Japan's PMDA Assesses Ethnic Factors On Clinical Data For Regional Trials – APEC Workshop
This article was originally published in PharmAsia News
TOKYO – Ethnic differences are heavy on the mind of drug agencies as the number of multi-regional clinical trials increases in Asia, and an interim analysis report released by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) showed that understanding ethnic differences in clinical trials may be even more complicated than previously thought.
PMDA is leading an effort on behalf of the drug regulators from Japan, China and South Korea to research ethnic factors' impact on clinical data.
From 2009-2010, the agency conducted pharmacokinetic studies to compare ethnic differences in Chinese, Korean, Japanese and Caucasian populations for three marketed products previously believed to show ethnic differences in PK analysis.
Prior to the start of the Nov. 1 APEC Multi-Regional Clinical Trials Workshop in Tokyo, PMDA revealed that the three drugs – moxifloxacin, simvastin and meloxicam – were found not to show ethnic differences in PK parameters for all populations, reversing former reports of the drugs.
PK And Pharmacodynamic Differences?
However, the committee determined the results are not yet conclusive, and said there still may be pharmacodynamic differences, even if not substantial PK differences, according to Naoyuki Yasuda, the international planning director at Japan's Ministry of Health, Labor and Welfare.
A previous study had shown the antibiotic moxifloxacin to have higher plasma concentration versus time curve (AUC) in Caucasians than of Japanese patients. PMDA's interim analysis results show similar PK parameters among Japanese, Chinese, Korean and Caucasian patients. Glucuronide-conjugate – which helps the body excrete toxins and drugs – showed a higher concentration and a higher urinary excretion rate among Caucasians compared to East Asians.
PMDA's research team said the ethnic difference may be linked to the genetic polymorphism of the UGT1At genotype. The genotype showed similar frequency rates among the East Asian populations, but all three differed from the Caucasian population.
Even when genotype frequencies are identified, they are not necessarily indicative of a drug's response to an ethnic population.
The simvastatin comparator study showed no large difference among the four ethnic populations, though simvastatin AUC was lower in Caucasians. The study had singled out the OATP1B1 allele for the study, and the carriers of that allele showed higher plasma concentrations of simvastatin. Caucasians had a higher frequency of the OATP1B1 allele, but Caucasians also had lower concentrations of simvastatin, suggesting that a different ethnic factor impacted the Caucasian population.
With the ability to identify genotype and allele variation, determining ethnic differences can also sometimes seem like a moot point. In PMDA's PK study for the NSAID meloxicam, the study showed that carriers of the CYP2C9*3 allele had higher plasma concentration of the drug than wild-type carriers. However, there was no difference in population frequency of the allele among the four populations.
Despite a previous study showing higher plasma concentration of the drug among Chinese patients than Japanese patients, similar PK parameters were seen among East Asian and Caucasian populations.
As U.S. FDA CDER Associate Director for International Programs Justina Molzin told the APEC workshop, there is a need to develop new nomenclature for discussing intrinsic and extrinsic factors. "’Regional' is distracting when we want to focus on comparing similar populations," Molzin said.
Tripartite Collaboration
PMDA, China's State FDA and Korea FDA have worked together since 2007 – convening annually for the China-Japan-Korea Tripartite Director General Meeting – to work on cooperation for clinical trials, particularly in identifying ethnic differences in clinical trials (Also see "More Talks Needed With China and Japan For Cooperation In Sharing Clinical Data - Korea FDA Official" - Scrip, 12 Jan, 2010.).
The three regulatory agencies agreed at the Oct. 31 tripartite director general meeting that ethnic differences should be assessed in clinical trials by using a single protocol that controls for extrinsic factors.
The director general meeting also recommended that trials should identify the genotypes of trial patients and "take them under consideration before evaluating the clinical data," Yasuda reported.
The committee agreed to continue its research on ethnic factors' impact on PK and PD analysis, and the next director general meeting is tentatively scheduled for autumn 2012 in China.
The PMDA-led, ¥400 million study only measured three drugs – hardly comprehensive – but signals the urgency the three agencies have to grapple with the growing number of multi-regional clinical trials.
During the APEC workshop, Yoshiaki Uyama, the director of PMDA's regulatory science research division, identified a handful of ethnic differences the agency has found: Sildenafil has higher adverse events among Japanese patients than Caucasians; Japanese patients on leflunomide have a higher risk of interstitial lung disease than Caucasians; etanercept is effective at a lower dose for Japanese patients; and rosuvastatin is effective for Japanese patients at half the dose of Caucasian patients.
Uyama cited a 2010 study that found that the U.S. initial dose was more than two times higher than the Japanese dose for nearly one-third of all drugs.
In addition, multi-regional clinical trials are on the rise in Asia. According to SFDA Drug Registration Director General Zhang Wei, China approved 10 multi-regional clinical trials in 2005, but approved 132 multi-regional clinical trial applications in 2009 and 158 in 2010.
During the Oct. 31 tripartite meeting, China proposed it would take the lead in developing regional clinical trial guidelines.