“I’ve been working on this for a long time,” says Mic McGoldrick, associate director global CMC policy at Merck, where he has been for more than 30 years. “It goes nowhere for a while, then it’s sort of like an earthquake: the pressure builds up and then it slips.” He’s talking about regulatory harmonisation and the global streamlining of clinical trial applications, which, as it stands, faces an arduous but urgent uphill struggle. “I would be surprised if we got a lot more harmonisation in the next five years,” McGoldrick says. “Maybe in ten years. Then you may see a much more reasonable push to get more harmonisation globally.”

Regulatory harmonisation boils down, essentially, to a global consensus on clinical trials documentation and procedures. It sounds simple enough: develop a single, cloud-based system that different countries can access and edit. But as McGoldrick explains, there are so many moving parts – at industry level, at agency level, at organisational level – that, time and again, the issues bottleneck.

The biggest obstacle by far has to do with country-specific regulatory requirements. “Different agencies have put together different requirements,” McGoldrick explains, “and there’s no place for anyone to reference one way of doing it. So anytime anyone creates legislation around it, they create it based on their own thoughts. It’s a never-ending change of requirements that keep popping up as more agencies put regulations in place.”

Still, things have improved in recent years. For one thing, the overhaul from paper to electronic documentation has had an enormous impact on clinical trial procedures. As Akira Yamaguchi, CTO at LORENZ Life Sciences Group explains, as recently as 20 years ago “all documents were printed and put into binders and then shipped. For bigger drugs with lots of technical data, you had tonnes of paper that would be shipped in trucks”. Then around 20 years ago there was a shift towards the use of PDF files, which could be “put onto CDs, DVDs, and other electronic media. So it didn’t require trucks anymore – FedEx was okay – but you still have to hand over the media”.

Easy access

In tandem with the development of electronic documentation, one of the most important strides in recent years has been the creation of an electronic Common Technical Document (eCTD) by the ICH – the International Council of Harmonisation, which was established in 1990 and has been growing steadily – to harmonise the structure of clinical information. As Yamaguchi explains, the eCTD is broken down into five discrete modules. “Module one,” Yamaguchi says “is region-specific, module two is the summary, and three, four, and five are where you have the description of your product, your toxicology studies, and your clinical study. So at least in terms of the structure, it has been harmonised”.

It’s a good start, but as Yamaguchi notes, it’s only the first step – the narrative sections of the document continue to throw up regulatory divergences. “In China”, for example, “all narrative documents need to be in Chinese and in English. In Japan, you need certain sections in Japanese. In Thailand you can stay with English. To date […] we probably have about 15 different regions with their own specifications.” And that’s just the content. There’s also the question, Yamaguchi adds, of “how XML files – control files – are structured differently. And unfortunately, these specifications are evolving. These are the challenges we are facing”.

The task feels Sisyphean: every time one of the moving parts gets fixed – say, a technological advancement that makes electronic documentation viable – another one shifts. For example, a new piece of region-specific regulation gets written. It’s easy to see why McGoldrick is sceptical about the pace of change, and why his earthquake analogy – the buildup of pressure and subsequent plateauing of progress – is so apt. From a certain angle, the global harmonisation of clinical trials documentation, simple though it may sound, looks like an impossible task.

Up in the clouds

But there are promising, if long-term, solutions on the horizon. One important part of the puzzle, as Yamaguchi sees it, is to get electronic documents onto a cloud, and to have specialised software companies like LORENZ take care of the documentation so that the pharmaceutical companies and health agencies don’t need to worry about technological challenges. To this end, LORENZ has been looking into the possibilities afforded by the Global Dossier Concept and Same Day Filing – cloud-based solutions that make clinical trials documents available almost in real time across the globe. The implications are huge, not only for the documentation itself, but for the future of clinical trial design.

“For bigger drugs with lots of technical data, you had tonnes of paper that would be shipped in trucks.”

Akira Yamaguchi

“It has an impact on your clinical activities from the beginning, if you start with a global focus,” Yamaguchi says. “We had few samples already where Same Day Filing was achieved. So on the same day [files were] submitted to the FDA to EMA and Japan. It’s a strategic aspect.” In other words, it is still early days, but if clinical trials can be designed with a global focus, then the practice of Same Day Filing itself could engender a mindset shift that would make a global dossier not only practicable, but vital.

LORENZ is blazing the trail when it comes to the creation of electronic dossiers that can be used across different countries, different industries, and different agencies. “We are helping our customers to create these dossiers electronically,” Yamaguchi says. “Our main customer is industry, but we’ve also managed to get the same software through to the agencies. Just to name [a few]: the FTA in Canada; some European agencies; China’s agency – they’re all our customers.” The technology looks promising, but it’s no magic bullet and, as McGoldrick points out, there are still “all the countries that fall in between. Different agencies have different levels of capabilities and technical savvy,” McGoldrick says. “And there are still a good 70 countries that can give problems in trying to get a single dossier out there.” Even among the countries that do have technical savvy, overcoming region-specific requirements remains a serious task, above and beyond the capabilities of high-tech electronic documentation. As McGoldrick points out, even the three founding members of ICH – the USA (FDA), Japan, and Europe (EMA) – are still not yet fully harmonised.

“You’re going to get groups that will pull certain countries together to harmonise and slowly they’ll bring other ones together. Even if you got regional harmonisation that would make things a lot easier.”

Mic McGoldrick

But the Covid-19 pandemic, and the development of a vaccine in record timing, may have edged along the mindset shift that’s needed to push something like global regulatory harmonisation to the next level. One of the key lessons learnt, McGoldrick says, has to do with reliance. During the development of the vaccine, “WHO did a review of the dossier based on a review done at the same time by the EMA. And once they gave approval, the 110 countries they worked with approved it within 10–15 days, which means they really didn’t do a lot of reviewing. They had to rely on WHO and EMA having done the work for them”.

The future of regulation

In addition, “they allowed for a lot of the information be given post-approval so you didn’t have to have validation completed on your product before it was allowed to get out there to people – but there was a commitment to provide the validation data later”. Will we see more reliance on health organisations, and more post-approval procedures in the development of day-to-day products, or will this kind of approach be reserved only for pandemics and cases of high medical need? That remains to be seen, but the fact that it was achieved looks promising for the future of regulatory harmonisation in the clinical trial setting.

So what does the future of regulatory harmonisation look like? “I think it’s heading more in the direction of cloud shared processing,” Yamaguchi says, “where shared means between industry, the submitting organisation, and the regulators. We have to think about some national specialities, but in the end, we’re all humans and [pharmaceutical companies] will be selling their drug worldwide, so this kind of global approach requires the sharing of agency information. We believe technology is only a fraction of it; the main challenge is still regulation within the legal piece.”

For all McGoldrick’s scepticism about the rate of change, he remains optimistic about the future of regulatory harmonisation. “I think it’s going to continue to move forward. You’re going to get groups that will pull certain countries together to harmonise and slowly they’ll bring other ones together. Even if you got regional harmonisation that would make things a lot easier. I think people want to work towards it. I know industry wants to work towards it. But how fast it will move is a mystery.”