Undisclosed Conflicts of Interest and Improper Conduct in Lectures and Prescribing Guidance

MHLW viewThe involvement of the pharmaceutical company was not disclosed.

MHLW viewThe involvement of the pharmaceutical company was not disclosed. In light of cases where conflict-of-interest information was not explicitly stated, healthcare professionals receiving promotional activities from pharmaceutical companies should take note of the following: they should verify whether the pharmaceutical company is involved in cited references and the like. (7) Reference Note: This case was included as a reference because it does not constitute promotional information directed at healthcare professionals.

MHLW viewBy describing the drug as "the only medicine" without sufficiently specifying the methods for which efficacy has been demonstrated and the scope of those effects, the description could create a mistaken impression among patients that other drugs have no effect. Conclusion As described in the Introduction, this project was implemented with the objective of creating a new promotional activity monitoring system, with the aim of building an environment to ensure appropriate promotional activities by pharmaceutical companies — through early detection of acts that constitute advertising violations, taking necessary measures such as administrative guidance, and encouraging voluntary initiatives by pharmaceutical companies and industry organizations. The implementation of this project revealed four key findings. First, inappropriate cases continue to be found in large numbers, including: (1) cases indicating unapproved indications, efficacy, or dosage regimens; (2) cases involving data manipulation that could cause factual misunderstanding; (3) cases using expressions that could cause factual misunderstanding; (4) cases using unreliable data; (5) cases downplaying safety concerns; and (6) cases where conflict-of-interest information was not explicitly stated. Given that this was only a short three-month monitoring period, it may be inferred that such inappropriate promotional activities remain widespread in clinical settings. Second, while cases of inappropriateness found in broadly published materials such as advertorial content were not numerous, there were many instances of inappropriate explanatory materials and oral explanations in so-called "closed" settings — such as when pharmaceutical company representatives visited medical institutions to provide product explanations and information to physicians, pharmacists, and other healthcare professionals. Among these were cases where information was provided only on-screen by MRs without distributing paper-based materials, raising suspicion that some companies were intentionally avoiding leaving a paper trail. Third, the provision of information via the internet — including company websites, healthcare professional information sites, and web seminars — is also widespread. Much of this online information is accessible only after registering one's name and affiliation, making it difficult for regulatory authorities to conduct advertising surveillance, which is where the monitoring role becomes essential. Fourth, as a secondary benefit, the project improved the surveillance capabilities of the primary contact persons (monitors) at the monitor medical institutions. Specifically, through questions and advice from academics and experts at case review meetings, and through sharing case reports from other monitors, monitors developed awareness of what kinds of cases are considered inappropriate from what perspectives, and what materials should be consulted when assessing appropriateness. The monitors themselves recognized this improvement and many raised it in the case review meetings. In light of these four findings, a number of issues requiring consideration emerge — including the future design of the promotional activity monitoring system — as part of efforts to build an environment ensuring appropriate promotional activities by pharmaceutical companies. First is the issue of confidentiality of monitor medical institutions and handling of case reports. For materials broadly published by pharmaceutical companies, administrative guidance can be issued for inappropriate cases as needed; however, when the information is provided in a "closed" setting between an individual MR and a healthcare professional, situations may arise where the monitor medical institution could be identified. There is a need to work out in greater detail how to handle such suspected-violation reports — in other words, what the "exit" should look like. Second, at seminars held in clinical settings or by pharmaceutical companies, information is often provided without leaving evidence. Because there is no evidence, it is difficult to issue administrative guidance through prefectural authorities, and the question of what strategies can be adopted to address such cases remains. Third, as sophisticated information provision via the internet and in "closed" settings without leaving evidence becomes increasingly common, the question of how to make the promotional activity monitoring system function more effectively arises. Increasing the number of monitor medical institutions and monitors may be one solution, but how to detect a greater volume of inappropriate information earlier and achieve improvements requires consideration from a long-term perspective. Fourth is the issue of recipients of information. Healthcare professionals in clinical settings want to obtain as much information as possible from pharmaceutical companies; however, what they want is reliable information. It is therefore important for them to have criteria for judging whether information provided by pharmaceutical company representatives is appropriate. Medical institutions with well-developed educational systems, such as university hospitals, may find it relatively easy to provide education on monitoring pharmaceutical advertising activities, but how to disseminate this more broadly remains a future challenge. With a view to addressing these challenges, from a short-term perspective, there is an urgent need to consider: (1) the number and selection method of monitor medical institutions; (2) the occupational categories of monitors; (3) how to utilize monitors who gained expertise in the current project; (4) selection of investigation targets (target therapeutic areas, advertising media, etc.); and (5) the design of information-gathering activities with the "exit" in mind, for the next fiscal year's promotional activity monitoring system. Additionally — related to the "exit" — there is a strong need to demand thorough compliance, including voluntary standards by pharmaceutical companies and industry organizations. It is unclear whether company headquarters are aware of and tacitly permitting inappropriate advertising and information provision activities, whether these are activities at the sales branch level that headquarters are unaware of, or whether they are the result of individual MR decisions; but in any case, it is strongly hoped that pharmaceutical companies and industry organizations themselves will work strenuously to ensure thorough compliance and improve their promotional activities to bring them in line with proper standards. From a medium- to long-term perspective, the importance of education and training for information recipients through the monitoring system and similar mechanisms can be highlighted. It is essential that physicians, pharmacists, and other healthcare professionals in clinical settings hold criteria of judgment and take a stance of demanding that pharmaceutical companies conduct appropriate promotional activities. While cultivating such an environment, it will also be necessary to consider mechanisms that make it easier to report inappropriate cases when discovered — or, from the other side, that enable earlier information collection. Through these efforts, it is strongly hoped that appropriate promotional activities by pharmaceutical companies will be ensured. Ministry of Health, Labour and Welfare, Pharmaceutical Safety and Environmental Health Bureau, Division of Pharmaceutical Affairs and Food Sanitation — Commissioned Project Pharmaceutical Promotional Activity Monitoring Project Report March 2017 (Heisei 29) Mitsubishi UFJ Research and Consulting Co., Ltd. 2-3-33 Marunouchi, Chiyoda-ku, Tokyo 100-8301 Telephone: 03-6733-1024

MHLW viewIn the product promotional video, the COI of the original referenced paper was not disclosed.

MHLW viewIn the explanatory slides, the COI of the original referenced paper was not disclosed. (2) Examples of Inappropriate Promotional Activities Based on suspected-violation cases gathered over the past three years, including the current project, and on the outcomes of case review meetings, the following is a summary of the main types of conduct identified as inappropriate in pharmaceutical company promotions. (1) Oral explanations by MRs (Explanations that hint at efficacy, indications, or dosage regimens outside the approved scope) - Introducing indications or efficacy approved overseas Example: "The approved indications in Japan are limited, but overseas ** is also approved as an indication." - Suggesting future expansion of the scope of indications Example: "In the future, ** will likely be approved as an indication in Japan as well." - Introducing adverse events as if they were efficacy Example: "(Regarding a drug that causes excessive levels of component ** as an adverse event) An increase in ** can be expected." - Introducing dosage regimens that are unlikely to be queried in insurance claim reviews Example: "It is off-label, but if prescribed as **, it will not be flagged in insurance reviews." (Explanations without evidence, or explanations that exaggerate efficacy, safety, etc.) - Introducing the reputation of other medical institutions, the views of the marketing authorization holder, or individual opinions in hearsay form without presenting scientific evidence Example: "It has a reputation at other hospitals as **," "They say at the manufacturer that **," "It tastes good / it is easy to use." - Claiming superiority over competing drugs using results of non-inferiority trials - Introducing characteristics of other drugs as if they were characteristics of this drug Example: "Our company manufactures drugs that are **, so this product is also **." - Claiming superiority based on unrelated facts Example: "This drug appears earlier in the guidelines than competing drugs," "The difference in dissolution between authorized generics and generic drugs affects efficacy." - Claiming superiority based on data or facts that do not correspond on a one-to-one basis with the comparator drug Example: "(Presenting data for a comparator with the same active ingredient but a different dosage form) This drug is superior to the comparator, which has the same active ingredient and dosage form," "(Regarding the fact that non-inferiority to existing drug A was shown only in the active phase, and to existing drug B only in the remission phase) Non-inferiority compared to existing drugs has been confirmed in both the active and remission phases." - Not providing information on the content of the Risk Management Plan (RMP) and adverse events (representative not sufficiently familiar with the content) (2) Promotional materials (Materials using unreliable data) - Introducing data other than materials used at the time of approval or peer-reviewed papers - Claiming superiority based on data with a small number of cases - Introducing non-clinical data unrelated to clinical data - Introducing only clinical trial results that most prominently demonstrate superiority - Not describing statistical analysis methods or results - Introducing data on unapproved dosage regimens or indications (Materials in which figures or tables from cited references have been modified) - Emphasizing differences by adjusting the maximum value or scale of axes - Emphasizing differences by adding reference lines, arrows, or coloring - Extracting only the favorable portions of figures or tables from cited references Example: Extracting only the company's own product from a comparison between the comparator and the company's own product; extracting only the single time point showing the greatest difference from a three-time-point comparison; extracting only the data for the comparator that shows the most favorable or relevant results from a comparison with multiple comparators - Adding data not present in the cited reference Example: The cited reference contained only data for the company's own product group and the placebo group, but data for the between-group difference were newly added to emphasize the difference - Changing the order of data presentation in the cited reference Example: In a bar graph showing multiple data points, repositioning data that make efficacy appear exaggerated or data showing secondary effects to a prominent position - Modifying data based on supplementary notes in the cited reference Example: The cited reference contained data combining the blinded and open-label periods (with supplementary notes on the open-label period), but this was changed to data for the blinded period only so as to increase the apparent difference (Materials using compositions or expressions that could cause factual misunderstanding) - Providing explanations on content different from the stated purpose of the product briefing Example: Mixing in data on "conventional indications" at a briefing on additional indications; recommending a drug not covered by the product briefing - Listing or treating on an equal footing information that should be clearly distinguished (data subject to approval review vs. data not subject to review, primary endpoints vs. secondary endpoints, reference information, etc.) - Using headings or titles that appear to exaggerate data Example: Using the heading "shows a trend like **" for content that cannot be implied by the data in question - Not clearly stating that a conflict of interest exists

MHLW viewIn the web lecture, the COI disclosure slide was displayed for such a brief time that attendees were unable to read its content.

MHLW viewFor a drug for which long-term prescribing was not permitted within one year of approval, the representative explained that prescribing more than 14 days' supply was possible through double-dose prescribing.

MHLW viewAlthough the sponsoring company bears responsibility for presentations at company-sponsored lectures, the speaker excessively promoted the sponsoring company's products. (2) Examples of Inappropriate Promotional Information Activities Based on suspected-violation cases gathered over four years, including the current project, and on the outcomes of case review meetings, the following is a summary of the main types of conduct identified as inappropriate in pharmaceutical company promotional information activities. (1) Oral explanations by MRs (Explanations that hint at efficacy, indications, or dosage regimens outside the approved scope) - Introducing indications or efficacy approved overseas Example: "The approved indications in Japan are limited, but overseas ** is also approved as an indication." - Suggesting future expansion of the scope of indications Example: "In the future, ** will likely be approved as an indication in Japan as well." - Introducing adverse events as if they were efficacy Example: "(Regarding a drug that causes excessive levels of component ** as an adverse event) An increase in ** can be expected." - Introducing dosage regimens that are unlikely to be queried in insurance claim reviews Example: "It is off-label, but if prescribed as **, it will not be flagged in insurance reviews." (Explanations without evidence, or explanations that exaggerate efficacy, safety, etc.) - Introducing the reputation of other medical institutions, the views of the marketing authorization holder, or individual opinions in hearsay form without presenting scientific evidence Example: "It has a reputation at other hospitals as **," "They say at the manufacturer that **," "It tastes good / it is easy to use." - Claiming superiority over competing drugs using results of non-inferiority trials - Introducing characteristics of other drugs as if they were characteristics of this drug Example: "Our company manufactures drugs that are **, so this product is also **." - Claiming superiority based on unrelated facts Example: "This drug appears earlier in the guidelines than competing drugs," "The difference in dissolution between authorized generics and generic drugs affects efficacy." - Claiming superiority based on data or facts that do not correspond on a one-to-one basis with the comparator drug Example: "(Presenting data for a comparator with the same active ingredient but a different dosage form) This drug is superior to the comparator, which has the same active ingredient and dosage form," "(Regarding the fact that non-inferiority to existing drug A was shown only in the active phase, and to existing drug B only in the remission phase) Non-inferiority compared to existing drugs has been confirmed in both the active and remission phases." - Not providing information on the content of the Risk Management Plan (RMP) and adverse events (representative not sufficiently familiar with the content) - Conducting promotions based on uncertain information, such as that the drug is expected to be recommended in future guidelines (2) Promotional materials (Materials using unreliable data) - Introducing data other than materials used at the time of approval or peer-reviewed papers - Claiming superiority based on data with a small number of cases - Introducing non-clinical data unrelated to clinical data - Introducing only clinical trial results that most prominently demonstrate superiority - Not describing statistical analysis methods or results - Introducing data on unapproved dosage regimens or indications (Materials in which figures or tables from cited references have been modified) - Emphasizing differences by adjusting the maximum value or scale of axes - Emphasizing differences by adding reference lines, arrows, or coloring - Extracting only the favorable portions of figures or tables from cited references Example: Extracting only the company's own product from a comparison between the comparator and the company's own product; extracting only the single time point showing the greatest difference from a three-time-point comparison; extracting only the data for the comparator that shows the most favorable or relevant results from a comparison with multiple comparators - Adding data not present in the cited reference Example: The cited reference contained only data for the company's own product group and the placebo group, but data for the between-group difference were newly added to emphasize the difference - Changing the order of data presentation in the cited reference Example: In a bar graph showing multiple data points, repositioning data that make efficacy appear exaggerated or data showing secondary effects to a prominent position - Modifying data based on supplementary notes in the cited reference Example: The cited reference contained data combining the blinded and open-label periods (with supplementary notes on the open-label period), but this was changed to data for the blinded period only so as to increase the apparent difference (Materials using compositions or expressions that could cause factual misunderstanding) - Providing explanations on content different from the stated purpose of the product briefing Example: Mixing in data on "conventional indications" at a briefing on additional indications; recommending a drug not covered by the product briefing - Listing or treating on an equal footing information that should be clearly distinguished (data subject to approval review vs. data not subject to review, primary endpoints vs. secondary endpoints, reference information, etc.) - Using headings or titles that appear to exaggerate data Example: Using the heading "shows a trend like **" for content that cannot be implied by the data in question - Not clearly stating that a conflict of interest exists

MHLW viewAt a manufacturer-sponsored web seminar, none of the presenters disclosed their COI.

MHLW viewFor a drug for which long-term prescribing was not permitted within one year of approval, the representative explained that prescribing a 28-day supply was possible through double-dose prescribing. (2) Examples of Inappropriate Promotional Information Activities Based on suspected-violation cases gathered over five years, including the current project, and on the outcomes of case review meetings, the following is a summary of the main types of conduct identified as inappropriate in pharmaceutical company promotional information activities. (1) Oral explanations by MRs (Explanations that hint at efficacy, indications, or dosage regimens outside the approved scope) - Introducing indications or efficacy approved overseas Example: "The approved indications in Japan are limited, but overseas ** is also approved as an indication." - Suggesting future expansion of the scope of indications Example: "In the future, ** will likely be approved as an indication in Japan as well." - Introducing adverse events as if they were efficacy Example: "(Regarding a drug that causes excessive levels of component ** as an adverse event) An increase in ** can be expected." - Introducing dosage regimens that are unlikely to be queried in insurance claim reviews Example: "It is off-label, but if prescribed as **, it will not be flagged in insurance reviews." - Explaining that it is acceptable not to follow the content described in the package insert Example: "There are cases where prescriptions are made even when only the physician has received training and other occupational categories have not." (Explanations without evidence, or explanations that exaggerate efficacy, safety, etc.) - Introducing the reputation of other medical institutions, the views of the marketing authorization holder, or individual opinions in hearsay form without presenting scientific evidence Example: "It has a reputation at other hospitals as **," "They say at the manufacturer that **," "It tastes good / it is easy to use." - Claiming superiority over competing drugs using results of non-inferiority trials - Introducing characteristics of other drugs as if they were characteristics of this drug Example: "Our company manufactures drugs that are **, so this product is also **." - Claiming superiority based on unrelated facts Example: "This drug appears earlier in the guidelines than competing drugs," "The difference in dissolution between authorized generics and generic drugs affects efficacy." - Claiming superiority based on data or facts that do not correspond on a one-to-one basis with the comparator drug Example: "(Presenting data for a comparator with the same active ingredient but a different dosage form) This drug is superior to the comparator, which has the same active ingredient and dosage form," "(Regarding the fact that non-inferiority to existing drug A was shown only in the active phase, and to existing drug B only in the remission phase) Non-inferiority compared to existing drugs has been confirmed in both the active and remission phases." - Not providing information on the content of the Risk Management Plan (RMP) and adverse events (representative not sufficiently familiar with the content) - Conducting promotions based on uncertain information, such as that the drug is expected to be recommended in future guidelines (2) Promotional materials (Materials using unreliable data) - Introducing data other than materials used at the time of approval or peer-reviewed papers - Claiming superiority based on data with a small number of cases - Introducing non-clinical data unrelated to clinical data - Introducing only clinical trial results that most prominently demonstrate superiority - Not describing statistical analysis methods or results - Introducing data on unapproved dosage regimens or indications (Materials in which figures or tables from cited references have been modified) - Emphasizing differences by adjusting the maximum value or scale of axes - Emphasizing differences by adding reference lines, arrows, or coloring - Extracting only the favorable portions of figures or tables from cited references Example: Extracting only the company's own product from a comparison between the comparator and the company's own product; extracting only the single time point showing the greatest difference from a three-time-point comparison; extracting only the data for the comparator that shows the most favorable or relevant results from a comparison with multiple comparators - Adding data not present in the cited reference Example: The cited reference contained only data for the company's own product group and the placebo group, but data for the between-group difference were newly added to emphasize the difference - Changing the order of data presentation in the cited reference Example: In a bar graph showing multiple data points, repositioning data that make efficacy appear exaggerated or data showing secondary effects to a prominent position - Modifying data based on supplementary notes in the cited reference Example: The cited reference contained data combining the blinded and open-label periods (with supplementary notes on the open-label period), but this was changed to data for the blinded period only so as to increase the apparent difference (Materials using compositions or expressions that could cause factual misunderstanding) - Providing explanations on content different from the stated purpose of the product briefing Example: Mixing in data on "conventional indications" at a briefing on additional indications; recommending a drug not covered by the product briefing - Listing or treating on an equal footing information that should be clearly distinguished (data subject to approval review vs. data not subject to review, primary endpoints vs. secondary endpoints, reference information, etc.) - Using headings or titles that appear to exaggerate data Example: Using the heading "shows a trend like **" for content that cannot be implied by the data in question - Not clearly stating that a conflict of interest exists