What Does the Growing Prominence of Asia Mean for Pharmaceutical Safety Management?

Keywords::

• counterfeit
• HLA-B*1502
• pharmacovigilance
• chinese traditional medicines
• fixed-combination

The growing prominence of Asia in the global pharmaceutical industry, especially in rapidly developing countries such as India and China, has several significant implications for the management of the safety of medicines. In many respects this change is long overdue. India and China each have a much larger population than the combined populations of the International Conference on Harmonization regions of the USA, Europe and Japan. The international nature of drug-safety management (we live in a world where the US FDA [101] may issue new warnings about genetic markers for serious skin reactions based largely on studies performed on Asian populations in Asia) means that the emergence of this region as a large pharmaceutical market and important contributor to global clinical trials will impact not just the Asian region itself, but is likely to significantly influence pharmaceutical safety management in the established pharmaceutical markets of developed countries.

Asia is growing in importance both as a location for clinical trials performed to generate data for new drug application submissions in the USA [1] and Europe [2], as well as for the strong annual growth in pharmaceutical sales in some of its rapidly developing countries. These two developments are interdependent. Although the primary reasons for locating clinical trials in Asia may be rapid patient recruitment and relatively lower costs, the local experience gained from performing clinical trials in these markets both speeds the application process for approvals and improves the sponsoring company’s contacts with leading clinical researchers in that country. As a result of the increase in clinical development and marketing of new medicines in Asia, we can expect more safety data from these populations, both from the controlled environment of clinical trials and the more variable source of spontaneous reporting during marketing of approved medicines. This editorial will not consider the other practical issues in conducting clinical trials in Asia, such as monitoring and site selection, which have been reviewed elsewhere [102], nor does this article intend to advocate that clinical trial sponsors rush into Asia without carefully considering the needs of their individual drug-development programs and appropriate patient-population selection.

There are various specific topics that warrant particular attention when considering the growing prominence of Asia: diversity in population; unique reporting requirements; distinct national characteristics and their impact on reporting rates; prevalence of herbal medications; and drug diversion and counterfeiting. These topics are discussed in more detail below.

A key issue in the evaluation of adverse reactions for drug-safety professionals stems directly from the large and diverse populations in Asia. In reporting the ethnicity of clinical trial participants it may be tempting to categorize Chinese, Indians, Japanese and Koreans under the single category of ‘Asians’, but in fact recent experience with identifying genetic factors for specific, serious adverse reactions shows that Asians should not be considered as representing a single or uniform category of susceptibility factors for reactions to medications. For instance, in recent years the human leukocyte antigen HLA-B*1502 has been shown to be a marker for risk of developing the potentially life-threatening skin reactions of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) after treatment with the antiepileptic carbamazepine. The effect was described in Han Chinese in Taiwan [3] and confirmed in a small number of Asian patients (individual patients from China, Vietnam, Cambodia and Reunion Island) with similar reactions living in Europe [4]. However, in a large series of cases of SJS and TEN related to antiepileptic drug treatment in Japan no association of HLA-B*1502 to either skin condition was detected, probably because of the much lower frequency of this antigen in the Japanese population compared with the Han Chinese [5]. This finding in Japanese patients does not decrease the significance of the remarkably strong association found between this marker and SJS in Han Chinese, but it does point to the significance of the variety of ethnic backgrounds in Asia and the widely varying incidences of genetic markers in different populations in this region. We should be cautious in lumping genetically distinct peoples into the single category of ‘Asian’ when performing population-based safety analyses either of clinical trial results or during postmarketing pharmacoepidemiologic studies.

Pharmacovigilance the collection, evaluation and reporting of adverse reactions associated with medical therapies, is today a highly regulated global enterprise and multinational pharmaceutical companies devote considerable resources to maintaining compliance with safety reporting regulations. Safety reporting in the developed world, especially the USA, EU and Japan, is largely harmonized under the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines and most developed countries now encourage or even require reporting of individual adverse reports in an electronic format that eases the logistics of meeting reporting requirements for companies [103]. By contrast, several of the rising Asian pharmaceutical markets require reporting in a unique, local language format or through a website run by the regulatory authority that requires manual re-entry of safety report information. The rules on which adverse events must be submitted as expedited reports differ from the rest of the world with, for instance, requirements to expedite ‘not related’ serious adverse events (i.e., adverse events that the clinical trial investigator and the company assess as not related to the investigational drug) during clinical trials. In some cases they also require periodic safety update reports, which are generally accepted in English worldwide, to be fully translated into the local language. These are significant additional logistical burdens for study sponsors and manufacturers and come with no clear added benefit for the safety of clinical trial subjects or patients. As these new markets grow in their integration into the global pharmaceutical marketplace, regulators in these countries would benefit from looking to the established standards for pharmacovigilance that have been adopted in the developed world.

There are some national characteristics of Asian countries that may influence the nature or reporting of adverse reactions to pharmaceuticals. Although the rate of ‘spontaneous’ (the unsolicited reporting of adverse reactions initiated either by healthcare professionals or consumers) reporting of adverse reactions is relatively low in all of these markets compared with the developed world, China stands out as a country where consumers do not hesitate to bring their complaints of product quality or possible safety concerns directly to the attention of the company marketing the product. In many cases this may be because the consuming patient has had to bear the cost of the medication and seeks a refund or compensation for additional medical therapy they felt was required because of the adverse reaction. Companies marketing drugs in China need clear policies and procedures for handling these requests for compensation or other claims associated with consumer reports of adverse reactions.

Another important characteristic of the Chinese market is the extensive use of traditional herbal medications. When adverse reaction reports are assessed by drug-safety physicians, one of the considerations is the possible role of concomitant medications either in contributing to the reported adverse reaction or in causing some form of drug–drug interaction that could augment or blunt the intended drug effect. When adverse reaction reports include several herbal therapies, which are unknown to Western physicians, it complicates the evaluation of these reports. Numerous herbal medications have been reported to cause adverse reactions that are classically associated with pharmaceutical therapies, including interstitial pneumonia [6,7] and nephritis [8], and one, aristolochic acid, has even been associated with a high incidence of urinary tract cancers [9]. Because much of the relevant literature is not available in English language journals and the Romanized spellings of the names of several of the herbal therapies are somewhat variable, it can be difficult for physicians to even begin to research the already known effects of herbal therapies mentioned as concomitant treatments on adverse reaction reports. This use of Chinese traditional medicines does not mean that the patients are not ‘naive’ to (or have not yet been treated with) typical first-line therapies used in Western countries. Clinical-trial sponsors are likely to find patient populations in Asia who have not yet developed resistance to typical early-line therapies in cancerous or chronic diseases. At the same time, in addition to the exclusion criteria used in clinical trials in Western countries to control the use of concomitant therapies that may interfere with the activity of the investigational agent, in China it may be wise to consider excluding concomitant use of some or all traditional Chinese medicines.

The Indian market, which also uses herbal and related Ayurvedic medicines with issues similar to those mentioned above, also has an unusually wide variety of fixed-combination drugs, perhaps in response to commercial pressures in the largely generic domestic pharmaceutical market [10]. Many of these fixed combinations, for instance combinations of vitamins with antibiotics or tranquillizers, are unnecessary in the sense that there is no advantage to dosing the two or more products in fixed combination, or irrational in that the drugs may work against each other or put patients at greater risk because of synergistic mechanisms for adverse reactions [11]. Some combinations have now been banned by the Drugs Controller General of India, but the Indian market continues to have a large number of drug combinations that will be unfamiliar to those outside the country. These can also present a challenge during the evaluation of adverse reactions reported from India.

Finally, drug diversion and counterfeiting are two of the most serious safety concerns in many Asian countries. Counterfeit drugs with origins in Asia reaching the USA or Europe are periodically discussed in the western press but in fact the problem of local counterfeit drugs is a much more serious problem in these countries [12]. Estimates vary widely but suggest that between 10 and 30% of drugs in the developing world are counterfeit or substandard [13,104]. The Pharmaceutical Security Institute’s tracking of incidents of seizure, transit or destination of illegal pharmaceuticals shows that Asia is the region with the greatest number of incidents [105]. Many of these are seizures of counterfeit drugs intended for sale in the developed world but local problems with counterfeiting, particularly making products appear to be from a trusted international manufacturer, continue to be an issue in Asia. In my experience the discovery of counterfeit products is more likely to come to a company’s attention through reporting of product complaints because of unusual packaging or the physical appearance of the counterfeit product, than through reporting of adverse reactions, but drug safety professionals should also be alert to this issue when evaluating adverse reaction reports.

The rapid growth in the numbers of global clinical trials in Asia and the attractive long-term growth potential of pharmaceutical markets in these rapidly developing countries holds great promise both for the peoples of Asia as well as for the international pharmaceutical industry. Attention to some of the particular characteristics of this region when evaluating drug safety issues will be important as these growth trends continue.

Financial & competing interests disclosure

Stewart Geary is a full-time employee of Eisai Co., Ltd, and owns stock in the company. The opinions stated in this article are those of the author alone and do not represent the official position of Eisai Co., Ltd, or its affiliates. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Stewart Geary is a full-time employee of Eisai Co., Ltd, and owns stock in the company. The opinions stated in this article are those of the author alone and do not represent the official position of Eisai Co., Ltd, or its affiliates. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.