For Cancer Uses, Medically Acceptable Uses of Antineoplastics and Biologics

A formal determination process has been developed to supplement the long-standing evidence-based process by AHFS for evaluation of off-label cancer uses of drugs and biologics. A Final Determination Report for each off-label use will be published on the AHFS website and will reflect the consensus vote of the members of the AHFS Oncology Expert Committee.

Determinations that appeared on this portion of the website prior to January 1, 2010, have been incorporated into the respective drug monographs in the AHFS DI database. Determinations subject to CMS’ revised definition of medically accepted indications, related to Section 182(b) of the Medicare Improvements for Patients and Providers Act of 2008 (MIPPA) and effective as of January 1, 2010, will be posted on this portion of the website as they are finalized.

The mission of AHFS Drug Information® (AHFS DI®) is to provide an evidence-based foundation for safe and effective drug therapy. AHFS DI has the unique distinction of being the longest published and only remaining federally designated drug compendium issued by a scientific and professional society — the American Society of Health-System Pharmacists (ASHP). As such, AHFS DI maintains a unique role in establishing medically accepted uses of drugs. Federal compendial recognition of this role exists under part 456 of CMS regulations governing utilization control for Medicaid and under sections 1927 and 1861 of the Social Security Act.

AHFS DI is a tested and proven source of comparative, unbiased, and evidence-based drug information. Drug monographs, and final determinations specifically published for medically acceptable off-label uses, are prepared by a professional editorial and analytical staff, who critically evaluate published evidence. AHFS does not accept authorship of material published in either a monograph or an off-label final determination from external sources (e.g., practitioners, pharmaceutical manufacturers). Instead, it relies solely on its own professional staff, qualified by education, training, and experience, to research, analyze, draft, and finalize information contained in AHFS DI monographs.

Using an independent, evidence-based, evaluative process, AHFS DI monographs and final determinations for off-label uses incorporate information from pertinent references in the literature and expert therapeutic guidelines and include clinical data on uses, dosages, and routes and/or methods of administration that may not be included in the FDA-approved labeling for the drug (“off-label/unlabeled uses”). An editorial independence statement, approved by ASHP’s Board of Directors, outlines the principles that AHFS staff apply in ensuring such independence.

Evidence-based Information Analysis for Off-label Uses

Analysis of information is an intramural process performed by a professional staff of drug information analysts and editors with strong scientific and therapeutic backgrounds. Conducting the process with a professional staff provides a high level of quality control and consistency in content development. The process involves assessment of the scientific merits of available data, typically drawn from numerous references.

When AHFS staff perform a review for an unapproved use, the following elements are considered:

• availability of published reports of well-designed clinical studies
• support in peer-reviewed literature
• assessment of the level of evidence reflected in published reports and systematic reviews
• absence of potential clinically important concerns about the drug such as increased toxicity with no substantial therapeutic gain
• positive therapeutic perspective as reflected by clinical evidence, expert opinion, best practices, and/or authoritative guidelines

The importance and severity of the disease, availability of alternative therapies and their relative toxicities, the number of patients affected by the disease, other patient population considerations (e.g., age, gender, pharmacogenomics), and other factors (e.g., cost and economic considerations) also are important considerations. Adding to the weight of evidence are the strength of efficacy data, availability of independent confirmatory studies, support in other peer-reviewed literature (e.g., meta-analyses and other systematic reviews, editorials, disease and drug therapy reviews), recommendations of authoritative groups (e.g., CDC, NIH), evidence of improved risk-to-benefit ratios (including compliance) relative to existing therapeutic alternatives, evidence of a new mechanism or site of action relative to existing alternatives, and evidence of improved pharmacokinetics or pharmacodynamics.

Positive commentary depends on the level of such evidence and expert assessment of the clinical role and importance of the drug as part of reasonable/good medical practice and care. Because of the descriptive nature of the type of drug information published by AHFS, the strengths and limitations of available evidence, as well as any lack of consensus, about the specific role of the drug can be described if necessary.

In addition to this descriptive method of presenting the evidence and recommendations concerning the use of drugs, AHFS DI initiated a codified process for objectively summarizing the level of evidence and strength of recommendation for drugs and biologics used in cancer chemotherapeutic regimens.

Codified Levels of Evidence-Cancer Specific

The decision to create a separate method resulted from the unique characteristics of evidence-based decisions that are applied to serious and life-threatening conditions such as cancer. The principal difference in assessing cancer use information is the inclusion of an indicator of the strength of study end points (e.g., survival, quality of life) in the evidence ratings. In addition, the types and quantity of clinical data that can support a given use will vary depending on the cancer use being evaluated, the availability and acceptability of other therapies, and the specific observations reported in the studies. For example, in refractory cancers where therapies with meaningful benefit are unavailable or there is evidence of improvement over other available therapies, evidence that is reasonably likely to predict clinical benefit (surrogate evidence) can be acceptable. Under such circumstances, even evidence from unblinded, single-arm studies with drugs exhibiting a relatively high degree of toxicity may be acceptable. This approach by AHFS is consistent with distinctions applied to evidence-based assessments of cancer treatments by both the National Cancer Institute (NCI) and FDA.

A formal determination process has been developed to supplement the long-standing evidence-based process by AHFS for evaluation of off-label cancer uses of drugs and biologics.

A Final Determination Report for each off-label use will be published on the ASHP website and will reflect the consensus vote of the members of the AHFS Oncology Expert Committee. Determinations that appeared on this portion of the website prior to January 1, 2010, have been incorporated into the respective drug monographs in the AHFS DI database.

Final Determination Reports

Listed below are the Final Determination Reports published for each off-label use. These reports reflect the consensus vote of the members of the AHFS Oncology Expert Committee.

• Off-label Use of Dostarlimab-gxly as Neoadjuvant Therapy for Adult Patients with Locally Advanced, dMMR/MSI-H Rectal Cancer
• Off-label Use of Ivosidenib for Treatment of IDH Mutant Glioma
• Off-label Use of Abiraterone Plus Prednisolone and Androgen Deprivation Therapy (ADT) for Nonmetastatic Castration-sensitive Prostate Cancer
• Off-label Use of Ripretinib as Second-line Treatment for Gastrointestinal Stromal Tumor (GIST)
• Off-label Use of Vemurafenib for Relapsed/Refractory Hairy Cell Leukemia

Approved by the American Society of Health-System Pharmacists Committee on Publications and Board of Directors

The mission of AHFS Drug Information (AHFS DI) is to provide an evidence-based foundation for safe and effective drug therapy. Information included in AHFS DI shapes treatment decisions made by clinicians and influences public and private health care policy and decisions. As a result, it is important that the information be authoritative, objective, and free of undue influence from pharmaceutical manufacturers, health insurers, pharmacy benefits managers, and other third parties who may seek to use the compendium to promote their own vested interests. Editorial decisions are evidence-based and made independent of such third parties; final decisions are made solely by the AHFS editorial staff, taking into account the advice of expert reviewers.

Widely trusted for its established record in refuting unfounded efficacy claims, its rigorous science-based editorial process, and its independence from the influence of pharmaceutical manufacturers, AHFS DI has remained true to its mission for almost 65 years.

AHFS DI is the only remaining official drug compendium published by a non-commercial entity (i.e., by a tax-exempt [“nonprofit”] professional association). The American Society of Health-System Pharmacists (ASHP) is an IRS 501(c)(6) tax exempt entity. ASHP is the national professional association that represents pharmacists who practice in inpatient, outpatient, homecare, and long–term–care settings. ASHP has a long history of fostering evidence–based medication use as well as patient medication safety—efforts designed to help pharmacists improve their delivery of pharmaceutical care.

AHFS DI is published by ASHP under the authority of its elected Board of Directors. As such, the Board exercises oversight through its ongoing Society considerations as well as through its Committee on Publications. This oversight by the Board also involves review and approval of relevant recommendations originating from its appointed Commission on Therapeutics and the advisory and best practices developments of its Councils, House of Delegates, and other policy–recommending bodies. In addition, experts participate in an ongoing extramural review process for AHFS DI. These experts must provide full disclosure of interest, including any affiliation with or financial involvement in the manufacturer of the drug(s) under consideration and directly competitive products.

ASHP considers it essential that interactions between AHFS and pharmaceutical manufacturers be limited to the legitimate exchange of the scientific and medical information needed to fulfill the mission of AHFS DI. To maintain independence from the undue influence of the promotional interests of pharmaceutical manufacturers, communications are directed to the scientific and medical information areas within the companies; contact with marketing areas is avoided.

ASHP holds in high regard the responsibilities attendant to the public and private trust placed in the evidence–based editorial deliberations of AHFS. As such, ASHP also considers it essential to protect the integrity and independence of the editorial decisions of AHFS staff by separating the Society’s business activities with pharmaceutical manufacturers (e.g., exhibits at educational meetings, journal advertising) from the editorial activities of its drug compendium. AHFS staff apply the following principles of editorial independence in weighing the propriety of their conduct:

1. AHFS staff should avoid participating in business discussions with pharmaceutical manufacturers and other ASHP staff should avoid engaging AHFS staff in such discussions.
2. AHFS staff must disclose any potential financial conflicts of interest or other external activities that may affect their editorial decisions on specific drugs. AHFS staff should not hold financial interests that conflict or may influence the conscientious performance of their editorial duty.
3. AHFS staff may not solicit or accept any gift or other item of monetary value from any individual or entity seeking official action or influence from the compendium nor from those whose interests may be substantially affected by the performance or nonperformance of the staff’s editorial duties.
4. AHFS staff have an obligation to act impartially and not give preferential treatment to any interested individual or organization that might influence their editorial decisions.
5. AHFS staff should avoid actions that might create the appearance that they are violating these principles of ethical conduct and editorial independence. Any such behavior shall be judged from the perspective of a reasonable individual in a similar situation with knowledge of the relevant facts. When necessary, the expert advice of other staff (e.g., professional practice, corporate counsel) should be sought.
6. On occasion, ASHP may determine that the Society’s interest in the staff’s participation in a particular activity or discussion outweighs any concern that a reasonable individual might question the integrity of the activity.
7. AHFS staff members with questions about their activities that are not addressed by these principles on editorial independence shall refer their questions to the Vice President of Publishing and Editor of AHFS.

The mission of AHFS is to provide an evidence-based foundation for safe and effective drug therapy. A key component to this mission is the ongoing evaluation of evidence concerning off-label uses of drugs. Section 1861 of the Social Security Act established AHFS DI as an official compendium for determining medically accepted indications of drugs and biologics used in cancer chemotherapeutic regimens under Medicare Part B. AHFS DI meets the definition of a compendium as established in Section 414.930 of the Code of Federal Regulations (CFR) and has implemented enhancements to meet the desirable characteristics of compendia for use in determining medically accepted indications of drugs and biologics in anticancer therapy as recommended by the Centers for Medicare and Medicaid Services (CMS) Medicare Evidence Development and Coverage Advisory Committee (MedCAC). AHFS DI also has implemented policies and procedures to comply with the conflict of interest and transparency requirements for compendia as established by amended CFR Section 414.930(a); these requirements apply to determinations of medical acceptance in anticancer therapy made on or after January 1, 2010.

The following procedures, effective as of January 1, 2010, outline the process used by AHFS for determination of the medical acceptance of off-label uses for drugs and biologics in cancer chemotherapeutic regimens under Medicare Part B.

The process for determination by AHFS is transparent and mitigates potential conflict of interest in order to preserve the compendium’s integrity and minimize bias. Strict firewall and conflict of interest polices are in place between AHFS staff and outside interests, to prevent any undue influence.

Selection of Off–label Oncology Uses for Consideration by the AHFS Oncology Expert Committee

Potential off-label oncology uses selected for consideration and review by the AHFS Oncology Expert Committee are identified by AHFS staff through either an internal process (i.e., ongoing literature review, advice of the Expert Committee) or an informal external request. External requests for consideration of off-label oncology uses may be submitted to AHFS via email to ahfs@ashp.org; the subject line of the email should state “Off-label Use Request”. AHFS employs a publicly transparent process for evaluating therapies as defined by CFR Section 4141.930(a) and that includes criteria used to evaluate the use, a listing of evidentiary materials reviewed by the compendium, and a listing of all individuals who participated substantively in the development, review, or disposition of the request.

For the purposes of establishing medical acceptance, preference is given to clinical studies that have been published in a peer-reviewed journal and present results addressing the study objectives defined a priori. Clinical information from professional meetings, in the form of abstracts, posters, or presentations, may be considered under certain circumstances, especially if the information represents fully completed studies or is in response to a data safety monitoring board (DSMB) request. In addition, information from professional meetings may be considered for use in updating descriptive information for a trial summarized in an existing off-label determination (e.g., to reflect data from longer-term follow-up of study participants). Interim results typically are addressed only when they add importantly to the understanding of an existing off-label use (e.g., new information about potential toxicity, evidence about major changes in outcomes relative to previous findings) or a major clinical breakthrough seems likely. Both the quality of evidence and the clinical importance of the use, as reflected by the following criteria, are considered by AHFS staff when selecting an off-label use for review by the AHFS Oncology Expert Committee:

• Clinical results from a well-designed and well-conducted phase 3 randomized trial comparing a novel regimen with a reasonable ‘standard of care’ (e.g., adequate sample size, full reporting of study end points)
• Clinical results from a well-designed and well–conducted phase 2 trial in rare and refractory cancers for which there is no well-established regimen
• Clinical results from a trial demonstrating a difference (improvement or worsening) in outcomes (responses, survival, quality of life, toxicity) compared with a reasonable standard of care
• Clinical results from a trial reflecting the use of a regimen in the context of advances in the understanding of the biology of a disease (e.g., newly identified biomarker or surrogate end point)
• Clinical results from a trial demonstrating a clinical difference (benefit or detriment) in a specific at-risk patient population (e.g., those with poor-risk cytogenetics, geriatric patients) or a subset of patients
• A regimen with potential for improved quality of life (e.g., oral versus parenteral regimen)
• A regimen/use described in a meta-analysis or an Agency for Healthcare Research and Quality (AHRQ)– or Cochrane-type evidence-based review

Once a potential off-label oncology use is identified, AHFS staff review and evaluate the relevant available evidence. After completion of the literature review, AHFS proposes an evidence-based rating for the specific off-label oncology use under consideration.

Determination of Medical Acceptance

The relevant clinical information, based on the literature identified by AHFS staff, is incorporated into a narrative summary, which is provided to the AHFS Oncology Expert Committee for review.

AHFS Oncology Expert Committee members are asked to perform an independent review, complete a voting ballot, indicate their vote on the Level of Evidence rating, and provide a Grade of Recommendation and supporting comments using an evidence-based analysis of the available literature.

Publication of the Final Determination

A Final Determination Report for each off-label use reviewed by the AHFS Oncology Expert Committee is published on ashp.org and reflects the consensus vote of the members of the Committee. The following information is included in the Final Determination:

• Name of the drug or drug combination
• Off-label use, to include specific patient population and disease information
• Strength of Evidence,
• Grade of Recommendation
• Narrative summary of the off-label use, including a description of the regimen, to facilitate consistent interpretation of the off-label recommendation
• Listing of references used as part of the off-label review
• Voting records
• Comments provided by AHFS Oncology Expert Committee members
• Listing of all individuals who substantively participated in the development, review, or disposition of the determination
• AHFS publication date

A comprehensive review of Final Determinations is conducted periodically, and relevant information (e.g., Level of Evidence and/or Recommendations) contained in the Final Determination is updated as needed.

Records pertaining to the publication of a Final Determination made on or after January 1, 2010, are maintained and available for not less than 5 years in accordance with CMS regulations. Such records will remain and be accessible on the ASHP website for a period of not less than 3 years, after which retention of the relevant information will be maintained for an additional 2 years by ASHP, thereby enabling public access to the material upon request.

The mission of AHFS is to provide an evidence-based foundation for safe and effective drug therapy. Information published in the AHFS DI compendium, including specific information on off-label uses, helps to shape treatment decisions made by clinicians and influences public and private healthcare policy and decisions. As a result, it is important that the information be authoritative, objective, and free of undue influence from drug sponsors (e.g., pharmaceutical manufacturers, sellers), health insurers, pharmacy benefit managers, and other third parties who may seek to use the compendium to promote their own vested interests. Editorial decisions are evidence-based and made independent of third parties; final decisions are made solely by the AHFS editorial staff, taking into account the advice of expert reviewers. In the case of balloted determinations made by the AHFS Oncology Expert Committee, decisions made through this process will prevail and will not be overturned by the AHFS staff.

Experts, including physicians, pharmacists, and other professionally qualified individuals, participate in an extramural review process for AHFS. These experts must provide full disclosure of interest, including any affiliation they have with or financial involvement they have with the sponsor of the drug(s) under consideration and directly competitive products. In the case of balloted determinations made by the AHFS Oncology Expert Committee, conflict of interest disclosure policies follow the definition of a publicly transparent process for identifying potential conflicts of interest as established in Section 414.930(a) of the Code of Federal Regulations (CFR).

1. Disclosure of Interests by Individuals Substantively Involved in the Oncology Off-label Use Determination Process
   • All individuals who substantively participate in the development, review, or disposition of an off-label oncology determination of medical acceptance are required to disclose direct and indirect financial interests. All AHFS Oncology Expert Committee members are required to complete disclosure forms listing direct and indirect financial interests that are relevant to matters considered by the Committee for themselves, their spouse, and any minor children upon appointment to the Committee and on an annual basis thereafter. In addition, prior to each off-label use review, those Committee members selected to participate in the review are required to update this disclosure information to identify any potential new conflicts of interests. AHFS staff members who substantively participate in the development, review, or disposition of a compendial recommendation for an off-label oncology use, as well as any outside experts (consultants) used to facilitate understanding and decision-making of the voting Committee members, also are required to disclose their own direct and indirect financial interests as well as those of their spouse and any minor children.
2. Process for Selection of Committee Member Reviewers and Experts
   • Members of the AHFS Oncology Expert Committee have been identified as experts through their affiliated professional organizations, which include the American Society of Health-System Pharmacists (ASHP), American Society of Clinical Oncology (ASCO), Hematology and Oncology Pharmacist’s Association (HOPA), and Oncology Nursing Society (ONS), and review by AHFS staff of submitted credentials. Committee members are selected on a rotating basis to participate in reviews of off-label oncology uses. However, at the discretion of the AHFS staff, specific individuals may be selected based on their area of expertise. Prior to each off-label use review, the AHFS staff screens Committee members’ current disclosure information and selects individuals who do not have direct or indirect conflicts of interest involving themselves, their spouse, or minor children that relate to the specific off-label use being reviewed. When the disclosures are evaluated for potential conflicts, interests or affiliations involving the sponsor of the drug under consideration, a potential competitor, or an affected firm or organization are all considered. An interest is considered relevant if the Committee’s decision on medical acceptance of the off-label use has the potential to result in a direct and predictable impact on the interest.
   • Committee members are not allowed to participate in the off-label determination process if they have disclosed relevant direct or indirect financial interests involving themselves, their spouse, or any minor child that have a combined value exceeding $50,000.
   • Committee members who have disclosed relevant direct or indirect financial interests involving themselves, their spouse, or any minor child that have a combined value of less than $50,000 are not asked to serve as reviewers. However, if the Committee member’s expertise is deemed to be required, the AHFS staff determines the merits of using the Committee member in an advisory capacity to provide expert review of the subject matter. The AHFS staff may decide to grant a waiver permitting the Committee member to participate in an advisory capacity, but the Committee member is not permitted to participate in the review of clinical materials or in the voting process.
   • Committee members who have affiliations with a sponsor or organization (i.e., consultant, speakers bureau) that are relevant to the off-label use under consideration, or whose spouse or any minor child has such affiliations, regardless of whether they receive any form of monetary compensation, are not asked to serve as reviewers. If the Committee member’s expertise is deemed to be required, the AHFS staff determines the merits of using the Committee member in an advisory capacity to provide expert review of the subject matter. The AHFS staff may decide to grant a waiver permitting the Committee member to participate in an advisory capacity, but the Committee member is not permitted to participate in the review of clinical materials or in the voting process.
   • AHFS may choose to use an outside expert (consultant) to facilitate understanding and decision-making of the voting Committee members, especially in cases where there is a lack of expertise amongst the existing Committee members. Consultants do not participate in either the review of clinical materials or in the voting process.
3. Availability of Information on Financial Disclosures and Conflicts of Interest
   • In accordance with the need for transparency, a conflict of interest statement summarizing the management of recognized conflicts of interest for individuals (e.g., Committee members, consultants, AHFS staff) who substantively participate in the development, review, or disposition of an off-label oncology determination of medical acceptance is published in the Final Determination report for that off-label use.
   • If no direct or indirect conflicts of interest have been identified during the screening and selection process, then this is so stated in the Final Determination.
   • If a Committee member has disclosed a relevant financial interest of less than $50,000 involving self, spouse, or any minor child or a relevant affiliation and the individual was granted a waiver permitting participation in an advisory capacity, the nature of the conflict is summarized in the Final Determination.
   • If the expertise of an outside consultant is required, the nature of any relevant conflict involving the consultant or the consultant’s spouse or any minor child is summarized in the Final Determination.
   • Additional information pertaining to conflicts of interest for each final determination is maintained and made timely available in response to public requests for a period of not less than 5 years after initial publication of the determination.

• John Villano MD, PhD
• Chase Ayres, PharmD, BCOP
• Jason Bergsbaken PharmD, MBS, BCOP
• Kirollos Hanna PharmD, BCPS, BCOP
• Donald Moore PharmD, BCPS, BCOP, DPLA, FCCP
• Kathleen Wiley MSN, Ran, AOCNS
• Eve Segal PharmD, BCOP
• Rachel Bubik PharmD, BCOP, BCPS
• Sandra Cuellar PharmD, BCOP, FHOPA, FASHP
• Caroline Clark MSN, APRN, OCN, AG-CNS
• Kate Taucher PharmD, MHS, BCOP, FASHP, FAPO
• Christine Gegeckas RPh, BCOP
• Andrew Li PharmD, BCOP
• Chelsea Gustafson PharmD, BCOP*
• Isabel Houlzet PharmD, BCPS, BCOP*

*Appointed in cooperation with the Hematology/Oncology Pharmacy Association (HOPA).

Levels of Evidence Rating System

Level 1: High Strength/Quality

• Evidence consists of at least one randomized, double-blind trial without important limitations (i.e., large treatment effect); intent-to-treat analysis used, confidence intervals reported. If more than one trial is available, these trials have consistent results. or
• Evidence consists of a meta-analysis of such trials with consistent results (i.e., low heterogeneity).

Evidence consisting of a non-blinded or single-blinded trial that meets study objective end points may be considered as Level 1 evidence in some cancer-related cases (e.g., NCI-sponsored cooperative group study or a multicenter trial).

Level 2: Moderate Strength/Quality

• Evidence consists of at least one non-blinded or single-blinded, randomized clinical trial. or
• Evidence consists of at least one non-blinded or single-blinded, non-randomized clinical trial. or
• Evidence consists of a meta-analysis of randomized, controlled clinical trials with heterogenous results if reasons for heterogeneity in individual trials are adequately discussed. or
• Evidence consists of at least one randomized, controlled clinical trial, but with important methodological limitations (e.g., large number of patients lost to follow-up and/or no intent-to-treat analysis and/or important data not recorded). or
• Evidence is inconsistent (i.e., two or more randomized controlled trials with unexplained, widely varying estimates of treatment effects, even if results of individual trials would constitute strong Level 1 evidence when considered alone).

Evidence consisting of a non-blinded, non-randomized trial (i.e., a phase II study) may be considered as Level 2 evidence in some cancer-related cases (i.e., rare cancers or cancers with limited available treatment options).

Level 3: Low Strength/Quality

• Evidence consists of observational studies, case reports, or case series; may also include randomized clinical trials with multiple serious deficiencies or study limitations.

Level 4: Opinion/Experience

• Evidence consists of expert consensus panel reports or expert reviewers’ comments.

Strength of Study End Points

(listed in descending order)

• Overall survival (total mortality)
• Cause-specific mortality
• Quality of life
• Indirect surrogates
  • Overall response rate (ORR)
  • Progression-free survival (PFS)
  • Disease-free survival (DFS)

AHFS Grades of Recommendation

1. Recommended (Accepted)
   The drug or biologic should be used, is recommended/indicated, or is useful/effective/beneficial in most cases.
2. Reasonable Choice (Accepted, with Possible Conditions) (e.g., treatment option)
   The drug or biologic is reasonable to use under certain conditions (e.g., in certain patient groups), can be useful/effective/beneficial, or is probably recommended or indicated.
3. Not Fully Established (Unclear Risk/Benefit, Equivocal Evidence, Inadequate Data and/or Experience)
   Usefulness and/or effectiveness is unknown, unclear, or uncertain or is not well established relative to the standard of care.
4. Not Recommended (Unaccepted)
   The drug or biologic is considered inappropriate, obsolete, or unproven; is not recommended, is not indicated, or is not useful/effective/beneficial; or may be harmful.