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Information on New Medicines New Medicines Profile Template Guidance Notes The profile should not exceed two pages, excluding the references and appended tables. Text should be 9-10 point size. 8.5 is an absolute minimum. Summary The summary is laid out in bullet points. It should accurately reflect the key points in the text and should not introduce any new information. The summary should include the following: A very brief description of what the medicine is and what it is indicated for. Information on whether it is a new class of medicine, new indication or new formulation and why the product may have been launched e.g. patent expiry of existing product, may also be useful. A brief outline of efficacy and safety. An indication of any advantages, clinical or practical, the drug may have over existing therapies. A comment on its likely/potential place in therapy. Cost implications. The summary should leave the reader with a clear message about the medicine even if they do not read the rest of the evaluation. Brand Name, (Manufacturer) Cite as e.g. Exelon, (Novartis) BNF Therapeutic Class Use BNF wording and section number or SPC description. Licensed Indications As per SPC, abbreviate if necessary. Dosage and Administration As per SPC Marketed Insert month and year New Medicines Profile: Template Guidance Notes Cost Comparisons Generally give the cost for 28 days but annual costs may be used for chronic therapy. State where the prices are from (usually the latest edition of MIMs or the Drug Tariff). Select no more than 5 comparator medicines and include midrange SPC doses or give ranges (not Defined Daily Doses). £5 Drug 1 Drug 2 £32 Drug 3 £15 £0 £5 £10 £15 £20 £25 £30 £35 N.B. Doses shown for general comparison and do not imply therapeutic equivalence Introduction Briefly describe what the medicine is and what it is indicated for. Outline existing treatment options and include prevalence of disease, if appropriate. Evidence Give a brief overview of the major studies (phase 3). Phase 2b studies should only be included as a last resort. Do not include dose ranging studies. The text should include a brief description of the trials and critique the trial data rather than detail them in depth. Use the table (appendix 1) to present details of the trials. Read papers thoroughly and conduct a fair, independent critical evaluation of the data. Ensure all statements can be corroborated. Do not express results as relative risks if possible. Try and use absolute risks and/or numbers needed to treat (NNTs) if appropriate. Do not rely on published NNTs - re-calculate. If there are no comparative trials this should be stated. Use fully published randomised controlled trials (RCTs) where available. State if using conference abstracts/posters or company ‘in-house’ data, although the latter should only be quoted as a last resort. The limitations of such data should be pointed out e.g. this requires confirmation in published studies. Include details of any patient impact assessments if possible e.g. quality of life studies. Include comment on pharmacoeconomic studies. Highlight whether studies are independent or sponsored and state if there are none. New Medicines Profile: Template Guidance Notes Checklist to help critically evaluate a study: a) Why was the study done? b) What type of study was it? c) If the inclusion and exclusion criteria were very strict what implication could this have for real world clinical practice? d) What were the outcome measures? Were they appropriate? Were they patient orientated e.g. death, MI, or surrogate measures e.g. blood pressure? e) Were scoring systems e.g. QoL questionnaires etc used validated methods? f) Were the numbers recruited sufficient? g) What was the drop-out rate? Were all drop-outs accounted for? h) Was the study adequately controlled? i) Was the study randomised - was the randomisation method described and appropriate? j) Was there a pre-randomisation study phase and what was the purpose of it? Were all potential subjects exposed to the study drug and only those who tolerated it then randomised? k) How was the study ‘blinded’? Were there any factors that might have jeopardised blinding e.g. was the active drug associated with a high frequency of a particular adverse effect? l) If there was a non-placebo comparator, was it a fair choice and used at an appropriate dose? Was the comparator an established evidence-based alternative? m) Were the study groups comparable? n) Was the analysis done on an intention-to-treat or a per protocol basis? What influence may the latter have had on the results? o) Has any sub-group analysis potentially introduced bias? p) Is the study credible? What is the quality of the results? How relevant are they to clinical practice? q) Are there confidence intervals? r) Are the results of the study consistent with other similar studies? Highlight any study deficiencies in the text. Avoid: i. ii. iii. iv. Quotation out of context. Biased selection of studies. Uncritical acceptance of conclusions. Representation of opinion as fact. All sources should be fully referenced. Safety Include the major and most common adverse effects with an indication of frequency, if possible. Refer to the SPC where appropriate. Include clinically important interactions. State if long term safety data are lacking. Include monitoring requirements if appropriate. New Medicines Profile: Template Guidance Notes NHS Impact Briefly discuss the existing treatment option(s) of choice for the condition and comment on the new products likely place in therapy. Include a statement as to when (or indeed if) it should be prescribed and to whom i.e. does it offer any advantages, clinical, service or financial, over existing therapies? Include those issues that local decision makers need to take into consideration. These could include: - likely target population - disease prevalence - limits on licensed indications compared to existing comparators - limits on who should prescribe it - relevance of drug comparators used in clinical trials - relative cost - any service implications (positive or negative) Recommendations should clearly reflect best available supporting evidence. Include the status and anticipated date of any NICE guidance. Risk Management Issues If applicable, discuss any issues which may increase the risk of medication errors. This could include information relating to compliance, packaging, administration and drug name. Other issues include whether any particular disposal methods are required, if there are environmental issues e.g. chemotherapy, or if disposal may have an adverse effect on the environment e.g. hormonal products. Include a picture of the product if it illustrates a risk issue or is a novel presentation. Author Details Insert author and name, address, telephone number of Medicines Information Centre. References Reference all sources used and highlight the key papers in bold. References are numbered in the order they appear in the text. The citation number should be placed in the text at the end of the appropriate sentence in superscript, after the full stop. References must be cited in the Vancouver style; using Index Medicus abbreviations for journal titles (see following examples). List the first three authors, followed by “et al” if there are more than three. Give the full title of the article, using US spelling if in the original. This is followed by the title of the journal, year of the publication, the volume number and the first and last page numbers in full. References to books should be given the names of the authors, any editors, the title, edition, place of publication and year. For references accessible via the web include a web address together with the date accessed. New Medicines Profile: Template Guidance Notes Examples: Journal Articles 1. Janne PA and Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med 2000; 342: 1958-1968. Abstracts 2. Raskin P, Kapp A, Gupta K et al. The effect of HOE 901 on glycemic control in type 2 diabetes. American Diabetes Association 58th Annual Meeting. Chicago, Il. 13-16 June 1998. Abs 404. Books 3. Mehta DK, editor. British National Formulary No. 52. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, September 2006. On-line Resources 4. Summary of Product Characteristics: Baraclude, Bristol Myers Squibb Pharmaceuticals Ltd June 2006. Accessed via www.medicines.org.uk on 20/03/07. 5. National Institute for Clinical Excellence. Dyspepsia: Management of dyspepsia in adults in primary care. Clinical Guideline No. 17. August 2004. Available at: www.nice.org.uk /CG017NICEguideline. Accessed 20/03/07. 6. Exubera, European Public Assessment Report Scientific discussion. Available at: www.emea.eu.int/humandocs/Humans/EPAR/exubera/exubera.htm. Accessed 25/05/06. Personal Communication (do not include name of person unless they have consented) 7. Personal Communication 20/03/07, Janssen-Cilag Ltd Appendix I: Table of Clinical Trials The table should be headed with a number and a title. The aim of the table is to present details of the trials in a concise manner. Some information may need repeating in the text. The table should be fully explanatory so that it can be understood without reference to the text. If necessary a key should be included. The table may be adapted as necessary but should include the following data as a minimum: ref no, trial design, trial population, treatment regimen, primary outcomes. Additional headings which may be required include: inclusion/exclusion criteria, secondary outcomes, comments. The following examples of tables illustrate appropriate alternative layouts. Date of preparation: August 2003 Last updated: July 2007 New Medicines Profile: Template Guidance Notes Example I: Table of key clinical trials evaluating omalizumab in patients with severe persistent allergic asthma Ref No Trial Design Ref 5 INNOVATE Multicentre, doubleblind, RCT over 28 weeks omalizumab vs. placebo 4 phases: 1 week screening 8 week run-in 28 week treatment 16 week follow-up (unpublished) Ref 2 Busse et al Multicentre, doubleblind, RCT over 28 weeks omalizumab vs. placebo 4 phases: 4-6 week run-in 16 week stable steroid phase 12 week ICS reduction 24 week extension Common Criteria - all trials Additional Criteria Inclusion Criteria Age 12 – 75 years Positive skin prick test to ≥ 1 perennial allergen Moderate to severe allergic asthma* Duration of asthma ≥ 1 year Total serum IgE ≥ 30 IU/ml to ≤ 700 IU/ml FEV1 ≥ 40 to ≤ 80% of predicted normal value and continuing asthma symptoms FEV1 reversibility ≥ 12% from baseline within 30 minutes after administration of inhaled β2 -agonist Exclusion Criteria Prior exposure or sensitivity to omalizumab Elevated IgE levels other than atopy *See individual trials for further details n=482 at entry n=419 efficacy analyses Additional Inclusion Criteria Severe persistent asthma (GINA 2002 step 4#), receiving ICS and LABA (100% patients) and additional controller medications including oral corticosteroids (22% patients) At least 2 exacerbations requiring systemic corticosteroids or 1 severe exacerbation resulting in hospitalisation or emergency room treatment in past 12 months Additional Exclusion Criteria Smoker Treatment for an exacerbation within 4 weeks of randomisation n=525 Additional Inclusion Criteria Severe allergic asthma requiring daily ICS Treatment with beclometasone dipropionate 420-840mcg/day or equivalent ICS for > 3 months prior to randomisation Additional Exclusion Criteria Acute upper respiratory tract infection within 1 month <3 months stable immunotherapy, regular treatment with β2 blockers Required dose omalizumab >750mg Outcome Measures Primary outcome Rate of clinically significant asthma exacerbations during treatment phase Secondary outcomes Severe exacerbation rate (PEF or FEV1<60% requiring treatment with systemic corticosteroids) Total number of emergency visits Hospital admissions Asthma-related QoL using Juniper AQLQ instrument >0.5-point improvement from baseline Improvement in FEV1 Primary outcome Mean number of exacerbation episodes per patient in stable steroid phase Secondary outcomes % of patients experiencing at least one exacerbation in stable steroid phase % of patients achieving >50% reduction in beclometasone dipropionate dose Mean change in PEF at week 16 Results Omalizumab 0.68 Placebo 0.91 P value 0.042 Rate ratio 0.738 (95% CI: 0.552-0.998) 0.24 0.48 0.002 50 93 0.038 Rate ratio 0.561 (95% CI 0.325-0.968) 13 25 Not sig 60.8% 47.8% 0.008 190ml 96ml Omalizumab 0.28 Placebo 0.54 P value 0.006 14.6% 23.3% 0.009 72.4% 54.9% <0.001 18.5L/min 6.9L/min New Medicines Profile: Template Guidance Notes Example II: Published short-term efficacy studies Ref No Trial Design Trial Population Treatment 1 Randomised, open-label, 6-month study 328 patients with type1 diabetes receiving a stable regimen of SC insulin 1. 2. Morning prandial Morning prandial and bedtime SC NPH plus preINH or and bedtime SC NPH plus preSI. Primary Outcomes Comments Mean HbA1c decreased similarly from baseline in the two groups (8.0% to 7.7% for INH vs. 7.9% to 7.8% for SI). Not ITT analysis. Mean HbA1c decreased from baseline similarly in the two groups (8.1% to 7.9% for INH vs. 8.1% to 7.7% for SI/NPH). Not ITT analysis. Mean HbA1c decreased from baseline similarly in the two groups (8.1% to 7.4% for INH vs. 8.2% to 7.6% for SI/NPH). Not ITT analysis. Mean HbA1c decrease from baseline was significantly greater with INH (9.3% to 7.9%)*, and INH plus OA (9.2% to 7.3%)*, compared to OA only (9.3% to 9.1%). Changing to, or adding, insulin is standard practice in people with type 2 diabetes poorly controlled on OA therapy. Insulins were titrated to achieve pre-specified glycaemic targets. 2 Randomised, open-label, 6-month study 335 patients with type1 diabetes receiving a stable regimen of SC insulin 1. 2. Pre-prandial INH plus a single bedtime dose of SC insulin zinc suspension or Two to three daily injections of a SI/NPH insulin regimen. Insulins were titrated to achieve pre-specified glycaemic targets. 3 Randomised, open-label, 6-month study 299 patients with type2 diabetes receiving a stable regimen of SC insulin 1. 2. Pre-prandial INH plus a single bedtime dose of SC insulin zinc suspension or At least two mixed SI/NPH injections per day. Insulins were titrated to achieve pre-specified glycaemic targets. 4 Randomised, open-label, 3-month study 309 patients with type2 diabetes uncontrolled on dual OA therapy 1. 2. 3. Pre-prandial INH only or Pre-prandial INH plus OA (at existing doses) or OA only. *(P<0.001 for difference vs. OA only) 5 Randomised, open-label, 3-month study 68 patients with type-2 diabetes inadequately controlled on OA 1. 2. Pre-prandial INH plus OA (at existing doses) or OA only. Mean HbA1c decrease from baseline was significantly greater with INH plus OA (9.8% to 7.5%), compared to OA only (9.9% to 9.8%). (P<0.001 for difference) As above