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January 23, 2017

FDA Releases Draft Guidance on Drug and Device Manufacturer Communication of Health Care Economic Information to Payors, Formulary Committees and Similar Entities Under FDAMA 114


Last week, the US Food and Drug Administration (FDA) issued a long-awaited draft guidance entitled "Drug and Device Manufacturer Communications with Payors, Formulary Committees and Similar Entities—Questions and Answers"1 (hereafter the "Draft Guidance"). Industry and related stakeholders have been waiting for this guidance since 1997, when Congress first enacted Section 114 of the Food and Drug Administration Modernization Act (FDAMA), which created a safe harbor for proactive manufacturer communication of health care economic information based on competent and reliable evidence, if such information directly related to the FDA-approved indication.

The timing of the Draft Guidance is interesting for three reasons. First, FDA published the Draft Guidance only days before President Trump entered office. FDA had listed FDAMA 114 guidance on its annual agenda for several years. Thus, it is unclear whether publication of the Draft Guidance suggests that FDA was truly finished with its draft or if the agency released it to stake out an agency position before the new administration could alter its content. Second, the publication comes only a few weeks after Congress enacted the 21st Century Cures Act, which made important amendments to FDAMA 114, as described below.

Finally, FDA released the Draft Guidance along with two other very important documents that address product communications by manufacturers: (1) Memorandum: Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products;2 and (2) Medical Product Communications That Are Consistent With the FDA-Required Labeling.3 Outgoing FDA Commissioner Robert Califf issued a press release announcing these new guidance documents, stating that the agency is "committed to an ongoing dialogue with industry and stakeholders" to help "provide clarity … on FDA's current thinking and recommendations for a few different types of communications about medical products."4 FDA has also opened dockets for public comment on each of the guidance documents.5 These documents come only a few months after FDA held a public meeting on the same topics back in November 2016, and also one week after the agency issued a final rule amending the "intended use" regulation as part of a broader rulemaking focused on the circumstances in which a product made or derived from tobacco will be subject to regulation as a drug, device, or a combination product under the Federal Food, Drug, and Cosmetic Act.6 Collectively, these documents set forth FDA's current positions on the First Amendment as it relates to manufacturer communications. It is possible that the Trump Administration could take different positions when the drafts are finalized. The Draft Guidance on payer communications provides useful insight into FDA's position on the standards and best practices in the creation and dissemination of HCEI.

FDAMA 114: Brief Overview and Recent Amendments

In 1997, Congress enacted Section 114 of FDAMA (21 U.S.C. § 352(a)). As enacted, FDAMA 114 permitted manufacturers to disseminate HCEI to formulary committees (or other similar entities). Under the statute, such communications did not constitute false or misleading promotion if the HCEI: (1) directly related to an FDA-approved indication; and (2) was based on competent and reliable scientific evidence.

In December 2016, Congress amended FDAMA 114 in several significant ways through section 3037 of the 21st Century Cures Act.

  • Revised HCEI Definition: HCEI (as amended by Section 3037) means "any analysis (including the clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis) that identifies, measures, or describes the economic consequences, which may be based on the separate or aggregated clinical consequences of the represented health outcomes, of the use of a drug." Notably, the amendments specify that such analyses "may be comparative to the use of another drug, to another health care intervention, or to no intervention."
  • Expanded Audience that May Receive HCEI: Manufacturers may disseminate HCEI to payors, formulary committees,7 or other similar entities, with knowledge and expertise in the area of health care economic analysis, carrying out responsibilities for the selection of drugs for coverage or reimbursement.
  • Removal of "Directly": Section 3037 provides that a communication must "relate to" an approved indication of the product and explicitly provides that HCEI that "relates only" to an unapproved indication is not protected. The word "directly" is removed.
  • Applicable Disclaimers: HCEI, where applicable, must include a conspicuous and prominent statement describing any material differences between the HCEI and the labeling of the approved drug.

Accordingly, manufacturers are now permitted to communicate HCEI materials that relate to an approved indication of a product but go beyond that specific labeled indication. Such communications may be to payors, formulary committees, or other similar entities.

FDA Q&A Guidance

The Draft Guidance provides examples and elaboration of the operative terms and conditions of Cures Section 3037.


  • FDA clarifies that "HCEI pertains to the economic consequences related to the clinical outcomes of treating a disease (or specific aspect of a disease) or of preventing or diagnosis a disease."
  • FDA also clarifies that "HCEI can be presented in a variety of ways that can include, but are not limited to, an evidence dossier, a reprint of a publication from a peer-reviewed journal, a software package comprising a model with user manual, or a budget-impact model."

Audience That Can Receive HCEI

  • The Draft Guidance proposes that an appropriate audience would include: (1) drug information centers; (2) technology assessment panels; (3) pharmacy benefit managers (PBMs); and (4) "other multidisciplinary entities that review scientific and technology assessments to make drug selection, formulary management, and/or coverage and reimbursement decisions on a population basis for health care organizations." FDA defined "healthcare organizations" to "include entities such as integrated health care delivery networks, hospitals, and hospital systems."
  • FDA asserts that these entities are "constituted to consider HCEI" through a "deliberative process" and should have the appropriate range of "knowledge and expertise in the area of health care economic analysis" "needed to interpret HCEI presented to them to inform their population-based decision-making process." Please note, however, that these proposed standards are derived from the pre-21st Century Cures legislative history, and the plain language of the statute as amended does not in fact require a formal deliberative process, but rather just the requisite expertise and responsibility of the audience for selection of drugs for coverage and reimbursement.
  • FDA states that the Draft Guidance does not apply to dissemination of HCEI to: (1) individual health care providers (HCPs) who are making individual patient prescribing decisions; or (2) consumers (e.g., dissemination via a public web site).

HCEI That "Relates To" an Approved Indication

  • To be considered "related to an approved indication," FDA explains that "HCEI analyses should relate to the disease or condition, manifestation of the disease or condition, or symptoms associated with the disease or condition in the patient population for which the drug is indicated in the FDA-approved labeling."
  • FDA offers 10 examples of HCEI analyses that the agency believes "could be considered related to an approved indication of a drug, despite information that does not appear within, and may vary in certain respects from, information presented in the FDA-approved labeling":
    • Duration of Treatment: HCEI analyses may incorporate information about long-term use of a drug over a period of time that is different from the FDA-approved labeling so long as the approved indication does not limit the duration of use.
    • Practice Setting: HCEI analyses may be based on use of the drug for its approved indication in practice settings that differ from the settings of the clinical trials submitted to FDA in the application (e.g., clinical trials could be extrapolated to a managed care or other setting).
    • Burden of Illness: HCEI analyses may be derived from studies of broad management of a disease for which the drug is indicated, including economic consequences of treatment on clinical outcomes (e.g., economic consequences of absent work days as a result of signs and symptoms associated with a disease).
    • Dosing: HCEI analyses may be based on data or studies of approved dosage forms and strengths of a drug for its approved indication, where the dosing regimen varies from the FDA-approved labeling (e.g., an observational study based on drug utilization data from a health plan database, where actual patient use of an approved dosage form and strength of a drug for an approved indication falls outside the recommended dosing regimen in the label, such as by taking at a different frequency or a different total dose than recommended).
    • Patient Subgroups: HCEI analyses may be derived from analyses of treatment effects in patient subgroups (e.g., demographics, disease severity, co-morbidities) that are within the patient population for the approved indication, even if these subgroup analyses were not pre-specified in the studies that formed the basis for approval of the drug. This is a significant change from FDA’s pre-Cures position that such non-pre-specified subgroup analyses were not permitted in proactive promotional HCEI materials.
    • Length of Hospital Stay: HCEI analyses may be derived from studies of treatment impacts on length of hospital stay.
    • Validated Surrogate Endpoints: HCEI analyses may be derived from clinical data demonstrating an effect on a surrogate endpoint that is known to predict clinical benefit (i.e., a validated surrogate endpoint). For example, blood pressure reduction is a validated surrogate endpoint for reduction in certain cardiovascular events (e.g., stroke, myocardial infarction) pertaining to antihypertensive drugs (e.g., calcium channel blockers, angiotensin converting enzyme inhibitors). FDA clarified, however, that if there is "insufficient evidence to demonstrate that a particular surrogate endpoint is capable of predicting clinical benefit, it generally should not be used as a basis for HCEI."
    • Clinical Outcome Assessments (COAs)8 or Other Health Outcome Measures (e.g., Quality Adjusted Life Year (QALY9)): HCEI analyses may be derived from studies involving the approved indication of a drug that assess COAs (e.g., patient-reported outcomes (PROs), such as compliance/adherence, work productivity, basic activities of daily living) or other health outcome measures (e.g., QALY) when they are evaluated using valid and reliable measures (as determined by experts who are familiar with evaluating the merits of a particular COA or other health outcome measure).
    • Persistence10: HCEI analyses may be based on data estimating patient persistence on a drug for its approved indication (e.g., estimates based on drug utilization data from a health plan database).
    • Comparisons: HCEI analyses may be derived from studies comparing the safety or effectiveness of a drug for its approved indication to another drug or intervention or to no treatment. This likely understates the comparative HCEI analyses that can be disseminated under FDAMA 114 as amended. In fact, the revised FDAMA 114 can now be read to permit robust comparative FDAMA 114 analyses – when appropriate qualifying information is provided and competent and reliable evidence exists to support clinical assumptions underlying comparisons – even when an adequate and well-controlled head-to-head trial between the products is not available.
  • Conversely, FDA proposes two examples of HCEI analyses that FDA would not be considered to relate to an approved indication.
    • An economic analysis of disease course modification related to use of a drug that is approved only to treat the symptoms of the disease. FDA offers two examples to illustrate: (1) an analysis of a drug indicated for the acute relief of angina discussing the effect of the drug on delaying the worsening of coronary artery disease (disease course modification); and (2) an analysis of a drug indicated for the treatment of the signs and symptoms of heart failure discussing prolonging patient survival (disease course modification) for patients with heart failure.
    • HCEI analyses derived from studies in patient populations that are not within the indicated patient population. For example, an analysis regarding the treatment of cystic fibrosis (CF) in patients with any mutation in the CF gene would not be considered to relate to the approved indication for a drug approved to treat only one specific CF gene mutation.

Competent and Reliable Scientific Evidence (CARSE)

  • FDA considers HCEI "to be based on CARSE if the HCEI has been developed using generally-accepted scientific standards, appropriate for the information being conveyed, that yield accurate and reliable results."
  • In evaluating HCEI, FDA states that it will consider the merits of existing current good research practices for HCEI substantiation developed by authoritative bodies (e.g., International Society for Pharmacoeconomic and Outcomes Research (ISPOR), Patient-Centered Outcomes Research Institute (PCORI)). For example, "when evaluating HCEI based on indirect treatment comparisons in the absence of data from head-to-head controlled clinical trials, FDA may refer to guidelines issued by external expert bodies regarding current rigorous methodologies and best practices for such comparisons (e.g., network meta-analyses)."
  • FDA also clarifies that it considers the CARSE standard "to apply to all components of HCEI, including inputs and assumptions related to both economic consequences and clinical outcomes (i.e., safety and/or effectiveness)."

Information That Should be Included When Disseminating HCEI

The Draft Guidance proposes that manufacturers should disseminate HCEI with "appropriate background and contextual information necessary to allow payors to fully understand the HCEI," including the following elements, which FDA said should be presented "clearly and prominently."

  • Study Design and Methodology: this includes a statement of the study objectives (e.g., clear description of the hypothesis and potential biases and/or confounders), as well as detailed descriptions and explanations of the following information:
    • Type of Analysis: (e.g., cost-minimization analysis, cost-effective analysis, cost-utility analysis, cost-benefit analysis, cost-consequence analysis) and the reason for its choice.
    • Modeling: an explanation of the model technique chosen, its scope, and its key variables and parameters, as well as the rationale and consequences of including and excluding specific variables in economic models.
    • Patient Population: including the number of patients and relevant demographic information (e.g., age, gender, ethnicity, clinical characteristics, and socioeconomic status).
    • Perspective/Viewpoint: (e.g., patient, employer, health care provider (e.g., clinician, institution), payor, regulatory body (e.g., government agency), or society (i.e., everyone impacted by the treatment)) to enable payors to understand the rationale for the selection of inputs (e.g., outcome measures, time periods, costs), and therefore, determine whether the HCEI is relevant to their particular health care organization.
    • Treatment Comparator (e.g., other drugs, other medical care, no treatment).
    • Time Horizon: including its relation to the major and relevant clinical outcomes (e.g., safety and effectiveness) and economic consequences related to the treatment of interest and its comparators.
    • Outcome Measures: including the sources of clinical and/or nonclinical data (e.g., clinical outcomes could include PROs (i.e., compliance/adherence, work productivity, basic activities of daily living) or QALYs). Data sources could include clinical and nonclinical studies or other sources, such as administrative databases (e.g., health plan databases), electronic health records (EHRs), and registries.
    • Cost Estimates: identifying all relevant resource items for the measurement and valuation of a treatment pathway, including the source of cost data and the date of pricing. Full disclosure of and explanation for any data manipulations and methods (e.g., discount rates, adjustments for inflation, currency conversion) should also be included.
    • Assumptions: including a comprehensive listing of all assumptions (clinical and nonclinical) and associated rationales explicitly in the explanation of the methodology for the economic analysis. Assumptions may include: (1) information related to patient demographics or characteristics; (2) natural disease course; (3) disease management/clinical practice; and (4) cost of clinical events. FDA further recommends that "[a]ll evidence to support assumptions should be provided."
  • Generalizability: The Draft Guidance explains that generalizability "refers to the applicability of HCEI obtained in one health care setting or patient population to another." Accordingly, FDA proposes that firms disclose any "factors which may limit the generalizability of the economic analysis."
  • Limitations: FDA proposes that HCEI include an explicit discussion of the limitations of the economic analysis, including, but not limited to: (1) limitations of the study design;11 (2) limitations of the data sources; (3) incomplete data; (4) assumptions made; (5) choice of comparators; and (6) exclusion of certain clinical outcomes. FDA also proposes that limitations and methodological issues with observational studies and indirect treatment comparisons should be "fully described, as they may inform conclusions that can be reliably made based on these analyses."
  • Sensitivity Analysis: The Draft Guidance proposes that HCEI identify any uncertainties from data sources, extrapolation, or analytic methods that could affect the conclusions in HCEI. FDA also proposes that manufacturers conduct a sensitivity analysis and include adequate disclosures and rationales regarding the method used for the sensitivity analysis, the variables chosen, and the ranges for those variables.
  • Additional Material Information for a Balanced and Complete Presentation: FDA contends that a balanced and complete presentation of HCEI should include the following "material information":
    • A conspicuous and prominent statement describing material differences between the HCEI and the labeling approved for the drug, as required under the statute. FDA also cautions that firms should "not misleadingly represent that clinical assumptions that vary from the FDA-approved labeling have been found by FDA to be safe and effective."
    • FDA-Approved Indication and Labeling.
    • Disclosure of Omitted Studies or Data Sources. The Draft Guidance warns that if "relevant data or information is available but was not considered and included" in the analysis, the HCEI would be considered misleading and incomplete. FDA emphasizes that this would be "especially true if the omitted data or information is from rigorous studies (e.g., adequate and well-controlled trials)."
      • Accordingly, FDA recommends that manufacturers "perform a comprehensive literature search and that their HCEI include an explanation of methods used in the literature search (e.g., databases or sources used, time period covered, and criteria/keywords used to search the databases and sources and to determine what data or information to include/exclude)."
      • "If HCEI is created without using all available relevant data, HCEI should clearly explain that certain studies or data sources were omitted from the analysis, the reasons they were not included, and how such a selective inclusion of studies or data sources may change or affect the conclusions."
    • Risk Information. FDA proposes that HCEI disclose "important risk information" associated with the approved use of the drug and "any additional risk information related to clinical assumptions in economic analyses that vary from the FDA-approved labeling (e.g., risks observed in a particular patient subgroup)."
    • Financial/Affiliation Biases. The Draft Guidance provides that HCEI should disclose potential financial or affiliation biases, including a manufacturer's role in funding the underlying research or in drafting underlying publications or presentations, as well as the names of any authors of studies or analyses who received compensation from the manufacturer or who had a significant financial interest in the firm, "to the extent reasonably known by the firm at the time of dissemination."

HCEI Communications Regarding Investigational Drugs and Devices

  • The Draft Guidance clarifies that FDA does not intend to object, under 21 C.F.R. §§ 312.7(a) or 812.7(a) or otherwise, to communications to payors prior to FDA approval or clearance when such communications are "unbiased, factual, accurate, and non-misleading." Examples of acceptable information that can be conveyed to payors include:
    • product information (e.g., drug class, device design);
    • information about the indication sought, such as information from the clinical study protocol(s) about endpoint(s) being studied and the patient population under investigation (e.g., number of subjects enrolled, subject enrollment criteria, subject demographics);
    • factual presentations of results from clinical or preclinical studies (i.e., no characterizations or conclusions should be made regarding the safety or effectiveness of the product);
    • anticipated timeline for possible FDA approval/clearance;
    • product pricing information; and
    • targeting/marketing strategies (e.g., outreach activities planned to generate prescriber awareness about the product) product-related programs or services (e.g., patient support programs).
  • FDA proposes that HCEI regarding investigational drugs and devices should include:
    • a clear statement that the product is under investigation and that the safety or effectiveness of the product has not been established; and
    • information related to the stage of product development (e.g., the phase of clinical trial in which a product is being studied and how it relates to the overall product development plan).
  • FDA also suggests that manufacturers "provide follow-up information to payors if previously communicated information becomes outdated as a result of significant changes or as a result of new information regarding the product (e.g., failure to meet primary effectiveness endpoint in the phase 3 trial) or its review status (e.g., an application is determined to not be ready for approval upon completion of the review cycle, a study is placed on a clinical hold)."
  • FDA asserts – consistent with its prior position on pre-approval promotion – that it would be inappropriate for a manufacturer to represent in communications that an investigational product is FDA-approved/cleared or is otherwise safe or effective for the purpose(s) for which it is under investigation.

HCEI Regarding Unapproved Uses of Approved Drugs

  • FDA states that communications of HCEI regarding unapproved uses of approved drugs are subject to three existing draft guidance documents: (1) Responding to Unsolicited Requests for Off-Label Information; (2) Good Reprint Practices; and (3) Distributing Scientific and Medical Publications.
  • FDA notes that manufacturers can disseminate HCEI regarding unapproved uses to payors consistent with the recommendations outlined in these three guidance documents. The Draft Guidance, however, did not provide any further insight or detail in this area, or address the First Amendment questions surrounding FDA's prior policies with respect to truthful and non-misleading information regarding unapproved uses of approved drugs.

HCEI and Contracting Discussions

  • FDA recognizes that communication of HCEI occurs during the course of discussions with payors related to risk-sharing and other value-based contracts. FDA confirms, however, that the Draft Guidance "is not intended to address the terms of contracts between firms and payors" as FDA does not regulate such contracts.

Post-Marketing Requirements

  • The Draft Guidance clarifies that HCEI disseminated in accordance with section 502(a) of the FDCA "is promotion, and, therefore, is subject to FDA's requirements for submission of promotional materials" at the time of initial publication or dissemination (using Form FDA 2253)(citing 21 C.F.R. § 314.81(b)(3)(i)). HCEI about drugs approved under the accelerated approval pathway or drugs based on animal studies must comply with the pre-dissemination submission of promotional materials.
  • FDA explains that all supporting information for HCEI should be "referenced" in the postmarketing submission.
  • FDAMA 114 permits FDA to request submission of information that is relevant to the substantiation of HCEI, which FDA states may "include the primary data and analysis methods used to support the HCEI."


  • FDA confirms that, for manufacturers that disseminate HCEI consistent with the Draft Guidance, the agency does not intend to consider such information false or misleading.
  • FDA further announces that the agency does not intend to cite dissemination of compliant HCEI as evidence of a new intended use.

Analysis and Impact of FDA's Draft Guidance

The Draft Guidance contains a significant amount of technical recommendations and considerations for manufacturers and related stakeholders regarding the creation, dissemination, and use of HCEI. While a number of the recommendations are consistent with longstanding industry practice, FDA's first official document addressing FDAMA 114 (as amended by the 21st Century Cures Act) now memorializes a number of important concepts and principles that companies will need to consider moving forward.

First, manufacturers should assess whether current practices for generating and substantiating HCEI are consistent with authoritative health care economic research bodies and are otherwise robust enough to meet the CARSE standard. In doing so, companies should update policies and procedures with the amended statutory definition of HCEI, as well as clarify the acceptable formats for which HCEI may be presented in (e.g., peer-reviewed journals, economic software models, etc.).

Second, manufacturers should consider documenting when and how the payor, formulary committee, or other similar entity audience for proactive HCEI has the requisite knowledge and expertise in the area of health care economic analysis and is carrying out its responsibilities for the selection of drugs for coverage or reimbursement.

Third, manufacturers should update HCEI research practices to ensure that studies are designed and modeled in a manner that will "relate to" a drug's FDA-approved indication. In particular, companies may want to create a checklist of the various examples used by FDA, and identify any other potentially acceptable study designs.

Fourth, companies should ensure that all components of HCEI, including inputs and assumptions related to both economic consequences and clinical outcomes, meet the CARSE standard, as clarified by FDA in the Draft Guidance. This standard will be particularly important to consider to ensure compliance when HCEI is comparative in nature and there is no underlying head-to-head clinical studies between the products addressed in the HCEI.

Fifth, manufacturers should assess whether current processes and procedures address the types of information that FDA expects to be disseminated along with HCEI (e.g., study design and methodology, limitations, sensitivity analysis, etc.). Companies should update promotional review processes (e.g., updated forms, checklists, or software) to ensure that all required information is compiled and submitted along with HCEI to allow for robust review and discussion to ensure compliance with the Draft Guidance. Particular attention to these details will be helpful given FDA's expectation that manufacturers include discussions about study limitations, incomplete data, assumptions, and omitted studies or data sources, as well as FDA's statutory authority to request data used to substantiate HCEI. Companies should also update promotional review processes, systems, and procedures to ensure that all "material information" outlined by FDA is included in HCEI packages (e.g., conspicuous statement, FDA labeling, conflicts of interest, and risk information), and postmarketing submission to FDA is addressed.

Sixth, companies should account for the different standards FDA outlined for the dissemination of HCEI regarding investigational products. Importantly, manufacturers should identify systems that will remind applicable personnel of when "follow-up information" may be required.

Finally, manufacturers should consider whether developing First Amendment case law may permit the proactive dissemination of robust, truthful, and non-misleading HCEI beyond the strict terms of FDA's interpretation of FDAMA 114.

Comments on this guidance are due by April 19, 2017 (Docket No. FDA-2016-2-1307).

  1. FDA, Draft Guidance, Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar Entities – Questions and Answers (January 2017).

  2. FDA, Memorandum, Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products (January 2017).

  3. FDA, Draft Guidance, Medical Product Communications That Are Consistent With the FDA-Required Labeling – Questions and Answers (January 2017).

  4. FDA Statement, Statement from FDA Commissioner Robert Califf, M.D. (January 18, 2017).

  5. Draft FDAMA 114 Guidance (Docket No. FDA-2016-D-1307); First Amendment Memorandum (Docket No. FDA-2016-N-1149); and Consistent With Label Draft Guidance (Docket No. FDA-2016-D-2285).

  6. See 82 Fed. Reg. 2193 (Jan. 9, 2017).

  7. FDA clarified in the Draft Guidance that formulary committees "refer{ } to multidisciplinary committees that have the responsibility for selection of drugs and the management of a drug formulary," and uses the example of pharmacy and therapeutic committees.

  8. FDA defined COA to mean "any assessment of a patient's clinical state by the patient or a clinician," and noted that there are four types of COA measures (i.e., patient-reported outcomes, clinician-reported outcomes, observer-reported outcomes, and performance outcomes).

  9. FDA defined QALY to mean "a measure of the value of a health outcome that is typically scored on a scale from zero (corresponds to death) to one (corresponds to perfect or optimal health), integrating the life expectancy and treatment impact on morbidity of the compared interventions that may be used in HCEI."

  10. FDA explained that persistence refers to "the duration of time from initiation to discontinuation of therapy" (citation omitted).

  11. Regarding study design limitations, FDA maintained that firms should disclose whether the study: (1) lacked randomization, blinding, or a control group; (2) lacked assay sensitivity; (3) failed to include pre-specified endpoints; (4) failed to include endpoints that are valid and reliable measures of the outcomes of interest; (5) failed to identify dosing, patient population, patient drop outs, selection and timing of endpoints; and (6) failed to meet the primary endpoint.