Stung by the spate of withdrawals in recent times, regulatory authorities are demanding more in-depth information about the molecules under investigation. The clinical trial process now reportedly consumes forty percent of drug development budgets. Cost of conducting clinical research in North America and Western Europe is steadily escalating. This is in part due to difficulties associated with subject recruitment and also due to complexities in the data generation process. (1)
In an effort to manage outgoings, companies are increasingly outsourcing clinical research to East European or Asian countries, where costs are significantly less. But outsourcing has its own challenges. The South East Asian region is considered here.
Tuft University scientists had predicted in 2007 that within a few years up to 65% of FDA regulated trials will be conducted outside US (2). Major portion of these will naturally migrate to Asia. Several Asian countries, like Singapore, Malaysia, Thailand, Indonesia, Philippines, led by India and China, have been considered for clinical research outsourcing. Majority of the outsourced research is phase III studies where large patient populations are targeted.
Why trials in Asia?
This region offers a genetically diverse population as large as 4 billion, often treatment-naïve. Recruitment is speedy and sample size targets are easily achieved. These countries often have a large affluent sub population that manifests lifestyle diseases common in western countries. India for example has a growing incidence of hypertension, heart disease, Alzheimer’s and degenerative orthopedic ailments. India is also called the diabetes capital, but that, more than the newly found affluence, is due to a genetic predisposition.
English is the business language in most of these countries and it is easy to recruit patients who understand enough to be able to respond to queries in various assessment scales. Many doctors have obtained all or part of their medical education abroad. They have been exposed to the clinical research culture and are interested in participating in research in their own countries. Lastly, although the proportions have decreased over the years, there is still a cost advantage in conducting studies in SE Asia.
Outsourcing of clinical trials has challenges of a different kind from the routine. Apart from the evolving regulatory systems, sponsors and CROs often find it difficult to handle cultural, ethical differences and paucity of infrastructure.
Regulations in most of these countries evolved over time. While about two decades ago, any international data was blindly accepted, over time, these countries began asking for bridging studies, bioequivalence studies etc. Multinational corporations reluctantly conducted the required local trials. With every study conducted, the clinical trial preparedness of the country improved and at the same time these companies started seeing an opportunity. The paraphernalia of ethics committees, CROs, labs grew around this and slowly these countries became trial destinations.
Governments too have realized the business potential of this activity and have tried to hasten the regulatory process. Most countries allow simultaneous submissions to the authorities and the Ethics Committees. The timeline for receiving trial permission is around 3 months. (3) There are some uncertainties in India but they should be addressed soon.
Even though English is the business language in most countries there are issues around translations. Translation requirements for regulatory and trial documents vary. While all countries ask for translation of the consent form into local languages, some also ask for translations of regulatory documents. In countries like India the consent form may have to be translated into multiple languages depending upon the spread of sites. Quality of the translation is a key element in such cases. (1)
Further, for a quick turnaround of the documents and for minimization of back and forth correspondence local personnel for follow up become essential.
Often standard of care issues have to be taken into consideration while finalizing the protocol, evaluation and statistical plan. Higher pain tolerance in Asia is a common example but let us take another. Let us see what the Eastern Asian Expert panel has opined on design of clinical trials on Hepatocellular Carcinoma (HCC) in the region.
There is variability in management practices both between Asia and the West and within Asia. Key differences are apparent in the etiology, diagnosis, staging, and treatment of HCC among countries. These differences complicate the conduct of international clinical trials. Asia has more HBV-related Ca than the West or Japan, where it is more HCV-related. In contrast to HCV, HBV reactivates with immune suppression. Consequently, treatment with antiviral drugs as concomitant medication is essential for best results. Hence, data needs to be stratified by HCC etiology, HBV or HCV. In China, local medicines are commonly used to delay cirrhosis or reduce ADRs of anticancer therapy. If used for the former, panel recommends that it be allowed.
Ca staging methods, therapies, and use of surgery differ within Asia, something that also has to be factored in the design. (4)
In spite of increasing number of trials being outsourced to this area, the support structure is still not optimal. There are insufficient numbers of trial sites. This is a very complex thought, since one is mentioning this against the background of many hospitals and teaching institutions. The problem here is the low doctor-patient ratio. Doctors are very busy providing service to the many patients; they do not have any inclination at the end of the day for research. So when we say “trial site”, we mean an institution with an enthusiastic, experienced investigator. A lack of well-trained investigators and trial coordinators, monitors and site managers is also a constraint. Accredited clinical labs and sample storage are still under development in some countries. (2)
A new development is presence of corporate hospitals catering to the affluent and the ‘healthcare tourism’. This brings forth subjects who are educated, can answer subjective scales well, and are from diverse ethnicities.
Availability of employable study monitors and other personnel is a challenge in most countries and companies have to invest in training and oversight of such candidates. (3)
Professional position, gender, age play a major role in Asian cultures. Physicians are highly respected and patient will depend on them to decide whether it is beneficial for him to enroll in a trial. Another practice is that physician explains details of a patients illness to close relatives and they play an important role in influencing the patient’s decision. All the above can affect the informed consent process. (1)
Pain tolerance in Asian population is high and so pain could be underreported. Herbal medicines are so commonly used that the patient may even forget to report them, a question that should not go unasked during history taking.
CROs commonly select centers based on telephonic interviews but it has been noted that investigators and key opinion leaders in Asia prefer face to face meetings. (3) It actually builds a relation of trust and helps in successful completion of the study.
Trial managers should understand and relate to the festival calendar of this region. They should expect fewer enrollments during Chinese new year in SE Asia and diwali, pooja, onam in India, and compensate by better recruitment in the West.
Culture of revering healthcare provider, poverty and illiteracy put informed consent at risk. Due to poverty, inclusion in a trial could itself be an incentive. In such a situation informed consent cannot be implemented by guideline alone; legislation of the rule seems necessary. (5)
Another ethical issue that arises is whether the participating society will benefit from the clinical trial. Will the product be marketed in the country from where many of the patients have been recruited? If not will the patients in whom the study drug showed a positive response, be provided with continuous supply of the medicine if no alternative is available?
Majority of future trials will be conducted outside US and EU. Asian countries seem to be welcoming foreign clinical trials which create job opportunities for researchers, scientists and medical professionals and, in many cases, bring new therapies to the country. As a result, some Asian countries have reformed regulatory regimes to simplify the procedure for approving clinical trials. (6)
India seems to have hit a roadblock due to social activists, media, judiciary, parliament, all gunning for the regulatory body. Such movements only improve the system but this period of change is difficult for business ?
Also, some patent-related judgments in India have not been very palatable to the West. Government believes, and rightly so, that this is good for the country.
Many companies are shifting focus to neighboring countries due to difficulties in India. Conditions similar to above could occur in other Asian countries too, in future. Are these companies ready for that?
Above is a sample of possible challenges one would face while doing trials in SE Asia. This is not to discourage globalization of studies to SE Asia but to preempt risks and further expand the involvement. With increasing globalization, public awareness and societal involvement regulations will be streamlined to the benefit of all stakeholders.
|Dr. Vishwas Sovani, March 2013|