Since the reform of the drug review and approval system in 2015, the domestic innovative drug industry has been developing rapidly, and finally it has come to the inflection point of differentiation in 2021 when the COVID-19 is not ended, innovation policies are frequently introduced and the international situation is changing. At present, more and more local pharmaceutical enterprises are no longer limited to the domestic market, but actively participate in the competition in the global market in accordance with international standards by increasing R&D investment, stepping out of the road of internationalization. So how should local enterprises do to go overseas successfully? Some experts point out that, in addition to strengthening communication with regulatory authorities, there is also a need to have a sufficient understanding of international clinical trials, the enterprise cannot internationalize for internationalization, but should lay out from the initial top-level design, even before the product enters the clinic. Facing the ever-changing and highly competitive industry situation, how can domestic CROs help improve the efficiency of clinical R&D of innovative drugs and expand the opportunities for the internationalization of innovative drugs? On October 14, Dr. Gang Chen, Chief Scientific Officer, Prof. Bei Hu, Chief Clinical Pharmacology Scientist, Dr. Kun He, Chief Statistician, Mr. Jigang Li, Chief Medical Officer, and Mr. Tao Wang, Senior Vice President of R&G, brought wonderful analysis and discussion to everyone focusing on the theme of "How to maximize the clinical value and internationalization opportunities of innovative drugs" in the live broadcast of "Friends of the Rubik's Cube". Due to the space is limited, only some wonderful views of all guests are sorted out below for readers to learn, please watch to the video version for the complete playback.
Single-arm remains single-arm, but rule is not a loophole
Dr. Gang Chen:
Firstly, whether the regulation is getting stricter or not cannot be defined unilaterally. In the 1990s, the US FDA had a very full discussion about single-arm trials, and when is a single-arm trial allowed? There are two necessary conditions, the first is urgent clinical need, these patients must be incurable, then any promising drug can be granted conditional approval, also known as accelerated approval in the United States.
Secondly, this drug should reflect the corresponding efficacy. Can Surrogate endpoints be used? This should be discussed as appropriate. Most of the applicable scenarios are for end-line patients, and from the perspective of regulatory authorities, it is permissible to use surrogate endpoints to preliminarily determine whether the drug can bring benefits to the patient. These two are the most basic conditions. Today, more than 20 years later, the basic interpretation of this rule should be consistent.
Now the situation is the same as it was in the 1990s, but it's also different. The same is that the fact of urgent clinical need remains objective. But the difference is that the patient's potential options are no longer unique. Then from a regulatory perspective, in this case, it is still desirable to have a control group to compare with the potential options, instead of simply doing a single-arm trial and then giving a conditional approval.
With regard to the requirement for control, in the late 1990s, there was a lot of discussion between the US FDA and the European Union, that was the theme of the best-known Declaration of Helsinki - maximizing the benefits of patients must be the highest goal. This derives the concept of non-inferiority, whether the control group can use placebo, whether the weaker standard of care is used, completely from the perspective of maximizing the benefits of patients, then we must give patients the best current treatment regimen during clinical trials, even for the control group, choose the one with the best quality.
So today, it's not so much stricter regulation as a return to international standards.
Dr. Kun He:
Since the 1990s, conditional approval for a single-arm trial has been used at the FDA. This is due to the consideration of maximizing the benefits of patients, giving inclination in the rules, but we cannot regard the rules as loopholes, so in 2006, an ODAC meeting was held at that time to pull out a list of conditionally approved drugs to see for which ones supplemental trials that were promised originally weren't done, and it was found that for many of them, supplemental trials weren't done, after all, the management and control means of the drugs after marketing were relatively limited, and there was a rule from then on, namely, the conditionally approved studies needed to be basically completed, or for the subsequent plan a consensus with regulatory authorities had to reach. Secondly, due to the lack of drugs or fewer patients without the conditions of randomized trials, a single-arm trial was always started from the end-line patients in the early years, but now this rule has a tendency to generalize, which leads to changes in FDA stance now, although not unacceptable, but most tend to be randomized trials.
In addition, there is a change in trend, previously small molecule drugs, theoretically with large doses and relatively good efficacy. Now with the outbreak of biological drugs, there are many differences in doses compared to chemical drugs, so a very high dose can lead to some problems. In fact, in 2010 and 2011, FDA made a statistic showing that about 80% of the approved drugs were at high doses and there were problems in PMC (post-marketing commitment) or PMR (post-marketing requirement).
Dr. Bei Hu:
From the perspective of clinical pharmacology, this issue is essentially still what data do regulatory authorities base on when approving a new drug? Is the confidence very high? In other words, for drugs approved by regulatory authorities through single-arm trials, it was later confirmed that no more trials were required, or some clinical problems have not been fully solved. Since single-arm trials relative to classical randomized controlled clinical trials are accelerated approval, it is particularly important whether some clinical pharmacology studies of single-arm trials are sufficient, because the essence of clinical pharmacology studies is to confirm the doses and effects of drugs. Effects include the construction of a relationship between clinical efficacy and safety signals. Therefore, such a relationship construction is a study that needs to be conducted throughout the whole process of clinical R&D and needs relatively sufficient data support, because various indicators are variable in the population, for the dose-response relationship obtained in the smaller population in the single-arm trial, it is not sufficient to judge whether the relationship between some indicators is stabe or not due to the deviation of sample size, and it needs to be subsequently confirmed in a larger population. Therefore, for different drug studies and the construction of quantitative relationship between different indicators, how large sample size is really required? Whether large-scale confirmatory randomized controlled clinical trials are necessary to confirm that the work on dose selection and dose optimization has been sufficient, this requires specific case analysis.
Mr. Jigang Li:
Regulatory review is not based on the book, but keeps pace with the times, for the mastery of a standard, sometimes there will be some flexibility. In 2014, Gilead's Idelalisib was the one that passed the conditional approval through the single-arm trial. But until 2021, there were new companies, with the same indication, applying for approval through the single-arm trial. From 2014 to 2017, 3 products with the same indication have been approved. So it's a possible potential loophole, thinking about it from the perspective of keeping pace with the times. Secondly, at that time, randomized controlled confirmatory studies were being conducted on these products, and the results had proved that there was no clinical benefit in survival, and even there may be clinical harm. At the beginning, when selecting the dose, we started to enter the phase 2 with the maximum tolerated dose to obtain the maximum efficacy. However, this dose now appears to be a significantly higher dose for different populations or different patients, so there will be relatively large toxicity and damage. Therefore, in the process of regulatory review, we cannot mark the boat to locate the sword and believe that the criteria five years ago and seven years ago will be applicable today.
Therefore, it is necessary to judge the trial design protocol in combination with clinical needs at present. Regulatory authorities may prefer to review and approve a product using surrogate endpoints if there is a very large unmet need at that time, and more confirmatory evidence may be required to approve the product if the associated treatment needs have been well addressed.
Maintaining communication is key to working with regulatory authorities to advance clinical trials
Dr. Gang Chen:
There are more and more strategies to apply in the United States or European Union and then use bridging trials in China or Japan, and MRCT (Multi-Regional Clinical Trial) has become increasingly inevitable as trends develop. ICH E17 and E5 have given clear guidelines on what kind of trial results can be accepted by regulatory authorities worldwide.
E5 points out that local first, for example, after the completion of European and American trials, local has to be found in Japan and China to make up for it. E17 requires that MRCT must meet certain conditions, and the recent ODAC meeting is also commenting on a problem of the single patient population.
So to move towards internationalization, we must be very familiar with ICH related guidelines and regulations.
Dr. Kun He:
Now to seek application in the FDA, the previous standards must not work, however it is not to say that they are getting stricter or tighter, but rather that we will unify the standards, considering the diversity of MRCT, and also understanding the local market situation, the scope of indications, and whether the clinical need is urgent, so as to make a comprehensive judgment.
For sponsors, we must value the opportunity to communicate with regulatory authorities, actively prepare to understand in advance the issues that regulatory authorities may care about, and the views we want to express and the issues we want to consult.
Dr. Bei Hu:
Now the globalization of innovative drugs is also a trend, and Chinese pharmaceutical enterprises will also go global in the future and face communication with reviewers of European and American regulatory authorities. In the face of regulatory authorities, the issues should be noted that whether it is product project approval, R&D strategy or protocol design, the sponsor should pay great attention to providing evidence and provide the basis for data selection from different dimensions. Only in this way can we improve the efficiency of communication. In addition, we should be particularly familiar with the regulatory authorities we communicate with, the general requirements for drug R&D in the corresponding therapeutic fields, or some general standards; thirdly, we should also be familiar with the specific requirements for similar products by regulatory authorities, so we should attach great importance to the collection and concreteness of data and evidence.
Mr. Jigang Li:
The CDE has intensively issued many guidelines in the past two years, 71 in the year before last and 87 in the last year. These guidelines are important references for project approval, including design. Therefore, clinical studies should start with the end in mind, and the whole registration pathways for a long time should be considered in phase 1 clinical trials.
Squeezing the value of every data is to reduce the cost and improve the efficiency
Mr. Tao Wang:
From the perspective of clinical operations, there are two main levels to reduce the cost and improve the efficiency, and all costs of clinical operations are divided into direct costs and indirect costs. The direct cost is actually very simple, and everyone can see that it is that we want to conduct a clinical trial, we need all the costs of labor, hospitals, suppliers and investigational drugs in all aspects. To improve the efficiency and reduce the cost of direct cost, on the one hand, it depends on more reasonable and scientific clinical design, such as sample size and follow-up arrangement. The second level is the implementation level of clinical operations. Bring higher efficiency from the implementation level of clinical operations.
Implicit costs, such as the speed of research which determines market share and the potential quality issues which determine the success or failure of research, are difficult to directly measure, and require empirical estimation.
At the same time, we should also objectively recognize that whether direct costs or indirect costs, some of them are rigid costs, which are objective and unavoidable, and such costs also determine the quality and efficiency of clinical research.
Mr. Jigang Li:
The product strategy is very important in reducing the cost and improving the efficiency, relying on scientific top-level design, avoiding competition, shortening cycle, controlling sample size, improving progress, and also meeting patients in terms of clinical needs.
At the same time, we should flexibly grasp the preferential policies of regulatory authorities, such as priority review, breakthrough, exemption from clinical trials, accelerated approval and so on. Clinical trial design is not only a medical issue, but also a comprehensive effort of all departments and specialties.
Mr. Gang Chen:
Clinical trial efficiency should be understood from multiple perspectives. In a sense, cost control should be put to the last, the first thing to consider is efficiency, and the most important is to improve the probability of success of the trial, because the measurement of cost is based on the success rate and efficiency. Therefore, the most important mistake to avoid is the failure of clinical studies of effective drugs due to mistakes in the design process.
There are only two reasons for the failure of clinical trials, one is natural disasters and one is man-made disasters. Under the premises of translational medicine and precision medicine, even in natural disasters, nothing has been achieved is rare, it is still possible to find a precise and small range of population which obtains benefits. But for man-made disasters, inappropriate design leads to the failure of clinical trials, which is irreparable in all dimensions.
Dr. Bei Hu:
The success of clinical trials is actually the need to maximize the benefit-risk ratio for each patient participating in the study. Considering individual differences, achieving this is still complex and requires a clear interpretation of the variation between various parameters of the various populations and the variation in the relationship between parameters. It is to squeeze out the value contained in each data.
