Development and Update of Guidelines

Introduction

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) are comprised of recommendations for the prevention, diagnosis, and management of malignancies across the continuum of care. The NCCN Guidelines^® currently apply to more than 97% of cancers affecting patients in the United States. The NCCN Guidelines incorporate real-time updates in keeping with the rapid advancements in the field of cancer research and management. Specific NCCN Guidelines have also been developed for cancer screening and prevention, supportive care issues, and specific populations. The NCCN Guidelines are intended to assist all individuals who impact decision-making in cancer care including physicians, nurses, pharmacists, payers, patients and their families, and many others. The development of the NCCN Guidelines is an ongoing and iterative process based on a critical review of the best available evidence and derivation of recommendations by a multidisciplinary panel of experts in the field of cancer. 

NCCN Guidelines Panel Composition and Roles

The NCCN Guidelines Development Group comprises the NCCN Guidelines Steering Committee, Panels specific to each of the Guidelines, and the NCCN Headquarters Team that supports the Panels and Guidelines activities. Each NCCN Guidelines Panel includes a Panel Chair, Vice-Chair (or Co-Chair), and a group of representatives from the NCCN Member Institutions. Panel membership may also include a primary care physician, a patient advocate, and, in special circumstances, additional members from the NCCN Member Institutions, for broad representation of specialties and clinical expertise.

NCCN Guidelines Steering Committee

The Steering Committee provides oversight to the processes and planning of the NCCN Guidelines and comprises representatives from each NCCN Member Institution. Committee members are also responsible for selecting topics for new Guidelines, developing Guidelines policies for ensuring consistency across disease sites and panels, overseeing the Institutional Review process (in the absence of a Panel Member for the institution), ensuring full participation of members from his/her Member Institution in the Guidelines process, and coordinating the implementation of NCCN Guidelines activities or processes within their institutions.

Committee members are nominated by the individual institutions—usually by the institution’s Board of Directors representative. The individual Committee members appoint institutional representatives to each Guidelines Panel, typically in consultation with the Panel Chair and NCCN Guidelines senior staff.

NCCN Guidelines Panel Chair and Vice Chair

The Panel Chair (or Co-Chairs) for each Guidelines Panel provides oversight to the content development activities pertaining to the specific Panel. The Chair provides input into the selection of institutional representatives to the Guidelines and ensures the inclusion and participation of relevant clinical expertise within his/her Panel. The Chair presides over the Panel meetings to ensure all agenda topics are reviewed and discussed, and that formal votes and determinations are made. In addition, the Chair ensures that Panel meetings are conducted in accordance with NCCN policies and procedures, and that any Panel Member with a meaningful conflict of interest is excluded from participating in Panel presentations, reviews, discussions, and voting relevant to the area of the conflict of interest.

The Panel Chair is nominated and selected by NCCN Guidelines Senior Staff in consultation with the Chair of the Guidelines Steering Committee.

NCCN Guidelines Panel Members

The Members of the individual Guidelines Panels represent their institutions for all reviews and deliberations of the Panel. In order to ensure multidisciplinary representation of the Guidelines Panels, the composition of Panel Members should represent all of the core medical specialties and clinical expertise involved in the care delivered by the specific Guidelines. In addition, a patient advocate and a primary care physician should be included as full members of each Guidelines Panel, whenever possible. Candidates for patient advocate representative(s) are identified by Panel Members, then reviewed and approved by the Panel Chair in consultation with NCCN Headquarters Guidelines staff, as needed. As a general rule, only one individual from a given Member Institution is represented in each Panel. In exceptional cases, additional professionals from the same Member Institution may be appointed to the Panel as full members to assure appropriate representation of clinical expertise. Panel Members actively participate in the evidence review, deliberations, and votes during the Panel meetings. They may also present data relevant to agenda topics, as assigned by the Panel Chair.

The Guidelines Steering Committee member of each institution appoints one of their institution’s members to each Guidelines Panel, typically in consultation with the Panel Chair and NCCN Headquarters Senior Staff. The final selection of institutional representatives to each Panel is at the discretion of the institution’s Guidelines Steering Committee member.

NCCN Headquarters Guidelines Team

The NCCN Headquarters Guidelines staff provides logistical and content development support for all of the Guidelines and includes administrative support staff, editors, oncology scientists/writers, coordinators, compendia staff, and the senior NCCN staff. The NCCN Guidelines staff work in close collaboration with the Panel to develop and update the algorithms and accompanying discussion section to reflect Panel recommendations. The Guidelines staff is also responsible for preparing and posting transparency documents associated with the Guidelines Panel meetings. In addition, members of the NCCN Guidelines team attend Panel meetings to record meeting minutes and to help clarify the NCCN policies and procedures during the Panel meetings.

Updates to the NCCN Guidelines

The NCCN Guidelines are reviewed and updated on a continual basis to ensure that the recommendations take into account the most current evidence. All active NCCN Guidelines are reviewed and updated at least annually. The annual review process is driven largely by the annual Institutional Review performed for each of the NCCN Guidelines (Figure). However, interim Panel meetings are conducted throughout the year, as needed, based upon new evidence from studies evaluating existing agents or regulatory approvals of new drugs or biologics that may change clinical practice standards. The need for an interim Panel meeting is determined by the Panel Chair and/or Vice-Chair in conjunction with NCCN Headquarters Guidelines staff.

Issues or clinical questions relevant to the specific NCCN Guidelines are identified during the annual Institutional Review process, by the Panel Chair/Vice-Chair, by literature review, and by Submission Requests. New evidence/clinical data to support the Panel deliberation process for the clinically important questions are requested during the Institutional Review or Submission Request processes, and/or are gathered by the Panel Chair or NCCN Headquarters Guidelines staff from recent publications.

Institutional Review

The annual Institutional Review serves as the cornerstone of the NCCN Guidelines update process (Figure above). During Institutional Review, the NCCN Guidelines are reviewed by clinical cancer experts (and additional experts in other clinical disciplines depending on subject matter) at the NCCN Member Institutions to identify areas where new data/evidence have changed either the standard of care or the way in which existing data are interpreted. Responses or comments are gathered and collated by the NCCN Headquarters Guidelines team. The responses gathered from the Institutional Review identify important clinical questions (and issues/topics for deliberation at the annual Panel meetings), which serve as one basis for possible revisions or changes to the recommendations contained in the Guidelines.

Literature Review

NCCN Guidelines staff perform an electronic search of the PubMed database (which is provided by the U.S. National Library of Medicine), prior to the annual update of the Guidelines, in order to obtain key literature published since the previous Guidelines update, and to provide a more rigorous, evidence-based review. The PubMed database remains the most widely used resource for medical literature and only indexes peer-reviewed biomedical literature. Specific information regarding the literature search for any of the Guidelines can be found at the beginning of the Discussion section in each Guideline. Articles from additional sources (e.g., e-publications ahead of print, meeting abstracts) deemed as relevant to the Guidelines may be included in the literature review process.

Submission Requests

External parties are invited to submit requests for specific issues or topics to be discussed by the NCCN Guidelines Panel. Examples of such parties include patient advocates, clinicians outside the Member Institutions, industry, and/or payers. Requests must be submitted at least 4 weeks prior to the scheduled Panel meeting for the specific NCCN Guidelines to allow for the Panel Chair to review the content of the requests and for the submission materials to be distributed to the Panel Members, as needed. Information on the Submission Requests process for external parties is available on the NCCN website.

As part of the NCCN practices to ensure transparency, any discussion and/or changes to recommendations in the Submission Request are listed in the transparency document along with the actions taken by the Guidelines Panel. Additionally, the original Submission Request materials are posted to the NCCN website concurrently with the transparency document.

Panel Meetings: Review and Discussion of Evidence

The NCCN Guidelines Panel meetings are held as live, in-person meetings, or as telephone conferences, with or without web conferencing. Interim Panel meetings are almost always conducted via telephone conference/web conference only. The NCCN Headquarters Guidelines staff assigned to the specific Guidelines attends the Panel meetings to take minutes of the Panel discussions and Panel votes, and to record audio of the meetings. All Panel meetings (annual and interim) are moderated by the Panel Chair (or Vice-Chair), and at least 50% of the Panel Members are required to attend in order for the meetings to proceed.

During the annual Panel meeting panelists review and discuss every comment from the Institutional Review or from published evidence. If applicable, panelists also review and discuss requests made by external parties via the Submission Requests process. In order to facilitate the discussions, the Panel Chair or Panel Members (as assigned by the Chair) may present clinical trial data or other evidence compiled from recently published literature, key presentations from medical society meetings, and/or submission of data from Submission Requests. Panels are not limited in their deliberations or Guidelines changes to requests/comments from the Institutional Review or from Submission Requests. The Panel discussion may or may not result in changes to the Guidelines.

A Panel vote is taken in cases where the outcome of the Panel discussion results in a substantive change in the Guidelines including, but not limited to, changes in assigned category of evidence, therapy, staging, follow up/surveillance, or in the priority, timing, and sequence of therapy. All external Submission Requests require a specific vote associated with the Panel’s response to the request. All results of Panel votes relating to drugs, biologics and/or biomarkers, and external submissions are included in the transparency document, which is posted to the NCCN website (see section above on Transparency of the NCCN Guidelines Development Process).

Cancer research represents a highly active field, and new data are constantly generated and published or presented at major medical society meetings. Moreover, new drugs and biologics, or new indications for existing drugs and biologics, are continuously added to the armamentarium of cancer therapeutics following approval by the FDA. In order to ensure that the NCCN Guidelines reflect recommendations derived from the most current evidence, interim Panel meetings are held as required by new evidence from studies evaluating existing agents or regulatory approvals of new drugs or biologics that may change clinical practice standards. The Panel vote requirements and processes during the interim Panel meetings are identical to those of the annual Panel meetings.

Development of Guidelines Recommendations

Recommendations within the NCCN Guidelines are derived from critical evaluation of evidence, integrated with the clinical expertise and consensus of a multidisciplinary panel of cancer specialists, clinical experts and researchers in those situations where high-level evidence does not exist. Panels are charged with evaluating the efficacy of treatment, utility of tests or evaluations, and toxicity of the various interventions. Recommendations (or changes to existing recommendations) are agreed upon by Panel Members following review and discussion of the evidence during the Panel meetings. The Panel Members deliberate on the interpretation of the clinical evidence, and vote on how the evidence should be incorporated into the existing Guidelines. The Panel Chair and Panel Members then develop the wording to denote the specific recommendations within the Algorithms.

The recommendations in the Guidelines are intended to apply to the vast majority of patients in a particular clinical situation; however, recommendations are not considered to be exhaustive or to apply to all patient situations. Situations expected to arise in less than or equal to 5% of cases may be omitted from the Guidelines at the Panel’s discretion. The NCCN Guidelines represent the breadth of appropriate recommendations for a given clinical situation. As such, they provide a range of options to allow individual clinicians the latitude to select the most appropriate intervention for each patient. In clinical situations where the Panel believes that one or more interventions is likely to be more desirable based on the effectiveness and/or toxicity profile compared with other options, the designation of “preferred” may be used. However, in many cases, head-to-head studies of alternate treatment options have not been conducted or published, prompting the Panels to include multiple alternatives. The order in which alternative interventions are listed does not indicate a Panel’s preference, unless specified.

Development of Guidelines Discussions

The Discussion sections provide the scientific rationale and clinical evidence supporting the recommendations outlined in the Algorithms. Additionally, the Discussion sections may expand upon a topic that is only briefly mentioned in the Algorithms (eg, footnotes) or may provide an overview of a subject matter relevant to, but not covered within, the Guidelines. Publications selected from the Literature Search are also incorporated into the Discussion update. These additions to the Discussion sections are generally determined by the Panel Chair or Panel Members during the annual and interim Panel meetings. The content of the Discussion sections are developed and revised or updated by the NCCN Headquarters Guidelines staff, Panel Chairs, Vice-Chairs, and Panel Members to reflect the contents of (and updates to) the Guidelines Algorithms. A comprehensive bibliography/reference list (including both published materials and proceedings or abstracts from medical society meetings) on which the guidelines recommendations are based is included for each Discussion section.

Levels of Evidence and Consensus for Recommendations

The NCCN Levels of Evidence and Consensus

The overall quality of the clinical data and evidence that exist within the field of cancer research is highly variable, both within and across cancer types. Large, well designed, randomized controlled trials (RCTs) may provide high-quality clinical evidence in some tumor types and clinical situations. However, much of the clinical evidence available to clinicians is primarily based on data from indirect comparisons among randomized trials, phase II or non-randomized trials, or in many cases, on limited data from multiple smaller trials, retrospective studies, or clinical observations. In some clinical situations, no meaningful clinical data exist and patient care must be based upon clinical experience alone. Thus, in the field of oncology, it becomes critical and necessary (where the evidence landscape remains sparse or suboptimal) to include input from the experience and expertise of cancer specialists and other clinical experts.

To this end, the NCCN categories for recommendations are based on both the level of clinical evidence available and the degree of consensus within the NCCN Guidelines Panel. The Panel considers evidence of both efficacy and safety of interventions. Because most cancer therapies are associated with adverse effects, the Panel weighs the overall balance of therapeutic benefit, efficacy, safety and toxicity before making their recommendations.

The level of evidence depends upon the following factors, which are considered during the deliberation process by the Panel: quality of data (e.g. trial design and how the results/observations were derived [RCTs, non-RCTs, meta-analyses or systematic reviews, clinical case reports, case series]), quantity of data (e.g. number of trials, size of trials, clinical observations only), and consistency of data (e.g. similar or conflicting results across available studies or observations). The degree of consensus within the Panel is based on the percentage of Panel votes, as shown in the Definitions for NCCN Categories section below.

In addition to the levels of evidence, some Guidelines have therapies stratified by levels of preference. Preference Stratification was instituted to clarify panel and institutional preferences for interventions, provide guidance to users of the Guidelines on which recommendation(s) is considered optimal, and continue to provide a wide range of recommendations to meet varying clinical circumstances and patient preferences.

Definitions for NCCN Categories

The specific definitions of the NCCN categories for recommendations are included below:

• Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate;
• Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate;
• Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate;
• Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

For the ‘uniform NCCN consensus’ defined in Category 1 and Category 2A, a majority Panel vote of at least 85% is required. For the ‘NCCN consensus’ defined in Category 2B, a Panel vote of at least 50% (but less than 85%) is required. Lastly, for recommendations where there is strong Panel disagreement regardless of the quality of the evidence, NCCN requires a Panel vote of at least 25% to include and designate a recommendation as Category 3. The large majority of the recommendations put forth in the Guidelines are Category 2A. Where categories are not specified within the Guidelines, the default designation for the recommendation is Category 2A.

The specific definitions of the NCCN Categories of Preference are:

• Preferred intervention: Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability
• Other recommended intervention: Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes
• Useful in certain circumstances: Other interventions that may be used for select patient populations (defined with recommendation)

All recommendations in the NCCN Guidelines are considered appropriate.

Transparency and Management of Conflicts of Interest

Transparency of the NCCN Guidelines Development Process

To ensure transparency of the NCCN Guidelines update process, the dates for all scheduled NCCN Guidelines Panel meetings are posted on the NCCN website.

A Transparency Document is posted on the NCCN website, documenting changes made to the recommendation category or indication of drugs or biologics, a short summary of the Panel discussion, and the rationale for the change. It includes references or literature supporting any changes (if applicable), and the results of the Panel vote for each of the changes listed (indicated as a subfolder for each Guidelines entitled “Minutes/Evidence” that can be found in the “Transparency: Process and Recommendations” tab under the NCCN Compendium section).

In addition, all external Submission Requests are made publically available on the NCCN website (indicated as “Submission Request History” under the NCCN Guidelines section) with the transparency document.

Managing Conflicts of Interests

The participation of the NCCN Guidelines Panel Chairs and Panel Members is voluntary, and Panel Chairs/Members do not receive compensation for their involvement in the NCCN Guidelines development and update process. The development of the NCCN Guidelines is solely supported by membership dues from the NCCN Member Institutions, and industry support is not accepted for any direct costs associated with the development of the NCCN Guidelines.

The pharmaceutical and biotechnology industry plays a major role in the field of cancer research and treatment. Research activity contributes to new advances in the treatment and care of patients with cancer. Many experts and clinical researchers not employed by industry (including some NCCN Guidelines Panel Members) have complex relationships with industry, which may include receipt of funding for conducting basic or clinical research, or compensation for participation as consultants in advisory boards or on committees. These activities, by way of experts providing their clinical expertise and participation in industry-funded research, often serve to further scientific knowledge, facilitate new treatments to the clinic, and educate both those in industry and in academia. Moreover, patients participating in industry-sponsored clinical research often benefit from having access to new or investigational treatments.

However, financial relationships with industry could have the potential to introduce conflicts of interest and biases. It is of paramount importance that NCCN Guidelines Panel Members reach their decisions in an objective manner without any influence from conflicting interests.

In order to safeguard the objectivity and integrity of the NCCN Guidelines development and update process, NCCN has put in place a comprehensive policy for disclosure of financial relationships and for management of potential conflicts of interest (publicly available on the NCCN website as the “NCCN Disclosure Policies and Potential Conflicts of Interest”). NCCN policy mandates the disclosure of external financial relationships for all NCCN Guidelines Panel Members and recusal of individuals from deliberations and/or votes when there is a meaningful conflict of interest. Specific disclosure of all relevant financial interests is required for every member of the NCCN Guidelines Panels, including the Chairs/Co-Chairs, Vice-Chairs, and Panel Members, as well as for the NCCN Headquarters Guidelines staff, members of the NCCN Guidelines Steering Committee, and the NCCN Board of Directors. Categories of disclosure include employment, ownership of equity, ownership interest in a privately held company, royalty, compensation for consultancy, participation in advisory committees, participation in speakers’ bureaus, and receipt of clinical research funding. Restrictions of financial relationships for Panel Chairs and Panel Members include limits in absolute dollar amounts received from industry ($20,000 from a single entity, $50,000 in aggregate from all sources) and should include the market value of relevant stock ownership. Mutual funds, blind trusts, and compensation relating to continuing medical education activities are excluded from the financial limits. The limits also exclude funding of clinical research activities because such funds are typically provided to the Member Institutions rather than to the individual, and are used to cover the actual costs of conducting research (often including defrayment of costs normally charged to the participating research subjects). In addition, since clinical research remains a core responsibility for academic clinicians, participation in data safety monitoring boards as part of clinical research is also excluded from the financial limits. Panel Chairs/Vice-Chairs are not permitted to participate in marketing focused activities; their involvement in scientific advisory board activities must fall within the dollar amount limits. Panel Chairs enforce Panel Member recusals from deliberations or voting in the event they have taken part in marketing focused activities for industry and/or have equity in relation to a company that markets a drug under deliberation or competitors of that drug. These standards also include any spouses, domestic partners, and dependent children of  Panel Members. The full list of financial disclosures are publicly available on the NCCN website for all members of the NCCN Guidelines Panel, NCCN Headquarters Guidelines staff, NCCN Management Team, members of the NCCN Guidelines Steering Committee, and NCCN Board of Directors. Conflict of interest forms are updated twice per year.

Development of NCCN Guidelines-Associated Content

To extend the utility of the NCCN Guidelines, associated clinical resources are being developed or updated for many of the NCCN Guidelines. These resources include the NCCN Evidence Blocks™, NCCN Framework™, NCCN Harmonized Guidelines™, and International Adaptations/Translations.

The NCCN Guidelines with NCCN Evidence Blocks™ are intended as a visual representation of five key measures that provide important information about specific recommendations contained within the NCCN Guidelines. These measures are 1) efficacy of regimen/agent, 2) safety of regimen/agent, 3) quality of evidence, 4) consistency of evidence, 5) affordability of regimen/agent. The goal is to provide information to help health care providers and the patients make informed choices when selecting systemic therapies based upon measures related to treatment, supporting data, and cost. To develop the NCCN Evidence Blocks™, NCCN Panel members score each measure using a standardized scale from “1” to “5” with “1” being the least favorable and “5” the most favorable. Resulting data are analyzed and final scores are then used to build the 5 x 5 table that constitutes the NCCN Evidence Block™ for  each particular intervention. Please click here for more information on NCCN Evidence Blocks™.

The NCCN Harmonized Guidelines™ represent both the optimal care that these countries aspire to provide and pragmatic approaches that provide effective treatment options for resource-constrained settings. As part of a joint project with the African Cancer Coalition (ACC), American Cancer Society (ACS), and the Clinton Health Access Initiative (CHAI), NCCN and members of ACC adapted the NCCN Guidelines to create the NCCN Harmonized Guidelines™ for Sub-Saharan Africa. The goal of this collaboration is to implement the NCCN Harmonized Guidelines™ along with training of an expanded group of cancer care providers to improve the availability of effective therapies for patients with cancer in Africa. In addition, International Adaptations of the NCCN Guidelines have been developed for regions including Asia, Europe, Latin America, Russia, the Middle East and North Africa. Translations of the NCCN Guidelines are also available in various languages.

Publication of the NCCN Guidelines

The most current NCCN Guidelines (both the Algorithms and the accompanying Discussion sections) are made publicly available free of charge under the NCCN Guidelines section of the NCCN website for clinicians. Guidelines are also selected for print publication (either in entirety or as a selection) in the JNCCN – Journal of the National Comprehensive Cancer Network. For newly developed NCCN Guidelines, the entire Guidelines are generally published in full in the JNCCN shortly after the launch of the new Guidelines. In addition, the JNCCN publishes the NCCN Guidelines® Insights, which are short articles intended to highlight the key changes made to the Guidelines and provide a brief summary of the rationale and deliberations that formed the basis for the Guidelines Panel recommendations.