Transparency in Drug Submission Processes of 3 Asian Countries

Introduction

Transparency in government affects the ability of stakeholders to work efficiently through a complex maze of regulations. Much has been written about the importance of transparency, and metrics have been developed to explore various aspects of transparency in governments generally. Little, however, has been written specifically about the transparency of drug-registration processes.

In this work we have adopted the definition of Finkelstein who states, “We use transparency to describe those policies that are easily understood, where information about the policy is available, where accountability is clear, and where citizens know what role that they play in the implementation of the policy.” ¹ Such transparency is difficult to ensure. In the US the importance of increased transparency has been underlined by the formation of President Obama’s FDA Transparency Task Force in 2009, and in the EU by the new transparency policy under discussion currently. ² At the international level, the presence of an active, well-supported International Conference on Harmonization (ICH) perhaps best reflects the importance with which the harmonization of regulatory approvals is viewed as a central activity to enhance regulatory transparency. ³

Transparency in pharmaceutical registration is challenging for newly emerging economies to achieve. Applicants attempting to register a drug can face a succession of hurdles related to local market dynamics, political structures, pricing, reimbursement policies, and, importantly, the highly complex drug registration process. ⁴ The complexity and lack of harmonization of registration processes, together with language barriers, limited personnel, and still-modest experience with regulatory oversight and review can contribute to the perception that registration processes at the governmental level lack transparency. ⁵ Yet little has been written specifically about more systematic measures or metrics by which different regulatory systems can be compared.

The use of metrics to compare social or governmental activities is not new. For example, to study corruption, Transparency International (TI) publishes an annual Corruption Perceptions Index (CPI), in which countries are ranked according to perceptions of corruption in the political system and bureaucracy. ⁶ The Global Corruption Barometer is another tool used to assess public views of corruption in 69 countries. ⁷ The only attempt to measure the transparency of the drug regulation process in emerging markets appears to be that conducted by the World Health Organization in 2003, 2006, and 2008. However, these studies and the resulting indices emphasized corrupt practices, and the effect of corruption on distribution, supply, and registration rather than on the transparency of the drug registration process specifically. ⁸

The transparency and corruption indices that now exist are not sufficiently granular to serve as good tools to compare the transparency of drug approval systems in different countries. However, they do provide an interesting model to guide the construction of a more specific and appropriate tool for this purpose. In this study, we have developed a survey instrument aimed at comparing drug registration transparency in 3 Pharmerging countries with the US, through the eyes of regulatory practitioners with experience in these constituencies. Results presented here describe its use to evaluate perceptions of transparency among regulatory professionals in 3 Pharmerging Asian countries.

Materials and Methods

Results

Survey Analysis

Surveyed countries differed across all 3 studied dimensions of accessibility, clarity, and accountability.

Accessibility

Respondents generally agreed that the US has a comprehensive Internet information system that is easy to use; in comparison, less than 20% of respondents agreed that the Internet information system was comprehensive and easy to use for the other countries (Figure 1A). The US was believed to have an effective mechanism to discuss questions and issues with the agency. For South Korea, approximately equal numbers of respondents agreed or disagreed that an effective mechanism existed, and for China and India, most respondents typically disagreed (Figure 1B).

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Figure 1.

Responses regarding relative degree of transparency on 2 criteria related to accessibility.

Respondents typically agreed that a lead person was identified, assigned, and accessible for each submission in the US and Korea (US, 30/31, 5 unable to judge; S Korea 14/18, 19 unable to judge). For China, experience was mixed (9/19, 18 unable to judge), and for India few respondents (2/9, 19 unable to judge) believed that there was a lead person identified and accessible at the regulatory agency. Similarly, to the question, “The lead person responsible for my dossier is accessible after the registration has been submitted,” the US ranked highest (27/29, 7 unable to judge), followed by South Korea (15/18, 19 unable to judge) and then China (9/18, 19 unable to judge) and India (4/8, 28 unable to judge). The ability to provide submissions electronically was viewed to be more challenging in the Asian countries than in the US, with South Korea viewed as somewhat more accessible than India and China (Figure 2).

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Figure 2.

Responses regarding ability to provide submissions electronically.

Additionally 3 participants commented in text. One identified the importance of in-country representation to support the submission process. The others spoke to the complexity and long process times required to gain drug approval in China and India.

Clarity

Responses regarding clarity reflected a view that the US was most transparent, and South Korea was somewhat more transparent than China and India. For the statement, “there are easy to understand written procedures on how to register a drug,” all but 1 respondent agreed or agreed strongly with respect to the US, slightly more than half agreed with respect to South Korea, and only a few respondents agreed with respect to China and India (Figure 3A).

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Figure 3.

Responses regarding relative degree of transparency on 2 criteria related to clarity.

Respondents presented with the statement, “there is an easy to use standard drug application format based on the ICH CTD format,” generally agreed that this feature was characteristic of the US system. Mixed responses were seen with respect to South Korea, and only a small minority agreed when queried about China and India. Similar patterns of responses were seen when queried about the presence of clear and well-defined requirements for the manufacture of clinical and commercial drug products (Figure 3B). However, when asked whether “all fees required for submission of the drug application are clearly defined,” most respondents agreed with the statement for all of the countries (Figure 3C). When asked whether “fees for submission of the drug application are standardized by product type and therapeutic area,” most respondents agreed with respect to the US and South Korea, but responses were mixed for China and India, and many respondents felt unable to answer this question (US:33/58; SK; 34/44; China; 34/44; India; 33/40).

Accountability

With regard to the statement, “the review committee reaches its decision on a drug application by means of documented procedures for decision making (e.g. a qualified majority or consensus),” respondents strongly agreed with respect to the US, but had mixed responses for other countries. The majority of responses agreed with respect to South Korea but more commonly disagreed than agreed for China and India (Figure 4A). When asked whether “the committee responsible for the drug application process provides an official written report to the applicant on decisions (e.g. accepted and rejected files) taken at key decision points of the application process,” respondents typically agreed with respect to the US and South Korea, and had mixed responses, with agreement outweighing disagreement, for China and India (Figure 4B). When asked whether “there is clear appeal process in place for applicants who have their drug applications rejected,” agreement was strongest with respect to the US, but mixed with respect to South Korea, China, and India (Figure 4C). When asked whether “the committee responsible for drug application review is also responsible for the final decision making for approval/rejection of the drug application,” most agreed with this statement for the US and South Korea, but were mixed for China and India (Figure 4D).

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Figure 4.

Responses regarding relative degree of transparency on 2 criteria related to accountability.

Additional narrative comments related to accountability included:

“In the USA, some applications are reviewed at higher level than the review Division. The review is done by the lead reviewer and final decision on our file is made by the lead reviewer and upper manager level. It is not a committee.”

“The registration process is clear and open to public but still requires experiences in this area to understand and apply it smoothly. The Committee responsible for drug application process provides an official written report to the applicant at the end once a decision is taken.”

“During the application process, questions regarding the dossier, raised by the various evaluators, are provided to the applicant so that the applicant can provide a reply to the questions raised.”

A “transparency score” summarized the responses with respect to each dimension and to the combined dimensions (Table 1). On the 5-point scale with 1 as most transparent, the overall US score was 1.8, that of Korea was 2.8, and those of India and China were 3.3 and 3.5 respectively. These same rankings held when comparisons were made for specific dimensions of accessibility, clarity, and accountability (Table 1).

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Table 1.

Transparency Scores by Dimension

Dimension	China	India	South Korea	US
Accessibility	3.6	3.5	3	1.8
Clarity	3.3	3	2.8	1.7
Accountability	3.5	3.2	2.7	1.9
Overall rank	3.5	3.3	2.8	1.8

The lower the score, the more transparent.

A summary question asked respondents to rank the 4 countries according to their overall perceived transparency. Respondents identified the US as the most transparent, South Korea as intermediate, and China and India lowest in transparency (Figure 5).

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Figure 5.

Responses to rate overall perceived transparency.

A preliminary examination was conducted to cross-tabulate the profiles of the respondents with their views on transparency. Few patterns emerged, and even the most relevant were weak. For example, for the statement, “there is an effective mechanism to discuss questions related to submissions requirements and issues” for South Korea, the modal value for individuals with 10 years of more of experience was agree whereas that for individuals with 5 years of experience or less was strongly disagree (P-value, chi square test: 0.13). For the statement, “there are clear and well defined requirements for the manufacture of clinical and commercial drug products,” in South Korea, the modal value of responses for individuals from companies of 500 or more people was agree, whereas that for individuals from small companies of less than 50 people was split between agree and disagree (P-value, chi square test: 0.23).

Discussion

When regulatory agencies approve drugs, their primary contacts are regulatory professionals. Regulatory professionals are therefore uniquely positioned to express views on transparency in the drug approval processes of different countries. However, the number of regulatory professionals with multiregional expertise in the target countries of China, India, and South Korea is still small despite recent expansion of global markets, and securing their views has been a challenging and potentially limiting aspect of this study. Some of those interviewed could only provide comparative insights into some of the countries under study. Furthermore, it is possible that even those views and insights were shaped by a relatively narrow experience with just 1 or 2 products.

In the present studies, efforts to validate the survey tool included both critical review by experts and evaluations of consistency with an overall ranking of the countries with regard to transparency by the participants themselves. However, the fact that most of respondents were based in the US may introduce bias into the results. Regulatory filings in Asia are often carried out by staff members native to the target country, who may hold different views about transparency because of their better knowledge of the regulatory landscape and language. Kim and colleagues ⁹ noted with regard to transparency in South Korea that culture and precedents are important features of interactions that may impede communication with regulators; this observation can probably be generalized to other countries in Asia as well. It would be useful in future to assess whether the results presented here are externally valid when applied to a respondents living and working within the targeted countries.

A major consideration with the use of electronic surveys is their sensitivity to low response rates, typically reported between 20 and 30%. ¹⁰ The response rate of 70% in this study is therefore surprising and may indicate the high degree of interest in this topic. Nevertheless, because the respondent sample was relatively small and data were often skewed, a substratification of the responses is probably of limited value. For example, it appeared from cross-tabulation that participants with greater regulatory experience had more positive views of transparency, particularly in South Korea. This might be expected if the greater experience allowed the respondent to develop resources and personal networks useful to facilitate system navigation. The fact that respondents from larger companies also scored transparency somewhat more positively than small companies may be related to a variety of factors, including, perhaps, greater resources and dedicated international experts who provide specialized advice as needed.

Results suggest that the Asian systems under study still have some way to go before their drug submission procedures are considered to be transparent when benchmarked against a very mature regulatory system such as the US. Do the strong US scores mean that little now needs to be done to improve US transparency? The US FDA seems to acknowledge that further work on transparency is needed as reflected in its 3-stage transparency improvement project that is now ongoing. ¹¹ A short, high-level survey such as the one used here may not be able to capture a full picture of transparency issues in a range of countries whose practices range from transparent to opaque, because it may lack sensitivity for countries at the far ends of the transparency spectrum.

South Korea was found to occupy a midrange ranking in this survey. The South Korean Food and Drug Administration has a relatively long history as a mature regulatory entity, and much recent activity in the South Korean FDA has been directed at further improving its transparency. In addition to improvements in process clarity and accessibility, improvements in accountability have included the formation of a “Corruption Reporting Center” under the Anti-Corruption Council that provides a 24-hour hotline for reports of corruption; the centralization of regulations and enforcement under a single ministry in some key areas of focus, such as the environment; simplifying language to increase the ability of the public to understand policies and practices; and emphasizing the use of international standards.⁹

The scorecards for China and India were mixed. For example, one area of strength appeared to be in the area of clarity with respect to fees associated with the submission processes. The positive scores on this attribute may be surprising and encouraging, since only a few years ago a major concern was the additional “nonauthorized” and unpublished payments to regulatory officials. ¹² However, in 2007, the Chinese regulatory system underwent a major reorganization to reduce the opportunity for officials to be compromised by illegal payments. That these measures were effective and taken seriously is reflected in the 2010 arrests for bribery of 5 officials employed in the drug registration and certification departments of the National Institute for the Control of Pharmaceutical and Biological Products. ¹² Thus the scores on questions related to fees may reflect the fact that “extra” payments over and above published fees are no longer to be tolerated.

In India, “extra” payments for services of regulators have also posed a problem. ¹³ However, India has been expending considerable effort to modernize its regulatory systems, and this may have resulted in a more positive experience for respondents. Nevertheless, we cannot dismiss the possibility that the wording of the question was not sufficiently specific to address bribery and corruption explicitly. The lower scores of India and China on several other questions may reflect the fact that the regulatory systems of China and India are still undergoing significant transition. In China, drug registration procedures are still often described as being underdeveloped, complex, and lacking in transparency. ¹⁴ India is also in transition with regard to its registration practices. New drug approval systems for traditional and fast-tracked products have been introduced, methods for exporting samples have been simplified and pre-review processes have been tightened. ¹⁵ It will be interesting to see whether these initiatives translate into a clearer and more accessible drug registration system particularly in the areas of accountability if a survey such as this is administered in future. The relative ranking of the 3 countries may also reflect the resources available to the respective regulatory agencies to do their jobs. Transparency initiatives are often expensive and require a large amount of infrastructure. It seems reasonable to anticipate that the scale of resources available to support transparency activities and task forces will be much lower for Pharmerging nations than for the US and the EU.

It is difficult to weigh the importance of the various questions and dimensions with respect to the overall assessment of transparency. We do not know, for example, whether it is more important to have an easily navigable website, or ready accessibility to the project manager of a regulatory dossier. This survey cannot rank the relative importance of the elements but rather uses several benchmarks with arbitrary weighting to compare the countries under consideration. Furthermore, this study does not presume that transparency is the only important element for an effective drug registration process. A system can be transparent and yet difficult and expensive to navigate. For example, the US system is typically judged to be quite transparent, yet time delays in approval, extended PDUFA dates or missed PDUFA dates, not uncommon in today’s system, may signal a less-than-optimal operational system. ¹⁶ All too often, and much to the surprise of the regulatory team who has numerous face-to-face meetings, teleconferences, and written correspondences, the end of the submission process can result in a delay or denial of marketing approval. Thus the decision itself can be opaque even in a relatively transparent regulatory system. ¹⁷

Conclusions

The present study suggests that large differences exist in the level of transparency in Pharmerging countries when compared with the US when evaluated with a systematic “transparency index.” A systematic evaluation of transparency can have 3 important outcomes. First, it can enhance communication by standardizing the way in which transparency can be discussed and compared across countries and time periods. Second, it can guide priority setting when regulatory teams are planning serially a global product launch. A systematic tool to evaluate transparency can help to pinpoint areas where problems with transparency may presage critical delays in product registration. Third, regulatory agencies can use the outcomes to identify specific areas where changes in policy or procedure would have a significant impact on transparency. Results can be used as part of benchmarking activities so that the effects of interventions or changes can be gauged.