In 2007, a £1-million order of pharmaceuticals made its way from the UK to the US. Ostensibly labelled as Plavix, the tablets were to be used as comparators in a clinical trial – until tests revealed them to be falsified, containing as little as 50% of the stated drug, clopidogrel. It was a happy save though, with investigators able to replace the counterfeit with the genuine product before the trial began. Had it been missed, however, the consequences could have been grave indeed, not only for the patients and trial company involved, but also for the industry as a whole.

A complex trail of criminal suppliers linked the scam to a sophisticated counterfeiting racket. But it’s a situation that couldn’t have arisen without the inclination of pharmaceutical companies at the time to stifle competition by refusing to supply their products as comparators.

As a result, a booming industry of third-party vendors and wholesalers has arisen, meeting customers’ trial requirements by accumulating drugs gradually across many different markets. Efficient as these third parties may be in sourcing the required volumes of drug, the many lines of communication through which a drug may pass before reaching the trial organiser means that, despite safeguards, counterfeiting remains a possibility. While this indirect route to drug sourcing yields many challenges, the risk of counterfeit and the urgency of ruling it out is surely the greatest incentive for supplier agreements between pharmaceutical companies.

Unacceptable risk

No wonder, then, that it was a key motivation in the decision by US non-profit TransCelerate to establish a comparator network in July 2013. Jason LaRoche was leader of the network for the two years up until July 2016 on secondment from member company Janssen, where he is now associate director of R&D operations innovation.

He recalls: “Everyone saw this risk and it was just unacceptable. Patients have this trust in us that we’re going to provide them safe and effective treatments when they join our clinical trial, and the success of trials is based on that trust.

“It’s already a very difficult decision for patients to join a clinical trial – probably even more so if you’re a parent trying to decide whether to enrol your child in a paediatric clinical trial – so if we lost that trust with patients it would really hurt the industry as a whole and our ability to innovate for people in need of medical solutions.

“That was one key reason for creating the comparator network as a way of mitigating the risk of counterfeit intrusion and providing a safe supply of the drug.”

As one of the original members at TransCelerate tasked with establishing the business model for the comparator network, LaRoche (who recently handed the reins back to original leader, GSK’s Terry Walsh, for a second term), is well aware of the benefits of a system built and run through collaboration.

The network approach also acknowledges the two fundamental flaws in the old competitive model of operation, LaRoche says. First, that denying the supply of comparators to trials ultimately hurts patients above all, because new therapeutics that could offer the treatment they need are delayed in reaching the market. And second, that – thanks to third- party suppliers – pharma companies get their hands on the comparators they need sooner or later anyway.

Rather than establishing a separate network-based sales system, TransCelerate instead agreed that member companies should set each other up as customers in their existing commercial systems. This has enabled swift, reliable transactions, without the protective practices of the past.

“As soon as that purchase order goes in, it goes into an automated process that picks, packs and ships the requested drug and it goes right out the door,” LaRoche says. “It’s very efficient. We agreed to the general principle that everything in your portfolio that’s marketed to normal customers should be available for sale, you can’t protect a product, and companies should exercise commercially reasonable efforts to provide that drug.”

Regional expecations

Conditions in which sourcing the required comparator can be deemed commercially unreasonable extend to regional marketing rights. For example, Janssen could not supply a member company with the drug Simponi in the UK because Merck Sharp & Dohme (MSD) holds the European rights.

A supply shortage would also be sufficient grounds for inability to provide the drugs, of course, but the cooperative nature of the network sometimes comes to the rescue.

LaRoche cites an example from last year of a member company’s large phase-III trial. A global active pharmaceutical ingredient (API) shortage meant that it would be four to five months before the selling company could produce new stock of the comparator drug used in the trial, and a costly postponement of the entire phase looked necessary. Instead, the selling company identified a potential solution in its inventory: a supply of drug not on sale on the market because it was within 11 months of its expiry date, but which it would be willing to provide to bridge the gap until new supplies became available.

LaRoche explains: “That transparency between the two companies and that open communication gave the buying company enough trust to take that risk. It ordered the short-dated drug, started up its phase-III trial on time, and, as predicted, the resupplies came in four to five months later, and it was then able to continue to supply the programme. So, a company went from having to delay an entire phase-III programme to starting it on time and continuing to maintain supply of drug all the way through.”

While TransCelerate’s comparator network currently counts ten members, the details of each order are visible only to the buying and selling party.

This supports a sense of trust between the two companies involved and better encourages members to be up front about their forecasted requirements for the drug.

This allows the supplying company to plan ahead and ensure the drug is available on time, and prevent the shortages in supply that can sometimes arise from large comparator orders.

More than peace of mind, the trust in the supply that this fosters also enables huge savings to be made. Added to the efficiency of purchasing directly through a supplier, rather than through a third party, trust in the availability and consistency of supply means no longer needing to build up large volumes of safety stock.

When sourcing from third parties, trial organisers often feel that this large buffer of drugs is required because of the perceived uncertainty of supply and the fear that a promised resupply may not arrive on time. According to a 2014 report by Clinigen, between 30 and 55% of purchased drugs are left over at the end of a trial.

Now, by forecasting their requirements with the vendor, pharma companies can instead make smaller, more frequent orders, avoiding unnecessary additional outlay.

“With this direct engagement with the comparator network, we see that trust and that level of transparency where companies are willing to reduce their safety stock levels and order just what they need,” LaRoche says. “Because they’re getting that feedback from the supplier to any changes in the ability to handle that resupply, they can make quick adjustments as needed.”

Import-export business

Efficiency also extends to regulatory hurdles, with member companies supplying the necessary documentation for import-export, and often able to step in at short notice to provide additional documentation required as the drugs pass through customs – an agility that, for temperature-controlled drugs, can be the difference between preventing deterioration, or not.

It’s perhaps in the perspective of the trial itself that the network approach allows the greatest degree of creativity. While the initial intention of the network was simply to provide drug in its final, commercially available formulation, an expansion of the programme has also allowed the network to consider means of improving the accuracy and efficiency of trials more directly.

LaRoche illustrates with a recent situation in which a manufacturer discovered that one of its inhaled products was being purchased and used in an active and placebo trial in a manner that could lead to inaccurate results and potentially reduced safety for patients. The trial company, wanting to blind the active drug against a placebo, was opening up the supplied inhaler and placing the drug into a generic inhaler device to match that of the placebo. The manufacturer’s inhaler was designed to deliver a specific dose at a specific rate, so repackaging the drug in a generic device meant that the dose delivery and ultimately the effectiveness of the active drug may have been affected.

With this in mind, LaRoche and his colleagues decided to create a framework through which companies could sell the same matching active and placebo formulations they used in the phase-III development of their drugs. TransCelerate set up a master quality agreement, and amended its master service agreement to facilitate this kind of exchange in future.

“The benefit to the buying company is that you don’t need to wait 12 months or more to develop a blinding solution in house, those costs and that lead time can be avoided if you can buy the matching active placebo readily from the innovator company,” he says. “You also ensure patient safety because you completely eliminate all the manipulation, you leave the technical challenges to the original innovator company, which knows the product, and what can and can’t be done with it.”

Improving cost efficiency in this way is crucial, LaRoche feels, because resources are limited and so every saving facilitates more trails and ultimately more effective medicines reaching patients sooner.

“A new drug that really is at the beginning of the development life cycle only has a very low success rate of ever making it to the market,” he explains. “So, the approach that a lot of companies are taking is really the more shots on goal – the more phase-I studies that can be run – the more opportunities there will be to identify those promising drugs that might make it further through the pipeline.”

Patients, please

Now back at Janssen full-time, LaRoche’s eye is no less trained on collaboration, but this time it is patients that his department – the R&D operations innovation team – is reaching out to. Developments include electronic consent forms that allow patients to access videos illustrating the trial process, helping them to make a more informed decision as to whether or not to take part, and designing ways to incorporate direct patient insights into trial design. One of the first in the industry to do so, Janssen has also created a secure online portal to give trial participants real-time access on demand to their individual lab data.

“If you look at trials historically, patients tend to get enrolled, they get treated during the trial and then the trial ends and they go home and never hear about the trial again,” says LaRoche. “With its innovation initiatives, Janssen is trying to make them a partner.”

Data and ease of use are key, with Janssen’s E-meds initiative looking to digitalise the trial process with everything from electronic labels to smart packaging and medication reminders to improve the patient experience during clinical trials, improve study adherence, and free up investigators to spend more time with patients. The R&D operations innovation team is also working with clinical partners to perform real-life simulations of aspects of the trial, with real patients and investigators (without real drugs) to address any potential enrolment and retention challenges before the trial begins.

Just as with the comparator network, the goal is to ensure the most efficient and accurate trials process. Well governed collaboration in this way – whether with patients, or within pharma itself – can only help effective therapeutics to reach patients faster.