Keio University Hospital
apan’s current regulatory framework for investigator-initiated trials (IITs) of drug candidates seems fragmented. IITs are categorized as either commercial or noncommercial.
Commercial IITs are intended to produce data used to supplement data from industry-sponsored trials for new drug applications (NDAs). Commercial IITs are regulated under the Pharmaceuticals and Medical Devices Act (PMD Act), Japan’s counterpart to the US Food, Drug, and Cosmetic Act (FD&C Act). The Good Clinical Practices (GCP) Ordinance under the PMD Act, which is compatible with the International Council for Harmonisation (ICH) GCP, applies to this type of IIT.
Noncommercial or academic IITs, the other category, are conducted out of scientific/medical interest to produce data for the advancement of medical sciences through publishing new guidelines, research, etc. Noncommercial or academic IITs are exempt from the PMD Act and are instead less strictly regulated under the Clinical Trials Act (CTA), even if the research employs a new chemical/biological entity or a novel indication of an existing drug product.
Japan’s dual regulation of IITs contrasts with the US and European regulatory frameworks, which operate within a single set of rules such as the US Investigational New Drug (IND) framework or EU Clinical Trial Regulation (CTR).
As of September 2023, Japan’s Registry of Clinical Trials (jRCT), analogous to the clinicaltrials.gov database in the US, indicates that more than 2,000 CTA-regulated IITs are ongoing, compared to less than 300 PMD Act-regulated IITs.
Though only a tiny fraction of CTA-regulated IITs deal with new drugs or usages, the question arises if data from such studies could also be incorporated into an NDA.
CTA and PMD Act
The CTA and PMD Act requirements for IITs do not differ greatly, as both are fundamentally compatible with ICH-GCP. Both laws are equally strict regarding the ethical treatment and safety of research participants. However, the GCP Ordinance within the PMD Act is much more detailed and prescriptive than the CTA regarding study management and data quality.
The CTA affords greater discretion for researchers, reflecting the generally lower risk of noncommercial IITs. It mandates monitoring but gives investigators the choice to not audit the data if (in their judgment) the risks of bias, fabrication, or otherwise improper data collection are small enough. On the other hand, monitoring and auditing are both mandatory under the PMD Act. The CTA also does not mandate preparing Case Report Forms (CRFs) and the Investigators’ Brochure. Requirements related to management of the investigational substance(s), records retention, and the contents of the final study report are also substantially fewer and less stringent under the CTA than those stipulated under the PMD Act.
As a law intended to regulate medical products, the PMD Act authorizes Japan’s primary health authority, the Ministry of Health, Labour, and Welfare (MHLW), to implement measures to ensure appropriate drug development and registration, while the CTA does not. The PMD Act also authorizes MHLW to suspend a clinical trial when MHLW deems it necessary to avoid a health risk or hazard, based on information in the Clinical Trial Notification submitted before study initiation. The PMD Act also authorizes regulatory inspections of the sponsor and trial sites to ensure compliance with GCP as well as reliability of the data. Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) offers consultations only for clinical trials falling under the jurisdiction of the PMD Act.
Academic Clinical Data in New Drug Applications
Theoretically, an investigator of a CTA-regulated IIT can choose to audit the data, prepare and retain the documents, and take other measures prescribed in the PMD Act (but not mandated under the CTA), so that the data quality may be sufficient for an NDA submission. Though the CTA does not authorize inspections by drug regulatory authorities to verify the study data, if the data have been submitted in an NDA, the PMD Act does permit retrospective inspection for verification.
This theory became a reality when MHLW approved an expansion of the indication for an anticancer agent already on the market based on the result of a noncommercial IIT. The news rekindled interest among Japan’s chronically resource-strapped medical academia as well as its pharmaceutical industry. In March 2023, MHLW published a Points to Consider document reaffirming and summarizing its stance on this issue:
- The authority makes a comprehensive judgment on the availability of CTA-IIT data for each NDA based not only on the reliability of the data but also on whether the study result is published and what the relevant guidelines suggest.
- The following are typical requirements to attain the level of data reliability needed for NDA. The investigator must demonstrate that they are fulfilled.
- The process from CRF to the data set, to its analysis, and to Final Report preparation, is adequate to maintain data reliability.
- Storage and management of the study drug is adequate.
- Methods of monitoring (on-site, remote, desktop, etc.), source data verification (exhaustive or sample), and auditing (if executed) are justified.
- The information on adverse events was adequately collected and managed.
- Study participants’ consent to use of the study data for drug registration is obtained.
Although there has not yet been a second approval based on noncommercial IIT data (as of September 2023), it is generally anticipated that accumulation of approval cases will deliver more clarity to these criteria. The Japan Pharmaceutical Manufacturers Association (JPMA) has already requested the authority to expand the use of academic clinical data for drug registration in its Policy Proposal.
In my view, the recently surfacing “drug-lag” and “drug-loss” problems leave Japan with little choice but to exploit every possible route to gather the clinical evidence required for drug development and regulatory approvals, be it academic IITs or medical records stored in hospitals.