Schlage Walter K, Titz Bjoern, Iskandar Anita, Poussin Carine, Van der Toorn Marco, Wong Ee Tsin, Pratte Pascal, Maeder Serge, Schaller Jean-Pierre, Pospisil Pavel, Boue Stephanie, Vuillaume Grégory, Leroy Patrice, Martin Florian, Ivanov Nikolai V, Peitsch Manuel C, Hoeng Julia
Max-Baermann-Str. 21, 51429, Bergisch Gladbach, Germany.
PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000, Neuchâtel, Switzerland.
Toxicol Rep. 2020 Sep 12;7:1187-1206. doi: 10.1016/j.toxrep.2020.09.004. eCollection 2020.
Cigarette smoking causes major preventable diseases, morbidity, and mortality worldwide. Smoking cessation and prevention of smoking initiation are the preferred means for reducing these risks. Less harmful tobacco products, termed modified-risk tobacco products (MRTP), are being developed as a potential alternative for current adult smokers who would otherwise continue smoking. According to a regulatory framework issued by the US Food and Drug Administration, a manufacturer must provide comprehensive scientific evidence that the product significantly reduces harm and the risk of tobacco-related diseases, in order to obtain marketing authorization for a new MRTP. For new tobacco products similar to an already approved predicate product, the FDA has foreseen a simplified procedure for assessing "substantial equivalence". In this article, we present a use case that bridges the nonclinical evidence from previous studies demonstrating the relatively reduced harm potential of two heat-not-burn products based on different tobacco heating principles. The nonclinical evidence was collected along a "causal chain of events leading to disease" (CELSD) to systematically follow the consequences of reduced exposure to toxicants (relative to cigarette smoke) through increasing levels of biological complexity up to disease manifestation in animal models of human disease. This approach leverages the principles of systems biology and toxicology as a basis for further extrapolation to human studies. The experimental results demonstrate a similarly reduced impact of both products on apical and molecular endpoints, no novel effects not seen with cigarette smoke exposure, and an effect of switching from cigarettes to either MRTP that is comparable to that of complete smoking cessation. Ideally, a subset of representative assays from the presented sequence along the CELSD could be sufficient for predicting similarity or substantial equivalence in the nonclinical impact of novel products; this would require further validation, for which the present use case could serve as a starting point.
吸烟在全球范围内导致了主要的可预防疾病、发病率和死亡率。戒烟和预防开始吸烟是降低这些风险的首选方法。危害较小的烟草产品，即所谓的改良风险烟草产品（MRTP），正在被开发出来，作为当前成年吸烟者的一种潜在替代选择，否则他们将继续吸烟。根据美国食品药品监督管理局发布的监管框架，制造商必须提供全面的科学证据，证明该产品能显著降低危害和与烟草相关疾病的风险，以便获得新MRTP的上市许可。对于与已批准的参照产品相似的新烟草产品，美国食品药品监督管理局已经预见了一种简化的程序来评估“实质等同性”。在本文中，我们展示了一个用例，它将先前研究中的非临床证据联系起来，这些证据表明了基于不同烟草加热原理的两种加热不燃烧产品的潜在危害相对降低。非临床证据是沿着“导致疾病的因果事件链”（CELSD）收集的，以系统地追踪在人类疾病动物模型中，通过增加生物复杂性水平直至疾病表现，减少接触有毒物质（相对于香烟烟雾）的后果。这种方法利用系统生物学和毒理学原理作为进一步外推至人体研究的基础。实验结果表明，这两种产品对顶端和分子终点的影响同样降低，没有出现香烟烟雾暴露未见到的新效应，并且从香烟切换到任何一种MRTP的效果与完全戒烟相当。理想情况下，沿着CELSD呈现的序列中的一组代表性检测方法足以预测新产品非临床影响的相似性或实质等同性；这需要进一步验证，本文的用例可作为一个起点。
