Clinical Trials Roadmap: A Go-To-Market Guide for Probiotics

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1 Clinical Trials Roadmap: A Go-To-Market Guide for Probiotics

2 Clinical Trials Roadmap: A Go-To-Market Guide for Probiotics Joshua Baisley, B.Sc., Director, Clinical Trials As dietary supplement regulations evolve and consumer demands shift, companies increasingly look to clinical trials to gain a competitive advantage. It can be difficult to balance marketing and science goals. But a well-planned study that takes the entire product lifecycle into consideration is key to success and maximizing return on investment. This guide outlines the pathway and steps probiotic manufacturers and brands should take when developing a successful clinical trials program.

3 1. Know the Environment The dietary supplement industry has evolved incredibly over the past two decades since DSHEA was implemented. Driving this change are regulatory bodies, consumer interests and demands, and desire for global market access. Companies must remain nimble and respond quickly to changes to succeed. At the same time, responses should be calculated to compete effectively in the marketplace. Companies continue to strive to find new ingredients and define active constituents. Probiotics are a promising segment that, like some other supplement ingredients, has potential to be further developed into an active pharmaceutical or biologic. Service providers have also expanded to address the evolution of dietary supplement manufacturers and suppliers. Regulatory consultants keep abreast of ever-changing regulations and nuances associated with different product types including live microorganisms. Contract research Companies must remain nimble and respond quickly to changes to succeed. organizations have evolved by taking a more pharmaceutical-style approach. This ensures that regulatory needs are being addressed to mitigate risks to the supplier/manufacturer. Laboratories have continually updated equipment and training as technology outpaces science and regulation. In all cases, the outcome is the same: a united industry continuing to evolve to ensure safe and effective products reach the market. 2

4 2. Understand Where You Are Firms typically have conflicting marketing and scientific goals. Managing these is a difficult task, and a research study, or research program, is often required to meet these goals. While getting to market quickly is essential, taking the appropriate time to plan a program is critical to minimize risk of rework and reduce costs. Taking a program management approach and thinking about the entire product lifecycle is critical for success and maximizing return on investment. The pharmaceutical industry has learned this lesson and has left a roadmap for streamlined product development through regulatory body guidance documents and templates. Although more time is required in critical planning stages, the less reworking or repeating required, the more time and money is saved. Thinking about the entire product lifecycle is critical for success and maximizing return on investment. It is important to understand what the objective of the study is and how it fits into the overall product lifecycle. Considering projects as stand-alone work orders may expedite individual research studies but often leave questions unanswered or data that does not meet the goal or regulatory requirement. This can strain relationships between study sponsors and third-party vendors. 3

5 3. Decide Where You Want to Go A product development plan provides a roadmap of what needs to be done and in what order to successfully market the product. For any type of ingredient, including probiotics, this process starts by envisioning the finished product. Knowing what claims will be made, where the product will be marketed, and what information is known about the ingredient will dictate the research strategy and allow the product development plan to be written. The strategies in a product development plan are intertwined, so firms should avoid developing a product in a siloed manner. For example, the clinical and regulatory strategy must go hand in hand to ensure the research produces acceptable results from a regulatory perspective. Manufacturing strategy will also be important to the clinical development strategy as clinical trial supply manufacturing must be aligned. This will initiate the clinical trial and incorporate full characterization and stability testing to ensure the batch used in the clinical trial is stable for the duration of the study period. This may be of concern where a product is more sensitive to heat or moisture, such as probiotics. 4. Arm Yourself with the Right Tools Clinical trials are complex. Unfortunately, many studies fail to use proper statistical power, adequate control for bias, or an appropriate target population for the claim to be substantiated (as published by regulatory authorities such as EFSA). Others neglect to use the same formulation the claim is being sought for, making it difficult or impossible to support the claim. 4

6 It is imperative that the clinical development team includes regulatory affairs personnel to mitigate risks to ensure appropriate endpoints and subjects are selected and designs are robust to meet the regulatory burden of proof. Furthermore, protocols should address shortcomings of prior trials and similar trials conducted by others as often regulatory bodies will assess the totality of evidence. Using the pharmaceutical clinical trial model, there are four key phases of clinical research in fixed trial design: Phase I, Phase II, Phase III, and Phase IV. In the dietary supplement industry, research is often confined to Phase II and Phase III which increases risk of failure of the study. The goals of dietary supplements and pharmaceuticals and biologics are inherently different. As such, most jurisdictions do not require premarket approval and not all phases of clinical development are necessary for supplements. However, there are key clinical phases that help reduce the risk of failure of a Phase II or Phase III pivotal study. It is imperative that the clinical development team includes regulatory affairs personnel to mitigate risks. These include pharmacokinetic studies, food effect studies, proof of concept studies, dose range and finding studies, and may also include mechanism studies. These studies provide the necessary characterization of how the product will work, how many doses to take and how to take (timing, with or without food, etc.). Proof of concept or pilot studies also provide information required to make an educated sample size estimation for your pivotal study that will support your label claims. Nuances also exist between product types, for example, a probiotic 5

7 clinical development plan may begin at phase II as pharmacokinetics are not applicable to this product class. 5. Anticipate Roadblocks One of the difficulties faced in a go-to-market strategy are missed opportunities and delayed product development. This can happen when using the classic fixed trial design paradigm, where standard trial design only allows for minimal learning during the conduct of the trial due to the clear separation of trials into various phases. This is of specific concern to the dietary supplement industry, including probiotics ingredients. The pharmaceutical industry has identified this drawback and adapted it to better encompass a more robust trial design. It is clear that this design should be applied in nutraceutical research in order to reduce the risk of failure when Phase II studies are designed as a pivotal study but do not achieve the endpoint. In these cases, the clinical development program may need to include additional early phase studies that can ascertain effect sizes and variability with the product of interest in the population of interest. Reflecting on the simple Phase I bioavailability study, how else could this design provide more information about the product? What effect does food have on taking the product? Does it reduce or increase absorption? What effect does a higher or lower dose have? Is there an increase or decrease in adverse events? How long does it take for the product to reach steady state in the blood? Can more information on safety or efficacy be gained in addition to absorption? Some of these adaptations to the common bioavailability study can be made to address 6

8 these questions without having substantial impacts on costs, thus providing a greater understanding of the product and, in turn, greater return on the initial investment. The team involved in development of the protocol and management of the clinical trials must include qualified clinical and regulatory professionals, and a biostatistician familiar with this level of product development. There is also the potential to use a novel clinical program design recently introduced and accepted in pharmaceutical development: adaptive design. The FDA defines adaptive design in their guidance document, Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data). Adaptive design can be a strategic advantage if the trial will be used as a pivotal study to substantiate claims. to as adaptive seamless designs) and sample size re-estimation. 7 While there has been much debate in the dietary supplement industry regarding adaptive design, the key to ensuring success is to follow the principle of adaptive by design. This means that they are prospectively planned and are not ad hoc, in order to maintain integrity and validity of the trial. When considering adaptive designs for pivotal trials, it can be a strategic advantage to engage the regulatory authority(ies) if the trial will be used as a pivotal study to substantiate claims. Most commonly, adaptive designs are referred to as adaptive randomization, group sequential designs, seamless phase designs (also referred

9 6. Use Existing Pathways to Your Advantage Often companies will adjust their sales and marketing strategy by targeting other regions or countries. One key to unlock this route easily and cost-effectively is following harmonized guidelines namely, Good Clinical Practices (GCPs). These are minimum thresholds that all clinical research studies should meet regardless of study design, study phase, or products being investigated. ICH published the guidance document E6 Good Clinical Practice (GCP) in 1996 with a recent revision in Many regulatory regions provide guidance of their own on the topic of GCP; however, companies that follow harmonized guidelines when investing in clinical trials have an advantage when it comes to acceptance in multiple jurisdictions. In fact, some countries mandate compliance with ICH guidelines when conducting clinical research on dietary supplements. This includes Canada. Following GCPs is resource-intensive but allows sponsors to manage risk over the life of the research trial. ICH s GCP guideline provides recommendations for the structure and content of essential documents including the clinical research protocol, informed consent forms, the investigator s brochure, monitoring plans and reports, data management plan, and trial master file. Additional guidance has been provided by ICH for the structure and content of the clinical study report, data sets and statistical programs. These core documents and practices provide the basic infrastructure for the operations of the clinical trial. 8

10 Core documents include: Project Management Plan (PMP) Transfer of Sponsor Obligations Communications Management Plan Trial Master File (TMF) Protocol Investigator s Brochure (IB) Informed Consent Form (ICF) Monitoring Plan Data Management Plan (DMP) Statistical Analysis Plan Clinical Study Report These documents provide a forum for collaboration between the Sponsor of the clinical research study and the research organization conducting the trial. They also provide clear objectives, timelines, and milestones which can be measured, analysed, and adjusted throughout the lifecycle of the trial. This helps ensure all parties are aware of risks, risk management strategies, and resolution as Sponsors are ultimately responsible for all aspects of clinical trials. Another more recent trend of interest in the pharmaceutical industry, which can be used as a safeguard, is pooling of data. Pooling data from multiple trials provides the benefit of reviewing a larger data set for trends of both safety and efficacy that may not be gleaned from a single clinical study dataset. It is therefore important to plan data management carefully and using standardized coding conventions (e.g. MedDRA, CDISC, CDASH, etc.) which will allow pooling of data. If care is not taken with respect to data collection, this can be a missed opportunity. 9

11 7. Prepare for Arrival There are many options for the commercialization of probiotics, including product claims. When paired with adequate regulatory insight, clinical research can be used to substantiate product claims and gain approvals in regions where pre-market approval is required. There is no one pathway to success, but many possible routes. The key is understanding where you are, where you want to go, and how to get there with the strongest clinical research possible. An experienced CRO with knowledge and experience in the probiotics sector will help you figure out how to get where you want to go, and what steps to take along the way the keys to planning and executing a successful clinical trials program for probiotics. Overall, focusing on the planning stage of a clinical trial, and considering the entire product lifecycle from concept to claim, provides firms with the greatest opportunity to maximize their return on investment. 10