The right way and wrong way of research and development of combined drugs

Source: medical economics report 2016-08-30 in clinical use, doctor's combination prescription is very common Since 2015, China has issued many notices on regulating and controlling the unreasonable growth of medical expenses in public hospitals The notices mainly focus on antibiotics, auxiliary drugs and nutritional drugs, which are often jointly prescribed by doctors On the one hand, from the perspective of clinical needs, in order to improve clinical efficacy, reduce drug toxicity, delay or avoid the emergence of drug resistance, appropriate combination of drugs has its necessity For example, when quinolones and fosfomycin are used in combination, because fosfomycin can destroy the cell wall of bacteria, the efficacy of quinolones in the treatment of drug-resistant typhoid and other diseases is enhanced But on the other hand, unreasonable combination of drugs will increase the probability of drug-induced events For example, the mixture of cephalosporins and aminoglycosides can inactivate each other, so it is necessary to prepare them separately in clinical use It is necessary to develop different dosage forms when they are administered in different parts So, what is the basic situation of joint drug development in China? The author classifies and summarizes the future trend of the combination of drugs, looking for the right way of the combination of drugs project Current situation in China: encourage or restrict joint use? It is a practical problem that "big prescription" is forbidden in clinical use In addition to economic considerations, the most important thing is that the interaction mechanism between drugs is not clear, and the incidence of adverse reactions is high There are many reasons for adverse reactions of drugs After all, the number of clinical trials for drug registration and listing is limited Adverse reactions can only be found gradually after clinical application for many years In addition, clinicians do not know enough about the interaction of combined drugs, and their vigilance is not high, which is also the main cause of adverse drug interaction events Even the most commonly used glucocorticoids, in the treatment of organ transplant patients at home and abroad, the dosage, administration frequency and withdrawal time of glucocorticoids are still controversial Glucocorticoid is an important part of the triple therapy consisting of calmodulin inhibitor (cyclosporine A / tacrolimus / sirolimus) + mycophenolate mofetil + Glucocorticoid (prednisone / prednisolone) However, it is very difficult to design a better clinical scheme: glucocorticoid can lead to a variety of adverse reactions, which need to be withdrawn in organ transplantation due to long-term or large dose of glucocorticoid application; however, the incidence of rejection is significantly increased after the withdrawal of glucocorticoid Therefore, the combination of drugs in clinical use should not be "one size fits all", but should be based on the comprehensive evaluation of economy, effectiveness and safety In China, according to the database of CDE drug clinical trial registration and information publicity platform, there are less than 250 clinical trials of combined drugs in the clinical trials registered since 2013, which shows that the process of new drug registration and application in China does not attach great importance to combined drugs "Frontline drug use" trial: the effect is questionable With the prescription doctors paying more and more attention to the treatment plans confirmed by clinical trial data such as guidelines and clinical routes, the manufacturers are willing to invest in the literature such as clinical observation reports In order to make their own drugs can be used in the "first-line drugs" of clinical prescriptions, manufacturers often carry out clinical trials of their own drugs and "first-line drugs" From the data level, it can be proved that the combination of the two drugs can shorten the course of treatment, reduce the side effects, etc., so as to draw the conclusion that the benefits of combined drugs are greater than the risks This will be beneficial to the clinical promotion of the target drugs after they are put on the market In fact, unless the efficacy is better than all the products on the market at present, and the safety is good, the behavior of "first-line medication" can only make the target drug in the second-line medication position or "first-line medication" in the late stage of the disease As far as drug classification is concerned, the modes of combination of Western medicine and Western medicine, traditional Chinese medicine and Western medicine, and traditional Chinese medicine and Chinese medicine The existing clinical pathway research and the package payment scheme based on disease diagnosis and treatment often do not have the joint scheme of Chinese and Western medicine, which means that with the promotion of clinical pathway and other policies, the medical insurance payment scheme is more inclined to pay for the scheme of Western medicine Western medicine combination From the data of clinical literature, the number of clinical observation literature of traditional Chinese medicine, especially the combination of traditional Chinese medicine injection and Western medicine, is the highest in the related research of combined use However, the re registered clinical trials need to be verified by self-examination The credibility of this kind of spontaneous clinical observation is in doubt, so it is difficult for Chinese medicine manufacturers to enter the guide or clinical path by virtue of the effectiveness reported by this kind of literature data Combined drug trials: the highest proportion of anti-tumor drugs Since 2013, more than half of the clinical trials on combined drugs registered by CDE are related to anti-tumor mechanism The proportion of protein tyrosine kinases is the highest Individualized targeting therapy of targeted drugs has gradually become one of the standard treatment components in clinical guidelines In the guidelines, protein tyrosine kinases are often combined with paclitaxel, gemcitabine and other chemotherapy drugs to achieve high remission rate and prolong the survival period of patients The clinical trial design of new drugs often refers to the clinical guidelines, and the safety and tolerance of combination therapy with paclitaxel, gemcitabine and other chemotherapy drugs are observed in phase I clinical, so as to determine the maximum tolerable dose (MTD) and / or the recommended dose (rptd) of phase II trial of new drugs combined with chemotherapy drugs For example, the phase I-B study of fiquitinib combined with paclitaxel in the treatment of advanced gastric cancer, the study of pyrrolidine maleate and capecitabine in the treatment of advanced breast cancer, the clinical study of famitinib combined with docetaxel in the treatment of advanced lung cancer, etc The results of such studies can not only promote phase II trials, but also serve as evidence for clinical guidelines Future trend: antineoplastic drugs: under the multi-channel and the combination of various mechanisms, as a whole, the research on the combination of antineoplastic drugs in China mainly focuses on how to apply for registration and the evidence needed for clinical promotion in the future Tumor immunotherapy involves many links, each link involves different molecules and related mechanisms, which means that the single target of tumor immunotherapy is very limited, and the joint use of different links of tumor immunotherapy is the focus of foreign research In 2014, the FDA approved PD-1 antibody (Bristol Myers Squibb's opdivo) was actively engaged in the clinical design of combined use with other immune target drugs to enhance the effect of immunotherapy It is reported that more than 100 clinical trials will be carried out soon Previously, the data of melanoma patients with metastasis treated by opdivo combined with CTLA-4 antibody and the data of opdivo single drug or combined chemotherapy in the first-line treatment of lung cancer showed that the remission rate and disease control rate of PD-1 combined were higher than those of PD-1 alone, but there was no detailed data of total survival rate It is worth noting that the side effects of PD-1 combination are also higher than that of single drug The combination of mAbs is often used in combination with first-line chemotherapy drugs, such as nitzumab combined with paclitaxel and cisplatin in the first-line treatment of metastatic esophageal squamous cell carcinoma, bevacizumab combined with capecitabine in the phase III test of HER2 negative metastatic breast cancer, etc Chronic disease medication: registration application is mainly used in combination with first-line medication In chronic diseases, hypertension, hyperlipidemia, diabetes and chronic nephritis are accompanied by other combined diseases, and combined medication is very common Because most patients with chronic diseases need to take drugs for life, the protection of target organs and the improvement of life quality are the focus of doctors' prescription But in our country, the clinical research on the combination of complication drugs is relatively less In the aspect of drug registration, clinical trials of combination drugs are often carried out with the current first-line drugs for the target indications of the drug For example, diabetes drugs are basically designed to be used in combination with metformin, while 90% of new diabetes drugs are designed to be used in combination with dipeptidyl peptidase-4 (DPP-4 inhibitor) and metformin in the treatment of type 2 diabetes; for example, the combination of retagliptin phosphate and metformin in the treatment of type 2 diabetes, and the combination of shagliptin and metformin in the treatment of type 2 diabetes In the aspect of hepatitis C, target drug combined with ribavirin (± interferon) treatment is the most common scheme, such as sofosbuvir combined with ribavirin (± interferon) treatment of chronic hepatitis C research, asc08 / interferon / ribavirin combination treatment of chronic hepatitis C phase II research, etc Precision medicine: joint development of companion diagnostic reagents in the context of precision medicine, through the research of genomics, epigenome, transcriptome, proteome, metabonomics and bioinformatics, it is expected to make more accurate diagnosis for patients With the rapid development of precision medicine, which is based on concomitant testing to determine the best treatment population, FDA has issued a new and more detailed draft guide to guide enterprises how to jointly develop complementary in vitro concomitant diagnostic reagents while developing therapeutic drugs On July 14, 2016, FDA issued a draft guideline for the joint development of in vitro concomitant diagnostic reagents and therapeutic drugs It is very common for new drug concomitant diagnostic reagents to be approved Since the approval of trastuzumab and the matching diagnostic kit HercepTest in 1998, the concept of joint development of therapeutic drugs and in vitro concomitant diagnostic reagents has been applied for the first time In 2014, more than 20% of new drugs and biological preparations were approved for marketing together with diagnostic reagents In 2015, the proportion of such approval was higher, reaching 28% approval rate At present, precision medicine outside the field of tumor has not been popular At present, omeprazole, warfarin, allopurinol and aripiprazole are the main gene detection varieties in China It is expected that the key signal pathways and regulatory factors in the process of disease occurrence and development will be revealed gradually, and the confirmation of new molecular targets will provide biological basis for combined drug use