NCCN Guidelines® & Clinical Resources
Development and Update of the NCCN Guidelines®
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 patients living with cancer 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, as well as for supportive care issues important to the management of patients with cancer. The NCCN Guidelines are intended to assist all individuals who impact the 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, which is 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), a group of representatives from the NCCN Member Institutions, a patient advocate, and in special circumstances, additional members from the NCCN Institutions, for broad representation of specialities 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 of the NCCN Member Institutions. Nomination of a committee member is made by the individual institutions, usually by the institution’s Board of Directors member. The individual Committee members appoint institutional representatives to each Guidelines Panel, typically in consultation with the Panel Chair and NCCN Guidelines Senior Staff. Committee members are also responsible for overseeing the Institutional Review process (in the absence of a Panel Member for the institution) and coordinating the implementation of NCCN Guidelines activities or processes within their institutions.
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 Panel Chair is nominated and selected by NCCN Guidelines Senior Staff in consultation with the Chair of the Guidelines Steering Committee. 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.
NCCN Guidelines Panel Members
The Members of the individual Guidelines Panels represent their institutions for all reviews and deliberations of the Panel. The Guidelines Steering Committee member of each institution has the privilege of nominating and appointing 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. 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, at least one patient and/or patient advocate should be included as a full member of each Guidelines Panel, whenever possible. Candidates for patient or 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.
NCCN Headquarters Guidelines Team
The NCCN Headquarters Guidelines staff provides logistical and content development support for all of the Guidelines, and comprises administrative support staff, editors, oncology scientists/writers, coordinators, and the senior NCCN leadership team. The NCCN Guidelines staff works 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/collect meeting minutes and to help clarify the NCCN policies and procedures during the Panel meetings.
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 to and made publicly available on the NCCN website (indicated as “NCCN Guidelines Panels Meeting Schedules” tab under the NCCN Guidelines section). In addition, important changes are posted to and made publically available in a transparency document. The transparency document captures changes made to the recommendation category or indication, or the addition/removal of drugs or biologics, and includes a short summary of the Panel discussion and rationale for the change, references or literature supporting the change (if applicable), and 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). The discussion and/or changes to recommendations based on external Submission Requests are also listed in the transparency document along with the actions taken by the Guidelines Panel. All external Submission Requests, whether or not they result in a change in the Guidelines, are concurrently posted to the NCCN website (indicated as “Submission Request History” under the NCCN Guidelines section) with the transparency document (see section below for further discussion on the Submission Request process).
Managing Conflicts of Interests
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 participating 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.
Financial relationships with industry have the potential to introduce conflicts of interest and biases into the NCCN Guidelines process. Given that the recommendations within the NCCN Guidelines are derived from evaluation of current evidence integrated with the clinical experience/judgment and consensus of multidisciplinary panels of experts, it is of paramount importance that NCCN Guidelines Panel Members reach their decisions in an objective manner without the influence of conflicting 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 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.
In order to safeguard the objectivity and integrity of the NCCN Guidelines development and update process, the NCCN has put in place a comprehensive policy for disclosure of financial relationships and for management of potential conflicts of interest (the full disclosure policy is available on the NCCN website under “NCCN Disclosure Policies and Potential Conflicts of Interest”). The 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 each member of the NCCN Guidelines Panel, 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. Restriction of financial relationships for Panel Chairs and Panel Members includes limits in absolute dollar amounts received from industry (i.e., less than $20,000 from a single entity; and less than $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, 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. Recusals from deliberations or voting of Panel Members who have taken part in marketing focused activities for industry and/or have equity in relation to a company that markets a drug under deliberation, as well as competitors of the drug, are enforced by the Panel Chairs. For equity and employment by industry, these standards extend to the Panel Member, their spouse, domestic partners, and dependent children. The full list of financial disclosures are posted and made 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.
Updates to the NCCN Guidelines
The NCCN Guidelines are reviewed and updated on a continuing 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 largely driven 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.
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.
The annual Institutional Review serves as the cornerstone of the NCCN Guidelines update process (Figure). During Institutional Review, the NCCN Guidelines are reviewed by clinical cancer experts (and additional experts in other clinical disciplines depending on the Guidelines 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.
Prior to the annual update of the Guidelines, an electronic search of the PubMed database, provided by the U.S. National Library of Medicine, is performed to obtain key literature published since the previous Guidelines update. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes only 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. 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.
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 industry, clinicians outside the Member Institutions, patient advocates, and/or payers. Requests must be submitted at least 3 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, the 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 concurrently to the NCCN website 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 audio record the meetings. All Panel meetings (annual and interim) are moderated by the Panel Chair (or Vice Chair), and attendance by at least 50% of the Panel Members is required for the meetings to proceed.
During the annual Panel meeting, each response or comment, gathered from the Institutional Review or from published evidence, is reviewed and discussed by the Panel. If applicable, requests made by external parties via the Submission Requests process are also reviewed and discussed. 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 must also have a specific vote associated with the Panel’s action 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, a range of options is provided 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 and clinical rationale for the recommendations put forth in the Guidelines Algorithms by providing a review of the relevant evidence and data pertaining to the recommendations. Additionally, the Discussion sections may expand upon a topic that is only briefly mentioned in the Algorithms (e.g., 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. A comprehensive bibliography/reference list (including both published materials and proceedings or abstracts from medical society meetings) is included for each Discussion section. The content of the Discussion sections are developed and revised or updated annually by the NCCN Headquarters Guidelines staff, Panel Chairs, Vice Chairs, and Panel Members to reflect the contents of (and updates to) the Guidelines Algorithms.
NCCN scientists develop the NCCN Compendia directly from the recommendations in the NCCN Guidelines. The NCCN Drugs & Biologics Compendium (NCCN Compendium®) reflects panel recommendations for the appropriate use of the agents used in disease management. The NCCN Biomarkers Compendium® reflects the predictive and prognostic biomarker testing recommended in the NCCN Guidelines. Additional Compendia relating to Appropriate Use of Imaging and Radiation Oncology will be published in early 2016.
Levels of Evidence and Consensus for Recommendations
The NCCN Levels of Evidence and Consensus
It is acknowledged that 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 to fill in the ‘gaps’ (where the evidence landscape remains sparse or suboptimal) with 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. Evidence of both efficacy and safety of interventions is considered by the Panel. Because most cancer therapies are associated with adverse effects, the overall balance of therapeutic benefit, efficacy, safety and toxicity are weighed by the Panels before making their recommendations. The level of evidence depends upon the following factors, which are considered during the deliberation process by the Panel: extent of data (e.g., number of trials, size of trials, clinical observations only), consistency of data (e.g., similar or conflicting results across available studies or observations), and quality of data based on trial design and how the results/observations were derived (e.g., RCTs, non-RCTs, meta-analyses or systematic reviews, clinical case reports, case series). 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. The NCCN does not formally consider cost of an intervention in its assessment; however, in some situations, Panels may consider the overall value of a treatment, especially when robust data from pharmacoeconomics studies are available for specific interventions.
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 vote from at least three Panel Members (representing at least three different Member Institutions) 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.
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. Sections of the Guidelines are also selected for print publication in every issue of the Journal of the NCCN. For newly developed NCCN Guidelines, the entire Guidelines are generally published in full in the Journal of the NCCN shortly after the launch of the new Guidelines.