Strategies for success with comparator clinical trials

Craig Morgan outlines why comparator clinical trials are useful and provides points to consider to ensure the best outcome.

In clinical trials, a comparator drug (defined as ‘an investigational or marketed product [i.e. active control] or placebo used as a reference in a clinical trial’[i]^,[ii]) is often required. Comparator studies typically focus on efficacy relative to a drug that is already on the market, rather than a placebo. The comparator study is used to compare the effectiveness of the investigational product to the existing drug.

Comparator studies are on the rise. Behind this demand are:

Intense market competition for new therapies.
Pressure from payers and regulators to deliver drugs that are proven to be substantially better than existing treatments.
Increasing complexity of protocols for sophisticated therapies. Some new clinical trial designs, such as the lung cancer master protocol design, allow several experimental drugs to be tested simultaneously[iii].
The rise of co-therapies for diseases that have not responded well to single therapies historically (e.g. HIV and oncology).[iv]
Marked increase in the number of clinical trials in emerging markets[v]. The prevalence of trials conducted in emerging markets is growing so quickly that by 2020 trial volume will be nearly equal to that of the US and Europe combined[vi]. Recent studies indicate that performing clinical trials in emerging countries can significantly reduce drug development costs, while providing access to large patient populations and making it easier to lower prices while maintaining gains.[vii]

The rationale for comparator studies

Unlike single-arm or non-randomised clinical trials, randomised clinical trials (RCTs) involve multiple patient groups that are randomly selected to receive different therapies in order to compare outcomes. The experimental drug arm is compared with control arms, which may receive an active comparator (another therapy used to treat the same condition as the experimental therapy), a placebo comparator (an inactive therapy), a sham comparator (an inactive therapy made to look identical to the active therapy), or no intervention. In an active comparator study design, the question of interest is, ‘how does this drug compare to another drug that has similar indications?’

Studies that compare an experimental treatment to an ineffective placebo remain the gold standard for testing drug efficacy and provide valid, reliable results that are readily accepted by regulatory bodies. According to the World Health Organisation, ‘most placebo-control trials are done not because there are no alternatives, but because it is easier to show an effect and therefore to claim efficacy to the regulatory authorities[viii]’.

So why undertake comparator studies? The most common reason that sponsors use a comparator drug rather than a placebo is often an ethical one. Participants in many clinical trials are suffering from life-threatening illnesses and have enlisted in a study in order to gain access to effective treatment. It would be unethical to give no treatment at all. Ethical issues aside, the current climate is driving an increase in comparator studies, with the FDA often promoting them over placebo-controlled trials in order to avoid approving drugs that have less efficacy or pose higher risks than existing drugsⁱⁱⁱ. Government agencies such as the Centers for Medicare and Medicaid (CMS) even sponsor research on comparative effectiveness.

Besides comparing efficacy, comparator trials (or so-called non-inferiority trials) have potential advantages for patients when factors such as safety, convenience or cost effectiveness are considered. Examples include a Cox-2 selective inhibitor with fewer gastrointestinal adverse effects, an orally-available iron chelator for children with thalassaemia, and an oestrogen patch replacing daily pills.[ix]

The key challenge: investigational product sourcing

Finding and qualifying suppliers in a large number of geographically diverse markets is a time-intensive task that is often fraught with risk. Comparative agents can be used in clinical studies in their commercial presentation (i.e. open label) or in a blinded presentation. Blinding, along with import/export considerations, presents a whole host of other challenges in the supply chain. For example, if the product is not commercially available in the country conducting the trial, its import may be prohibited. If the product is sourced outside the US and will be imported for further packaging, a United States Department of Agriculture (USDA) permit may be required and/or import may be prohibited unless there is an active Investigational New Drug (IND) application. If the product has been coated, there may be issues with countries flagging the product as counterfeit during import/export; there may also be legal issues with regards to trademark.

Many sponsors lack the resources and expertise to take on these critical tasks and partner with supply chain intermediaries to assist. However, partnering with such third parties can result in delays, introduce security concerns, and may pose challenges in obtaining the proper documentation. In response, the non-profit organisation TransCelerate has created a ‘Comparator Network’, which assists by providing an established channel through which participating member companies can reliably and rapidly source quality comparator products from each other for use in clinical trials. TransCelerate states that the network is required owing to a ‘decreasing supply, increasing demand and cost of comparators (along with opportunities for counterfeits to arise’.[x]

Throughout the supply chain the logistics involved in managing comparator drugs has grown vastly more complex in recent years. Clinical studies are increasingly conducted in remote locations and many of today’s biologics require sophisticated cold chain supply capabilities.

Impact on study start-up and cycle times

Investigational product (IP) and related supply chain issues in comparator studies often result in significant delays and increased study cycle times. A key milestone in comparator studies is getting to IP release; how can you ensure that you optimise study startup in comparator clinical trials? Like any study, comparator studies require significant upfront planning, but there are important considerations specific to comparator studies that should be considered in the risk assessment process:

Greater complexity. Potential stakeholders in the decision process for comparator sourcing include regulatory affairs, GMP QA, clinical operations, pharmaceutical sciences (CMC), clinical supplies, import/export personnel, and vendors (speciality wholesaler, CRO, packager). This increases operational complexity and risk due to additional coordination and communication among team members. In comparator studies, vendor selection and qualification are a necessary step to ensure that the comparator drug in its final form is available on time and in the quantities required. When sourcing from emerging markets, additional up-front planning and research is required to ensure availability of the quantity required, in the markets from which it is sourced. In some cases, a product may be licensed in a particular market, yet not available for purchase.

Be flexible and prepare to act quickly. As one industry expert states, ‘target the perfect solution, but be prepared to accept a compromise[xi]’. You may plan for one global distributor but may have to accept a regional alternative due to regulatory hurdles or unforeseen logistical challenges. You may have an issue with the packaging or QA that result in the need to resupply. Product documentation may be inadequate, or you may need additional time for permits. Your project schedule and budget should allow for such issues and build contingency resources into the plan.

Build contingency plans. Based on the study risk assessment, identify which scenarios are most likely and most impactful, and develop contingency plans accordingly. To allow for quicker response to unexpected issues, initiate agreements and partnerships required if a back-up option becomes necessary.

Communication is critical. The constant flow of communication regarding needs, issues and timelines is essential in comparator studies. With the added complexities of the supply chain and sourcing, having a central system to manage study timelines, tasks, and dependencies with internal and external stakeholders is crucial. Additionally, tracking study cycle metrics for such studies is an important exercise that can save time in future studies and help sponsor organisations leverage best practices.

Proactive planning
An essential element to successful trials is proactive planning; for comparator studies, this is imperative. Even with proper planning, issues such as resupply shortages and delays, gaps in supply chain security, inadequate product documentation and import/export challenges may still occur. However, these risks can be mitigated with contingency planning, flexibility, good team communication, and retrospective debriefs (i.e. team learning from prior experiences).

References:

[i] European Commission, Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 13: Manufacture of Investigational Medicinal Products (EU-GMP Annex 13, February 2010)

[ii] ICH Harmonised Tripartite Guideline, Guidance for Industry, E6(R1) Guideline for Good Clinical Practice

[iii] Friends of Cancer Research. Randomized and Single-Arm Trials.

[iv] Getz, Ken. Tracking Trial Cost Drivers: The Impact of Comparator Drugs and Co-Therapies. Pharmaceutical Executive. 1 May 2013.

[v] Tannoury, Maya and Attieh, Zouhair. The Influence of Emerging Markets on the Pharmaceutical Industry. Current Therapeutic Research. Volume 86, 2017, Pages 19-22.

[vi] Whitepaper: Comparators. Myoderm.

[vii] Global Pharmaceutical Industry: Overview & Success Factors, A closer look at the factors affecting growth and development.

[viii] WHO Drug Information Vol. 17, No. 4, 2003.

[ix] WHO Drug Information Vol. 17, No. 4, 2003.

[x] Comparator Network Initiative. TransCelerate. Accessed in January 2018.

[xi] Thomas, Patricia. Takeda Pharmaceuticals. Presentation. Comparator sourcing for clinical trial materials. 9th Annual Clinical Trial Supply East Coast 2011: Cutting edge technologies and essential new strategies to optimise the efficiency of your clinical supply chain.

About the author:
Craig Morgan is Head of Marketing at goBalto.