"It is off-label, but..." "There are physicians at other institutions who use it that way." These phrases mark the entry point into the most persistently repeated category of deviation in pharmaceutical sales information activities. The conduct takes many forms: implying efficacy in unapproved diseases, disregarding prescribing conditions or dosing intervals written into the package insert, explaining that a tablet without a score line "can be split in half." Each act distorts physician prescribing decisions and directly creates risk of patients receiving unvalidated treatment. From FY2019 through FY2025 — seven consecutive years — this category of deviation was recorded every year without exception.
So What / So Why — The Core of This Category
Drug approval is the government's certification of the "scope of use" for a medicine — the scope within which sufficient evidence has confirmed both efficacy and safety. Indications (which diseases the drug may treat) and dosage regimens (when and how much to administer) are approved together as a set. Everything outside that approval is a domain where evidence either does not exist or is insufficient.
Even so, the motivation for company representatives to share unapproved information with healthcare professionals is straightforward: a broader prescribing population means higher sales. If a physician can be made to think "this drug apparently works for X as well," the drug gains priority consideration whenever an approved-indication patient presents. And it is easy to fall into the illusion that prefacing a statement with "it is off-label, but" immunizes whatever follows. The Guidelines on Sales Information Activities for Prescription Drugs (hereafter "the Guidelines") explicitly reject this logic. The current rules are clear: provide unapproved information only when the healthcare professional asks for it, and a separate process governs the few cases where provision is permitted.
The consequences become vivid when viewed from the patient side. Suppose a physician adopts a shortened dosing interval after being told it would not trigger insurance rejection. If a serious adverse reaction that the package insert had flagged then occurs, there is no causal record and the patient falls outside the net of post-marketing safety surveillance. Hearsay — "there are physicians at other hospitals who prescribe it this way" — is not a substitute for evidence. Medical history has repeatedly documented how off-label practices that spread through word of mouth became the precursor to drug-induced injury.
It is no accident that the Guidelines place Category 1 — presenting unapproved indications or dosage regimens — first on the list. Every other form of deviation (exaggerated claims, explanations without evidence, downplaying safety) occurs downstream of the collapse of the foundational premise: speak accurately within the approved scope.
What / Where / Why / How — What Guideline Provisions Were Violated
What: The specific conduct involved
The incidents fall into four broad patterns. (1) Implying efficacy in unapproved diseases — "it is also effective for X," "there are physicians at other institutions who use it that way." (2) Recommending dosing outside the approved regimen — "shortening the interval will not trigger an insurance rejection," "the tablet can be split," "there are cases where it is administered at 0.3 mg/kg/hour." (3) Proactively providing pre-approval or pending-approval information without being asked — "approval is expected," "we are currently in the application process, but..." (4) Implying that prescribing conditions can be skipped — "there are cases where it is prescribed as long as the physician has completed training, even if other staff have not."
Where: The channels and settings involved
Verbal explanations by medical representatives — product briefings within hospitals and individual meetings — account for the largest share, but incidents occur across every contact channel: online meetings, telephone calls, web seminars, training sessions hosted on healthcare professional information sites, and joint briefings co-hosted by pharmaceutical and medical device companies. From FY2024 onward, slide decks distributed at sponsored lectures have also come under scrutiny.
Why: The underlying psychological drivers
Among the four deep psychological drivers identified in the Guidelines framework, the two that operate most strongly in this category are "local rationalization" and "motivated reasoning." Representatives excuse themselves through situational justifications — "I prefaced it with 'off-label,' so there is no problem," "the physician asked, so I answered" (local rationalization). Or a prior conviction — "this drug really should work for X" — drives a search for evidence to support it after the fact (motivated reasoning). In pre-approval information cases, a third driver overlaps: "responsibility externalization," where the representative guides the conversation toward the topic while maintaining the fiction that the healthcare professional initiated it.
How: The specific guideline provisions violated
The Guidelines (MHLW Notification No. 0925 Dai-1-go, dated September 25, 2019) state explicitly that sales information activities must not include descriptions outside the approved scope regarding indications and dosage regimens (Guidelines Section 3-2(1)(a)), and must not proactively provide unapproved information unless the healthcare professional requests it (Section 3-2(1)(b)). Information on pre-approval products is subject to separate restrictions under Section 3-2(2).
The applicable statutes are Article 66 of the Pharmaceuticals and Medical Devices Act (prohibition of false or exaggerated advertising) and Article 68 (prohibition of advertising pre-approval drugs). The Standards for Appropriate Advertising of Pharmaceutical Products (Ministry of Health, Labour and Welfare) prohibit expressions that exceed the approved scope of indications and dosage regimens. The Japan Pharmaceutical Manufacturers Association Code on promotional materials likewise requires that indications and dosage regimens remain within the approved scope.
Incidents — A Complete Account
FY2019 — 8 incidents
Channel / Product area: Analgesic / verbal (product briefing)
What was done: After prefacing the statement with "it is off-label," the representative stated that "there are physicians at other institutions who use it for respiratory depression," implicitly recommending off-label use.
Where the deviation lies: A disclaimer prefix does not change the fact that describing off-label use cases constitutes a recommendation.
Original statement: "There are physicians at other institutions who use it for respiratory depression."
Channel / Product area: Dyslipidemia drug / slide and verbal (hospital study session)
What was done: A slide labeled "general discussion" included a patient profile showing diabetes and a postprandial triglyceride graph, creating the impression that the drug was effective in diabetes — an unapproved indication. At a separate institution the representative stated that "a substance extremely close to this drug" "improves insulin responsiveness."
Where the deviation lies: A labeling device was used to wrap an unsupported association and imply an unapproved indication.
Original statement: "A substance extremely close to this drug" / "improves insulin responsiveness."
Channel / Product area: Antifungal drug / verbal (new drug hearing)
What was done: For a disease outside the approved indications, the representative explained without any basis that "it is probably thought to be effective."
Where the deviation lies: Efficacy in an unapproved disease was presented as speculation rather than evidence.
Original statement: "It is probably thought to be effective."
Channel / Product area: Parkinson's disease drug / verbal
What was done: Despite the package insert specifying a dosing interval to prevent serious adverse reactions, the representative explained to multiple institutions across the region that "there is no clear evidence for the dosing interval, and shortening it will not trigger an insurance rejection."
Where the deviation lies: The representative used the absence of an insurance penalty as justification for permitting deviation from the package insert dosing interval restriction.
Original statement: "Shortening it will not trigger an insurance rejection."
Channel / Product area: Diabetes drug (combination product) / verbal (hearing)
What was done: After discussing the weight-reduction effect of a component ingredient, the representative presented "the effect of this drug on body weight" as reference information, implying efficacy in weight reduction — an unapproved indication.
Where the deviation lies: The "reference information" framing was used to imply an unapproved indication.
Original statement: (Reference to the drug's effect on body weight presented as supplementary information)
Channel / Product area: Chronic constipation drug / training session on a healthcare website
What was done: At a training session titled "Preventing Drug-Induced Constipation," the drug was explained after a general discussion of drug-induced constipation (an unapproved indication). The unapproved nature was relegated to a footnote; the main explanation stated only "softens stool and promotes evacuation" and "the indication is chronic constipation."
Where the deviation lies: The training session's title itself implied an unapproved indication, and disclosure of the unapproved nature was inadequate.
Original statement: "Preventing Drug-Induced Constipation" (session title)
Channel / Product area: Antithrombotic drug / verbal
What was done: When the hospital declined to adopt a new formulation (20 mg) under a one-in-one-out policy, the representative proposed discontinuing the existing 2.5 mg and crushing the 3.75 mg to adjust dosing. No crushing administration guidance appears in the package insert; the proposal constituted off-label use.
Where the deviation lies: To avoid losing a listed product, the representative proposed off-label crushing administration as an alternative.
Original statement: (Proposal to crush the 3.75 mg and adjust dosing)
Channel / Product area: Dyslipidemia drug / verbal
What was done: The drug requires co-administration with another agent. The representative stated: "If you prescribe a cheap drug like a generic alongside it and tell the patient there is no need to take it, you can use this drug as monotherapy without triggering an insurance rejection. There are actually physicians who prescribe it that way."
Where the deviation lies: The representative proposed a prescribing manipulation to evade insurance review, effectively nullifying the combination therapy that the package insert presupposes.
Original statement: "There are actually physicians who prescribe it that way."
FY2020 — 11 incidents
Channel / Product area: Chronic constipation drug / verbal (product briefing)
What was done: Despite the approved dosing being once daily before meals, the representative told individual healthcare professionals before the briefing that "it works even as an as-needed dose, though that is off-label" and "taking it after meals is not a problem." At a pharmacy department briefing the representative spontaneously stated that "administering after meals does not cause particular problems," recommending off-label use.
Where the deviation lies: As-needed and post-meal use — both deviations from the approved regimen — were actively introduced and recommended.
Original statement: "Using it after meals is not a problem."
Channel / Product area: Depression treatment drug / product briefing
What was done: Despite the approved dosing being once daily at bedtime, the representative stated: "Taking half the dose in the morning and half at night suppresses drowsiness better, and there are physicians who do it that way."
Where the deviation lies: Split morning-and-night dosing — differing from the approved regimen — was recommended by citing "other physicians" as examples.
Original statement: "Taking half the dose in the morning and half at night suppresses drowsiness better, and there are physicians who do it that way."
Channel / Product area: Anticancer drug / verbal
What was done: The drug had efficacy data after treatment with Agent A but not after Agent B. When a physician was considering it as second-line therapy after Agent B, the representative explained verbally that "no other drug has data for second-line after Agent B either, so there is no particular problem using this drug."
Where the deviation lies: The absence of data for other drugs was used to justify off-label use without evidence.
Original statement: "There is no particular problem using this drug."
Channel / Product area: Analgesic / verbal (pharmacy department briefing)
What was done: Prefacing the remarks with "it is off-label" and "overseas guidelines state," the representative — without being asked — described that "effects can be expected for dyspnea and cough cases, similar to morphine" and that "it may be the first-choice drug in dyspnea patients with renal impairment," introducing indications not approved in Japan.
Where the deviation lies: Regardless of the disclaimer, unapproved indications were proactively introduced and recommended without solicitation.
Original statement: "Effects can be expected for dyspnea and cough cases, similar to morphine."
Channel / Product area: Chronic constipation drug / verbal (department explanation)
What was done: The representative told a department's physicians that "compared with non-stimulant laxatives, this drug has the shortest time to onset of action," which led to recommendation of as-needed use. As a result, the department incorporated the drug into a clinical pathway as a pre-procedure preparation agent — an off-label use.
Where the deviation lies: An explanation of the drug's characteristics systematically embedded off-label as-needed prescribing into institutional practice.
Original statement: (Emphasis on shortest onset time led to clinical pathway adoption for an off-label indication)
Channel / Product area: Antibacterial drug / web seminar
What was done: The representative presented data showing that "other drugs have poor tissue penetration in diabetic foot lesion patients" and that "this drug achieves tissue concentrations equivalent to blood concentrations," then concluded that "efficacy can be expected in diabetic foot lesions as well." However, diabetic foot lesion patients had been excluded from the drug's clinical trials, making efficacy in that population unclear.
Where the deviation lies: Data from an excluded patient population was used to imply efficacy in an unapproved indication.
Original statement: "Efficacy can be expected in diabetic foot lesions as well."
Channel / Product area: Antipsychotic / verbal (immediately before an in-hospital study session)
What was done: Asked whether prescriptions at other hospitals were increasing, the representative answered: "Rather than Disease A (the approved indication), it is often used in patients with Disease B or Disease C (unapproved indications) who have difficulty with oral intake," creating the impression that use in unapproved diseases is common.
Where the deviation lies: The response went beyond the scope of the question and implied that prescribing for unapproved diseases is standard practice.
Original statement: "It is often used in patients with Disease B or Disease C (diseases not in the approved indications)."
Channel / Product area: Anticancer drug / verbal
What was done: The company representative requested an appointment on their own initiative — the pharmacist had not made any inquiry. One day before regulatory approval, the representative provided information on a pre-approval combination regimen involving Drugs A and B.
Where the deviation lies: One day before approval, the company proactively provided pre-approval information without any request from the healthcare professional.
Original statement: (Pre-approval combination therapy information was provided one day before regulatory approval)
Channel / Product area: Dementia drug / verbal
What was done: The representative opened the conversation by asking whether a generic would be coming out the following month. When the pharmacist said they were not sure, the representative guided the conversation toward the drug's name, then said "we cannot bring this up before approval" while proceeding to promote a pre-approval product. The pharmacist had not voluntarily made any inquiry; the direction came from the representative.
Where the deviation lies: A pre-approval product was actively promoted while creating the appearance that the healthcare professional had initiated the inquiry.
Original statement: "We cannot bring this up before approval" (stated while conducting promotion)
Channel / Product area: Renal anemia drug / verbal (physician explanation)
What was done: When explaining a switch to a generic, the representative described only the drug pricing of the generic product and made no mention whatsoever of the difference in approved indications between the originator and the generic.
Where the deviation lies: Critical approval information — the difference in indications — was withheld, creating the potential for inappropriate use.
Original statement: (No explanation of the difference in approved indications between the originator and generic was provided)
Channel / Product area: Tissue adhesive / joint briefing by pharmaceutical and medical device companies
What was done: At a joint briefing, a medical device company representative delivered a detailed presentation — with photographs — on off-label use of the tissue adhesive following tongue cancer resection. The pharmaceutical company representative did not contradict any of this explanation.
Where the deviation lies: The joint briefing format was used to effectively endorse and jointly promote off-label use.
Original statement: (Off-label use after tongue cancer resection — where tissue closure by suture is possible — was described in detail, with no rebuttal from the pharmaceutical company)
FY2021 — 4 incidents
Channel / Product area: Antipsychotic / online meeting
What was done: An indication had been approved for the injectable formulation but not for the oral formulation. The representative verbally explained that "the indication available for the injectable is also approved for the oral formulation."
Where the deviation lies: The representative conflated the approved indications of the injectable and oral formulations, effectively recommending off-label use of the oral product.
Original statement: "I was verbally told that the indication available for the injectable is also approved for the oral formulation."
Channel / Product area: Anti-influenza drug / explanation by pharmaceutical wholesaler representative
What was done: The representative said: "Approval is expected for an expanded indication — would you be all right without stocking this product?" thereby referencing an unapproved indication while promoting stock acquisition.
Where the deviation lies: An anticipated but unapproved indication expansion was used to drive inventory purchasing — a promotional act based on pre-approval information.
Original statement: "Approval is expected for an expanded indication — would you be all right without stocking this product?"
Channel / Product area: Alcohol dependence treatment drug / verbal (company information line)
What was done: The package insert requires training completion by physicians, nurses, and other relevant staff as a prescribing condition. The representative stated: "There are cases where it is prescribed as long as the physician has completed training, even if other staff have not received training."
Where the deviation lies: The representative implied that the prescribing conditions explicitly stated in the package insert need not be followed, undermining the risk management framework.
Original statement: "There are cases where it is prescribed as long as the physician has completed training, even if other staff have not received training."
Channel / Product area: Insomnia drug / verbal
What was done: The drug was within one year of approval and long-term prescribing was not yet permitted. The representative proposed: "By prescribing two tablets of half the dose for 14 days, you can effectively provide a 28-day supply."
Where the deviation lies: The representative actively recommended a prescribing workaround that circumvented the regulatory intent behind the long-term prescribing restriction — namely, confirming the real-world safety profile of a new drug within a short period.
Original statement: "By prescribing two tablets of half the dose for 14 days, you can effectively provide a 28-day supply."
In the source report, this incident is classified under ⑧-1 (other); it is included here because the conduct involved actively promoting a dosage regimen workaround that circumvented the approved prescribing period restriction.
FY2022 — 3 incidents
Channel / Product area: SGLT2 inhibitor / in-person
What was done: Without any request from the healthcare professional, the representative stated: "There is no approved indication for HFpEF (heart failure with preserved ejection fraction), but efficacy has been reported in the literature. Because a chronic kidney disease indication has been added to this drug, physicians are saying it has become easier to prescribe for HFpEF patients by assigning a chronic kidney disease diagnosis." The cited literature was data from a competitor's product.
Where the deviation lies: The representative recommended prescribing for an unapproved disease through diagnosis coding manipulation — a method of achieving off-label use in a form that passes insurance review.
Original statement: "Physicians are saying it has become easier to prescribe by assigning a chronic kidney disease diagnosis."
Channel / Product area: Insomnia drug (no score line) / telephone
What was done: When a physician said it would be easier to use at half the dose, the representative told the physician that "this tablet can be split in half" and then called the pharmacy department to say "it seems the pharmacy staff are not aware that this tablet can be split in half." The tablet has no score line. A check with the company's call center confirmed "there is no data on half-tablet administration." The company's own website stated "we do not recommend splitting the tablet."
Where the deviation lies: The representative actively spread information to multiple departments claiming a tablet could be split, contradicting the company's own official information and without any supporting data.
Original statement: "There is no data on half-tablet administration." (Call center confirmation)
In the source report, this incident is classified under ③-5 (explanation without evidence); it is included here because recommending tablet-splitting for a product with no score line and no supporting data constitutes a deviation from the approved dosage regimen.
Channel / Product area: Anesthetic / in-person
What was done: Without being asked, the representative stated: "At institutions that are actually using it, administration at 0.6 mg/kg/hour or 0.3 mg/kg/hour is used rather than 1 mg/kg/hour" — a dosage regimen not in the package insert. When asked to provide supporting literature, the response was: "It is a newly launched drug, so there are no published papers or conference presentations; they will probably be published in the future."
Where the deviation lies: An off-label low-dose regimen was recommended without solicitation, and the absence of any supporting evidence was subsequently acknowledged.
Original statement: "Administration at 0.6 mg/kg/hour or 0.3 mg/kg/hour is used."
In the source report, this incident is classified under ③-10 (dosage regimen without evidence); it is included here because the conduct involved proactively recommending dosage regimens not described in the package insert.
FY2023 — 1 incident
Channel / Product area: Monoclonal antibody / in-person
What was done: The approved indication is "pruritus associated with *** (only in cases where existing treatments have been inadequate)." The representative explained that "efficacy has been observed for skin rash occurring after pruritus." The supporting data cited was a secondary endpoint (EASI improvement) from a domestic Phase 3 trial.
Where the deviation lies: Efficacy in skin rash — an unapproved condition — was described using secondary endpoint data, effectively recommending off-label use.
Original statement: "Efficacy has been observed for skin rash occurring after pruritus."
FY2024 — 2 incidents
Channel / Product area: Dermatitis drug (approved for atopic dermatitis) / in-person (pharmacy department hearing)
What was done: At a pharmacy department hearing, the representative stated that "this drug is being used for pruritus in dialysis patients." When the approved indication was verified and data was requested, the representative answered "there is no data."
Where the deviation lies: Use in an unapproved population (dialysis patients with pruritus) was presented as established fact, carrying the potential to lead the listener toward off-label use.
Original statement: "This was an explanation that could cause misperception leading to recommendation of off-label use." (Report assessment)
Channel / Product area: Diabetes drug / in-person
What was done: Asked why the product comes in multiple strengths, the representative replied that the drug "is intended for anti-obesity use" and "overseas, the higher strengths are used for anti-obesity." Without being asked a follow-up question, the representative added: "It is off-label in Japan, but an application for the anti-obesity indication is currently under review."
Where the deviation lies: Without any request from the healthcare professional, the representative proactively mentioned a pending application for an unapproved indication.
Original statement: "There was also an explanation that an application for the anti-obesity indication is currently under review."
In the source report, this incident is classified under ⑥-2 (efficacy-only emphasis); it is included here because the conduct included unsolicited reference to an unapproved indication and proactive disclosure of a pending application.
FY2025 — 2 incidents
Channel / Product area: Antineoplastic drug / in-person (hospital product briefing)
What was done: An MR and a medical affairs officer visited the hospital. The medical affairs officer stated: "The current approval covers only *** cancer, but the target protein is expressed in almost all solid tumors. It will become usable across all cancer types. Both Drug A and this drug are expected to expand their indications, and either will be an option going forward."
Where the deviation lies: Without any request from the healthcare professional, the representative proactively provided information on planned indication expansions to numerous unapproved cancer types.
Original statement: "Despite no request from the healthcare professional, unapproved indications were discussed." (Report assessment)
Channel / Product area: Allergy drug (injectable) / slides at a company-sponsored lecture
What was done: At a company-sponsored lecture, the physician speaker repeatedly described short-infusion and low-dose long-term administration methods differing from the approved dosage regimen. Without any supporting evidence, the speaker stated that "Drug A and Drug B are completely identical, so switching is safe," and presented examples of switching from a competitor's Drug B. The final slide stated "Drug A is safe, simple, and offers great patient benefit." Slides prepared by the speaker were distributed to attendees without prior review by the company's sales information oversight department, and subsequent corrective action was inadequate.
Where the deviation lies: This is the most serious incident in the dataset, combining multiple guideline violations: recommending an unapproved dosage regimen, an unsupported equivalence claim (disparagement of a competitor product), omission of safety information, and distribution of materials that had not undergone mandatory prior review.
Original statement: "Materials prepared by the speaker were distributed to attendees who wished to receive them without prior review by the sales information oversight department."
Learning from Past Incidents ── Map of 9 chapters
- Part 1: Data Misuse and Manipulation That Risk Factual Misrepresentation
- Part 2: Selective Data Extraction, Manipulation, and Presentation
- Part 3: Claims Without Evidence / Unreliable Data
- Part 4 (this chapter): Presenting Unapproved Indications and Dosage Regimens
- Part 5: Exaggerated Claims
- Part 6: Efficacy-Only Promotion / Safety Information Neglect
- Part 7: Disparagement of Competing Products
- Part 8: COI Non-Disclosure
- Part 9: Other Improper Sales Practices
- "It is off-label, but. .." does not constitute a disclaimer. Providing unapproved information after such a preface is a guideline violation in exactly the same way as providing it without one. The default rule is: do not provide it unless asked.
- The absence of an insurance penalty and clinical safety are separate matters. Telling a physician that a non-standard dosing interval "will not trigger an insurance rejection," or that a diagnosis can be coded in a way that makes off-label prescribing pass review, destroys the foundation of safety oversight — this is not a procedural issue but a direct patient risk.
- A tablet without a score line split in half, a dosage lower than the package insert specifies, a prescribing condition quietly dropped — these may appear to be minor deviations, but they place patients outside the net of post-marketing safety surveillance. Incidents where representatives actively spread information contradicting their own company's official guidance have also been reported.
- Guidelines on Sales Information Activities for Prescription Drugs (Ministry of Health, Labour and Welfare, Notification No. Yakusei-Kanma-hatsu 0925 Dai-1-go, September 25, 2019)
- Monitoring Program for Sales Information Activities on Prescription Drugs — Annual Report FY2019 (MHLW commissioned project)
- Monitoring Program for Sales Information Activities on Prescription Drugs — Annual Report FY2020 (MHLW commissioned project)
- Monitoring Program for Sales Information Activities on Prescription Drugs — Annual Report FY2021 (MHLW commissioned project)
- Monitoring Program for Sales Information Activities on Prescription Drugs — Annual Report FY2022 (MHLW commissioned project)
- Monitoring Program for Sales Information Activities on Prescription Drugs — Annual Report FY2023 (MHLW commissioned project)
- Monitoring Program for Sales Information Activities on Prescription Drugs — Annual Report FY2024 (MHLW commissioned project)
- Monitoring Program for Sales Information Activities on Prescription Drugs — Annual Report FY2025 (MHLW commissioned project)
- Pharmaceuticals and Medical Devices Act (PMD Act), Article 66 (Prohibition of false or exaggerated advertising) and Article 68 (Prohibition of advertising pre-approval pharmaceuticals)
- Prescription Drug Advertising Monitoring Program — Annual Reports (Ministry of Health, Labour and Welfare)
- Guidelines for the Preparation of Prescription Drug Product Information Summaries (Japan Pharmaceutical Manufacturers Association)