Organisational and methodological challenges of CAR-T manufacturing in the Russian Federation

Despite their widespread clinical implementation, chimeric antigen receptor T-cell (CAR-T) therapy products, including those manufactured by industrial processes, are still not legally available or used in the Russian Federation.The aim of the study was to describe the current challenges associated with specific aspects of CAR-T manufacturing in the Russian Federation and the potential ways to overcome them.This article discusses the regulatory, legal, organisational, and methodological challenges of CAR-T manufacturing. It analyses differences in the interpretation of CAR-T therapy products under national and supranational law. According to Russian Federal Law No. 180-FZ “On Biomedical Cell Products” of 23 June 2016, CAR-T therapy products are considered biomedical cell products. However, according to Decision No. 78 of the Council of the Eurasian Economic Commission “On the Rules of Marketing Authorisation and Assessment of Medicinal Products for Human Use” of 3 November 2016, CAR-T therapy products are considered advanced therapy medicinal products (ATMPs). This article provides a detailed overview of the difficulties in obtaining starting biological materials (i.e. the inability to consider the patient as a donor) and transferring the materials for CAR-T manufacturing (i.e. the inapplicability of national law). In addition, this article describes export aspects specific to biological materials. The authors reckon that CAR-T therapy products should be categorised as ATMPs and that the corresponding active pharmaceutical ingredients, genetically modified autologous lymphocytes, should be defined as starting materials. Therefore, genetically modified autologous lymphocytes should be regulated under the requirements for starting materials for the manufacturing of active pharmaceutical ingredients that are set forth in Decision No. 77 of the Council of the Eurasian Economic Commission “On the Adoption of the Rules of Good Manufacturing Practice of the Eurasian Economic Union” of 3 November 2016. In conclusion, the authors recognise the need for national and supranational law harmonisation. For this task, it is necessary to establish expert groups that will include clinicians, legal experts, and representatives from the relevant authorities and the pharmaceutical industry

Организационно-методические проблемы производства CAR-T в Российской Федерации

Despite their widespread clinical implementation, chimeric antigen receptor T-cell (CAR-T) therapy products, including those manufactured by industrial processes, are still not legally available or used in the Russian Federation.The aim of the study was to describe the current challenges associated with specific aspects of CAR-T manufacturing in the Russian Federation and the potential ways to overcome them.This article discusses the regulatory, legal, organisational, and methodological challenges of CAR-T manufacturing. It analyses differences in the interpretation of CAR-T therapy products under national and supranational law. According to Russian Federal Law No. 180-FZ “On Biomedical Cell Products” of 23 June 2016, CAR-T therapy products are considered biomedical cell products. However, according to Decision No. 78 of the Council of the Eurasian Economic Commission “On the Rules of Marketing Authorisation and Assessment of Medicinal Products for Human Use” of 3 November 2016, CAR-T therapy products are considered advanced therapy medicinal products (ATMPs). This article provides a detailed overview of the difficulties in obtaining starting biological materials (i.e. the inability to consider the patient as a donor) and transferring the materials for CAR-T manufacturing (i.e. the inapplicability of national law). In addition, this article describes export aspects specific to biological materials. The authors reckon that CAR-T therapy products should be categorised as ATMPs and that the corresponding active pharmaceutical ingredients, genetically modified autologous lymphocytes, should be defined as starting materials. Therefore, genetically modified autologous lymphocytes should be regulated under the requirements for starting materials for the manufacturing of active pharmaceutical ingredients that are set forth in Decision No. 77 of the Council of the Eurasian Economic Commission “On the Adoption of the Rules of Good Manufacturing Practice of the Eurasian Economic Union” of 3 November 2016. In conclusion, the authors recognise the need for national and supranational law harmonisation. For this task, it is necessary to establish expert groups that will include clinicians, legal experts, and representatives from the relevant authorities and the pharmaceutical industry.Несмотря на широкое внедрение в клиническую практику терапии Т-клетками с химерным антигенным рецептором (chimeric antigen receptor T-cell, CAR-T), на территории Российской Федерации данные препараты до сих пор официально не представлены и не используются, в том числе и произведенные промышленным (индустриальным) способом.Цель работы — описание текущих проблем, связанных с особенностями производства CAR-T в Российской Федерации, и потенциальных путей их решения.Рассмотрены трудности, связанные c регуляторными, юридическими и организационно-методическими аспектами производства CAR-T. Проанализированы расхождения в трактовке понятия CAR-T в национальном и наднациональном праве: как биомедицинского клеточного продукта согласно Федеральному закону от 23.06.2016 № 180-ФЗ «О биомедицинских клеточных продуктах» и как высокотехнологического лекарственного препарата (ВТЛП) согласно Решению Совета Евразийской экономической комиссии от 03.11.2016 № 78 «О Правилах регистрации и экспертизы лекарственных средств для медицинского применения». Подробно рассмотрены трудности на этапе получения исходного биологического материала (невозможность рассматривать пациента как донора биологического материала); на этапе передачи биологического материала для производства CAR-T (невозможность применения национального права); особенности экспорта биологического материала. По мнению авторов статьи, CAR-T следует относить к ВТЛП, активной фармацевтической субстанцией (АФС) которых являются генетически модифицированные аутологичные лимфоциты, а последние должны быть определены как «исходный материал», и к ним должны применяться требования как к исходному материалу для производства АФС, указанные в Решении Совета Евразийской экономической комиссии от 03.11.2016 № 77 «Об утверждении Правил надлежащей производственной практики Евразийского экономического союза». Сделано заключение о необходимости гармонизации национального и наднационального права, что требует формирования экспертных групп, объединяющих врачей-клиницистов, специалистов в области права, представителей профильных ведомств и фармацевтической индустрии

Increased Nucleotide Diversity with Transient Y Linkage in Drosophila americana

Recombination shapes nucleotide variation within genomes. Patterns are thought to arise from the local recombination landscape, influencing the degree to which neutral variation experiences hitchhiking with selected variation. This study examines DNA polymorphism along Chromosome 4 (element B) of Drosophila americana to identify effects of hitchhiking arising as a consequence of Y-linked transmission. A centromeric fusion between the X and 4(th) chromosomes segregates in natural populations of D. americana. Frequency of the X-4 fusion exhibits a strong positive correlation with latitude, which has explicit consequences for unfused 4(th) chromosomes. Unfused Chromosome 4 exists as a non-recombining Y chromosome or as an autosome proportional to the frequency of the X-4 fusion. Furthermore, Y linkage along the unfused 4 is disrupted as a function of the rate of recombination with the centromere. Inter-population and intra-chromosomal patterns of nucleotide diversity were assayed using six regions distributed along unfused 4(th) chromosomes derived from populations with different frequencies of the X-4 fusion. No difference in overall level of nucleotide diversity was detected among populations, yet variation along the chromosome exhibits a distinct pattern in relation to the X-4 fusion. Sequence diversity is inflated at loci experiencing the strongest Y linkage. These findings are inconsistent with the expected reduction in nucleotide diversity resulting from hitchhiking due to background selection or selective sweeps. In contrast, excessive polymorphism is accruing in association with transient Y linkage, and furthermore, hitchhiking with sexually antagonistic alleles is potentially responsible

Identification and localization of layers in the ionosphere using the eikonal and amplitude of radio occultation signals

By using the CHAllenge Minisatellite Payload (CHAMP) radio occultation (RO) data, a description of different types of the ionospheric impacts on the RO signals at the altitudes 30-90 km of the RO ray perigee is given and compared with the results of measurements obtained earlier in the satellite-to-Earth communication link at frequency 1.5415 GHz. An analytical model is introduced for describing propagation of radio waves in a stratified medium consisting of sectors with spherically symmetric refractivity distribution. This model gives analytical expressions for the phase, bending angle, and refractive attenuation of radio waves and is applied to the analysis of radio wave propagation phenomena along an extended path including the atmosphere and two parts of the ionosphere. The model explains significant amplitude and phase variations at altitudes 30-90 km of the RO ray perigee and attributes them to inclined ionospheric layers. Based on this analytical model, an innovative technique is introduced to locate layers in the atmosphere and ionosphere. A necessary and sufficient criterion is obtained for a layer to be located at the RO ray perigee. This criterion gives both qualitative and quantitative estimation of the displacement of an ionospheric and/or atmospheric layer from the RO ray perigee. This is important, in particular, for determining the location of wind shears and directions of the internal wave propagation in the lower ionosphere, and, possibly, in the atmosphere

Identification and localization of layers in the ionosphere using the eikonal and amplitude of radio occultation signals

By using the CHAllenge Minisatellite Payload (CHAMP) radio occultation (RO) data, a description of different types of the ionospheric impacts on the RO signals at the altitudes 30–90 km of the RO ray perigee is given and compared with the results of measurements obtained earlier in the satellite-to-Earth communication link at frequency 1.5415 GHz. An analytical model is introduced for describing propagation of radio waves in a stratified medium consisting of sectors with spherically symmetric refractivity distribution. This model gives analytical expressions for the phase, bending angle, and refractive attenuation of radio waves and is applied to the analysis of radio wave propagation phenomena along an extended path including the atmosphere and two parts of the ionosphere. The model explains significant amplitude and phase variations at altitudes 30–90 km of the RO ray perigee and attributes them to inclined ionospheric layers. Based on this analytical model, an innovative technique is introduced to locate layers in the atmosphere and ionosphere. A necessary and sufficient criterion is obtained for a layer to be located at the RO ray perigee. This criterion gives both qualitative and quantitative estimation of the displacement of an ionospheric and/or atmospheric layer from the RO ray perigee. This is important, in particular, for determining the location of wind shears and directions of the internal wave propagation in the lower ionosphere, and, possibly, in the atmosphere