Successful bridging strategy based on ICH E5 guideline for drugs approved in Japan

Abstract

For a drug to be approved under the Pharmaceutical Affairs Law of Japan, clinical data in Japanese are, in principle, necessary for evaluating the efficacy and safety of the drug, even if foreign clinical data are available. However, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has actively discussed how to globally share information from clinical studies among regulatory authorities in different regions to minimize duplicative work. The ICH E5 guideline entitled “Ethnic Factors in the Acceptability of Foreign Clinical Data,” issued in 1998, describes factors that could lead to different responses in different ethnic groups, including differences in pharmacokinetic (PK), pharmacodynamic, and clinical properties.1 Acknowledging the potential importance of such differences, the guideline recommends that satisfactory foreign clinical data (ie, foreign data that satisfy all of a new region's requirements, except for being foreign) can be used to support approval in a new region if there is 1 additional bridging study that will allow the new region to believe the drug will behave similarly in both regions. The conduct and use of bridging studies have come to be known as a bridging strategy. A bridging study, in addition to allowing extrapolation of phase 3 trial data from one region to a new region,2 will often provide a comparison of dose-response relationships between the 2 regions. Whether foreign clinical data can be extrapolated to the new region, allowing approval of the drug without many new studies in the new region, depends on the design and results of the bridging study. In this article, we summarize the use of a bridging strategy in the new drug applications (NDAs) approved in Japan since the establishment of the guideline in 1998 to 2003. The Pharmaceuticals and Medical Devices Evaluation Center of the National Institute of Health Sciences (PMDEC), our predecessor organization, was responsible for the review of NDAs for chemical and biologic products since 1997.3 The information sources used for analysis in this study are the review reports prepared by the PMDEC for each NDA and the summaries of data submitted by applicants, both of which are publicly available on the Web site.4,5,6 This study includes for analysis only those cases in which the bridging strategy led to approval. Cases in which there were already Japanese data sufficient for approval, in addition to the foreign data available, are excluded. The ICH E5 guideline was received officially notification in Japan on August 11, 1998.7 Since then, new drug approvals based on a bridging strategy have been gradually increasing (Fig 1), from 3.2% in 1999 to 24% to 25% in 2002 and 2003. The 26 total NDAs that have been approved in Japan based on a bridging strategy are shown in Table I. These include only new drugs such as new molecular entities and certain combinations subject to review by the Pharmaceutical & Food Sanitation Council, an official consultative body to the Minister, the Ministry of Health, Labour and Welfare. Data for other drugs of this kind were basically obtained in Japanese populations so that a bridging strategy was not necessary for approval—that is, clinical trials (phase 2 and 3) for global development of a drug were repeated in Japan. Trends of approved new drug applications (NDA) based on bridging strategy. Solid columns, Total number of approved NDAs in Japan each year. Open columns, Number of approved NDAs based on bridging strategy. Circles with lines, Percent of approved NDAs based on bridging strategy. These numbers include only applications for new drugs and new biologic products (eg, new molecular entities and certain combinations). Other applications, such as supplemental NDAs and NDAs for generic and over-the-counter drugs, were not included. Fig 2 shows trends in the target diseases included among the 26 NDAs listed in Table I. Neuropharmacologic diseases (migraine, 5; Alzheimer's disease, 1; and Parkinson's disease, 1) were the most popular targets, followed by cancer (n = 5), allergy and immunologic diseases (n = 5), endocrinologic disease (n = 4), and viral disease (n = 3). Target diseases in bridging study. A numeric value in the figure shows numbers of NDAs for each group. Abbreviations in parentheses indicate names of target disease. Note that the total number is 27, because 2 bridging studies were included in 1 of 26 NDAs. AD, Alzheimer's disease; MI, migraine; PD, Parkinson's disease; PC, prostate cancer; BC, breast cancer; CC, colon cancer; LC, lung cancer; Rh, rhinitis; Ur, urticaria; RT, renal transplantation; RA, rheumatoid arthritis; OP, osteoporosis; DM, diabetes mellitus; ED, erectile dysfunction; Flu, influenza infection; RSV, respiratory syncytial virus infection; GC, glaucoma and ocular hypertension; AMD, age-related macular degeneration; Hp, Helicobacter pylori eradication. “Dosage and Administration” recommendations in labeling in each of the 3 ICH regions are summarized for the 26 drugs in Table I. Differences between Japan and the United States/European Union are noted in Table I. Some of these differences reflect, at least in part, differences in pharmacokinetics. For example, the dose of risedronate sodium was set at 2.5 mg/d in Japan, compared with 5 mg/d in the United States/European Union, because of a PK finding that the drug concentration with 2.5 mg/d in Japanese subjects (area under the plasma concentration-time curve [AUC] from 0 to 24 hours, 2.90 ± 1.54 ng · h/mL) corresponded to those at 5 mg/d in the foreign study population (AUC from 0 to 24 hours, 2.52 ± 1.23 ng · h/mL). In addition, the effect (bone mineral density) at 2.5 mg/d in the bridging study was the same as that at 5 mg/d in the comparable foreign study. The main reason for the PK differences was considered to be ethnic differences in absorption. The PK differences were also a reason for the different recommended doses for alendronate sodium and omeprazole plus clarithromycin plus amoxicillin (INN, amoxicilline). A second reason for different recommended doses was adverse reactions in the bridging study at the United States/European Union dose. For example, maximal doses of eletriptan hydrobromide were set at 40 mg/d in Japan in contrast to 80 mg/d in the European Union, based on a bridging study that demonstrated the dose-dependent adverse events. The frequency of adverse events, such as nausea and somnolence, was significantly higher in Japanese at 80 mg/d than that seen in the foreign population (nausea, 10.4% versus 5.7%; somnolence, 16.9% versus 6.6%), although maximum plasma concentration and AUC at the single oral dose (10–40 mg) were significantly lower (approximately 30%-40%) in Japanese subjects than those in the foreign population. In the case of sildenafil citrate (INN, sildenafil), the large US/European Union dose (100 mg) caused increased adverse events in Japanese subjects but added no further effectiveness. Thus adverse events such as abnormal vision were observed dose-dependently (50 mg, 3.4%; 100 mg, 10.8%), but the efficacy was similar between 2 doses in Japanese populations (the mean values of the primary end points [International Index of Erectile Function (IIEF)] question 3: 50 mg, 3.82, and 100 mg, 3.80; question 4: 50 mg, 3.53, and 100 mg, 3.60). In contrast, in the US study, questions 3 and 4 of the IIEF were increased dose-dependently (question 3: 50 mg, 3.65, and 100 mg, 3.99; question 4: 50 mg, 3.51, and 100 mg, 3.94). The values of SE were similar between Japanese and US studies. Finally, in some cases, the different dosing recommendations simply reflected different dose setting in the bridging study. Thus the starting dose of pramipexole dihydrochloride was set at 0.25 mg in Japan versus 0.375 mg in the United States because of the slightly different protocol used in the bridging study, whereas the maintenance dose was the same in both regions. Differences in the bridging study protocol were also a reason for cases of donepezil hydrochloride (INN, donepezil) and leucovorin calcium (INN, calcium folinate) plus tegafur/uracil. More details regarding the discussions on the review for each application are described in the review reports, which are available on the Internet.4,5,6 Apart from substantial differences in recommended dosing in labeling, the exact wording in the “Indication and Usage” sections was often different in Japan and the United States/European Union. The differences in most cases seem to reflect different customs in the regions in describing target diseases, rather than actual attempts to direct treatment to different patients. For example, the “Indication and Usage” for triptan drugs such as rizatriptan benzoate (INN, rizatriptan) was defined as just “migraine” in Japan, whereas the indication was “acute treatment of migraine attack with or without aura in adults” in the United States. Similar differences were present in the labels of other antimigraine drugs. However, more detailed information regarding the appropriate target population for a drug is usually provided in other sections of the prescribing information in Japan so that actual target populations for these drugs would not be significantly different in Japan and the United States. One of the few exceptions is the labeling of brinzolamide for glaucoma. It is labeled as a first-choice treatment in the United States and European Union but only as a second choice in Japan, because it is Japanese practice for a drug that shows less effect on intraocular pressure than a first-choice drug such as timolol to limit the indication to use as a second choice. Therefore, the indication for brinzolamide was limited to cases where other drugs do not have sufficient effect or where other drugs are not appropriate to administer because of the occurrence of adverse events. In another case, labeling for infliximab in Japan did not include a claim for long-term preventive effects on progression of joint damage in rheumatoid arthritis, because the short-period bridging study (14 weeks) was focused on comparing the effects on ACR20 and, even in the 36-week follow-up of the bridging study, the preventive effects on progression of joint damages were not examined. Although the general long-term effects of infliximab for rheumatoid arthritis based on American College of Rheumatology (ACR) evaluation could be extrapolated to Japan, it was concluded that long-term preventive effects on progression of joint damage should be examined in a clinical trial in Japan, because an effect on ACR20 (ACR 20% improvement criteria) does not directly demonstrate preventive effects on the progression of joint damage. Thus effects on rheumatoid arthritis and effects on progression of joint damage were treated as distinct claims that need to be evaluated in a population. A bridging study is used to study the efficacy, safety, and dose-response relationships of a drug in the new region, aiming to confirm that the efficacy, safety, and dose-response relationships of the drug in the new population are similar to those in the population evaluated in the foreign studies. If a drug shows no difference in clinical efficacy and safety (eg, dose-response relationships and adverse event rate are not statistically different in 2 populations), the data in the foreign clinical study can be considered applicable as pivotal data for a regulatory submission in the new region. There are no predefined statistical criteria for a bridging study for evaluating similarity in 2 populations. However, criteria for a successful bridging strategy should be set on a case-by-case basis through a consultation with the regulatory authority in a new region. Although the bridging study is the most important component of a bridging strategy, Japanese experience indicates that locally relevant PK data are also needed to evaluate the similarity of PK profiles in the 2 regions and to help determine the appropriate dose in the new region. According to ICH E5, locally relevant PK data are an expected part of a complete clinical data package, although these were not considered a bridging study. Moreover, it is often possible to obtain these data as part of the bridging study. The patterns of the PK and clinical studies submitted in the 26 NDAs can be categorized into 4 groups. For pattern A, the PK study in healthy volunteers was conducted independently of the bridging study. For pattern B, the PK study in patients, as well as healthy volunteers, was conducted independently of the bridging study. For pattern C, no independent PK study was conducted but pharmacokinetics was measured in the bridging study. For pattern D, an independent PK study was conducted and pharmacokinetics was also measured in the bridging study. Fig 3 shows that, among the 26 NDAs studied, the trends in decreasing order are as follows: pattern A, 12; patterns C and D, 5 each; and pattern B, 4. Most PK evaluations were based on a standard PK study, but in several cases, a population PK approach was taken. Pharmacodynamic properties were also measured in some PK studies. Patterns of pharmacokinetic (PK) and bridging study (BS) on application for bridging strategy. Patterns could be categorized into 4 groups. The figure shows numbers of NDAs for each pattern. For pattern A, a PK study in healthy volunteers was conducted independently of the bridging study (sildenafil citrate, donepezil hydrochloride, fexofenadine hydrochloride, oseltamivir phosphate [adult], zolmitriptan, sumatriptan succinate, alendronate sodium, omeprazole plus clarithromycin plus sumatriptan rizatriptan and For pattern B, a PK study in patients, as well as healthy volunteers, was conducted independently of the bridging study risedronate sodium, and pramipexole Note that differences in the PK properties between regions for and risedronate sodium were evaluated on the basis of data in healthy For pattern C, no independent PK study was conducted but pharmacokinetics was measured in the bridging study oseltamivir phosphate and leucovorin calcium plus For pattern D, an independent PK study was conducted and pharmacokinetics was also measured in the bridging study eletriptan and Note that an independent PK study for was conducted in but not in healthy volunteers, and differences in the PK properties between regions for eletriptan hydrobromide were evaluated on the basis of data in healthy The ICH E5 guideline that in many cases a bridging study should be a dose-response that is, one that not only the drug effects in a new population but also information allowing dose in a new population. Fig 4 the bridging study in Japan. the studies in 26 at least 1 including or a different dose (Fig More than 1 dose was used in and of these a as There were 5 other studies studies were that did not have more than 1 drug dose. of bridging studies. A, of B, of C, The figure shows numbers of bridging studies for each Note that the total number of studies was for 26 because 2 bridging studies were included in 1 Fig B, shows the number of treatment A design was most used followed by 1 3 and 4 Fig C, shows that of studies were The studies included 3 studies of 2 studies of disease on renal age-related macular and 2 studies of viral disease. The mean number of in the bridging studies was ± (n = (Fig 5), and were used to study cancer and If studies cancer and diseases are the in the bridging study was ± ± = the other the number of in the foreign pivotal studies target of the bridging was ± ± = although among the studies. numbers in bridging study based on of target Note that the numbers are as mean ± except for the in which the number is the mean value of 2 studies. Use of a bridging strategy to minimize duplicative in each region is expected to clinical development in a new region. examined the of clinical development in Japan for the 26 approved NDAs that used a bridging strategy from 1998 to and compared these with those of drugs approved the same that did not use a bridging strategy. from the of phase 2 studies phase 3 studies phase 2 studies were not to NDA submission in Japan were because the bridging study is usually to be a for the phase 2 and 3 studies in the new region that would be part of a development Note that this analysis 2 cases, as follows: The study was conducted the review NDA NDAs for virus drugs were approved without clinical trial data in Japan. The was (n = for NDAs where a bridging strategy was which is significantly than the for the other NDAs which a bridging strategy was not = by NDAs bridging strategy have been increasing by and the bridging strategy has an important in the clinical development of drugs in Japan. The number of NDAs bridging strategy is expected to not only in Japan but in other and other regions. The 26 NDAs described were approved in Japan, because the results of the bridging study extrapolation of the results of foreign clinical including long-term to the Japanese population. It should be that of 26 NDAs were approved with for more safety The bridging strategy results in been examined in clinical trials in the new region, compared with those in development although ICH E5 points that the new region could for additional safety as well as a study. the total in the new region will be less than so that in Japan a would often be necessary for drugs approved based on a bridging strategy. It has been that some additional properties such as effects and drug should be examined to ethnic that, in drug safety should be drug approval. such as and prescribing a drug also be necessary for a drug with of adverse events. that PK in the new population is important for a successful bridging strategy (Fig 3) to a bridging study and to evaluate the of an dose in a new region. PK properties can in healthy volunteers and or in different PK in bridging studies is also ethnic differences in pharmacokinetics between populations have been and were in some of the studies. If differences in PK properties are observed between the that these significantly efficacy and safety of the drugs to be the relationships of PK responses to clinical effects can to the data The results shown in 4 and 5 that, in Japan, the bridging study is usually a study that often has more than 1 dose because a in Japan is the dose of the foreign studies is for Japanese that a bridging strategy should not be a strategy to the foreign data to a new region. Data from the region only a that the data be applicable to a new region. A dose-response should be examined it is the same or different between the new and regions in a bridging strategy. Data from an appropriate bridging strategy will be and support approval even where the dose in the new region is different from that of the region, whereas an bridging strategy does not in drug In in some cases the “Dosage and Administration” in labeling was different for Japan from the US/European Union dose can be on only as a of the in bridging studies in a new region. It should be noted that were in each bridging study, which was less than of the number in the foreign pivotal study target of the bridging The population in the bridging study from numbers but not from statistical The study numbers could be because the foreign study data provided information to set the most appropriate doses in the bridging study in Japan. data also indicate that 1 appropriate bridging study in Japanese subjects for a disease is usually sufficient to foreign study data for approval. However, we that the bridging study should be conducted in Japanese subjects if data in a bridging study are used to evaluate drug efficacy or safety in Japanese subjects and a drug is to be approved in Japan, because ethnic differences even among In if drug is by a of a relevant to the drug ethnic differences should be into in dose finding in the bridging study. be to observed differences in dose between populations. There are some NDAs that were not approved because of use of an bridging strategy. of the bridging strategy in many cases from the that the dose would be the same between regions. there were some cases in which the Japanese population different dose-response relationships from those in the foreign population because of the and dose in the bridging studies. In these cases the dose could not be for the Japanese population. A different dose-response in the Japanese population from a foreign population usually in higher rate of adverse events or adverse events and in It is most to use a dose-response study with or an appropriate for the bridging study. There are some other cases that were not approved because of the use of the bridging strategy even for that is, the results were by differences in 2 regions in standard or to the of an appropriate bridging strategy and bridging regulatory authorities should be responsible for for clinical trial details be provided because information regarding drugs is not available to the The differences in the “Indication and Usage” on labels between Japan and the United States/European Union were usually some cases different in the region (eg, In addition, the design of the bridging study (eg, is used to data between 2 could a for “Indication and such as the case of It should be noted that if the end in the bridging study does not directly demonstrate an efficacy for other another bridging study or clinical development is necessary in a new region for evaluating the efficacy for other It is also important to to the that in some bridging the was a clinical of a drug could be examined in a clinical trial even drug approval. Clinical development for drugs by use of a bridging strategy were by 24 than the for drugs not subject to this strategy. This difference should be because there were many in clinical development However, this that a bridging strategy can the for clinical development in a new region. It should be noted that, for most of the 26 NDAs a bridging strategy, clinical development including phase 1 studies in Japan was because the ICH E5 guideline was not at that the guideline was clinical development for these drugs were to a bridging strategy. believe that the for clinical development can be if a bridging strategy is from the as a clinical development approach in a new region. If a bridging strategy is for drug development in the new region can also be because another large phase 3 trial and long-term study in a new region, which are can be or that a bridging strategy drug development and minimize duplicative in each region. However, is for a successful bridging strategy, and drug safety should be approval. a bridging strategy is being we all available and bridging study will drug development and the to approval in a new region. an bridging strategy, it will be to have discussions between the regulatory authority in a new region and the from the of drug It is also that the conduct of clinical trials is more in drug These trials allow direct comparison of results in different regions. These information described will also be in for which it will provide points to be and Center for Evaluation and US Food and for on the There is no of with to this work. The are the of independent and do not the and of the National Institute of Health Sciences and Pharmaceuticals and Medical Devices