Comparators have been a crucial part of the clinical trials supply chain for decades. Ever since the Declaration of Helsinki set out the ethical guidelines for clinical research back in 1964, it was inevitable that the market would start to move away from the use of placebos and towards comparing new drugs with therapies already on the market.

“It is the duty of the physician to promote and safeguard the health of the people.” So stated the original text of the Declaration. It also acknowledged that medical progress is based on research that ultimately must rest in part on experimentation involving human subjects, but stressed that, even then, considerations related to the well-being of the subject should take precedence over the interests of science and society.

The message has been made much clearer with subsequent amendments, particularly since 2000, when it was specifically emphasised that “the benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods”.

While this did not exclude the use of placebo in studies where no proven prophylactic, diagnostic or therapeutic method exists, or where there are compelling and scientifically sound methodological reasons for the use of a placebo, it greatly fuelled the demand for comparators.

“The industry really changed more than 15 years ago, when we really started following the Declaration of Helsinki, which essentially said that clinical trials need to follow the Hippocratic Oath – first, do no harm – and that to use a placebo could be seen as doing harm in certain therapeutic areas,” says Steven Jacobs, president of Global BioPharm Solutions and the chair of the Global Clinical Supplies Group.

Take, for example, cancer patients receiving chemotherapy. A study that replaces the best available treatment with a placebo in order to gauge the efficacy of a new drug – and, furthermore, makes it impossible for patients and their families to tell whether they are receiving something designed to cure them or playing out a terminal pantomime for the benefit of a data set – can hardly argue that it isn’t harming human subjects.

“It is a long way from when there used to be morbidity and mortality trials,” adds Jacobs. “It used to be that when a certain number of people on the placebo died then you had the results of your trial. So, comparator-led trials are the most ethical way to do clinical research. In oncology, the switch to using comparators happened really quickly, as it is a therapeutic area where it is important to not only compare drugs to a standard of care, but also give patients the best chance to heal.”

Moreover, using a comparator control rather than a placebo for a baseline ensures that newly approved drugs are, in Jacobs’ words, “equivalent, or at least non-inferior” to those already on the market.

The fundamentals of sharing

The dual emphasis on better trial outputs and the ethical treatment of trial participants has driven a rapid rise in demand for comparators over the past two decades, resulting in the emergence of specialist suppliers, which act as middlemen to source the drugs specifically for clinical trials.

This new sector of the clinical supply chain has wasted no time in proving its value. “The comparator companies have been a real boon,” observes Jacobs. “You need to get as much of the same lot as possible or with the longest possible expiry date for clinical trials, and those companies can help avoid trial supply interruptions and trial delays.”

That takes money, which is certainly good news for specialist comparator and clinical trial supply companies – but it’s not like they don’t earn it. Middlemen or no, pharmaceutical companies have very little incentive to provide their drugs for clinical trials that could help a competitor capture the market. Why volunteer profitable products to a process that could see them superseded?

“Some companies don’t want you to use their drugs as comparators,” says Jacobs. “If you create a similar or better drug then they could possibly lose their market share. Sometimes, they might ask their wholesalers to find out if there have been any big orders that might come from their drug being used as a comparator. Some companies even say that they don’t want anyone to use their drugs as comparators.”

It’s sometimes possible to source generic versions of patent drugs for use as comparators and, in such cases, disobliging pharmaceutical companies may already have lost the battle to monopolise the market – and might even be losing out on valuable business by refusing to sell large quantities of their drugs to competitors. Either way, as demand for comparators rises, driven not only by the search for better treatments and profits, but also by the increasing interest in combination therapies, constraints on supply bite harder.

That said, when a trial seeks to incorporate a comparator in a new combined therapy, it could actually work in the supplier’s favour by opening a new application for the drug and expanding its market. “When a trial uses a combination of drugs, like a concomitant therapy to get a synergistic outcome, then companies are more than willing to help out by providing their drugs as comparators,” Jacobs remarks.

Equally, when the required comparator is a drug that is widely available on the market, usually a source can be found. The biggest issues emerge when a company is seeking to test a new drug candidate against a medication that can only be obtained directly from the manufacturer. At that point, all that’s left is negotiation. That’s not necessarily a fool’s errand: there are instances where companies willingly allow their drugs to be used as comparators – with caveats, of course.

“Very few companies say yes, you can use our drug, but the ones that do expect the favour to be returned by the requesting company whenever they ask at a future time,” says Jacobs. “That usually shuts down the conversation pretty quickly.”

Problems of place and time

Typically, comparator companies try to circumvent all of those issues by buying drugs from wholesalers and selling them on with a mark-up. This can solve the problem of sourcing sufficient quantities and the best specialists have networks that enable them to supply trials rapidly, but it also drives up cost.

Take, for example, an oncology drug that costs thousands of dollars per vial and is used across thousands of patients over an extended time period. The price mounts up quickly, even without the additional costs of sourcing.

Then there are regional issues to factor in. The EU, for example, will not allow the use of comparator drugs that have not been cleared for sale in Europe. Similar issues arise in other regions. It is often necessary, therefore, to source comparators locally and, in some parts of the world, this can make it hard to find sufficient supplies of a particular drug.

Such problems have been exacerbated by the many challenges that have arisen from the Covid-19 pandemic, which has created new logistical challenges and forced the supply chain to reallocate resources to the immediate challenge of stopping it. Jacobs points to the market disruptions caused when certain drugs were mooted as possible Covid-19 treatments. “Once that happened, the supplies were either bought up quickly or their prices spiked, which was a problem if you wanted to use that drug as a comparator.”

Even if a possible comparator wasn’t being touted as a miracle cure, and the trial that required it hadn’t been suspended, there was still the challenge of getting it to sites and participants. “Even though manufacturing continued,” Jacobs says, “the supply chain experienced other problems. Commercial air traffic, which is what 70% of our clinical supplies travel on when shipped, fell to 15–20% of what it was pre-pandemic.”

Make do or mend?

There have been other attempts to make the comparator supply chain flow more freely. TransCelerate BioPharma, a not-for-profit formed to help standardise clinical trials and promote collaboration, debuted a more reliable and rapid model in the form of its Comparator Network in 2013, which supports companies willing to share drugs with one another and also helps to keep counterfeit drugs out of the loop.

“One of its tenets was to create a more collegial comparator sourcing model,” explains Jacobs. “It has limitations, in that companies can only share drugs with other TransCelerate members. It does, however, complement the comparator supply chain.”

If anything, that role might be proof that the supply chain is already robust enough to counterbalance the self-interest of the companies it serves. “There are some problems with the current model the market uses, but it actually works well enough for now,” says Jacobs. “Realistically, the industry is okay with the model it is using. TransCelerate did not replace that, it added another part to it.”

For now, no revolution is set to take place. Each player in the comparator supply chain knows its role and understands the constraints on supply.

“If there’s a comparator sourcing model that could work better, we haven’t discovered it yet,” Jacobs explains. “Manufacturing and purchasing companies would have to make a conscious effort to collaborate to create one. For now, we will continue to rely on the middlemen. When it comes to sourcing comparators, the best thing you can do is to plan and communicate early.

“As complicated as it is, to make the model work better it would require greater communication, collaboration and better relationships between the pharmaceutical companies that are buying and selling. Those are areas we can always improve on.”

Digital comparators

In some cases, irrespective of competitors, middlemen or networks, it’s simply not possible to use comparator medications. For severe cancers and orphan diseases, issues with the drug supply are secondary to the fact there are often too few patients to randomise into different arms – making even placebo controls infeasible. As such, while comparator-controlled trials have become central to the trial landscape, there has also been a steady growth in the number of products approved on the basis of non-randomised and single-arm trials, which, as much as they might help patients, provide far lower-quality evidence.

Increasingly, regulators are supporting the use of real-world data (RWD) to form ‘external comparators’ or ‘historical controls’ that can act as control groups for single-arm trials or increase the statistical power of RCTs with underpopulated control arms. Nonetheless, the lack of direct regulatory guidance has limited their use. In a recent paper in Drug Safety, Gray and her team presented a framework for evaluating RWD external comparator studies in terms of the control’s exchangeability with trial participants. The four-step method requires trial designs to identify key factors affecting bias; adjust for differences in the measured variables between trial participants and external comparators; assess the threat of bias through quantitative bias analysis (QBA); and, in the case of underpowered RCTs, combine internal and external control outcomes via Bayesian borrowing.

Previously, regulators have requested extra data or analysis addressing exchangeability and bias from studies using external comparators, and have rejected applications on the basis of their own informal bias assessments. The authors argue that rigorous QBAs “can be used to better assess, both before and after the conduct of the trial, whether a trial would benefit from additional external comparator data”, and potentially make it possible to approve submissions that might otherwise be viewed unfavourably by regulatory bodies.

Source: Drug Safety