Experiences and Challenges of Clinical Research in Traditional Medicines

Dennis Chang

(President, School of Science and Health, Western Sydney University; Asian Department of Research Cooperation and Partnership, NICM Institute of Health, Australia)

Good afternoon, everyone. I'd like to acknowledge DIA for the invitation. I will spend next 25 minutes to briefly talk about the research in Australia and complementary medicine (CM) there. Most importantly, I'd like to introduce a case that I was involved in the last 10 years, which was about developing a new herbal medicine for vascular dementia (VaD). I would actually highlight the issues in it as well as the experience and lessons.

Obviously, the acceptance of CM has grown very rapidly worldwide, especially in China and Australia. The acceptance of CM in Australia is probably the highest among western countries. There is also huge growth in CM acts. Actually, national registration of traditional Chinese medicine (TCM) doctors in Australia is the only way to achieve western country national registration of TCM practitioners. Interestingly, establishing the registration in Australia had been earlier than Chinese registration for TCM practitioners here, which happened in 2016, and we started in 2012, 4 years earlier than China.

Here is a process of new drug development, which is a very lengthy and expensive. Whether this process is suitable to be used in TCM development or not? I'll give you differences between TCM and single-target medicine, which are really what I try to address in my case later on. We have mentioned some gold standards in randomized controlled trials (RCT), and this is uniform that we actually accept worldwide. But there are some considerations intensely how to design the study, and how the study can be a tune-up to commutate for some unique features of TCM as well. So I am going to briefly talk about that. An example I am going to use is the one as saying at the beginning which is the development of a novel herbal formula for the treatment of VaD. This work was finished in collaboration with China Academy of Chinese Medical Sciences in Beijing. So, it doesn't mean I did it by myself. This is on the basis of a large amount of clinical development about Chinese herbs in Xiyuan Hospital.

VaD is a huge healthy problem, and we are concerning elderly population. More importantly, VaD is the second most common type of dementia out of all dementia cases, as no cure. We commonly have no pharmaceutical options for VaD. Doctors use anti-enzyme medicines for the control of dementia symptoms. But they haven't be able to prove any long term effects of this or safety of that. So that is why we target this. We talked to our Chinese partners about the opportunity for TCM, based on the area where there was lacking of pharmaceutical medicine options, or they were too expensive. This is exactly why we chose to work this VaD area in the last 10 years. So the herbal formula was called SLT, consisting of standardized extracts of 3 commonly used Chinese herbs, which I tend to call them herbs A, B and C. There are other Chinese herbs used in VaD, but the commercialization is not very prevalent now.

So this is actually a raw chart showing you how the pharmaceutical herbs form SLT and its process of development. Actually you can see that this is very similar to that I showed you previously. Except that, you can see that we actually engage a huge number of studies such as using distillation process and identifying the key active component from each herb. And then on those bases, we developed quality assurance mechanism. In fact, we had 10 different bioactive components, which were used to define the final product. So on that base, we started doing some preclinical studies, looking at its mechanism action, efficiency, and pharmacokinetic framework. We also did a curing clinical study to look at those in animals, and to look at toxicity for herbal medicines, before we move onto clinical study. We did 2 phase Ⅰ studies looking at inclusive and tolerant ability of that medicine in helpful volunteers. We also did 2 phase Ⅱ studies. The second one was just finished in China last year, and we did the first one in Australia 7 - 8 years ago. At the moment, we are in phase Ⅲ, including 2 studies: one in Australia, and one in China. The scale is bigger than the Australian one in the phase Ⅱ.

How did we optimize the trials, and how did we achieve the best ratio among those trials? We used some animal tests, looking at individual herbs. How actually they could improve the escape of damage, which was related to ischemia dementia. We identified the optimized ratio of herbs by responses of mice. Base on this study, we actually came up with a ratio of 20:20:4. We also came up with a very similar ratio of 15:15:3. That was how we get a termination - 5:5:1 (5 parts for herb A, 5 parts for herb B, and 1 part for herb C).

After we did that, we had to develop a quite vigorous quality-control mechanism. So basically, we quantified 10 biologically active components which is regulatory agency's requirement, even in China. Each herb has at least 1 biomarker with bioactivity, and we have identified 10 biomarkers as Quality Assurance (QA) markers. We also set the standard for contaminants like heavy metals and pesticides. That is how we develop formula and how we control the quality for the final products. We engaged series of animal studies. We also want to do clinical study to look at efficiency and mechanism of action of that herb formula. From the perspective of biology, we look at the testing behaviors and the genetic study in different animal models. And we evaluate if the efficacy as well as the mechanism of action of the final herbal formula product are suitable for human herbal products.

This table looks very simple, but we spent 3 years on it. The A, B and C herbs are summarized by this tablet. Basically you can see that each of the herbs in that herbal formula has different biological components. Here are therapeutic targets associated with excessive damage of VaD, such as calcium overload, energy depression, amino acid over lost, and oxidative stress, which all actually regulate cholinergic system and cell scaffolding. Actually you can see that individual components work on different targets, which is a true so called multi-component and multi-target approach. So on that base, that's how we design to do some safety studies.

We did one phase study with 4 months treatment in Australia. And then we proved that it worked clinically, and then we also did another large scale study in China with 325 dementia patients to further prove the efficacy we gained from the study in Australia. This is a scale that we used in Australia during the phase Ⅱ study. Actually you can see that the SLT significantly induced about 4 units of improvement and the placebo for 1 unit of improvement. The best index was 2.7 or 2.8 for other VaD drugs, and that of the SLT was quite higher. More interestingly, we also scanned 17 patients' brains, looking at how the blood flow being improved in the brain, because this was one of the mechanisms of action of the herbal formula. We can see that in the frontal lobe, the anterior cerebral region of the brain, there is improvement in blood flow, which is exactly the region responsible for memory or attention, and the function we target.

We also did a bigger study with longer intervention period in China. Here we had 2 study groups: one was the placebo, and one was high-dose herbal medicines. In this study, we gained a similar result as the one in Australia, which gave us a lot of confidence, both in clinical studies and clinical trials. Both 2 herbal trials proved the efficacy of SLT. Therefore, we designed 2 phase III trials. The phase III trial in China includes 600 to 700 patients at the moment. In Australia, resources are limited, so we have recruited about 250 patients, who are from 10 different hospitals, as well as regional centers, and we anticipate the trial to end in 2020.

We choose very rigorous diagnosis criteria of VaD. And we identify Alzheimer's disease (AD) and VaD, among which, we focus on solving problems for VaD.

We choose very standardized clinical indexes to measure the safety of this medicine. This is a very brief table, just showing you that we are doing baseline assessments (half-year and 12-month assessments) in safety to ensure it is ok, no side effects.

This is a very brief introduction for the development process of SLT, and next, I want to talk some issues that we identify. For example, the clinical research design, the No.1 issue we have discussed.

Then the regulatory and human requirements, they are challenges. And the cost of clinical trials is really a problem, and then the research teams and training. Recruitment is the most difficult challenge in trials. Strategies of it and retaining compliance are other issues.

Let's look at the clinical trial design. I bet that if you have experience in such clinical research, you probably have common approval review. When you look at the approval review on herbal medicines, you will see that it is often classic situation: there is preliminary evidence to suggest this herbal formula can have some effects. However, there are many methodological issues to those clinical trials, which is very classic. Almost 8 out of 10 are approval reviews on herbal medicines, which really highlight the issue in relation to methodology. For example, diagnostic criteria. We use very rigorous international regularized diagnostic criteria in our study. However, we also mentioned that there must be a diagnosis of pattern can be used in clinical trials. If we can use TCM diagnostic method as one of the diagnostic criteria or not? We also know some trials that people use the diagnostic criteria in their company, which is not fully accepted within the international society. The best situation I've seen in these years was applying very rigorous western medical diagnosis supplemented by TCM diagnosis. It's a challenge, because you have to visit TCM doctors, helping you to look at pulse and tone etc. to make TCM diagnosis. And treatment duration is another challenge, because often we find that many of the trials do not have enough intervention to draw some conclusions. It is very different in individual disease, for example, AD. People often spend 6 - 12 months for treatment. But the progress of VaD is slower. Therefore, it may take 12 months. We need to make sure that the intervention of this drug really affects the progression, and make sure you can feel the changes during the intervention. We have to consider that if combined medication is allowed or not, and what control group can we use. Sometimes, there is no control group. I see many of TCM trials using one TCM formula to compare with another TCM formula, which is a not correct design. You don't have a gold standard as a control group. The control group should use the gold standard or a placebo. You can't compare one herbal formula which is uncertain with another one which is also uncertain. That is a common problem that we find in many clinical trials.

Whether you use some recognized methods to measure outcomes or not? Some people use internal methods or some people even use TCM measures, which are fine. But we still have to find scientifically based parameters for diagnosis of pattern, and sample size.

Many regulators say that in phase Ⅰ trials, there should be at least 20 people; phase Ⅱ trials, 100; phase Ⅲ trials, 300. That is too arbitrary. In fact, a proper sample size is base on calculation, not just to say 20 or 300. So recognition is a big issue.

Next issue is relating to regulatory barriers, because we use patients in clinical trials, which are highly regulated areas. For example, the legal compliance and the guide issue for the caregivers to the sign informed consent for patients. Like dementia patients or pediatric patients, the process lasts very long. And you also expect the committee CRO to regular and monitor your drugs. The cost is a big issue. Over the last 30 to 40 years, the cost of clinical trials increased dramatically. Similarly, lots of herbal companies do not have ideas: how much they need to invest in this area, or they think simply that their size is not enough to support that. We went to different hospitals, to say to them, "this is a herbal trial and a preclinical study, and we need to collect data". Some of them were very interested in it. When they asked how much money to pay for the patient, we said 5,000 yuan. Then, they said, "sorry, we are interested, but 5,000 yuan is not even cover our labor cost", and they said their pharmaceutical trials needed 20,000 to 30,000 yuan per patient. The consequence of that is you have to choose a small center with less experience. And there are some problems, because they are not enough trained to do trials. You are worried about the quality of data collection and worried about whether they actually have fully complied with clinical trials, which is another issue on clinical trials.

For clinical trials, you really need people to help you, for each of those patients involved, and participants involved in the trials. You have to provide training programs such as Good Clinical Practice (GCP) training, protocol training, rate training, etc.

Basically, you can see that a range of potential issues affecting your recruitment. Over the years, we have developed some strategies to do with that. Simultaneously, we have this retaining compliance issue, because VaD is targeting at people over the age of 75, and many of our patients are 80 years old. So we have a huge problem with compliance, and the drop out rate is relatively high than expected. We have to face such issues, and then simultaneously, come up with the strategies.

The final slide is about a real life case study, demonstrating a novel and herbal intervention for the treatment of a serious disease. In the past, there was no pharmaceutical option for this disease. If we are successful in phase Ⅲ, we will go to register, and communicate with CFPA in China. It can really treat with a very serious disease. Clinical trials are facing many different challenges, requiring full collaboration between regulators and their patients, participants, caregivers and doctors. Thank you very much!