The past year marked significant regulatory updates and changes across the globe, as regulators tried to keep up with the evolving and maturing clinical trial industry.
While the US Food and Drug Administration (FDA) finally released its draft guidance on decentralised clinical trials (DCTs) and efforts to improve trial diversity, the European Medicines Agency (EMA) said farewell to the old clinical trial platform for new trial applications.
After several chaotic years, the UK seems to be on the mend in the commercial clinical trial sector, yet the Medicines and Healthcare products Regulatory Agency (MHRA) may be a bit too ambitious with its plans.
While looking back at the most significant regulatory events in 2023, Clinical Trials Arena spoke with industry experts to understand if regulators are in step with clinical trial sponsors and other stakeholders.
FDA’s take on DCTs and diversity
After a few years filled with promises, the FDA finally released its landmark draft guidance on DCTs, as it was signed into law by US President Joe Biden in the Fiscal Year 2023 Omnibus Spending Bill in late 2022.
The draft guidance helped crystalise the concepts surrounding DCTs, which will guide sponsors in writing better protocols and describe the responsibilities of different stakeholders included in the trial, says Julie Ozier, senior vice president of IRB/IBC regulatory at the research compliance solutions provider Advarra.
Still, the long-awaited draft guidance left several important questions unanswered. But as with every draft guidance, there was a comment period to poke holes, which will result in final guidance that has even better information, Ozier adds.
Another item on the Omnibus Bill included a guidance on diversity action plans in clinical trials, which should be issued no later than 12 months after the enactment of the Bill, according to the document.
Even though there are set timelines, it is difficult to predict when exactly the FDA will release the guidance, especially as the DCT draft guidance was issued later than expected, says Kevin Potgieter, vice president of regulatory affairs at Medable.
The upcoming guidance is unlikely to be different to the draft guidance, which was released last year, as it would be too disruptive, says Shiva Memari, senior director of global solutions at Lokavant, a clinical trial intelligence company.
However, it may cause clinical trials to slow down as sponsors will have additional requirements to recruit underserved populations. The guidance may also not address the overall problem of mistrust in medicine and research, explains Ozier.
Additionally, there is no regulatory mechanism that has “teeth” that would allow the FDA not to approve trials and request the trial to be redesigned in the investigational new drug stage, notes Potgieter. He explains that sponsors are likely to be able to waive this requirement, which is a valid claim for rare diseases. Yet, there is a risk that sponsors will submit waivers in any disease space. “The fear there is that going to become the norm and not the exception,” Potgieter adds.
In addition to DCTs and diversity, there were notable developments in digital health regulation and growing acceptance of self-reported outcomes for primary endpoints, says Katie Rodammer, director of clinical operations for digital therapeutic biotech Click Therapeutics.
“By embracing digital health, the FDA is fundamentally changing its oversight of clinical trials to advance novel methodologies that improve access and convenience,” she adds.
EMA leads with transparency and innovation
Across the Atlantic Ocean, the EMA started the year strong, with the Clinical Trials Information System (CTIS) becoming the only platform for new clinical trial applications in the EU. Later in the year, the EMA revised its transparency rules that shortened the time for sponsors to publish clinical trial data.
However, the impact of CTIS and the EU Clinical Trials Regulation (CTR) is causing “heartburn” for sponsors, as reduced timelines and changes in workflow to move faster are never well received, says Potgieter. Indeed, new requirements are putting a lot of pressure on sponsors as shorter trial applications and question response timelines mean increased coordination between multiple stakeholders, notes Memari.
Additional pressure and penalties may make it more prohibitive to conduct studies in Europe and sponsors may consider going elsewhere, Memari says. This was also reflected in conversations regarding EU Pharmaceutical Legislation, which may stifle innovation. The EMA itself did not deliver on promised timelines to respond to trial applications, but while it may be reasonable for the first year of CTIS adoption, they need to be answered over the next year, she adds.
The EMA also released a reflection paper on using single-arm trials as pivotal evidence in marketing authorisation. While randomised controlled trials (RCTs) are considered a “gold standard”, there are other ways to answer research questions, Ozier says. Memari agrees that such a regulatory move will be beneficial, especially in the rare disease space, and because it can take longer to understand the data after an RCT is conducted.
UK’s ambitious trial approval scheme
While the EMA is shortening timelines for sponsors, the UK’s MHRA is doing it to itself. In October, the agency released a new scheme, which aims to accelerate trial applications for low-risk Phase III and IV trials. While this is a reasonable attempt, the scheme may be a bit too ambitious for the MHRA due to staffing needs and shortages, says Memari.
However, there are several confounding factors behind the MHRA’s initiatives. “This needs to be taken into the context of Brexit, split from EMA and forcing MHRA to have its own approval pathway without the luxury of being able to tie onto other countries’ efforts,” Potgieter explains.
While the intent is good, it remains to be seen if this scheme is realistic and makes a meaningful difference in a short period of time, without sacrificing scientific validity and patient safety, he adds.
After several turbulent years as the number of commercial clinical trials declined, there may be a light at the end of the tunnel for the UK sector. According to the latest report by the Association of the British Pharmaceutical Industry, there has been a small increase in UK-based clinical trials in the past year. The UK government was also confident that the commercial sector will continue to improve as the industry has received several financial initiatives over the past several months.
Other notable global regulatory moves
As the EMA closed last year with the so-called Christmas gift by releasing a DCT recommendations paper and the FDA issued its draft document a few months later, it started a domino effect across the globe. During the summer, both China’s National Medical Products Administration (NMPA) and Taiwan’s FDA released their respective guidelines for DCTs.
Recently, Argentina’s National Administration of Drugs, Food and Medical Devices (ANMAT) outlined its requirements for decentralised elements in clinical pharmacology studies. Potgieter explains that is not unusual for smaller markets to piggyback off concepts that were generated by bigger regulators like the EMA or FDA.
In general, China has become a big player in the clinical development space. “We are still seeing some challenges with regards to data residency and privacy, but less so on the actual clinical side,” Potgieter says, adding that Chinese regulators are quite accepting of new digital approaches such as electronic signatures or electronic informed consent. Memari notes that China is revamping itself and is trying to make it easier for sponsors to work in the country, even if they do not have local headquarters.
On the international stage, the International Council for Harmonisation (ICH) is working to update its Good Clinical Practice (GCP) E6(R3) draft guideline. Regulators such as the FDA are basing their own guidance on the ICH’s revision. “It was good to see this 21st-century incorporation of technology, software, and remote elements and methodologies into the broader concept of clinical studies,” Potgieter notes.
