Comparator studies are a complex field and are understood properly by few outside the pharmaceutical industry. They – and blind comparator stability testing – demonstrate to experts whether a drug is equivalent, or superior, to marketed products in its therapeutic class.

Comparator studies also provide important points of reference for clinical trials by helping to assess relative bioequivalence, efficacy and safety, in which context, they are extremely important. And what one company finds important, will also surely apply to another. While working together is clearly in the interests of scientific enquiry, commercial considerations unfortunately often take precedence. So how do companies balance cooperating to improve standards, and saving time and money with safeguarding their commercial interests?

A problem shared

Comparators are either marketed drugs, or are in development. The comparative dissolution rate of the active pharmaceutical ingredient (API) from a new solid oral dosage form, in particular, is an important regulatory consideration for formulation development. In short, they ensure a kind of balance for the pharma industry.

Tanya Momtahen, vice president of global procurement, scientific and clinical, at French pharma giant Sanofi, discussed the idea of being able to reap the rewards when overcoming comparator sourcing challenges at the recent Clinical Trial Supply East Coast conference. “Emphasising the value of shared knowledge between pharmaceutical companies, and evaluating the pros and cons of outsourced versus internal comparator sourcing is used to understand which model is most effective for your company,” she said.

She added that “investigating scenarios through which comparator prices can be lowered to minimise overhead costs and sharing strategies used by clinical trial teams to acquire blinded comparators for global trials” would be beneficial for all.

The issue of cost comes up time and again in comparator guides. “Using a past price of the investigated firm as a comparator will provide a direct comparison of how much the price has changed due to the lack of competition,” writes researchers Pinar Akman and Luke Garrod from the ESRC Centre for Competition Policy at the University of East Anglia in a paper on competitive pricing. “When the market structure has changed from one that is competitive to one that is uncompetitive. A problem may arise with the use of the past price if the market structure has always been one that is uncompetitive.”

While this may be an uncomfortable topic for those discussing it, ways to reduce cost do exist and can be used if necessary.

Keen believers

The comparator industry advocacy group TransCelerate Biopharma strongly believe in the value of teaching and to promote sharing.

“Research and development organisations must work smarter and faster to deliver safe and effective pharmaceutical products to patients in a cost-effective manner,” states a paper entitled ‘A Knowledge Management Framework and Approach for Clinical Development’. “Product development can be enhanced by promoting employee collaboration, providing ways to capture and access knowledge, and leveraging collective experience.”

Managing knowledge and working cohesively with partners makes better results possible. “Common approaches that enable sharing of and searching for knowledge across organisational and geographic boundaries facilitate consistent quality of execution, enhanced efficiency, and continual improvement of business processes,” the paper’s writers say.

“A knowledge-seeking and sharing culture coupled with supporting business processes and people are critical for the successful integration of [these programmes] approaches into routine work.”

Momtahen’s ideas are not as widespread as they should be and other aspects of cooperation may require new approaches.

Research and development organisations must work smarter and faster to deliver safe and effective pharmaceutical products to patients in a cost-effective manner.

Philippe Muller from Fisher Clinical Services wrote in an essay that drug developers addressing the issue of comparator drug sourcing and working hard to change the way they manage comparator products in clinical trials was extremely positive.

“Getting comparator sourcing right is crucial, because there is increasing pressure from patients and payers to develop drugs that are substantially better than existing treatments,” he said, “but managing comparator drugs has grown vastly more complex; clinical studies are conducted in remote locations and biologics development demands sophisticated cold chain supply capabilities.”

Muller adds that academic and corporate pharma specialists have also noted that one of the most pressing challenges was a lack of robust supply chain management practices. “A major reason for this… is that companies are so shocked at the high cost of purchasing comparator [trials] that they become overly distracted by this line item, rather than looking ta how they could save money and mitigate risks overall by taking a more strategic approach.” Like Momtahen, Muller believes that lowering costs is key for comparator cooperation. He also emphasises the importance of planning. “Advance planning provides maximum flexibility and options,” he wrote, “and enables the ability to better identify risks. Know all the facts, list key details about the clinical study for planning purposes.”

Details such as countries, number of sites and subjects, duration, strength and maximum volume of the comparator are “required to accurately predict supply needs and conduct the planning work necessary for reaching optimal solutions”.

He also advises to adopt strategic thinking. “Sourcing comparator for clinical trials is not merely a purchasing or procurement exercise,” he advises. “Evaluate every sourcing factor and create a customised plan with multiple options.”

The most important thing is to be sensible and think clearly. “Select a single partner that is known, trusted and experienced,” said Muller. “When conducting a comparator trial, the fewer touchpoints, the better off you’ll be.

“Advanced planning and a thorough analysis of the clinical protocol, strategic thinking and an integrated supply partner: all of these considerations will go a long way towards making comparator trials less costly.”

Learning to cooperate

These strategies, however, require more care and consideration than working solo, and a more globalised market means more bureaucracy to deal with when running trials.

Peter Trimboli, the group leader for drug supply management and clinical supply operations at Bristol- Myers Squibb, discusses overcoming the issues surrounding comparator importation. “A comparator provision strategy depends upon the regions in the globe we may need to support, whether we are providing a US or EU sourced comparator, and the countries we plan to ship to,” he says.

“Upon initial or subsequent importation of the comparator to some countries, we may experience some delays, or holds on import approval, as some of the information we may have on file from the innovator for the comparator may not be sufficient enough to allow import approval.

Sourcing comparator for clinical trials is not merely a purchasing or procurement exercise. Evaluate every sourcing factor and create a customised plan with multiple options.

“This could include a certificate of analysis, stability data, or a complete batch genealogy listing all manufacturing sources.”

He says that delays in importation – or being unable to import at all – can present significant challenges for clinical study enrolment timelines, and can also affect patient care, with regulatory barriers representing the main reason for difficulties in importing supplies.

“There is a continual evolution of import regulations that differ from country to country. In a given year, you might be able to import a drug without complication,” says Trimboli.

“However, in subsequent years, you may not, as regulations may change, affecting either product labelling or importation documentation requirements. The end result is not being able to import more [of the] drug, which could ultimately affect patient care.”

He adds that generic markets for medications, and the concern for counterfeit drugs, underline the need for such strict importation requirements and changing regulations across the globe.

The way forward

Like Momtahen and Muller, Trimboli believes good planning and early research will enable companies to securing fair prices and ensure that they are able to forge stronger links with partners.

“Get as much product information as you can at time of purchase,” says Trimboli. “Additionally, making contact in advance with your regulatory colleagues in that region would be a good idea.”

It all comes back to cooperation. Like many aspects of clinical trials, comparators is currently feeling its way through a change in course, as the industry takes a look at its very nature in the mirror and wonders how best to proceed.

Being open, accessible and ready to work together may help comparators and the wider industry find ways to lower costs, improve cooperation and make clinical trials less stressful.