China’s clinical trial shake-up

Clinical trial sponsors working in China have long found a disconnect between the country’s potential and reality.

On paper, China offers a huge patient population that accelerates clinical trial timelines. In practice, arduous regulations and underdeveloped infrastructure slow progress, causing companies to conclude China is more trouble than it’s worth. Now however, China is making changes that could finally unlock its full potential.

A large part of China’s appeal rests on its scale. With 58% of China’s 1.4 billion residents living in urban areas, the country offers sponsors access to more patients, in greater concentrations, than most other markets.

Many of these patients have diseases of interest to Western drug developers. For example, around 40% of new lung cancer diagnoses worldwide are in China. With a relatively high proportion of these patients being treatment- naïve, sponsors can enrol a high number of subjects quickly, at least in theory.

However, multiple barriers have slowed sponsors down. Long, inconsistent clinical trial authorisation (CTA) timelines made it hard to incorporate Chinese study centres into global programmes and deterred sponsors from operating in the country. Sponsors that persisted found a hospital-based research network with limited knowledge of good clinical practices (GCPs), resulting in problems such as records being changed without audit trails being created.

These issues led to China being under- represented in clinical trials. In 2007, 1% of trials registered on US government portal ClinicalTrials. gov included a Chinese study centre. Today, of all the trials ever registered on ClinicalTrials.gov, fewer than 5% feature a site in China. That rise from 1% to 5% is one sign that the Chinese clinical trial sector is waking up. As of early December 2018, 4,253 active, enrolling trials with sites in China were registered on ClinicalTrials.gov. That means 9% of all registered enrolling trials worldwide had a site in China. The surge in clinical trial activity in China has happened, in part, because of the blossoming of drug development in the country. Once seen as a manufacturer of generics rather than a developer of innovative drugs, China is now involved in half of all enrolling cancer trials of CAR-T cell therapies.

Sites in the US are involved in one-third of the studies. Chinese authorities have supported the local R&D boom and made the country more attractive for overseas companies by overhauling clinical trial and drug approval processes. These changes have made it possible for companies to get drugs approved in China on the strength of data generated overseas, and sought to improve the process for sponsors that run trials in the country.

Streamlined processes

The reform agenda has been a major undertaking. Since 2015, Chinese authorities have published more than 250 guidance documents, policies and opinions. These texts have addressed long-standing grievances with the regulation of clinical trials in China.

Officials have lifted restrictions on the conduct of phase 1 clinical trials, opening the door to more early-phase research in China. In parallel, China has moved away from its old system for certifying clinical trial sites, thereby enabling more hospitals to participate in research.

The full impact of these changes will only become clear as more sponsors run trials in the country, but the effect of other revisions is more immediately noticeable. Perhaps most importantly, China has moved to a US-style clinical trial application (CTA) system that guarantees sponsors will wait no more than 60 days to learn whether they can initiate a clinical trial. The change represents a dramatic acceleration of the CTA process, which could take up to a year under the old system.

China slashed CTA timelines by increasing staffing at the Center for Drug Evaluation (CDE) and taking steps to clear the backlog of filings facing the agency. From 2015 to 2018, headcount at the agency went from around 100 to around 600. Over the same period, a drive to get companies to voluntarily withdraw low-quality submissions reduced the agency’s workload.

The changes mean the CDE is better equipped to perform timely evaluations of CTAs. Sponsors need to file CTAs to run most phase 1, 2 and 3 clinical trials. After receiving a submission, the CDE performs formality, technical and administrative reviews of the filing and, if everything is in order, issues a CTA.

Different organisations are involved in other steps in the CTA review process. A drug control institute or third-party laboratory tests drug samples to verify compliance with quality standards. The final step involves an ethics committee, which reviews the protocol, informed consent and CTA to ensure the rights and interests of subjects are protected.

Both these steps have been affected by the reforms, which have opened the door to testing at more sites and eliminated the need for duplicated ethical reviews.

Raising standards

The upshot of these changes is that the process of getting clearance to start a clinical trial in China is more streamlined than ever. However, that only addresses some of the historical problems. It is of little use having a fast CTA process if the country lacks the regulations and infrastructure needed to ensure the generation of high-quality, GCP-compliant clinical data.

Recognising that, China has also made changes intended to raise the standards of clinical trials. China indicated it would no longer tolerate inauthentic or incomplete clinical data when it asked companies with pending new drug applications (NDAs) to self-assess their submissions. When faced with the threat of punishment if they proceeded with substandard submissions, the applicants withdrew around half of NDAs awaiting review.

The self-assessment requirement served to help clear the backlog of substandard submissions. Going forward, all NDAs must include clinical trial self-inspection reports, giving the system a safeguard that could deter sponsors from running substandard studies and submitting flawed data.

Studies must follow GCPs and the protocol that received ethics committee approval. In theory, the adherence to GCPs should ensure that the anonymity of patients is protected. The rules in place in China also mandate the maintenance of physical and electronic records that can only be shared with third parties in certain circumstances.

China has adopted these requirements alongside rules about the reporting of clinical trials. While sponsors are under no obligation to publicly release detailed results from their studies, they do have to share information about the trials themselves. These reporting rules require sponsors to upload information such as endpoints and eligibility criteria to www.chinadrugtrials.org.cn

Investigators and sponsors are also subject to rules about the reporting of adverse events. When a serious adverse event occurs, the investigator must inform the sponsor, ethics committee and the National Medical Products Administration (NMPA). The sponsor must then investigate the event and share its findings with all investigators involved with the study. If the findings force the sponsor to stop the trial, it must tell the NMPA, investigators and the ethics committee and explain its decision.

China’s future

The consequences of the changes made in China will become clear with time but there are reasons to think it is heading in the right direction. When viewed alongside the draft data protection rules China released in 2018, the changes to the regulation of clinical trials address many of the problems sponsors have encountered in the country.

Not all the barriers have come down, however. The liberalisation of the rules covering study sites means more hospitals should be able to participate in trials but doubts about the ability of Chinese sites to comply with GCPs and protect patients will likely linger for longer, as may the problems that underpin those doubts. These are difficult problems that Western sites still struggle to overcome.

The wait for the Chinese clinical trial sector to fulfil its true potential may therefore continue for some time. However, the rise of local R&D and government actions over the past few years suggest the country will continue to improve as a research location in the years to come.