Pharma Focus Asia
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New Demand, New Horizons

Iylen Benedict, Sanofi-Aventis Malaysia

The Asia Pacific region has seen spectacular growth in large-scale clinical trials in recent years. Iylen Benedict highlights the reasons for the shift and outlines some of the challenges and synergies involved.

Both the quantity and the quality of multinational, multicentre trials conducted in the Asia Pacific region are on the increase, as more and more trials are shifted from developed Western nations to developing countries in Asia, Latin America, and Eastern and Central Europe.

So why is Asia Pacific in particular such a popular option? There is a projected global pharma growth from 2003 to 2007 of 9-12 per cent and projected R&D expenditure growth of 9-12 per cent for the same period. Since 1990, global research has grown from 28 to 79 countries. The amount of FDA research has multiplied sixteen-fold, and ICH E5 allows the use of foreign data in drug approvals. There is a definite demand for more clinical trials worldwide. These demands can be broadly divided into business or consumer demand, regulatory requirement, or the scientific quest for knowledge.

The compelling business need to conduct more clinical trials in the region arises from:

  • Increasing business and product competition
  • Increasing market penetration
  • The need to rush products to market in the shortest possible time
  • The need to increase sales to maximise return on investment (ROI)
  • The need to build product experience,
  • End-user demand for drugs which are safe, efficacious and cheap

The regulatory requirement is mandatory and originates from the ICH guidelines, especially those pertaining to issues of safety and efficacy, real-life safety data and country-specific guidelines. There is also a scientific search for new data on epidemiological differences across ethnic origins and population demographics and variations, and a need to communicate these findings effectively to ensure better healthcare and management.

Traditional clinical centres in developed countries are moving towards early-phase trials, molecule detection and genomic studies. The non-traditional sites in developing are already conducting large multinational, multicentre trials, more late-phase trials and some early-phase trials. The major advantages of conducting multinational, multicentre trials in developing countries include the economic benefits, the lower cost of subject recruitment and investigator fees, and the lower cost of human resource management.

The setting up of disease registries in the region has taken precedence over interventional clinical trials in recent years. The importance of collecting baseline data before conducting any interventional study is now widely recognised. Some of the salient differences between registries and clinical trials are: registries usually involve non-interventional data collection; they look at the current knowledge, attitude and practice (KAP) in a particular field of disease management; there is minimal monitoring; and a very small percentage of clinical study sites are audited. Examples of disease registries in the region are the Cancer Registry and the Renal Registry.

Selecting the Right Site

One of the key factors in choosing a particular country, site or centre is the availability of facilities and equipment. Asia Pacific has a vast geographical spread. More and more clinical sites are either being built as standalone centres or attached to a referral government hospital or attached to academic institutions. A good majority of these centres have made it mandatory for clinical investigators to undergo Good Clinical Practice (GCP) training before taking on a particular clinical trial. Supply of computers and integrated computer networks, an effective refrigeration or cold-chain system, effective telecommunications and transportation can create problems in some countries, especially when the terrains and temperatures are unpredictable.

During a site feasibility study, it is crucial to have a checklist of all the minimal requirements for a particular trial and to compare this with what is readily available at each of these centres. Many countries overcome their shortcomings by sharing best practice within the region. A good example is the use of an offsite data management centre to manage all data entry, analysis and write up of the clinical trial for the region, and having sub-analysis for country-specific data.

Although English is a global language and widely used in Asia, certain documents in a clinical trial require translation and back translation. Examples include patient information leaflets and consent forms. Where the accuracy of translation may be questionable, back translation may be required to ensure the medical context of the original document is not modified or skewed in content. A word from a single Chinese dialect may carry different meanings in different countries. Some countries may follow the traditional Chinese characters while others may follow the simplified Chinese characters. Many countries in the region have overcome these shortcomings by language outsourcing and having a simple internal system for validation of local terms.

Culture is an unspoken language containing a community's core values. Large trials must therefore build internal and external relationships with subjects, investigators and regulatory bodies. Specifically, they must respect cultural differences, be sensitive to these differences and have an additional local resource to manage the local investigator (this is especially useful if the sponsor's culture is very different from that of the country where the clinical trial is being conducted).

To overcome the challenges of ethics committee approval, some countries have a fast-track approval system. In one country, ethics approval can take as long as a year while in another it might be as short as a month. In some countries the ethics committee/IRB application and clinical trials import licence can be handled concurrently, to hasten the initiation of a clinical trial. It is very important to know these differences when seeking approvals for the conduct of a clinical trial.

In some countries, the signatories of clinical contracts is the CEO of the company while others need the head of hospital and not the principal investigator to sign off the contract. Clinical data protection and export in this region has varied outcomes. Some countries in have a clause forbidding the exportation of these raw data, whilst others allow the export of clinical data in its entirety. Some countries allow the export of only modified data, whilst others allow only the export of unmodified clinical data. One country only allows partial export (10 per cent) of raw data.

In large multinational, multicentre trials, there tends to be a faster recruitment and retention rate, but there may be cases where patient communication and reminder cards become critical in patient recruitment, and incentives can be offered to help minimise drop out rate.

The culture of compliance creates concerns in documenting informed consent. In countries with a more litigious culture, investigators are more cautious with patient recruitment and consent form signatures. Usually, a full discussion of risks requires time, patience and effort on the part of investigators. In some countries with low literacy rates, patient consent may be taken but may not be documented properly, or the risks and benefits may not be documented at all. In China, Korea and Taiwan, a personal seal is used rather than the standard 'dated/signed by the principal investigator'.

In quality assurance and clinical audits of multinational, multicentre trials, input errors and varied terminology can be minimised through simple computer-friendly clinical research forms, computer programs that prompt 'incomplete entry' during data entry or data standardisation via benchmark standards.

In conducting multinational, multicentre trials, the sponsor retains overall control of study, an investigator provides regular reports to the sponsor, thus preventing undue delays in clinical trials, and regulatory approvals become easier because of credibility of the sponsor. All of this has a domino effect on the outcome of the trials.

Some governments provide incentives by way of a grant, for the conduct of research in the private sector, in a bid to increase the number and quality of clinical trials conducted in the region. Examples include the Industrial Research Grant, the Commercialization of Research and Development Fund, the Technology Acquisition Fund and the Human Resource Development Fund, all of which are available in Malaysia and Australia.

There are numerous challenges in conducting multinational, multicentre trials in Asia Pacific, and it is important that local cultures and sensitivities are respected, requirements for bridging studies to be conducted are met, and existing pockets of expertise within the region are well utilised. Effective partnerships and a best practice approach will be crucial in ensuring that the advantages outweigh the areas of concern.

References can be obtained from the author:

Author Bio

Iylen Benedict
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