Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BACKGROUND: A previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak. METHODS: In order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). RESULTS: Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available. CONCLUSION: Off-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.

Origins of the prohibition against off-label promotion.

The statute and regulations administered by the Food and Drug Administration ("FDA") do not explicitly prohibit the promotion of drugs and medical devices for unapproved uses, yet the government has collected billions of dollars in penalties for such "off-label" promotion. The statutory interpretations and regulatory provisions relied on by the government to take enforcement action against off-label promotion are the incidental by-products of initiatives undertaken by FDA through administrative action and litigation early in its implementation of the Federal Food, Drug, and Cosmetic Act. The actions were designed to obtain FDA authority over therapeutic claims made in advertising, even though Congress had assigned authority over advertising to the Federal Trade Commission, and to establish a prescription-only drug system, even though FDA lacked statutory authority for such a system. The principal purpose of both efforts was to prevent inappropriate self-medication. This article describes the history of those strategies, including expansion of the definition of the term "labeling" to encompass matter that was initially regarded as advertising; creation of the rule that the labeling of drugs must have adequate directions for all "intended" uses; and construction of the prescription-only drug system in a manner that allowed FDA to use the statutory requirement for labeling to have "adequate directions for use" to prohibit the off-label promotion of prescription drugs.

[Topical chemotherapy for conjunctival tumours - the medical and legal bearings of the case]. / Lokale Chemotherapie von Tumoren der Bindehaut - interdisziplinär medizinische und administrative Aspekte.

The treatment management of malignant tumours is characterised and limited by specific features of the topographical structure of the eye. The anatomic characteristics of the conjunctival sac, the movable tissue structures and the need to take care of corneal transparency and conjunctival stability are the main concerns of the experts. Clinical studies have revealed adjuvant chemotherapy to have a positive effect as a therapeutic treatment for neoplasia of the conjunctiva and cornea. Although mitomycin and interferon are widely used, there are no phase III studies on local adjuvant chemotherapy (interferon, mitomycin, 5-fluorouracil) that evaluate the proof of effectiveness, potential adverse effects or interactions with other drugs. For this reason, the currently available studies fail to comply with the jurisdiction of the German Federal Social Court. Hence, the Medical Service of the Health Insurance Funds (MDK) regionally does not accept the medical preconditions for reimbursement of the costs in adjuvant local chemotherapy. A doctor's unquestioned acceptance of such an MDK decision could have legal consequences. An off-label use is acceptable by law if there is no alternative treatment available with a higher evidence level that conforms to the medical standard. It is therefore recommendable for the Joint Federal Committee commissions the experts in ophthalmology and oncology on off-label use, to review the scientific evidence regarding adjuvant therapy of malignant tumours of the ocular surface. Only in this way can regional disparities in patient care, and intrusions on the doctor-patient relationship, be avoided.

[Criteria for good prescribing practice in children]. / Inhaltliche Kriterien für eine gute Verordnung bei Kindern.

Paediatric prescribing is complex. A whole range of aspects needs to be considered to achieve an efficacious and safe drug therapy for children. Legal requirements for prescribing are clearly insufficient for this purpose. Children are immature individuals under constant growth and development. Consequently, based on age and cognitive abilities of the child individual drugs and dosing regimens have to be chosen. Frequent off-label use and a lack of age-appropriate formulation worsen the situation. Additionally, not all dosage forms are similarly adequate in different age groups. Taste significantly influences patient adherence. Dose calculations based on body weight are prone to errors, putting a point on the wrong place or mixing up measuring units easily result in ten-fold dosing errors. Computer-based tools to enhance prescribing are promising but, however, not yet widely implemented in paediatrics because of missing evidence-based data sources and the hugely complex process. Communication between clinicians and pharmacists as well as with the patient remains very important.

Who are the PDCO?

In January 2007, the Paediatric Regulation entered into force and established the Paediatric Committee (PDCO) within the European Medicines Agency. The goal of the PDCO is to improve the health of the children of Europe by increasing high-quality research for medicinal products and promoting the development and authorization of such medicines at the EU level. A major function of the PDCO is to formulate and authorize Paediatric Investigation Plans and Paediatric Use Marketing Authorisations. The EU's Seventh Framework Programme for Research has facilitated the establishment of consortia whose ultimate goal is to answer important clinical questions involving medicines commonly used "off-label", in children. The benefits of these consortia include enhanced collaboration amongst paediatricians, scientists and small to medium enterprises whose ultimate goal is to obtain an authorization for a new indication or formulation for use in the paediatric population. It will be interesting in a number of years time to measure the success of this very important European initiative.