actions, shifts in consumer demand and globalization reshaped the market, forcing probiotics companies to evolve quickly or risk losing ground on their competitors.
The fast pace of change continues to do this day and companies must factor this into their clinical trials. Success is built on up-to-date knowledge of how regulators approach probiotics, and insights into how to satisfy these agencies’ demands for pharmaceutical-style trials that comprehensively demonstrate safety and efficacy.
This is a new challenge for many probiotics companies, which are well versed in discovering novel ingredients and defining active constituents but have less experience of regulations and clinical trials. Recognizing a gap in their skill sets, companies are working with consultants and contract research organizations (CROs) to access the necessary knowledge and capabilities.
The operating environment expertise provided by these third parties gives probiotics companies one of the foundational pieces of successful trials. To establish the next foundational piece, companies need to assess their own goals and how they map onto the regulatory and commercial environment in which they operate.
Assessments of goals typically reveal competing pressures and opportunities, with companies keen to contain costs and accelerate time to market while running comprehensive studies that validate a product and open up new commercial horizons. Focusing too much on any one of these priorities can be detrimental to the others.
If, for example, a company runs a narrowly-focused clinical trial, it could get to market quickly and cheaply but leave key questions unanswered. These outstanding questions may create commercial and regulatory barriers that can only be cleared by a second trial. Similarly, a company may rush into a pivotal program without running early-stage trials, raising the risk that inadequate understanding of the probiotic or the sample size needed to show efficacy will cause the study to fail.
Companies can avoid these costly, time-consuming complications by being more methodical about their plans and goals upfront. By taking a program management approach that considers the entire product lifecycle, companies can plot out what claims they want to make in which markets and craft development strategies that deliver the data needed to seize the opportunities.
The value of highly-skilled teams
Exactly what data is needed will depend on the nature and purpose of the study. In early-phase trials, companies seek to learn the optimal dose of their products, assess how they interact with food and otherwise gather information to support larger, longer and more expensive clinical trials. Failure to gather this information cuts the chance of success in pivotal trials.
Considering these questions before starting a pivotal trial pushes back the start date of the study and adds to near-term costs. However, longer, more expensive delays await companies that fail to plan. The history of clinical trials shows upfront effort results in streamlined development programs and long-term savings of time and money.
Once companies have a broad vision of their clinical development plans, they can drill into the details to ensure the individual trials generate the required data. This stage of the planning process requires a detailed knowledge of statistics, acceptable clinical endpoints and other factors that ensure a trial answers the sponsor’s questions and meets regulatory requirements.
The focus on these factors reflects the complexity of clinical trials. Studies fail for a myriad of reasons unrelated to the probiotic itself. These reasons include a lack of statistical power and inadequate controls against potential sources of bias. Even trials that avoid these pitfalls and deliver seemingly positive data can come unstuck, for example by using an endpoint that is not accepted by regulators or testing a formulation that differs from the commercial product.
Expertise is needed to manage to these challenges. Establishing a team with a broad range of skills spanning clinical development, regulatory affairs, data management and biostatistics — or working with a specialist service provider — equips companies to design trials that are free from major problems and deliver the required data.
Such teams also enable companies to use data from one clinical trial to unlock multiple markets, thereby maximizing return on investment. The ability to use data in multiple markets is predicated on the standards followed in the clinical trial. If a trial follows globally-harmonized good clinical practices (GCPs), the data it generates is more likely to be accepted by multiple regulatory agencies. Following GCPs requires resources but companies that make this commitment are rewarded with the ability to manage risk and generate data that unlocks multiple markets.
Some companies are going a step further by designing adaptive clinical trials that can be tweaked mid-study in response to interim data. These adaptive designs have started to gain popularity in the pharmaceutical industry and are accepted by regulators, provided they are performed properly. To maintain the validity and integrity of the trial, the changes must be formally pre-planned. Companies cannot make unplanned, ad hoc changes to studies without diminishing the validity of later findings.
Partnering to access expertise
The interest in adaptive trials is indicative of the growing sophistication of probiotics studies and the expanding skill set needed to succeed in the sector. Few companies have this expertise internally, and few probiotic developers have product pipelines big enough to justify establishing it. Faced with those dynamics, companies have identified partnering with experienced CROs as the most efficient way to access the knowledge and capabilities they need.
Partnering with a CRO early in clinical trial preparations enables companies to approach each task from understanding the operating environment onward equipped with insights gleaned from years of experience.
Equipped with this support, companies can take a methodical approach to clinical development that considers the lifecycle of their probiotics from concept to claim. In doing so, companies will design roadmaps that bypass pitfalls and take opportunities, resulting in streamlined development programs that maximize returns on investment.