The Regulation of Cell Therapy and Gene Therapy Products in Switzerland.

This chapter describes the regulation of cell and gene therapy products (CGTPs) in Switzerland and its legal basis. The Swiss Agency for Therapeutic Products, Swissmedic, is the lead Regulatory Authority and its ATMP Division is responsible for the regulation of these products at the level of clinical trials and marketing authorization. CGTPs are regulated similarly to medicinal products. The legal basis is set by the Therapeutic Product Act, the Transplantation Act, the Human Research Act, and associated ordinances. The ATMP Division is involved in processes such as scientific advice meetings, presubmission advice meetings, pharmacovigilance, market surveillance, import/export approvals, manufacturing license approval, and inspections. In Switzerland, guidance documents relevant for cell and gene therapy provided by PIC/S, OECD, ICH, Ph.Eur., EMA, or FDA are considered. In order to harmonize requirements for CGTPs, the ATMP Division is in constant exchange of information with foreign Regulatory Authorities and part of working groups of ICH, IPRP, and Ph.Eur. As CGTPs are biologically and technically complex, a risk-based approach is applied on a case-by-case basis for the evaluation of clinical trial and marketing applications. A substantial part of this chapter will provide requirements with respect to the manufacturing and quality, nonclinical and clinical evaluation of CGTPs. Furthermore, information will be provided regarding the use of real-world evidence in evaluation of clinical long-term efficacy and safety in case of rare diseases where the numbers of patients are too small for statistically meaningful analysis during clinical trials. Finally, the chapter will provide information on a health technology assessment (HTA) program that was launched in 2015 in Switzerland by the federal authorities.

Bisphosphonates reduce biomaterial turnover in healing of critical-size rat femoral defects.

Treatment of osteoporotic patients with bisphosphonates (BPs) preserves bone mass and microarchitecture. The high prescription rate of the drugs brings about increases in the numbers of fractures and bone defects requiring surgical interventions in these patients. Currently, critical-size defects are filled with biomaterials and healing is supported with bone morphogenetic proteins (BMP). It is hypothesized that BPs interfere with biomaterial turnover during BMP-supported repair of defects filled with ß-tricalcium phosphate (ßTCP) ceramics. To test this hypothesis, retired breeder rats were ovariectomized ( OVX). After 8 weeks, treatment with alendronate (ALN) commenced. Five weeks later, 6 mm diaphyseal femoral defects were applied and stabilized with locking plates. ßTCP cylinders loaded with 1 µg and 10 µg BMP2, 10 µg L51P, an inhibitor of BMP antagonists and 1 µg BMP2/10 µg L51P were fitted into the defects. Femora were collected 16 weeks post-implantation. In groups receiving calcium phosphate implants loaded with 10 µg BMP2 and 1 µg BMP2/10 µg L51P, the volume of bone was increased and ßTCP was decreased compared to groups receiving implants with 1 µg BMP2 and 10 µg L51P. Treatment of animals with ALN caused a decrease in ßTCP turnover. The results corroborate the synergistic effects of BMP2 and L51P on bone augmentation. Administration of ALN caused a reduction in implant turnover, demonstrating the dependence of ßTCP removal on osteoclast activity, rather than on chemical solubility. Based on these data, it is suggested that in patients treated with BPs, healing of biomaterial-filled bone defects may be impaired because of the failure to remove the implant and its replacement by authentic bone.

Healing of fractures in osteoporotic bones in mice treated with bisphosphonates - A transcriptome analysis.

Bisphosphonates (BP) are inhibitors of bone resorption and are used to treat postmenopausal osteoporosis. Long-term treatment with BP attenuates bone remodeling, possibly leading to detrimental consequences for the bones' ability to repair defects. To test this hypothesis, an animal model was established. Twelve week old mice were ovariectomized (OVX). Following confirmation of bone loss 8 weeks after OVX, the animals were treated with Alendronate (ALN) until sacrifice. After 5 weeks of ALN injections, the femoral bones were osteotomized and the osteotomies were either rigidly or non-rigidly stabilized. In rigidly fixed defects, no callus developed between 1 and 5 weeks after osteotomy, whereas after non-rigid fixation, callus development occurred. The administration of ALN resulted in an increase in newly formed bone at the defect site 5 weeks after osteotomy, irrespective of the estrogen status or fixation system. Transcriptome analysis demonstrated that both rigid and non-rigid fixation affected gene expression primarily during the middle phase of bone repair. Furthermore, the number of differentially expressed genes in tissues from non-rigidly fixed defect sites increased in animals treated with ALN over the course of bone repair. This indicates that ALN-dependent repair processes become increasingly dominant in the late phases of the healing process. Ranking of the factors affecting the composition of the transcriptome and their impact on the healing process revealed fixation at the defect site to be the strongest causative factor, followed by bisphosphonate treatment and estrogen deficiency. The present study suggests that the continuous administration of ALN is detrimental to bone repair, eventually causing a delay in healing in mechanically compromised situations. Consequently, rigid fixation may prove essential for a successful intervention.