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The Road Less Travelled – Navigation through the do’s and don’ts of running Oncology studies in Asia Pacific
Alek Safarian: Good morning everybody and welcome to this session on The Road Less Travelled – Navigating through the do’s and don’t of running oncology trials in Asia Pacific. Our speaker today is Julie Gargano. Julie has worked in the pharmaceutical and clinical trial industries for almost 20 years. She began her career as a research assistant in molecular biology and then spent several years working in diagnostic haematology laboratories before transitioning into Clinical Research as a trial coordinator, initially, within the haematology and oncology areas.
Julie joined the pharmaceutical industry in 1994 with Aventis Pharma, at the time Rhone-Poulenc Rorer. She’s held various positions of increasing responsibility, starting from … as a CRA to acting Clinical Research Manager. She has been responsible for the development of a local and international Phase III trial and project management of Phase I-III trials in haematology, CNS, cardiovascular and oncology indications.
Julie has been with Novotech since 2001, working in positions of increasing seniority from Senior Project Manager to her current role as Therapeutic Area Director for Oncology. The role provides sponsors with Julie’s extensive oncology and clinical research experience. It contributes to the development of oncology protocols. Julie also supports Novotech project managers for oncology projects across the Asia Pacific, particularly in selecting and managing high performing sites and meeting recruitment and data quality objectives.
With that, it’s my pleasure to pass you on to Julie.
Julie Gargano: Thank you, Alek. Firstly, I’d like to you and thank you all for joining in on this presentation of this today. We Aussie’s usually say, “G’day,” but right now it’s around 1:00am in the morning and it seems a bit strange to be saying this.
My presentation today will review the running of clinical trials in Asia Pacific, with a focus on oncology trials. To some study sponsors, this may be a familiar path, but it appears that many sponsors are yet to venture into the region. I hope that by the end of this presentation, I will have provided you with a better understanding of the clinical trial process in Asia Pacific.
During my presentation today, I will provide a brief outline of Novotech and I’ll then provide an overview of the Asia Pacific region and focus on the regulatory and operational considerations, which are vital in making your trial a success.
Novotech is Australia’s largest-full service CRO, it operates out of 15 locations in eight countries. It’s a full-service CRO, providing assistance from first-in-man studies right through to Phase IV studies. We, we have numerous departments providing services such as regulatory, biometrics and statistics, clinical trial services as well as providing independent quality assurance services.
Novotech has vast experience in working on global studies under a variety of operating models. The therapeutic areas that Novotech is … has and is working on covers a vast majority of the areas, but in particular, Novotech clinical trial areas have focussed on oncology and haematology, and this group of trials comprise up to 30% of our project load. And this appears to be a reasonable reflection that a large percentage of oncology trials are being run in Asia Pacific.
Our project experience covers all phases of clinical trials, with an emphasis on earlier phase trials. Phase I and II trials comprise more than 50% of our workload. Phase I also includes our first-in-man trials. Our other major component is Phase III and as you can appreciate, the huge populations from Asia are an excellent recruitment advantage for large clinical trials.
Novotech’s coverage includes the following countries: Australia, India, Malaysia, New Zealand, Singapore, South Korea, Taiwan and Thailand. When reviewing Asia Pacific, I’ll focus on these countries, as I believe I can provide you with some good first-hand experience.
In more recent times, we are seeing a number of changes to the global clinical trial environment. We are seeing that the trials being developed are larger trials, which require a greater number of patients. The complexity of trials is increasing, with requirements such as biomarkers, central laboratory tests, molecular essays, complex PK assessments are all becoming part of trial assessments.
In order for trials to be competitive, they must be run faster, leading to more aggressive study timelines. The number of clinical trials is also increasing. The western trial sites are often saturated with large numbers of clinical trials, leading to poor recruitment and extended study timelines. The cost of running trials in centres is also rising and there is a need to identify more cost effective sites, which can deliver good quality data.
Historically, most first-in-man and early phase trials have been run in the US and Europe. Due to the competitive environment and delays in regulatory approvals, companies are looking at other countries to run these studies. I believe a number of these trends have assisted in the growth of clinical trials in Asia Pacific.
And at this stage I think it might be a good opportunity to just include a few questions to gauge the audience’s experience in trials in Asia Pacific.
Alek Safarian: Thank you, Julie. So the first question we have is: Have you previously or are currently run clinical trials in the Asia Pacific? If you can click on Yes or No there.
And moving onto the results.
And the next question: If you have run or are currently running clinical trials in Asia Pacific, what phase were they; first-in-man, Phase I, Phase II, Phase III or Phase IV?
And if we can move onto the results please.
Thank you. And the last question: Were these trials run as marketing studies for local registration or FDA studies as part of a global development effort? So if you can just put Marketing or Development. Thank you.
And moving onto the results now. Good. Thank you very much. And we’ll go back to the slides.
Julie Gargano: Thank you Alek.
Clinical trial activity in Asia Pacific has exponentially increased. It is estimated almost 2,000 trials are being run in South Korea, 1,700 in Taiwan and 1,300 in India. This growth is due to a number of key drivers, some of which I’ve reviewed in my previous slide. All of these factors now make Asia Pacific an integral part of global drug development.
Some additional key factors, which have influenced the growth of clinical trials in Asia Pacific, include Asian markets becoming powerhouse markets. Running clinical trials in these regions can provide the opportunity to penetrate some of the fastest growing pharmaceutical markets in the world.
Cross considerations are key factors in any clinical trial program. Cost savings from Asia Pacific is substantial, resulting from a combination of the following factors: investigator and site fees are approximately half of those in the US, so the cost to the sponsor for providing trial related medication, investigations and hospitalisation could be low as 30% of those in America; domestic travel costs for monitoring sites are lower because of the concentration of sites in major cities; the cost of labour is less but it is very important to ensure that sufficient investments are made in the training and support systems of staff to ensure data quality.
With more than four billion people, Asia offers sponsors a deep pool from which to draw clinical trial participants. Competition for clinical trial participants in some Asia Pacific countries is increasing, for example, Australia and China. But countries such as South Korea, Taiwan, may offer less competition.
The regulatory bodies in Asia Pacific are evolving their processes to ensure the clinical trial environment is becoming more supportive for sponsors. For example, South Korea, Taiwan and Singapore have adopted an FDA flavour to their practices. Australia is working towards a national ethics application, which will remove the need to submit individual ethics committees.
The local pharmaceutical industry in Asia has historically been dominated by generic pharmaceutical companies. Not surprisingly, innovate Pharma has concerns about the protection of their intellectual property. Investigational products, protection legislation is evolving as a result of international pressures as well as domestic economic development. For example, India is a country that is embracing IP protection legislation, enlisting numerous changes to their legislation. Singapore has been ranked as the top Asian country for strong IP protection and legal enforcement.
Clinical trial data from all Asia Pacific countries has now been accepted by international regulatory authorities with pivotal studies. FDA has audited hospitals in Taipei, Hong Kong, India, Australia, with no major findings.
Asia Pacific has an availability of numerous hospitals well suited to serve as investigative sites.
The vast majority of speciality care in Asia is provided by state funded general hospitals. The university teaching hospitals have state of the art facilities and technologies for thousands of inpatient beds to provide diagnostic, therapeutic and supportive services. It is these types of sites the majority of clinical research in Asia Pacific is conducted.
For example, Tata Memorial Hospital in Mumbai, India, is a speciality oncology centre that is well suited to participate in global clinical development. Each year, 25,000 cancer patients visit the hospital. Each day, 1,000 patients attend outpatient clinics and there are 441 inpatient beds. Over 5,000 radiotherapy and chemotherapy treatments are delivered each year. The centre is equipped with state of the art facilities, included … including spiral CT scanners and bone marrow transplant facilities.
Most of the region’s leading specialists have received postgraduate training from the US or UK and as such, the standard of care in Asia Pacific is often similar to that in the western world. In particular, breast cancer, lung cancer treatments, as well as numerous other oncology treatment practices, are all very similar.
In the next few slides, I just wanted to focus on some of the key areas that I’ve listed previously. This slide reviews the populations of the various countries. And as you can see, the inclusion of some or all of these countries could significantly increase the patient pool for your clinical trial.
This next slide outlines the ageing population of each country, as well as the average life expectancy. And as one would expect, the more developed countries have a longer life expectancy.
Looking at new studies in Asia Pacific, this graph on the screen reviews the number of studies that have been initiated in 2006 and 2009 in all therapeutic indications. You can easily see the growth in the number of trials over the three-year period and this growth has continued.
Looking specifically at oncology indications, as I highlighted from the breakdown of Novotech’s clinical trials, this graph reflects the large number of oncology studies ongoing and planned in Asia. Some of the most common trial indications include non-small cell lung cancer, hepatocellular carcinoma, colorectal carcinoma, breast and gastric carcinoma.
Specifically looking at the ongoing oncology trials in Asia, we can see that the majority of the trials that are ongoing are in fact Phase II studies and these make up more than 50% of all oncology trials.
A key driver for the popularity of running trials in Asia Pacific is the cost benefit. This table outlines a comparison of the average trial fee from South Korea, Australia, US, Taiwan and India. One can easily see the cost benefits of including sites from Asia Pacific.
Even for drug developers with established clinical trial sites in Asia, expanding from one country to the next can pose challenges. Selecting the optimal Asia Pacific country in which to expand a clinical trial depends on unique goals and priorities of each sponsor, as well as the indication and type of treatment being developed. This is why many companies, from biotech start-ups to large Pharma players, engage experienced CRO partners with in-depth knowledge of the Asian landscape.
Some of the key considerations include different government and regulatory processes, the varying medical practice standards, shortage of experienced staff and cultural variability, both intra and inter-country.
These Asian Pacific countries are a melting pot of different ethnic groups and cultures. The variety in ethnic group may be beneficial from a data perspective but it is imperative that each country’s cultural requirements are respected and followed. This is one of the reasons why key factors to the success of a trial would be to utilise the knowledge of local clinical trial personnel in each country.
An example of this is that during the feasibility phase of the study, it is usual practice in western countries to make phone or email contact with potential investigators to obtain feasibility information. In countries such as South Korea, Taiwan and Singapore, investigators often will not respond to correspondence unless it is a face-to-face meeting. If a face-to-face meeting is not requested it can be regarded by the investigator as a sign of lack of respect. Unlike many western investigators, these investigators will make themselves available for a meeting at short notice. In countries like India, a high degree of patient respect for physicians can translate into high compliance and low dropout rates.
Perhaps one of the challenges of working in these countries with vast ethnic groups is the need to translate documents. Countries such as Korea, India, Taiwan, Thailand require translation of the complete dossier, which is submitted to their health authorities, whereas Malaysia and Singapore only require translation of patient information and consent forms, as well as patient diaries and patient information.
Language barriers can be easily overcome by CRO partners with offices across Asia. We all know how vitally important communication is in the success of a trial. When identifying the clinical research staff to run and manage your trial, staff with a command of English, as well as the local language, is priceless. This will ensure site staff and investigative staff are able to communicate easily. But just as importantly, you as a sponsor can communicate effectively.
PIs in the US and Europe have been running clinical trials for 40 plus years. But their counterparts in Asia have less experience. Sponsors should be prepared that Asian trial sites may need more assistance when it comes to following protocol and differentiating between medical practice and clinical research. Similarly, sponsors should note assume that all potential Asian trial sites will have the infrastructure needed for a clinical trial. A benefit for any sponsor is to have local expertise. Local expertise will help a sponsor worth with investigators to bring such sites what they need.
A major driver of success for a trial is identifying good trial sites. As with most countries, the ideal trial site profile in Asia Pacific can be described as a site that is usually a teaching hospital with a strong focus on research. These sites often have research units attached to the main hospital unit. To ensure good representation of patients are identified, a mix of both public and private institutions can also be beneficial. Ideally, we are looking for units with vast experience in oncology. The trial group needs to be well resourced with experienced staff available. Sites with known successful track records can ensure data quality and study requirements will be achieved.
It is always recommended that an in-depth feasibility assessment is tailored to each individual protocol to be undertaken. This should ideally include a targeted questionnaire, assessing site capabilities of recruitment potential, experience, interest in trial and understanding of the protocol.
Other items we should … which should be assessed include potential competing trials, previous experience and investigator commitments. As discussed previously, some investigators may require a face-to-face meeting to review and complete these questionnaires.
Countries throughout Asia Pacific are often well equipped to support clinical trials. Most countries have validated drug depots with the capabilities in managing logistics of distribution and tracking of study drug and study supplies. Working with local depots will ensure rapid turnaround of studies supplies.
I now just wanted to move onto the regulatory considerations for any clinical trial. And this is perhaps the most critical step when planning any program. The understanding of the regulatory requirements for each country really is vital. The study sponsor should consider their regulatory strategy in Asia Pacific as part of their overall business study, not as an afterthought. It’s a process that needs to be started early. A good planned strategy will help a sponsor deliver the data needed for approval, save money on registration and ensure effective reimbursement.
Working with experienced local representatives can assist in identifying the rate limiting steps and ensuring slower start-up countries are prioritised. If rate limiting steps are identified early in the process, potential delays can be avoided.
As you know, Asia Pacific includes a multitude of countries and for purposes of time, I’ll only review some of the key country regulatory requirements. This should hopefully provide you with a general understanding of what some of these requirements are. It will also highlight the differences between each country.
The ethics and regulatory process in Australia is a sequential process. Ethics submissions are made to either local or regional ethics committees and once ethic committee approval is received from individual ethics groups, the Australian Regulatory Authority and the Therapeutic Goods and Administration – or TGA – are notified of the trial. The trial is acknowledged by the TGA and study activation can occur.
Investigational product can be imported into Australia as soon as the first acknowledgement is received from the TGA. If this investigational product is of a biological origin, an additional AQIS permit is required. Application for this permit can be made concurrently during the ethics review process. The permit is usually obtained within two to three weeks and is not a rate limiting step. The usual start-up time is three to four months.
The ethics and regulatory process in New Zealand, on the other hand, is a parallel process. Study documentation is submitted to both the IRB and the regulatory authority, Medsafe. The regulatory authority guarantees review and comment within a maximum period of 45 working days. Usual ethics review time is up to eight weeks. Once regulatory approval is obtained, drug importation can be triggered. No specific importation permits are required once regulatory approval is received. And the usual start-up time for New Zealand is approximately three months.
Just a brief overview of Australia/New Zealand. The population comprises of approximately 25 million people, which are concentrated in seven major cities. As I mentioned, the ethics review process time is approximately two to three months and the process is well defined. We have a number of experienced sites that specialise in oncology and I believe we probably have up to 40 to 45 sites spread across the two countries and there is always a high level of interest from our investigators to work with new compounds and earlier phase trials.
The ethics and regulatory review process in South Korea is a parallel process. The process mirrors the US guidelines. Study documentation is submitted to both the local IRB and the Korean regulatory authority, the KFDA. Review and approval time for this step is around three to four months. Once KFDA approval is received, drug importation can occur. It is important to note that the regulatory and ethics submission documentation need to be translated into the local language. This process usually takes three to four weeks. To avoid any delays, this process can be commenced during the site identification process.
South Korea has a population of around 48 million people with more than 10 people located in the greater Seoul area. The ethics and review process is around three to four months and standards of medical care are comparable with those of the US and the UK. The ethics and regulatory process is well defined and transparent and, as I mentioned, there’s a need to translate into the Korean local language.
The regulatory submission process in Singapore is a parallel process to the ethics submissions. Casual approval time takes between two to three months and once approval is obtained from the Health Science Authority and the ethics groups, drug importation normally takes a maximum of ten days. Regulatory and ethics submitted documents are usually acceptable in English and only patient documents such as diaries, consent forms require translation into local languages.
The population of Singapore is around four and a half million people and English is widely spoken and used in business. The ethics and regulatory review process is around three months and again, the process and pathway is well established for clinical trials.
The regulatory and ethics submission process in Hong Kong is a sequential process. Documentation is submitted to the Cluster Ethics Committee for review and approval. This process usually takes four to six weeks. Once ethics approval is received, an application is made to the Department of Health for approval for an import licence. This process also takes up to six weeks in total. The approval time for Hong Kong can be up to four months.
The population of Hong Kong is around seven million people. As mentioned, the regulatory and ethics review and approval time is approximately four months and the … there is a high level of availability of experienced English speaking investigators.
The Taiwan regulatory and ethics approval process is also a parallel process. Study documentation is submitted to either joint IRBs or local IRBs and to the Department of Health. Review and approval by both groups usually takes up to four months. Once approval is obtained, import licence is available for the shipment of investigational product.
The population of Taiwan is approximately 23 million people. As mentioned, the review of ethics and regulatory process is approximately three to four months and there are a large number of teaching hospitals with vast experience in conducting clinical trials. Translation of documents are required and usually the patient’s information is translated into traditional Chinese language.
The ethics and regulatory review and approval process is India is a parallel process. Study documentation is submitted to both IRBs and the Indian Health Authority. Review and approval can be as fast as one to two months for Category A protocols and three to four months for Category B protocols.
We define Category A protocol as a protocol that has been previously approved by specified countries and some of these countries include the US and Australia. A Category B protocol is a protocol that has not been previously approved by one of these countries.
Drug importation can very much occur once regulatory approval is received.
The population of India, as we all know, is huge. There’s over 1.1 billion people. The ethics and review process can take up to four to five months, depending on what type of protocol is being reviewed. Including the country facilitates fast recruitment and potential low trial costs.
Numerous Indian sites have been audited by both FDA and all study sponsors. Even though there may be potentially a slightly longer approval time, it is definitely worth the wait. Once studies are initiated, recruitment often is extremely fast.
So in conclusion, in order to leverage the opportunities in Asia Pacific for timely, quality and cost effective clinical development, in a risk controlled fashion, the sponsor must have access to the following capabilities: knowledge of local regulatory processes, relationships with local physicians and medical centres, understanding of the requirements of international regulatory authorities and application of international standards to the local clinical research environment.
Sponsors should then be able to select countries in Asia Pacific best suited to meet their clinical development objectives with minimal risks. Sponsors who lack the above capabilities can access them with the assistance of CROs. Utilising resources from these local experts can remove the uncertainty and risk of the road ahead.
Thank you for your attention today. I hope you found this presentation helpful and I look forward to receiving your questions.
Alek Safarian: Thank you Julie. We will … thank you, Julie. We will now move onto the question and answer sessions. Julie is actually not available for the Q&A session so we will do that in conjunction with my colleague, Julia Jones. Julia, do we have any questions yet?
Julia Jones: Yes, we do. The first one is: What are the most common reasons sponsors approach Novotech to expand their oncology studies into Asia Pacific?
Alek Safarian: Great question. Well there’s a variety of reasons that we have been approached to run studies in Asia Pacific ourselves.
A lot of the studies that we do run or have run are in Phase II and III and typical reasons that people have considered their expanding their studies to our region has been either slow or poor recruitment in the original countries that they, that they initiated their trials in or projects where a global approach was taken from the get-go.
So, so usually they’ll be either a large start-up from the beginning or, or some kind of rescue strategy. And depending on the type of study and the needs of the … things like the start-up timelines in the various countries and patient availability has been the key reasons why, why people have come to, to our region, in our experience.
Julia Jones: The second question that we have is: How do you find the quality of data from some of the Asian countries?
Alek Safarian: Again, good question. What, what we’ve found ourselves, we … Novotech has been running studies in Asia for a little over three years now. And it’s clear that the region is coming up on the quality tree very, very rapidly. Our experience has been excellent in the studies that we’ve run. I’m thinking of a number of different oncology indications, in particular with sites in South Korea, Taiwan, Singapore and Malaysia, where the quality has been, has been very good.
Having said that, you do need to pick the sites very carefully and all the usual oversight and diligence and site selection processes that apply anywhere else are also paramount, of course, in Asia.
We’ve also seen that the quality of data coming from India has been improving very significantly in recent times. So that, that has been a very positive thing in, in our experience in Asia.
So all in all, the, the general quality, we found, has been, has been positive to very good and … but as I said, a big part of it has to do with having good local knowledge and oversight of the sites that are being used.
Julia Jones: Thank you. I don’t have any other questions yet.
Alek Safarian: I see a question has just come in on...
Julia Jones: Yes, I do. I’ve got a new question about whether we’ve got any experience in clinical trials in small countries like Sri Lanka.
Alek Safarian: Sri Lanka; we ourselves haven’t actually run studies in Sri Lanka as yet, so I can’t really speak for the regulatory or the research environment in that country as yet. But the general comment … Julie mentioned in her talk about six or seven of the larger countries that, that we have direct experience in. But what is also clear is that some other countries, such as Vietnam, Sri Lanka, Indonesia, are also all coming on line very rapidly. So I have no doubt that over the next sort of three to five years, we’ll hear a lot more about, about these countries as well. But unfortunately I can’t speak for Sri Lanka directly.
Okay, if there are no other questions, I’d like to thank everybody for your participation and questions and we will wrap up there. Thank you very much.