Talking Only About Efficacy, Staying Silent on Risk — The Structure of Safety Information Neglect and Seven Years of Documented Cases

Medium / Product category: Product introduction video on a healthcare professional information website / Analgesic

What was done: Adverse events associated with high-dose use (hepatic disorder, ALT elevation) were described as "transient, with a tolerance effect." The representative further cited the absence of a correlation with a separate novel biomarker for which evidence was insufficient, and concluded that "ALT elevation does not directly reflect adverse events."

Why it was a violation: The original publication documented multiple cases of substantial dropout due to ALT elevation — hardly "transient." The package insert also carried a warning about high-dose use. This constituted a minimization of an adverse event that warranted serious caution.

Source quotation: "ALT elevation does not directly reflect adverse events" / "Transient, with a tolerance effect"

Medium / Product category: Oral explanation by company representative / Oncology drug

What was done: During product explanations on two separate occasions, the representative provided information only about efficacy and provided no safety information whatsoever. The drug in question was subject to an optimal use promotion guideline, making appropriate use requirements especially stringent.

Why it was a violation: Safety information was not provided not once but twice. Given the product's profile, the importance of safety information provision was particularly high.

Source quotation: (Report) "On two occasions during product explanations, the company representative provided information only about efficacy and did not provide any safety information."

Medium / Product category: Roundtable article on a healthcare professional information website / Antidiabetic drug (combination tablet)

What was done: The combination product's characteristics were described solely as "HbA1c-lowering effect regardless of renal function level." The precaution for patients with renal impairment in the package insert and the RMP key risk of "polyuria/pollakiuria" were addressed with the statement that "symptoms resolve within a few days after starting the medication, so fluid intake counseling within one week of initiation is sufficient" — a minimization of the safety concern.

Why it was a violation: Key items explicitly stated in the package insert and RMP were minimized and the duty to provide that information was neglected.

Source quotation: "Regarding polyuria/pollakiuria, which is listed as a key risk in the RMP, the article stated that 'symptoms resolve within a few days after starting the medication, so fluid intake counseling within one week of initiation is sufficient' — an article that appeared to minimize safety."

Medium / Product category: Oral explanation by company representative / Glaucoma/ocular hypertension drug

What was done: When a physician asked about the 14-day prescription limit applicable to new drugs, the representative explained: "A single bottle lasts one month, so monthly visit intervals are fine."

Why it was a violation: The representative encouraged a usage pattern that violated the prescription-day restriction for new drugs.

Source quotation: "A single bottle lasts one month, so monthly visit intervals are fine."

Medium / Product category: Oral explanation by company representative / Chronic constipation drug

What was done: At a company-sponsored study meeting, the representative was asked about the prescription-day limit for the new drug and replied that "dose titration is possible, so long-term use with appropriate adjustment is fine." The representative also volunteered — unprompted — that the drug is "a useful medication with few adverse events in the pediatric setting and should be recommended to physicians," without any explanation of the restriction that use is limited to cases where other constipation treatments have been inadequate.

Why it was a violation: In addition to encouraging use contrary to the prescription-day limit, the explanation omitted information about the use restriction (second-line status), creating an imbalance in safety and appropriate-use information.

Source quotation: "A useful medication with few adverse events in the pediatric setting and should be recommended to physicians" (without any explanation of the use restriction)

Medium / Product category: Presentation slides and oral explanation by company representative / COPD drug

What was done: A slide stated that "essentially all patients with asthma-complicated COPD are candidates for this drug." Although there are patients for whom use is not recommended due to an adverse event (increased pneumonia risk), the representative's oral explanation contained no mention of adverse events whatsoever.

Why it was a violation: Information provision that gave no explanation of adverse events and emphasized efficacy alone.

Source quotation: (Report) "In the MR's oral explanation, there was no mention whatsoever of such adverse events."

Medium / Product category: Web seminar on a healthcare professional information website / Chronic constipation drug

What was done: The web seminar emphasized only efficacy — "improvement in the change from baseline in spontaneous bowel movement frequency was demonstrated even in elderly patients" and "please make use of this drug for treating elderly patients" — while the review report, package insert, and interview form all stated that "data on safety in elderly patients are insufficient, and careful observation for adverse events is required." That information was not provided.

Why it was a violation: Efficacy-only information was provided while safety data in elderly patients remained inadequate.

Source quotation: "Please make use of this drug for treating elderly patients" (with insufficient safety information provided)

Medium / Product category: Oral explanation by company representative / Drug for renal anemia

What was done: When asked about the malignancy risk documented in the package insert and RMP, the representative named a competing product and replied: "The RMP for the competing product also lists a similar risk, so the RMP entry for our product should not be seen as a significant concern."

Why it was a violation: By invoking a competitor to relativize the risk, the representative presented the drug's own risk as though it were not a negative point — a minimization of safety.

Source quotation: "The RMP for the competing product also lists a malignancy-related risk, so the RMP entry for our product should not be seen as a significant concern."

Medium / Product category: Web seminar on company website (20-minute viewing time) / Anti-allergy drug

What was done: Throughout the web seminar, there was no reference to the patient population indicated or to the important precautions listed in the interview form. Safety information — including contraindications and precautions for use — was provided only by projecting the package insert for approximately ten seconds during the final slide.

Why it was a violation: Information provision was skewed toward efficacy. The ten-second projection of the package insert at the very end was functionally meaningless as safety information provision.

Source quotation: "Safety information — including contraindications and precautions for use — was provided only by projecting the package insert for approximately ten seconds during the final slide."

Medium / Product category: Materials provided by company representative / Parkinson's disease drug

What was done: At a product information meeting, RMP materials (appropriate use guide, patient medication guide) were distributed, but no explanation was given of those materials as defined under the RMP risk minimization plan, leaving safety explanation insufficient.

Why it was a violation: The RMP risk minimization plan was not carried out and safety explanation was insufficient.

Source quotation: "No explanation was given of materials such as the appropriate use guide as defined under the RMP risk minimization plan, resulting in information provision with insufficient safety explanation."

Medium / Product category: Materials provided by company representative / Chronic heart failure drug

What was done: At a product information meeting, explanation of the indicated patient population and potential risks necessary for risk-benefit assessment was insufficient. Implementation of the RMP risk minimization plan was also inadequate.

Why it was a violation: Information provision based on the RMP and explanation of the indicated patient population were insufficient, and necessary safety explanation was not given.

Source quotation: "Explanation of patient indication and potential risks necessary for risk-benefit assessment was insufficient."

Medium / Product category: Online meeting (explanation by company representative) / Drug for renal anemia

What was done: Despite the absence of comparative safety data against other drugs, the representative explained: "No adverse events were observed in domestic clinical trials, so this drug is safer than other agents."

Why it was a violation: Without comparative data, only the fact that no adverse events were observed was highlighted, and superiority over other agents was claimed without scientific basis.

Source quotation: "No adverse events were observed in domestic clinical trials, so this drug is safer than other agents."

Medium / Product category: Online meeting (explanation by company representative) / Drug for renal anemia

What was done: Without any quantitative data on Drug B, the representative made a comparison based solely on pharmacological mechanism differences and explained that the product produces a more gradual and superior hemoglobin rise than Drug B.

Why it was a violation: Superiority was claimed on the basis of pharmacological mechanism alone, without presenting quantitative data from trials demonstrating a difference.

Source quotation: "A comparison with Drug B was made based solely on differences in pharmacological mechanism."

Medium / Product category: In-person materials provided by company representative / Drug for Duchenne muscular dystrophy (DMD)

What was done: The representative described the drug as "highly safe" solely on the basis that no adverse events were observed in clinical trials.

Why it was a violation: A blanket claim of high safety was made on the basis of a single limited fact (no adverse events in the trial), ignoring the limitations of the trial's scale and duration.

Source quotation: "An explanation was given that the drug is highly safe, based solely on the fact that no adverse events were observed in clinical trials."

Medium / Product category: Online meeting (explanation by company representative) / Ophthalmic VEGF inhibitor

What was done: No slide materials were prepared for the primary endpoint; only the secondary endpoint that showed statistical significance was explained. The primary endpoint was not mentioned orally either.

Why it was a violation: The secondary endpoint with statistical significance was selected for explanation while the primary endpoint was deliberately omitted — a selective use of data.

Source quotation: "Explanation was received only for the secondary endpoint that showed statistical significance" / "No necessary explanation was provided for the primary endpoint."

Medium / Product category: Online information meeting (company representative) / Heart failure drug

What was done: Only the results of an overseas phase III trial showing statistical significance on the primary endpoint were explained; results of the domestic phase III trial that failed to reach statistical significance were not explained at all. The same pattern was confirmed at multiple facilities.

Why it was a violation: Only the favorable overseas trial results were selected for explanation, and the domestic trial (no significant difference) — an important evaluation document in the approval review — was deliberately omitted. Identical bias confirmed at multiple facilities indicates systematic information selection at the organizational level.

Source quotation: "Results of the domestic phase III trial that failed to show statistical significance were not explained at all" / "The same pattern was confirmed at multiple facilities in this case."

Medium / Product category: Video content in an online seminar organized by a sponsoring company / Antihypertensive

What was done: The presenter showed subgroup analysis results for the drug that had not been discussed in the review report or original publications, and emphasized the drug's efficacy in patients with a specific symptom profile. The sponsoring company had not reviewed the content in advance.

Why it was a violation: Efficacy was emphasized on the basis of subgroup analysis results not examined during regulatory review, creating the misleading impression that clinical utility had been established.

Source quotation: "The presenter showed subgroup analysis results for the drug that had not been discussed in the review report or original publications, and emphasized that the drug is effective in patients with that symptom profile."

Medium / Product category: Product brochure (mailed to medical institutions nationwide; same content also posted on the web) / Antidiabetic drug

What was done: Results from a long-term combination therapy trial — for which safety was the primary endpoint under the Guidelines for Clinical Evaluation of Oral Hypoglycemic Agents — were presented starting from the secondary endpoint (efficacy) results at the top of the brochure, foregrounding efficacy. The same content appeared in a PDF and video on the company website and in the interview form.

Why it was a violation: The order of results in a trial designed primarily for safety evaluation was reversed to put efficacy first. The trial design and sample size calculation were both based on safety evaluation, making it inappropriate to use the results as evidence of efficacy superiority.

Source quotation: "The results of the secondary endpoint (efficacy) of the domestic phase III long-term combination therapy trial were shown at the top" / "Efficacy was emphasized."

Medium / Product category: Online (company hearing for a pharmacy and therapeutics committee) / Cardiovascular drug

What was done: Although the package insert states that "the effect of suppressing progression to renal failure may be weaker in Japanese patients," the company representative made no mention of this during a hearing for the pharmacy and therapeutics committee. The point was disclosed only after being asked directly, via a separate slide not shown in the initial presentation. The review report states that superiority in the Japanese patient subgroup could not be demonstrated.

Why it was a violation: Despite ample time allotted by the hospital, negative information was apparently withheld — a skewed form of information provision.

Source quotation: "The effect of suppressing progression to renal failure may be weaker in Japanese patients" (stated in the package insert) / "Despite the hospital securing sufficient time for explanation, this appeared to be information provision in which negative information was deliberately not disclosed."

Medium / Product category: Online (information meeting for a hospital pharmacy department) / Antidiabetic drug

What was done: The representative projected a graph showing only the company's drug group from an animal study and explained: "Concentration-dependent increases in lactate levels have been confirmed in the concurrently conducted comparator group, which suggests that our drug carries a lower risk of lactic acidosis." The comparator group's graph was not shown. Lactic acidosis is designated as an "important potential risk" in the RMP.

Why it was a violation: Despite lactic acidosis being an RMP important potential risk, only a reduction in that risk was emphasized, without providing the accompanying safety information.

Source quotation: "Our drug is expected to carry a lower risk of lactic acidosis" (despite being designated an important potential risk in the RMP)

Medium / Product category: Direct in-person meeting (explanation by company representative) / Drug for congenital metabolic disorder

What was done: Information about a relaxation of the dosing limit in pediatric patients (now up to 30 mg) was provided, but the entire content amounted to "the dose can now go up to 30 mg," with no background, supporting data, or safety information. When the basis was requested, the representative replied "I cannot answer right away." Two weeks later, the only follow-up was delivery of an interview form with sticky notes attached. The adverse event section of the package insert had also been revised at the same time.

Why it was a violation: When communicating a change to dosing limits that directly affects prescribing, safety information was not provided alongside — skewed information provision. The concurrent revision to the adverse event section of the package insert was also left uncommunicated.

Source quotation: "Promotion that conveyed only that the dose can now be increased to 30 mg, without communicating any safety information."

Medium / Product category: Direct in-person meeting (explanation by company representative) / Drug for hyperkalemia

What was done: The representative told a physician that "[the drug] lowers potassium levels more than [a competitor's product]," but did not explain that the drug requires potassium monitoring for safety reasons.

Why it was a violation: Efficacy information alone is insufficient as safety information provision. This constituted safety-minimizing information provision.

Source quotation: "That point was not explained. This can be characterized as information provision that minimized safety."

Medium / Product category: Direct in-person meeting (explanation by company representative) / Antidiabetic drug

What was done: Asked why the product comes in many dosage strengths, the representative replied that "use for anti-obesity is anticipated; overseas, higher doses are used for anti-obesity indications." Without being asked, the representative also explained that the anti-obesity indication — not approved in Japan — was "under application." Weight-loss-related safety is designated as an "important potential risk" in the RMP.

Why it was a violation: Information that should be communicated as a safety concern (weight-loss risk) was presented from an efficacy standpoint, and off-label use was implied.

Source quotation: "There was also an explanation that the anti-obesity indication is currently under application" (weight loss being an RMP important potential risk)

Medium / Product category: Direct in-person meeting (explanation by company representative) / Antidiabetic drug

What was done: Showing a slide labeled "Reference information" and "Efficacy evaluation endpoints," the representative stated: "This drug is effective not only for diabetes but also for lipid parameters." The review report evaluates lipid effects as safety information linked to cardiovascular event risk — not as an efficacy parameter.

Why it was a violation: Presenting safety information as efficacy information gave clinicians a mistaken impression and also constituted an explanation that departed from the approved labeling.

Source quotation: "The relevant section was described as a safety parameter — not as an efficacy parameter."

Medium / Product category: Email direct mail (mass distribution) / Antiviral drug

What was done: When quoting a drug interaction table from the Japanese Society of Hepatology's hepatitis C treatment guidelines, the majority of interaction entries for the company's own product were not included, while interactions for competitor products were selectively presented. The email also made no mention of the contraindication in the package insert (patients with eGFR below 30) and described the drug as offering "consistent cure across patients with varied backgrounds."

Why it was a violation: The content created the false impression that the company's product has few drug interactions and is easy to use, while minimizing safety information including contraindications.

Source quotation: "The content was such that it created the false impression that the company's product has few drug interactions and is easy to use, while competitor products have many interactions and are difficult to use."

Medium / Product category: Direct in-person meeting (product information session in a pharmacy department) / Cardiovascular drug

What was done: At an approximately 20-minute in-person product information session in a pharmacy department, the representative concluded the explanation with statements such as "in two international joint clinical trials, significant reductions in a composite cardiovascular endpoint and a composite renal endpoint were each confirmed." The drug has a history of initially being denied regulatory approval in Japan because the hazard ratio for renal failure events in the Japanese patient subgroup exceeded 1; it was ultimately approved on the condition that a warning be added to the package insert. This history was not mentioned at all.

Why it was a violation: Despite ample time available, the explanation covered only benefit, without explaining risk-related safety information — skewed information provision.

Source quotation: "Explaining only benefit without explaining risk-related safety information constitutes skewed information provision."

Medium / Product category: Direct in-person meeting (explanation by company representative) / Metabolic drug (pediatric)

What was done: The representative communicated that the dosing limit for pediatric patients had been relaxed (up to 30 mg now allowed), but the entirety of the communication was limited to "dosing up to 30 mg is now possible," with no background, supporting data, or safety information whatsoever. When supporting data were requested, the representative replied "I cannot answer right away." Two weeks later, the only response was delivery of an interview form with sticky notes. The adverse event section of the package insert had also been revised at the same time.

Why it was a violation: When communicating a change to the dosing limit — a change that directly affects prescribing — safety information was not provided alongside. The concurrent revision of the adverse event section of the package insert was also not communicated.

Source quotation: "Promotion that conveyed only that the dose can be increased to 30 mg, without communicating safety information."