Trials and tribulations of clinical trial life cycle

12 January 2018

Dr Sanjay Sethi is a leading clinical trials manager in CPOD from the University of Buffalo, with a wealth of experience running trials with corporate and government agencies. He speaks to Andrew Putwain about setting clinical team expectations with early protocol involvement, and the logistical and operational factors one must evaluate when going through a trial’s life cycle.

It takes a staggering amount of money and time to get a new drug to market. The estimated cost to develop it from research lab to patient is about $360 million over 12 years. That’s only slightly less than the entire GDP of Tonga. While the Pacific Island kingdom is unlikely ever to trouble the world’s superpowers with its economic might, it does suggest the scale of resources needed to make a new substance fit for use. One of the main issues with this process is the trial supply stage; namely delays, hold ups and errors that dog the trial throughout its early life. Improving clinical study startup and lifetime operations by enhancing clinical supply team communication with clinical operation teams is one of the most important factors for any new trial, says Dr Sanjay Sethi.

He’s worked with big names – including AstraZeneca and the US National Institute of Health – on high- profile trials, and knows the problems from all sides: corporate, academic and regulatory.

Sethi believes that getting that start-up phase right, and making sure everything is in place, is the most important thing one can do for a trial, bar patient recruitment.

Trials and tribulations

Sethi believes that one of the largest operational targets for any clinical trial, especially in the start-up phase, centres on communication and reliability.

This was corroborated by Tim Holmes, manager for performance operational capabilities at Biogen, during his presentation ‘Improving clinical study start-up and lifetime operation by enhancing clinical supply team communication with clinical operation teams’ at the Arena international Clinical Trial Supply Southeast 2017 in May 2017.

The key factors to getting a trial off the ground on time and on budget, according to Holmes, are: setting clinical team expectations with early protocol involvement, evaluating study protocols from a clinical supply perspective, identifying what materials are needed through the trial life cycle, and the importance of upfront information that can provide clinical teams with the date they need to meet supply demand.

It is essential to ensure that staff and providers are given thorough and effective technological training so as to avoid any potential mishaps.

Holmes believes, as many in the industry do, that hold-ups are easily fixed with common sense; budgeting issues may be solved by finding sustainable funding for supplies, and managing the chain can help to avoid over-runs.

These are all ideas with which Sethi agrees. He explains that the primary operational targets in clinical trial supply in this day and age are that there is “more focus on start-up and recruitment”. He openly admits that his own side of academia is just as frequently the cause of start-up delays as its corporate counterparts, “one of the biggest challenge for academics is understanding that it’s time-critical.”

Issues can be caused, he explains, by “timeliness of the relaxed academic attitude”, but it’s the different set-ups and IRBs that are more frequently an issue.

“From the industry and CROs side, the biggest problem is communication and delays with that,” Sethi says.

“The ‘to and fro’, especially in the contract negotiations stage, is a problem. The research organisation and CROs sometimes experience lengthy delays, and this means that negotiations can take a long time.”

One of the main causes of this is the difference in what should be a uniform contract language.

If a piece of paperwork uses specific wording regarding the trial supply, then it needs to be repeatedly used throughout all the bureaucratic hurdles needed to set up the trials.

This doesn’t always happen, which can cause problems. “It’s often the case of that the bigger the company, the bigger the problem,” Sethi says.

“With the smaller companies you are dealing with a small team or just one person in the legal or public affairs department, and they use the same language over and over again. But when you have a team, such as in the bigger companies, different language gets used and that can become imprecise.”

Improvements may vary

So, what are the best ways to improve clinical study start-up times when the delays come from such a wide range of areas (industry, academia and hospital) and are human errors? “We had a uniform agreement, an accelerated confidential disclosure agreement (ACDA) and an accelerated clinical trial agreement (ACTA),” Sethi explains. “Lots of those in the industry signed up, but no one followed them,” Sethi explains.

The wording of contracts and ACDAs were complex, and led to open ended debates and confusion, because – as Sethi, a man of science, puts it – “Uniformity matters, because that’s where the hold-ups are. Taking documents and following them, and saying that I’m happy with these,” he says, is important.

There is also the difficulty of lawyers becoming involved. Arguments between attorneys, Sethi states, can add on months, and protracted battles between lawyers can derail a timeline over such rights as ownership of intellectual property and identification.

These are often debates that must be filed to be compliant, but are often for hypothetical situations, and end up taking up valuable time. A streamlined process with paperwork that is quickly drawn up, uses a uniform language and contains no errors would be of great help to trial supplies and start-up times.

Other ways to improve the lifetime operations of a trial, especially regarding improving communication with clinical operation teams, involves pre-screening and identifying patents while the organisers are waiting for everything else to be one. This could save time, and act as a dry run for the trial stakeholders while the final paperwork is confirmed.

As well as site location, Sethi recommends that visits should be as close to approval as possible to avoid delays and enable trial suppliers to build relations at an early stage. This also allows any communication and logistics glitches to be ironed out, and ensures that all stakeholders are on the same page.

“Using more database tools is so important for the future,” Sethi says, speaking of the importance of modern technology. One easy way to derail a trial supply chain is to improperly digitise or not take advantage of the databases on offer. It is therefore essential to ensure that staff and providers are given thorough and effective technological training so as to avoid any potential mishaps.

It’s also important to set expectations with early protocol involvement, particularly around operational issues. “If you’re lucky enough to have drugs on site, it’s a bonus,” says Sethi.

Everyone needs to play an active role; there’s often a lot of passivity, which is an issue that must be curbed.

“But everyone needs to play an active role; there’s often a lot of passivity, which is an issue that must be curbed.”

Oversupply issue

Evaluating study protocols from a clinical supply perspective – such as identifying what materials are needed throughout a trial’s life cycle – should run smoothly. Sethi uses the word “oversupplied” freely, claiming that it’s easily identified as the one aspect that isn’t problematic.

“It’s very rare to run out, and there is a heavy emphasis on logistics,” he explains. Providing an endless oversupply is not cheap however, and putting in deals such as ‘just-in-time’ (JIT) manufacturing and logistics procedures could have an effect on the bottom line. It has to be done sensibly, without creating a hole in the very place where the trials previously ran seamlessly.

When looking at the necessary elements to incorporate into a trial, clinical teams must know the trials needs before they can act. From the perspective of medical workers, what aspects of the pharma industry’s strategies need improvement? Or, what are the most common aspects that require further work?

To meet supply demand, clinical teams must first have the necessary data regarding the needs of the trial when considering what to incorporate in it. What aspects of the pharma industry’s strategies would Sethi say need improvement, or what aspects require further work? “There is a trend of sharing strategies, but not for all trials,” he explains, “and, yes, we’re competing, but the ultimate goal is to get the trial done.”

This camaraderie is essential when considering budgeting controls, including such tasks as identifying sustainable funding for supplies, or avoiding overruns by managing the chain effectively. As Sethi explains, “In academic situations, it’s not a profit-driven scenario, and there’s no real direct benefit to the investigator.

Some of the companies are relying on CROs to negotiate budgets and there seems to be an incentive to keep things tight. There have been delays, and even cancelled trials,” he says.

These are the issues that stakeholders often face: “Uniformity would be good, and if you’re working together again and again, why not set terms for different parts of the budget?” asks Sethi.

The next big thing

The next big thing in clinical trial supply is bound to be complex as technology continues to develop and the industry changes. As alternate research budgets are shrinking, clinical research development holds fast, mostly due to government intervention, creating an odd mix.

“I think things will improve, although they will become more complex as the paperwork keeps growing,” says Sethi. Variables like country selection, import licence timing, co-meds, rescue meds and comparator sourcing will always affect trial supply.

There are factors in sourcing equipment and ancillary supplies that need to be addressed by all stakeholders, and shipping considerations that need to be monitored, but Sethi believes everything is on the right track – and if communication continues to improve between stakeholders, there is definitely a way of improving cost.

“Most work in a trial is done in the first few months – once you’ve recruited, you go into a maintenance phase,” he says. He believes trials will always be successful if well organised, and it’s hard not to agree.

In a climate of dwindling budgets and increasingly complex technology, a well-organised trial stands the best chance of being a successful one.

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