High Rate of Awarding Compensation for Claims of Injuries Related to Clinical Trials by Pharmaceutical Companies in Japan: A Questionnaire Survey

Introduction

International norms and ethical standards have suggested that compensation for research-related injury should be provided to injured research volunteers. However, statistical data of incidence of compensation claims and the rate of awarding them have been rarely reported.

Method

Questionnaire surveys were sent to pharmaceutical companies and medical institutions, focusing on industry-initiated clinical trials aiming at new drug applications (NDAs) on patient volunteers in Japan.

Results

With the answers from pharmaceutical companies, the incidence of compensation was 0.8%, including 0.06% of monetary compensation. Of the cases of compensation claims, 99% were awarded. In turn, with the answers from medical institutions, the incidence of compensation was 0.6%, including 0.4% of serious but not death cases, and 0.04% of death cases. Furthermore, most claims for compensation were initiated by medical institutions, rather than by the patients. On the other hand, with the answers from clinical trial volunteers, 3% of respondents received compensations. These compensated cases were 25% of the injuries which cannot be ruled out from the scope of compensation.

Conclusion

Our study results demonstrated that Japanese pharmaceutical companies have provided a high rate of compensation for clinical trial-related injuries despite the possibility of overestimation. In the era of global clinical development, our study indicates the importance of further surveys to find each country''s compensation policy by determining how it is being implemented based on a survey of the actual status of compensation coming from statistical data.     

Characterization of Porphobilinogen Synthase from an Aerobic Photosynthetic Bacterium, Erythrobacter sp. Strain OCh 114

Porphobilinogen synthase (formerly 5-aminolevulinic acid dehydratase,EC 4.2.1.24 [EC] ) was purified 7,405-fold from an aerobic photosyntheticbacterium, Erythrobacter sp. strain OCh 114. The molecular weightof the enzyme was determined to be 260,000 by Sephadex G-200gel filtration. The enzyme had a single pH optimum at 8.0 andshowed no requirement for metal ion and thiol compound for itsmaximum activity. The K_m value for 5-aminolevulinic acid was0.29 mM. 4,5-Dioxovaleric acid and levulinic acid were foundto be competitive inhibitors of the enzyme, with K_i values of0.65 and 0.80 mM, respectively. The enzyme was extremely labilein acidic pH and almost completely lost its activity within1 h at pH 6.0 and 30?C. This Erythrobacter enzyme seems to besimilar to the enzyme from the anaerobic photosynthetic bacteriumRhodobacter capsulatus in its molecular and catalytic properties. (Received February 17, 1988; Accepted May 9, 1988)     

Characteristics of hepatitis B virus isolates of genotype G and their phylogenetic differences from the other six genotypes (A through F)

Eight hepatitis B virus (HBV) isolates of genotype G were recovered from patients and sequenced over the entire genome. Six of them had a genomic length of 3,248 bp and two had genomic lengths of 3,239 bp (USG15) and 3,113 bp (USG18) due to deletions. The 10 HBV/G isolates, including the 8 sequenced isolates as well as the original isolate (AF160501) and another isolate (B1-89), had a close sequence homology of 99.3 to 99.8% among themselves (excluding USG18 with a long deletion) but of <88.7% to any of the 68 HBV isolates of the other six genotypes with the full-length sequence known. The eight HBV/G isolates possessed an insertion of 36 bp in the core gene and two stop codons in the precore region, as did the AF160501 and B1-89 isolates. The 10 HBV/G isolates clustered on a branch separate from those bearing the other six genotypes (A through F [A-F]) in the phylogenetic tree constructed from full-length sequences of 78 HBV isolates as well as in those constructed from the core, polymerase, X, and envelope genes. Despite two stop codons in the precore region that prohibited the translation of the HBV e antigen (HBeAg), all of the eight patients with HBV/G infection possessed the HBeAg in serum. By restriction fragment length polymorphism of the surface gene, all of the eight patients were found to be coinfected with HBV of genotype A (HBV/A), which would be responsible for the expression of HBeAg in them. It is worthy of examination to determine how coinfection occurs and whether HBV/G needs HBV/A for replication.     

Purification,Properties and Recognition Sequence of Site-specific Restriction Endonuclease from Gluconobacter cerinus IFO 3285

A type II restriction endonuclease, designated as GceGLI, was purified from cells of Gluconobacter cerinus IFO 3285. The purified enzyme was found to be homogeneous on Polyacrylamide gel disc electrophoresis. The enzyme worked best at 37°C and pH 7.5 and required 7 mM MgCl₂ and 100 mM NaCl. The purified enzyme was stable when preincubated over a pH range of 7.5 to 9.5 for 12 hr at 4°C and a temperature range of 37 to 40°C for 5 min at pH 7.5. The enzyme was shown to cleave λ φX174 RF, SV40, pBR322, M13 mp7 RF and Ad2 DNAs at 4, 1,0, 0, 0 and 25 or more sites, respectively, and to recognize the DNA sequence of 5′-C-C-G-C-G-G-3′ and to cut between C and G on the right side of the sequence, being an isoschizomer of SacII of Streptomyces achromogenes ATCC 12767.     

Radial Columnar Patches in the Chimeric Cerebral Cortex Visualized by Use of Mouse Embryonic Stem Cells Expressing β-Galactosidase

Presumed radial migration of neuroblasts from the ventricular to pial surface during formation of the cerebral cortex predicts radial columnar patches in chimeric brains. Lack of adequate cell marker for neurons, however, has hindered such chimera analysis. We used a mouse embryonic stem cell line expressing β-galactosidase gene to produce chimeric brains. Patches of the labeled cells were examined by whole mount staining and also by computer-assisted three-dimensional reconstruction from serial paraffin sections. Our study revealed presence of coherent radial columnar patches in the prenatal cerebral cortex, thus giving a direct evidence for the radial migration of neurons. These columnar patches were less clear in adult brains, suggesting cell mixing during later development and maturation.     

Enzymatic Conversion of Pheophorbide a to the Precursor of Pyropheophorbide a in Leaves of Chenopodium album

Soluble proteins extracted from leaves of Chenopodium albumcatalyzed the conversion of pheophorbide a to a precursor ofpyropheophorbide a, putatively identified as C-13²-carboxyl-pyropheophorbidea. The precursor was then decarboxylated non-enzymatically toyield pyropheophorbide a. Soluble proteins and pheophorbidea, as the substrate, were required for the formation of theprecursor, and boiled proteins were enzymatically inactive.The maximum rate of conversion of pheophorbide a to the precursoroccurred at pH 7.5. The K_m for pheophorbide a was 12.5 µMat pH 7.0. Both pheophorbide b and bacteriopheophorbide a couldserve as substrates, but protopheophorbide a could not. Formationof methanol was detected during the enzymatic reaction, an indicationthat the enzyme is an esterase. Among seven alcohol analogstested, only methanol inhibited the enzymatic activity uncompetitively,with a K₁ of 71.6 mM. Mass-spectrometric (MS) analysis of theprecursor yield a peak at m/z 579 that indicated the releaseof a methyl group from pheophorbide a. It appears thereforethat the enzyme catalyzes the demethylation of the carbomethoxygroup at C-13² of pheophorbide a by hydrolysis to yield methanoland the precursor, C-13²-carboxyl-pyropheophorbide a, whichis converted to pyropheophorbide a by spontaneous decarboxylation.We have tentatively designated the enzyme "pheophorbidase".The presence of the enzyme was dependent on plant species andit was expressed constitutively. ¹Present address: Faculty of Science, Shizuoka University, Ohya,Shizuoka, 422 Japan     

Purification and Characterization of Two Isozymes of Chlorophyllase from Mature Leaves of Chenopodium album

Chlorophyllase (Chlase) was purified from mature leaves of Chenopodiumalbum, and its enzymatic properties were investigated. Chlasewas extracted from acetone powder of C. album and purified bythe following chroma-tographic procedures: hydrophobic chromatography,Con A Sepharose, Heparin affinity chromatography, Mono Q ion-exchangechromatography, and gel-filtration. Con A Sepharose affinitychromatography and gel-filtration were the most effective stepson the purification. On Mono Q chromatography, the Chlase preparationseparated into two major and one minor fractions that exhibitedChlase activity. The two major Chlases were purified to homogeneity.Their molecular masses were estimated as 41.3 kDa and 40.2 kDaby SDS-PAGE. The optimum pH and K_m values of these two Chlaseswere similar. Their N-terminal amino acid sequences were almostidentical except for a deletion in the tenth amino acid residuein one of the Chlase; there was no homologous protein detectedby database search. ³Present address: Department of Biology and Geoscience, Facultyof Science, Shizuoka University, 836 Ohya, Shizuoka, 422 Japan.     

Formation and Degradation of Protochlorophylls in Etiolated and Greening Cotyledons of Cucumber

The formation, degradation and phototransformation of protochlorophylls(Pchls) in the etiolated and greening cotyledons of cucumber(Cucumis sativus L.) werestudied using high-performance liquidchromatography. The pigment analysis of etiolated cotyledonsshowed the presence of four Pchls esterified with phytol, tetrahydrogeranylgeraniol(THGG), dihydrogeranylgeraniol (DHGG), and geranylgeraniol (GG).The content of Pchl THGG rapidly increased during dark developmentof seedlings and reached a maximal level at 4th day, then decreasedgradually. Unlike Pchl THGG, Pchl DHGG and Pchl GG showed asmall peak at 3rd day followed by a one-day lag, then accumulationbegan. The content of Pchl DHGG reached a maximal level at 12thday, then decreased rapidly, while Pchl GG continued to increaseand its maximal stage was not attained at 15th day. The contentof Pchl phytol remained very low during dark growth. These resultsmay indicate that with increasing age, the inactivation of hydrogenationof the alcohol moiety of Pchl proceeds stepwise at the sitesof Pchl THGG, Pchl DHGG and Pchl GG, in that order, withoutaffecting the esterification of Pchlide. The content of four Pchls remained unchanged before and after30-s illumination, indicating that none of the four Pchls istransformed to chlorophyll by light. Under continuous illumination,Pchls decreased exponentially or linearly at a rather slow rate.Thus, the four Pchls are not direct precursors for chlorophylland are metabolized slowly under greening. (Received December 6, 1982; Accepted April 13, 1983)