The logic behind comparators is simple: with the market so competitive, new drugs have to be substantially more effective than their predecessors if patients and payers are going to be kept happy. If a new treatment can be blinded and tested against a copy of a pre-existing product, then companies can be sure that what they are putting on the market is good value for money and will really make a difference to patients.

“The industry is talking a lot about comparators, but what they really mean is head-to-head comparisons,” says Niklas Mattsson, head of comparator sourcing for pharmaceutical giant Merck. “You’re comparing the new drugs with the standard of care in the market, and you’re trying to prove you’re either the same or better.

“If you get approval for them, then there are all sorts of ones you can use: rescue medications or painkillers for headaches. You’d call them comparators, but the phrase really encompasses a lot of things: it’s a head-to-head comparison of a blinded programme.”

In an indication of the growing debate in the pharmaceutical industry, WHO last year released formal guidance on the best way to source comparators, as part of a broader report by its expert committee on specifications for pharmaceutical preparations.

“In recent years, the need for the regulation and assurance of quality of medicines has continued to increase,” the committee reported. “Large numbers of multisource [generic] medicines are being produced by many different companies and in different countries; this may result in different products.

“On a global level, there is a need to address not only the quality, safety and efficacy of multisource products that are exported and imported, but also their possible interchangeability.”

Leading a team of four other comparator specialists at Merck’s Centre of Excellence in Luzern, Switzerland, Mattsson’s work is largely strategic: choosing vendors, managing supply chains and monitoring trial timelines.

The process begins with a company developing a drug. Comparator sourcing experts such as Mattsson find the best branded, competitive product on the market, and they blind it to make it indistinguishable from the one being worked on before it is given to patients, who ultimately don’t know if they’re taking the competitor’s comparator or a drug under development. Efficacy is then tested and the results are compared.

A notorious challenge

Comparator sourcing, however, is notoriously challenging, even more so where clinical trials happen in remote locations and the use of biologics requires well-managed temperature-controlled cold-chain supply capabilities. In the context of long, drawn-out trials, making sure that the comparators do not expire, as well as organising supply and distribution timelines, is essential to a successful drug development process.

In addition, getting hold of comparator drugs is not cheap – and for good reason. Companies with a product on the market are not willing to provide it in large quantities to a competitor looking to replace it in the near future.

“There are Merck drugs that we are using as comparators, too,” says Mattson. “But it’s usually a one-off purchase, mostly through a vendor because they usually have contact with the manufacturers and it’s the most practical approach.”

It is clear that cost will continue to dominate the conversation. Up to half of a clinical supply budget may be spent on comparators, according to a 2014 report by the Tufts Center for the Study of Drug Development (CSDD), part of one of the most recent industry-wide surveys of the field.

“The challenges in obtaining the right drugs for clinical trials – in the right quantity at the right time and at the right price – are formidable,” said Kenneth Kaitin, Tufts CSDD director, at the time of the report. “The lack of fully robust supply chain management practices, growing emphasis on expensive biologics, changing regulatory requirements and growth of counterfeit medicines are forcing drug sponsors to rethink and redesign their comparator drug supply chains to support drug development that increasingly crosses international borders.

“Most importantly, sponsors of clinical trials, who understand that substantial benefits will accrue to those who are first to market with a new therapeutic, are investing in their comparator supply chains to improve in-house capabilities, and aligning with external service providers.”

These difficulties mean that comparators are not given the funding they need. Costs grow, and while this makes them an attractive product to sell, it means that companies may simply choose to sideline them and to buy from smaller companies.

High prices also lead to a lack of well-organised supply-chain-management practices. Companies are often so taken aback by the costs of comparators that they become overly focused on this line item, instead of examining how they could save money and mitigate risks overall by taking a more strategic approach, writes Philippe Muller of Thermo Fisher Scientific in a blog offering advice to pharma professionals.

Muller writes that sourcing comparators for clinical trials is not simply about purchasing or procurement. It is rather about developing a strategy that considers the “big picture” to evaluate all the necessary sourcing factors to create a customised plan with multiple options. “Remember, the ultimate goal is managing the supply chain from day one through the conclusion of the trial,” he writes.

Suitable timeframes

Managing timelines around trial size and requirements is critical, especially in the context of broader supply chain deadlines. Comparator sourcing experts, such as Mattsson, need to excel at resolving timing issues if products are going to be delivered on time.

“Certain manufacturers habitually take up to six to eight months to manufacture a lot, especially in Europe,” Mattsson says. With smaller amounts of drugs, where you know you have good expiry dates coming from the US, it could be just a couple of weeks. You just need to have the experience to make that judgement, and obviously you need vendors with the best contacts all over the place.”

Making these connections isn’t always easy, especially when entering unfamiliar markets. Establishing strong networks of vendors, however, is one way to hedge ones’ bets: many have between 300 and 500 partners worldwide and can call on contacts to help.

“You really want to have a vendor, a very large distributor, who is distributing drugs for manufacturers,” says Mattsson. “Or you can pick one locally, but then you have to qualify it. So, we normally use our preferred vendors most of the time.”

Often this works on a case-by-case basis, depending on the market the company finds itself in, and flexibility is essential to keep things running smoothly. Drugs in some markets are locked in for hospital use, for example, making central sourcing in these regions more complex.

“Real central sourcing in this context is the hospital pharmacy just picking the drugs at the site of use,” says Mattsson. “In this situation, you may have to source from one vendor and arrange some kind of hybrid model of central and local.”

This is common: companies sourcing and procuring centrally and distributing it locally. It’s a growing trend particularly in China, Canada and the US.

“Then you can have the European drugs for use worldwide, and you have to choose Chinese drugs in China,” he explains, “which is very particular and unique to the region.”

Managing timelines to make sure there aren’t delays also requires close relations with partners. Mattsson holds regular meetings with vendors to check on ongoing orders and requests, and to make sure that manufacturers are on track. “We have something like three meetings a week,” he says, “one to check quality and two for sourcing.”

With comparator sourcing returning to the forefront of discussions in the pharmaceutical business, supply chains will become more efficient and trials will be better managed. What this means for the industry can only be good, with consumers getting more effective drugs at more competitive prices. How long this will take, of course, is another question entirely.  

WHO guidelines

A national regulatory authority has several options when selecting a comparator product:

  • the innovator product for which quality, safety and efficacy has been established – whether this product has been granted a national marketing authorisation (nationally authorised innovator)
  • national market leader product for which a national marketing authorisation has been granted
  • WHO-recommended comparator product included in the international list of comparator products or, if different and if it exists for the active pharmaceutical ingredient in question, the one suggested within the context of the prequalification team
  • an innovator product approved by a stringent regulatory authority: for instance, a country associated to The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
  • a product that has been granted approval in an ICH-associated country
  • in a case where no innovator or comparator product can be identified according to the above, the choice of the comparator should be made carefully and should be justified by the applicant. In this case, the most important selection criteria to consider, in order of preference, are:
  • prequalification by WHO
  • extensive documented use in clinical trials reported in peer-reviewed scientific journals
  • long period of post-market surveillance.