Preparatory Online Survey
20 participants were invited, 18 questionnaires were completed. Table 1 shows participant characteristics.
6 statements of the online survey had an agreement >75% and were directly included into the final guide.
Using the free answers in the comment fields of the preliminary online-survey and the explorative open questions, six domains with 2-9 statements each (a total of 25 statements) were generated for inclusion in the Group Delphi process. The six domains were: a) identification of relevant drugs, b) identification of relevant drug uses, c) identification and assessment of available evidence, d) formulating therapy recommendations, e) consenting therapy recommendations, and f) updating recommendations.
Group Delphi Workshop
A panel of 15 experts participated in the consensus process (Table 1), with most experts working in palliative care and with more than 10 years professional experience. The Group Delphi process was conducted in three rounds and with three groups of 4-6 persons each.
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Online Survey
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Workshop
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Number of participants
· Women
· Men
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20
10
10
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15
8
7
|
Professional background
· Physician
· Pharmacist
· Nurse
· Other
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12
4
3
1
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10
3
2
0
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Focus in palliative care
· Hospital (university)
· Hospital (other)
· Outpatient
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6
4
7
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6
3
5
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Professional experience in the field
>10 years
<10 years
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19
1
|
14
1
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Table 1 sample description
The Delphi Rounds
From the 25 statements subject to the first round of the Group Delphi process, 11 were agreed upon and therefore dismissed in the second round. The remaining 14 statements were discussed and partially rephrased and included in the second Delphi round. Of these, two were agreed upon and the remaining 12 entered the third Delphi round after discussion and further rephrasing. After the three Delphi rounds including rephrasing of some statements, consent was achieved on all 22 statements eventually, including 3 rejections (Table 2). In combination with the results of the preliminary survey, this resulted in a total of 28 statements. The summarised results were sent to all participants after the workshop for their information.
Key Outcomes
The key outcomes include mandatory key recommendations for the preparation and consensus process as well as additional recommendations which can, but do not have to be followed depending on available resources. The key outcomes are displayed in Table 2.
Key recommendations
The key recommendations for the six topics are as follows:
Identification of relevant drugs
All drugs mentioned in the evidence and consensus based German guideline "Palliative care for patients with incurable cancer" are considered relevant for the off-label-use database.9 The following sources should also be considered for the identification of further potentially relevant drugs in palliative medicine: the WHO list of drugs essential for palliative care, the German Palliative Care Formulary16, and relevant queries to the German Drug Information Centre for Palliative Medicine.17
Identification of relevant drug uses
The German guideline "Palliative care for patients with incurable cancer" should be used for the identification of potentially relevant drug uses beyond the approval.9 Further, potentially relevant areas of application outside the approval can be identified in a drug-specific way via the German Palliative Care Formulary as well as relevant queries to the German Drug Information Centre for Palliative Medicine.16, 17
Identification and assessment of available evidence
For the identification of the underlying evidence, the databases Embase, Medline and Cochrane Library should be searched using keywords or MeSH terms. Evidence will primarily be evaluated by the German Drug Information Centre for Palliative Medicine and then checked by other predefined professionals following the system of the Scottish Intercollegiate Guidelines Network (SIGN).18
Formulation and presentation of therapy recommendations
Potential drug-specific therapy recommendations for the various areas of off-label-use should be formulated based on the identified literature, the potential area of off-label-use, the available alternatives, and general side effects. These therapy recommendations are not intended to release the clinician from making patient-specific treatment decisions, but to provide guidance. The aim is therefore to convey these recommendations in such a way that they represent a guiding system in everyday practice. Therapy recommendations should therefore be presented in the form of a two-part system consisting of a four-tier evidence assessment and a four-tier grade of recommendation. Levels of recommendations will be formulated based on the German guideline system with the term “must” as strong recommendation, “should” as recommendation and “can” as open recommendation.
Irrespective of the type of recommendation, all therapy recommendations should list factors to be considered for each individual patient and, if necessary, name possible (approved) therapy alternatives.
Consensus of therapy recommendations
Therapy recommendations will be drafted by the German Drug Information Centre for Palliative Medicine.17 In a second step, consensus on these therapy recommendations will be reached by a web-based Delphi procedure. A core team plus external experts (topic-specific selection) will be involved in the consensus process on a temporary basis. Experts will be pharmacists, physicians and nurses with research experience as well as those with practical experience in palliative care.
Updating
For each drug, approved and non-approved indications and underlying evidence may change. A regular review and, if necessary, evaluation of the data situation is therefore necessary to provide professionals with the current state of knowledge at any time. At the same time, limited available resources must be considered. These two factors must be considered when determining the time interval between the development and update of a monograph.
Important data should be continuously incorporated and sent with an "alert system" or made identifiable.
Scope of recommendations
Because of limited resources, participants clearly supported the need for mandatory requirements for the identification of drugs, indications and evidence. These requirements can be supplemented by optional possibilities of identification of drugs, indications and evidence. These can be identified by the term "can" in the statements. The participants were in favour of limiting the process first to Germany and then to the German-speaking area. This was also related to differences in the approval of available drugs internationally. Furthermore, dealing with off-label-use varies in different countries, e.g. regarding reimbursement of costs.
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Agreement
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Rejection
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Survey/Workshop
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1. Identification of relevant drugs
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Key recommendations
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1.
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All drugs mentioned in the German guideline "Palliative care for patients with incurable cancer" in key recommendations and background texts are considered relevant for the off-label use database.
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x
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Survey
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2.
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The following sources should also be considered for the identification of further potentially palliative medically relevant drugs: WHO list of drugs essential for palliative care, book "Arzneimitteltherapie in der Palliativmedizin" (2018; German Palliative Care Formulary), as well as an evaluation of the inquiries to the Drug Information Centre Palliative Medicine at the Department of Palliative Medicine, University of Munich.
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x
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Survey
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Additional recommendations
|
|
Further sources for the identification of relevant drugs
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|
3.
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Other relevant drugs are to be identified through a survey among members of the German Society for Palliative Medicine DGP (initiated by DGP).
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x
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Workshop
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4.
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Other relevant drugs can be identified by random sampling in outpatient and inpatient palliative care facilities.
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x
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Workshop
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5.
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Other relevant drugs can be identified by searching for specific guidelines and websites.
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x
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Workshop
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6.
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Other relevant drugs can be identified via palliative care specific websites such as Caresearch - Palliative Care Knowledge Network (information portal on palliative care from Australia) and palliativedrugs.com.
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x
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Workshop
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7.
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Identification of off-label use should be carried out by an advertising of the project via e.g. newsletter of the German Society for Palliative Medicine, or a column in the German Journal Palliative Medicine
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x
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Workshop
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2. Identification of relevant drug use
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|
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Key recommendations
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|
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8.
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For the identification of potentially relevant drug uses beyond the approval, the topics used in the S3 guideline "Palliative care for patients with incurable cancer" must be used. The identification of further, potentially relevant areas of application outside the approval should be carried out in a drug-specific way via the German Palliative Care Formulary as well as via an evaluation of the inquiries to the drug information service “palliative medicine” at the Department of Palliative Medicine, University of Munich.
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x
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Survey
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Additional recommendations
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Further sources for the identification of relevant uses
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9.
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Further relevant areas of application are to be identified through a survey among the members of the German Society for Palliative Medicine DGP (initiated by the DGP).
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x
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Workshop
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10.
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Further relevant fields of application can be identified by a sample of the most frequent indications on an outpatient and inpatient basis.
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x
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Workshop
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11.
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Further relevant areas of application can be identified via palliative-specific websites such as Caresearch - Palliative Care Knowledge Network (information portal on palliative care from Australia) and palliativedrugs.com.
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x
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Workshop Workshop
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3. Identification and assessment of available evidence
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|
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Key recommendations
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|
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12.
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A search in the Embase, Medline and Cochrane Library databases must be carried out in order to identify underlying evidence.
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x
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Survey
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13.
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The literature search in the databases must be carried out using keywords or MeSH. For this purpose, the substance name is combined with the previously identified relevant fields of application outside the approval using Boolean operators.
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x
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Survey
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14.
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The evidence evaluation must be carried out primarily by the central off-label-use office and then checked by other persons.
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x
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Survey
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15.
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The evaluation of the evidence identified in the literature search must be carried out according to the system of the Scottish Intercollegiate Guidelines Network (SIGN) 18
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x
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Workshop
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Additional recommendations
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Further possibilities for the identification of evidence
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16.
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To identify further evidence, palliative-specific websites such as Caresearch - Palliative Care Knowledge Network (information portal on palliative care from Australia) and palliativedrugs.com as well as Uptodate can be integrated into the research.
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x
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Workshop
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17.
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In order to identify further evidence, current textbooks with content related to symptom control can be integrated into the research.
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x
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Workshop
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4. Formulation and presentation of therapy recommendations
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Key recommendations
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|
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18.
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An evaluation system must be structured in a way that overrides patient-specific factors.
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x
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Workshop
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19.
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Therapy recommendations are to be presented in the form of a two-part system consisting of a four-level evidence evaluation and a four-level recommendation level.
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x
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Workshop
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20.
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The presentation of the evidence evaluation is similar to the SIGN-classification (I-IV) used in guidelines.
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x
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Workshop
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21.
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The presentation of the degree of recommendation can be shown both in the form of an arrow system and over +/-/0.
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x
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Workshop
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5. Consensus of therapy recommendations
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Key recommendations
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|
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22.
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The consensus of the therapy recommendations must be obtained as a Delphi procedure (internet-based).
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x
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Workshop
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23.
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A core team plus external experts (topic-specific selection) must be involved in the consensus-building process on a temporary basis.
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x
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|
Workshop
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24.
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Pharmacists, doctors and nurses with research expertise as well as those with practical experience in palliative care should be involved in the consensus-building process.
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x
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|
Workshop
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25.
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Palliative care physicians from specialised inpatient and outpatient palliative care should be involved in the consensus-building process.
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x
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Workshop
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26.
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Pharmacists, doctors and nurses from other European countries are to be involved in the consensus-building process.
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x
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Workshop
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27.
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The German Society for Palliative Medicine (Deutsche Gesellschaft für Palliativmedizin e.V.) should be involved in the consensus-building process.
|
x
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Workshop
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6. Updating
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|
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Key recommnedations
|
|
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28.
|
The monographs must to be checked every 3 years for their actuality.
|
x
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Workshop
|
|
|
|
|
|
|
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Table 2. Results of the group Delphi study