Second chance saloon - the sale of unused comparators

Twenty years ago, long before the Declaration of Helsinki changed the industry, medical research was dominated by placebo-controlled studies.

If a company was running a clinical trial and testing a new drug, all it needed to prove to the authorities was that its product worked better than a placebo.

Today, though, that often isn't enough. The requirement that new products perform better than those already on the market and the ethical concern around giving sugar pills to chronically ill trial participants have meant the increased use of comparator drugs. According to a recent study by Clinigen Group, the comparator market's estimated worth is $1.5-2.0 billion annually, with growth of around 8% expected each year in the short term.

"Comparator drugs are now the norm," says Steven Jacobs, president of Global BioPharm Solutions. "After the Helsinki Declaration on ethical principles for medical research, we really pushed hard not to use placebos in certain trials. Now, any trial that involves a debilitating condition - such as oncology, or muscle and nerve issues - falls under the category where you have to go and source comparators."

Possession is a sixth of the law

The challenges involved in obtaining these drugs are, by now, well known. Companies have to make sure they have the right supplies to finish long-running trials, meaning expiry dates have to be accurate, and distribution and supply timely, and companies must be willing to share drugs that may potentially be replaced.

There is one issue, however, that has been discussed far less by the sector. Once a clinical trial is completed, most companies tend to feel like the job is done. But what happens if they are left with a large amount of unused comparators? As the industry is acutely aware, sourcing comparator drugs can be costly, so why, according to the same Clinigen report, are 30-55% of the drugs left over and wasted at the end of the trial?

"When we go ahead and manufacture supplies for clinical trials, we have a tendency to produce an overage, or a buffer, based on demand," says Jacobs. "Because of the way trials are designed, if the drug isn't there when the patient walks into the clinic, then we are in big trouble because we can't afford to let any one patient walk away. That means there is a tendency to go ahead and overproduce what you need.

"I've seen some cases - and thank goodness, this is rare - where companies with purchasing and planning processes that aren't as evolved as they could be will actually produce almost 100% overage for all of their clinical supplies through fear of running out. If you actually take a look at a standard average, most companies are trying to get down to anywhere between 5 and 20% overage, but most are somewhere between 20 and 50%."

There are a number of consequences of this, but the most obvious is cost. Sourcing comparator drugs for clinical trials is an expensive, complicated process. With companies looking to minimise drug development costs and increase efficiency, wasting vast amounts of money on unused products is a major problem.

"Back in the old days, ten to 15 years ago, if you took a look at the entire clinical development budget, clinical supplies made up around 5-8%," Jacobs says. "That number has now gone up to 10-15% based on the staggering cost of the comparators we are sourcing. When something takes up nearly a sixth of the cost of development, then clearly it has become an issue that we really have to deal with."

Pocket of resistance

So how much is actually being done to sort out the problem? Though some companies have shown interest in finding solutions, it isn't being considered in the majority of cases, according to Jacobs.

"Each company has its own culture, so it does depend," he says. Some companies focus a lot on cost, and how they can increase efficiency and get rid of waste. Other companies really aren't as concerned with waste as long as they can get the product on the market at the end of the day. They'd like to deal with it, of course, but once they have their drug approved, they just don't care what happens.

"It really ranges: you have ridiculous cases involving companies that say, 'Just get rid of it' and others storing it like it's the warehouse from Raiders of the Lost Ark. You have that real spectrum but, overall right now, I would say it's not a big spot on the radar."

One of the reasons companies are yet to really get a grip on the problem, Jacobs believes, is their size. "Clinical supply units are really lean these days," he says. "Many have outsourced operations and are partnering with their vendors much more, so there isn't much time or bandwidth for some of these companies to say, 'Hey, let's look at what we do with our leftover comparators'.

"It's hard enough for everyone trying to package the next clinical trial that's coming up, as well as trying to decrease cost, overage and waste. Once the trial is done and the company has moved towards approval for the product, there's a much, much lower level of interest in what to do with the material that's left behind."

Another major reason is fear over liability. One solution to the problem would be to sell unused comparator drugs and circulate them back into the supply chain but, with so many regulations around counterfeiting, temperature control and storage conditions, the industry is unsurprisingly reluctant to buy products it cannot necessarily vouch for.

"The concept of reusing the product is a neat one," Jacobs says. "It's a great idea but only if you can absolutely ensure the product has been kept in the proper storage conditions for the entire time. I think this is our biggest issue, especially with regard to clinical trials; products have to be stored at specific temperatures, and that can be at room temperature or -80°C.

"There has been a massive growth in terms of new requirements and regulations, and extra scrutiny, especially with the advent of the good distribution practices that came out in 2013.

"There is a big emphasis on how we control things - the temperatures we keep stuff at and the documentation we maintain during the process. In a way, that means we have a much better shot at possibly reusing these comparators but, at the same time, there has to be a drive to ensure integrity, to make sure that not only are temperatures being maintained, but nothing has been dropped or shaken either, especially if it's a biotech product.

"There are a number of comparator companies that are considering doing this that clearly see it as an opportunity to pull some of these things back and resupply the suppliers that gave them the material.

"But, once again, from the perspective of liability, there are a lot of people that will say, 'Once it has left my control, I'm not really keen on getting it back from you or your customer'. So there are a lot of protocols that would have to be put into place before the industry could recirculate them into the population for use."

Getting more companies to recognise this as a problem won't be easy either. On top of the challenges that already exist, the financial case for reusing comparator drugs is yet to really be made.

"If you could find someone that could do a quick conversion based on the estimate of how much overage there is, that could be very useful," Jacobs says. "If you could monetise the problem, and actually show companies what they might be able to make back by reselling them to the suppliers and distributors, I think that would certainly create more interest.

The benefits of changing minds wouldn't be limited to the companies actually sourcing the drugs. According to a recent report by Premier, 90% of hospitals surveyed had experienced at least one episode of drug shortage in the past six months. The implications of this for patient safety and hospital finances are stark. According to Jacobs, avoiding the waste of comparators could make a big difference.

"A couple of years ago, there was a big drive from FDA to put better controls in place," he says. "It wasn't just because of counterfeiting: a couple of key companies were found very wanting when it came to the quality of materials. When they were shut down from production, it had a dramatic impact on the supplies for patients in the US, to the point that FDA was working with foreign regulators trying to figure out how they could get products to make up for the shortages around the country. Reusing comparators could be wonderful for patients, especially in drug-shortage situations that regulators are now definitely trying to avoid."

Whatever the benefits, a sea change is unlikely to come soon. Companies may try to improve purchasing and planning processes in the meantime, but overcoming the reluctance to buy won't be easy.

"The pharmaceutical industry is staggeringly risk averse," Jacobs concludes. "Any concern around the integrity of the product is going to have a direct impact on people trying to do this, but I do think it's important for companies to start considering it and really hope things start to change."