Abstract: Dialogue with Dr. Gang Chen, Chief Scientific Officer and Dr. Kun He, Chief Statistician at R&G.
Operating revenue was 326 million yuan, up 10.82% year-on-year; net profit attributable was 61,308,400 yuan, up 21.98% year-on-year — the first semiannual report handed over by R&G after listing on GEM, with a gratifying growth rate.
As a CRO, behind the rapid growth of R&G, it is inseparable from the dividends of continuous expansion of the biomedical industry in recent years. But it needs to be pointed out that what really sets it apart needs to return to its own differentiation. From 2019 to 2021, the total numbers of new drugs registered and applied by R&G for customers were 20, 26, and 20, respectively, and the success rate of the application remained at 100%. This somewhat proves the strength of the team.
According to Dr. Gang Chen, Chief Scientific Officer at R&G, Shenogen’s Icaritin project reflects the services level of our company. This innovative traditional Chinese medicine, which has been developed for more than a decade, once missed the approval almost.
In 2017, R&G took full charge of the design and implementation of the registered phase 3 project of Icaritin. In the clinical progress of the project for nearly one year, the R&G team believed that the efficacy results might be very different from assumptions through the interpretation of blinded efficacy data.
Chief Scientific Officer at R&G
"If the problem arises in the middle and late stages, most of the time it is quite powerless." Dr. Gang Chen explained. R&G communicated and discussed with CDE and clinical oncologists for several months to modify the original design protocol with innovative design ideas and methods in precision medicine, that is, considering the enriched design method of precision population, and finally the success of the trial was achieved. Earlier this year, Icaritin was conditionally approved by the NMPA for marketing and became the first innovative small molecule immunomodulator of traditional Chinese medicine.
There is no absolutely perfect clinical design, and it is important how to discover and solve the issues in the process, which is Dr. Gang Chen's opinion and the concept agreed by Dr. Kun He, chief statistician at R&G. To fully apply regulatory guidelines to address the issues, R&G applied “adaptive design" to more than 30 trials from 2019 to 2022.
The so-called "adaptive design" is simply understood as adjusting the subsequent protocol according to the data results obtained from the previous trial after the start of the trial, so as to increase the probability of success of the trial, accelerate clinical progress and reduce investment costs, without compromising the integrity of the trial and other benefits. However, "adaptive design" is not easy to do, and CDE did not issue the Guidelines for Adaptive Design of Drug Clinical Trials until May 2020. It is worth noting that the main authors of the guideline include Dr. Gang Chen and Dr. Kun He.
Another commonality of these two is that both have worked at the FDA for many years. This naturally raises R&G's starting point a bit higher. After returning to the Chinese industry, Dr. Kun He felt that the local clinical research environment changed greatly.
For example, the Guidelines for Clinical Value-Oriented Clinical Research and Development of Antineoplastic Drugs and the Technical Guidelines for the Applicability of Single-Arm Clinical Trials to Support the Marketing Application of Antineoplastic Drugs in the past two years have revealed the high level of clinical research requirements in China. However, not all CROs and pharmaceutical enterprises can keep up with the tide. Moreover, the setback of local innovative drugs going overseas also implies that there is still a gap between China's new drug industry and international level.
COVID-19 spread, regulations came out repeatedly, how should the clinical development of innovative drugs through the cycle? What experience and assistance can R&G provide as a "water seller" CRO? In this regard, the Tongxieyi conducted an in-depth dialogue with Dr. Gang Chen and Dr. Kun He from the perspective of the industry.
01 Escalating clinical development environment
Tongxieyi: From a regulatory perspective, is the current requirements for clinical trials mature and stable enough? Is there any possibility that some original clinical trial designs may lag behind regulatory requirements due to the introduction of new regulations?
Dr. Kun He:
Regulatory requirements for clinical trials have changed dramatically over the past 20 years. A new approach has just come out, is not familiar to everyone and may not be so easily accepted. After a period of time, it is confirmed that the new approach can solve the new problem, and at the same time it is methodologically feasible, and everyone slowly starts to accept it in practice. Since there are methodological changes, there should be corresponding regulations to standardize, such as adaptive design guidelines. The traditional design is relatively mature, but by no means enough, it is difficult to predict when new problems and new design methods will appear.
For example, recently, FDA is promoting the popularization of real-world data and real-world evidence. In terms of statistics, regulations or data quality, although there are still many problems, everyone is slowly accepting. For rare diseases, the same problems will be encountered, and the FDA is promoting balance in this field. Each new approach that emerges leads to regulatory authorities making appropriate regulatory policy adjustments.
Validated traditional approaches will not fade, but new approaches will continue to emerge as the times develop. All criteria are the same from the cornerstone, so don't worry too much. The change always exist, it is a gradual process. Looking back at once, there were a lot of changes during the past 20 years, but the change is not so fast in every year compared with that in the previous year.
Tongxieyi: What has been the biggest change in clinical trials over the past 20 years?
Dr. Kun He:
In terms of tumors alone, the biggest change is in precision medicine. Lung cancer has not been particularly well characterized 20 years ago, and a trial covers many cancer types. So at that time, it was very difficult to develop innovative drugs, and a drug could not have an effect on all patients and all cancer types.
Given the peculiarity of cancer diseases, almost all new designs have aroused from cancer trials. More representative new approaches, including the Master Protocol, various enriched designs (part of precision medicine) based on biomarker, and many adaptive designs. These new approaches have also been gradually recognized and widely used by us.
Dr. Gang Chen:
In 2019, FDA issued the Adequate Evidence Guidelines. I think new regulations around adequate evidence will continue to emerge. New drug R&D itself is based on evidence-based science, which is simply to search for evidence. Can the evidence be found? Is the evidence found reliable? These are all problems. Developing drugs is not pure science, but a comprehensive issue, and we always find a balance.
FDA identifies itself as a science based administration organization. Science is the foundation, so science must be combined with specific situations of policy and society. But at different times, the proportion of each part will vary. For example, in the 1990s, regulatory authorities strictly reviewed adaptive design, non-inferiority design and other design methods, which were conservative at that time, worrying that such a design will lead to increased probability of destroying the integrity of trial data and false positives. After 2010, new regulatory guidelines have been issued successively to allow some innovative trial designs. It is not to say that the policy environment has become loose, but that there is a further balance between regulatory policies, science and practice.
New regulations will continue to be issued, especially in innovative clinical practice. There are two points about innovation, one is breakthrough innovation in a real scientific sense; the other is breakthrough innovation in regulatory policies. It is better understood scientifically, and the key is that trials should have strong scientific significance. Regulatory innovation and breakthroughs pose risks that are alternative and difficult to be controlled; regulatory innovation is not easy, and FDA has been making a variety of attempts for many years.
I am impressed by the two guidelines of Master Protocols and Cohort Expansion issued by FDA. The former includes basket design, umbrella design, platform design, etc.; the latter breaks the boundary of clinical phase 1, 2 and 3. There are many loopholes in relevant problems from a rigorous and scientific perspective, it is of great significance for breakthroughs and innovations at the regulatory level.
Tongxieyi: how to view the relationship between regulatory breakthroughs and practical breakthroughs in new drug R&D? How to interact between the two to make regulations change continuously and bring breakthroughs in drug innovation?
Dr. Kun He:
Based on my experience in FDA review, these are driven from the enterprise first. Enterprises always try new approaches when encountering new problems that cannot be solved, and regulatory authorities may not accept them at the beginning, but if the approaches are confirmed to have no major problems and are very necessary, they are recognized by academia and business in various professional conferences, more and more such projects are submitted to regulatory authorities, and regulatory authorities will also consider including them in regulations, after all, FDA does not directly conduct clinical trials.
Of course, with regard to innovation point, enterprises will discuss it with the FDA and get approval before they do it. FDA also frequently invites experts from all walks of life to hold meetings to discuss their concerns and approaches. All kinds of academic conferences have this special topic of speech, which is discussed much and may eventually form some form of consensus. FDA also allows enterprises to try and see the results of clinical trials first to accumulate experience, and through these steps, a new approach is slowly accepted and included in regulatory guidelines.
Dr. Gang Chen:
In the field of new drug R&D in the United States, regulatory authorities and enterprises are relatively more professional and experienced, and there is a regular communication mechanism between them, such as the working group of enterprises (Pharma) in conjunction with the FDA, which can help enterprises to normalize communication with the FDA. This mechanism also plays an important role in the generation of new guidelines and regulations.
In China, we may not have enough expertise and experience in the field of new drug R&D. Although there are many local innovative pharmaceutical enterprises in China, they are just beginning compared with these large "century-old enterprises" in the United States. Now China has joined the ICH, and a process of effort is also required to understand the ICH guidelines and see whether they can be fully implemented in the field of new drug R&D.
Tongxieyi: From the perspective of clinical trials, has there been a substantial change in China's integration with international standards after joining ICH?
Dr. Gang Chen:
The requirements are stricter and more standardized. The change is still substantial after joining ICH. For example, in terms of the implementation of the ICH E9 (R1) guideline, it leads to great changes in the design of the clinical trial protocol, and it can be said that even the writing of the traditional protocol has changed.
Previously, a clinical protocol was designed, as long as the major elements of population, endpoints, treatment regimens, and analytical methods were considered separately. But after we started implementing ICH E9 (R1), all protocols had to carefully define the estimation target. The estimation target is a complex containing 5 major elements. In addition to the 4 elements mentioned above, concomitant events were added. For example, in clinical trials, a treatment regimen was originally determined, but other treatment regimens were used in the process, which is a concomitant event. As to how to handle the concomitant events, several handling strategies given in the guidelines should be carefully applied according to the trial design. This is an example of ICH having a substantial impact on the design and implementation of clinical trials.
The other is ICH E17, in short which focuses on how to meet the design requirements of MRCT with global synchronous R&D requirements for new drugs, what MRCT design and results can be recognized by global regulatory authorities and others. In the case of Innovent's Sintilimab, FDA questioned the NDA almost in all five aspects: population, endpoints, control group selection, data quality, and ICH E5/E17 guideline requirements. ICH E17 is an important guideline for the simultaneous development of clinical trials worldwide, and if new drugs are going overseas in the future, MRCTs must be rigorously designed and performed in accordance with ICH E17, so that different regulatory authorities can accept the obtained trial results.
02 What barriers do new drugs need to cross when they go overseas?
Tongxieyi: At present, more and more enterprises are doing applications in both China and the United States. What are the main differences in the requirements for clinical trials between the regulations of the two countries? What problems will arise during the actual implementation?
Dr. Kun He:
CDE and FDA have many similarities in regulations. Theoretically, the trial can be conducted without FDA approval for IND, FDA will accept NDA/BLA submissions, and I have previously received such application at FDA. However, in this stage, once the FDA has concerns or important requirements for the trial, enterprises may not be able to respond, as was the case with Innovent's application for the lung cancer indication.
In my opinion, the most appropriate approach is to communicate with both Chinese and American regulatory authorities in the IND stage when performing MRCT for the same product. In fact, whether these are applications in two-country, applications in three-country or applications in four-country, it is necessary to solicit the opinions of various regulatory authorities before applying to see what requirements are available. Enterprises try to meet them and give explanations when they cannot meet them. Regulatory authorities do not arbitrarily ask for requirements, all for reasons, because in many cases, regulatory authorities deal with more trials than enterprises, and thus know more, enterprises do not know the circumstances behind some requirements.
If enterprises want to do applications in both China and the United States, they have to be prepared for applications at the beginning to follow the requirements of various regulatory authorities. Unless enterprises feel particularly confident that their products will certainly be approved by regulatory authorities, it is another matter. Even so, communication is the best strategy at the beginning.
Dr. Gang Chen:
If you want applications in both China and the United States be successful, one thing is to understand the regulatory application process. You may not be familiar with the FDA registration application process and fear will arise if you do not understand it. This part is not difficult to be solved, just need to ask a company that understands the process to complete it.
The key lies in the difference in details, such as EMA, CDE, PMDA and FDA. Although the five principles mentioned earlier have little difference among regulatory authorities under the framework of ICH, there will be some differences in details. Because of this, enterprises must communicate frequently and adequately with regulatory authorities about the trial design and then conduct the trial after obtaining agreement. So in a sense, good communication with regulatory authorities is an important part of the success of the trial.
Tongxieyi: FDA requires two phase 3 trials for many clinical trials, which is not required by China CDE. Is this a big difference?
Dr. Gang Chen:
FDA's requirements of two phase 3 clinical trials are part of the guideline issued in 2019. As far as I understand, China CDE will eventually issue similar guideline on adequate evidence.
What is adequate evidence? The first is the "quality" of evidence and the second is the "quantity" of evidence. The “two phase 3 trials” is depicted from a "quantity" perspective. In general, two phase 3 clinical trials are required to support registration, while for diseases like tumors, only one phase 3 trial is required in most cases. In other words, when there is urgent clinical need, critical illness, very clear drug mechanism, or the results of a clinical trial are particularly significant, so that ethical problems will arise when a second trial is conducted, only a phase 3 trial is required to support clinical registration.
From a "quality" perspective, there are clear requirements in FDA's guideline for prospectiveness, rigorousness, type I error control and others of trial design. For China CDE, it is not necessary to follow FDA guideline completely, but it has a good reference significance. Several major regulatory authorities, including CDE, have almost identical requirements for clinical evidence for registration trials.
Dr. Kun He:
FDA's guideline serves only as a guide, and every specific clinical trial can be discussed with FDA, which is relatively flexible. For example, I approved clinical trials with p > 0.05 in FDA. In addition to oncology, FDA has also approved many marketing applications based on only one trial.
Tongxieyi: For the active comparator, the SOC varies from country to country and will this lead to different clinical results when conducting clinical trials?
Dr. Kun He:
To quote, Substantial evidence of safety and effectiveness. Substantial evidence suggests that it is better than placebo, but in practice, the trial is not completed with placebo. If a drug is approved on the market, although the FDA does not require a new drug to be compared with an approved drug, in fact, trials on many diseases cannot be conducted without comparing with an approved drug because doctors are reluctant to use placebo when recruiting patients because this is not responsible for the patient and ethical issues may also arise. The Declaration of Helsinki states that patients are to receive the best treatment.
If a competitor product is approved in the United States, some pharmaceutical enterprises will conduct trials in countries where it has not yet been approved, and the results will also be accepted by the FDA, but with some explanation. This cannot be said to be exploiting loopholes, and the FDA will approve the trial depending on the circumstances. In this way, pharmaceutical enterprises can complete the trial as soon as possible, otherwise, if your drug is not better than competitor products, it will be difficult to do it subsequently. Regulatory authorities do not require that new drugs be better than all drugs on the market when conducting clinical trials, but have unique value.
Tongxieyi: In the case of COVID-19, valid clinical data from previously enrolled patients may not be available because of containment issues. How to deal with this situation?
Dr. Gang Chen:
Firstly, what can be done is "decentralization", which dynamically adjusts the clinical site with the enterprise. Secondly, do some reasonable processing of the data. In the case of tumors, when patients are enrolled, they cannot visit due to the COVID-19, and statistical methods can be used to minimize the deviation caused by incomplete data in terms of technology; of course, no matter what method they participate in, enterprises need to fully communicate with the CDE.
03 Water seller: Value boxout of CRO
Tongxieyi: Do most enterprises have foresight or hindsight about changes in regulations? What kind of help can a CRO provide?
Dr. Gang Chen:
Unfortunately, there are many enterprises that have neither foresight nor hindsight, and they may be more unconscious. Due to various reasons, many enterprises set up a "simple" team with a few chemists, biologists, and investors, and then start to carry out clinical trials. Another is the transformation of traditional enterprises, such as those that have previously developed generic drugs, whose thinking may still stay 20 or 30 years ago. There are, but not many, enterprises that have foresight and can keep up. This depends on the quality of the team, who needs to have a comprehensive understanding of clinical trials and regulations from professional and regulatory policy perspectives.
As to what kind of help a CRO can provide, it depends on what stage has the problem. If it is only in its infancy, everything comes from scratch, the cost is not great; and if the problem arises in the middle and late stages, most of the time it is quite powerless. In today's regulatory context, trial designs must be prospective and rigorous. Without prospectiveness, it's useless to look for a bright point later. The design is full of loopholes and cannot be repaired in the later stage.
At the macro level, we should have a comprehensive and profound understanding of regulatory policies and consider strategies and designs under the framework of existing national regulatory policies. In the early stage of the trial, from the perspective of the whole R&D strategy, CRO can make some suggestions according to the particularity of the product; of course, CRO needs to consider from the perspective of enterprises how to design the trial to improve efficiency, improve the probability of success, ensure quality and reduce costs.
However, what we often see is that enterprises overemphasize costs (the lowest bidder wins the bid) and ignore the most important parts of efficiency and quality. The most critical thing for new drug R&D is to study new drugs.
Tongxieyi: what is the core of R&G?
Dr. Gang Chen:
R&G is a first-class CRO providing all-round services based on scientificity and professionalism for drug R&D enterprises in China. We currently have nearly 2,000 employees and rank first echelon in the country. Professional teams follow each link in drug R&D.
In line with the purpose of improving the success rate of drug R&D, shortening the R&D cycle and reducing R&D costs, R&G makes full use of our rich experience and professional knowledge in the field of new drug R&D from a scientific perspective to provide scientific, effective and executable strategies and top-level design for new drug R&D for enterprises.
Of course, although the top-level design of clinical strategies is very important, trials will fail if the quality of implementation is problematic no matter how well the strategy is and how cleverly it is designed. How quality and processes are controlled in each stage of clinical R&D is also critical. In terms of the understanding of processes and regulations, R&G is very professional, and we and enterprises have a common goal, that is, we hope to finally make the project successful and push new drugs to the market as soon as possible.
New drug R&D is a system engineering, which can only be accomplished by working together of seven or eight specialties. Each specialty plays an important role in new drug R&D and is indispensable. The importance of different specialties may vary in different stages, for example, in the preclinical stage, pharmacology, toxicology, chemistry specialties are more important, and in the clinical trial stage, the medicine and statistics specialties are decisive. Different projects may have different requirements for various specialties.
Tongxieyi: What are the typical cases that represent R&G?
Dr. Gang Chen:
In 2017, after the end of the phase 2 trial of Icaritin, the customer outsourced all registered phase 3 clinical trials to R&G. After taking over the project, I joked that I became the key person in charge of the project at their company, I would follow up the progress of the entire project, and I attended each important meeting. This is really important, and the initial design of a project may not be sufficient, and problems found during the conduct of the trial need to be solved in a timely manner. If the project is designed, do it silently for three years, just wait for the results, this will have problems.
One year after the Icaritin trial was conducted, the efficacy hypothesis population at the time of design was found to be potentially problematic based on blinded data analysis. In order to solve this problem, we have fully communicated with investigators and regulatory authorities, revised the protocol and added an enriched population. Finally, the results showed no difference in efficacy between the test group and the control group in the whole population group, but Icaritin was significantly effective in the enriched population. Based on this result, Icaritin was conditionally approved by the NMPA.
The challenge for us in this project was twofold. The first challenge was how to conduct it with quality and quantity based on the original design according to the requirements of the project, which required the efforts of the entire team. Because this project was a traditional Chinese medicine project, it was challenging from enrollment. The second challenge was that although we hope to make the whole population successful, how can we reasonably modify the protocol according to the regulatory guidelines to make the protocol design more reasonable and adequate during the course of the trial? Adequate communication with regulatory authorities is critical.
There is no perfect phase 3 design, it is only possible to identify problems and actively address them during the course of the trial. To solve the problem, it is necessary to start from two aspects: one is to fully understand and apply the innovation guidelines; the other is to communicate with the regulatory authorities, and the two sides should reach an agreement before protocol modification and subsequent trials can be carried out. Of course, there may be risks in the process, and it is necessary to consider the risks in advance that may be encountered and take the means of risk control.
Dr. Kun He:
I share some interesting cases.
In 2019, we took over a consultation and programming case where a phase 3 trial was ongoing, being recommended by the DMC to change from superiority to non-inferiority, but non-inferiority was unsuccessful. FDA's pre-BLA meeting initially had a very negative opinion and the hope of approval was slim. At our suggestion, the pharmaceutical enterprise re-analyzed the data from this phase 3 trial according to completely different ideas and gave completely different interpretations, and finally successfully persuaded the FDA to approve the drug.
In 2020, we took over a design of drug for the COVID-19. At that time, the FDA received hundreds of INDs, and other divisions helped review them. FDA requested in the IND response that pharmaceutical enterprises must conduct an independent phase 2 trial before conducting a phase 3 trial. This has a great impact on small pharmaceutical enterprises in terms of both fund and time. We made some modifications to the submitted phase 3 protocol and presented rationales in a entire page to discuss why the submitted phase 3 protocol could be exempted from independent phase 2 trial, ultimately persuaded the FDA. Because the enterprise omitted additional phase 2 trial, had completed the phase 3 trial quickly, outperformed other competitors in time, and was immediately successfully acquired by another large pharmaceutical enterprise for more than 400 million yuan.
We also took over a consultation case about biosimilar to Avastin to NSCLC. When the regulations on biosimilar were just issued, I was responsible for all trials of biosimilar to Avastin to NSCLC. FDA also has no experience in this field, and protocols submitted by more than a dozen pharmaceutical enterprises differ in the choice of cut-off value and sample size. At that time, John Jenkins, director of the FDA Office of New Drugs, was also responsible for biosimilar, and he asked us to develop a rule so that we published in the form of an article, and the FDA later asked all pharmaceutical enterprises to study our article and adopt the same rule.
FDA has never previously approved similar trials with sample sizes less than 600, which was a quarter smaller in this trial. When receiving this case, the first response was to think of an idiom, that is, refute sb. with his own way. After carefully reviewing the trial in all its aspects, many reasons were used to successfully persuade the FDA. Of course, they are all my former FDA colleagues in charge of these jobs, but they do not know that I am helping pharmaceutical enterprises. FDA agreed to submit a BLA, and a robust programming team at R&G was responsible for BLA programming.
In summary, the requirements did not actually change when designing and consulting. What is considered at FDA is what aspects of a submitted IND or NDA/BLA are likely to be problematic. What is considered is how to avoid these problems or dispel FDA's concerns when designing and consulting from a enterprise perspective. The problems are the same, see which aspect is the focus. However, the problems are best avoided in the design stage, and it is generally difficult to remedy them after the end of the trial, which should be particularly paid attention to and noticed by pharmaceutical enterprises.
