Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and further notice)

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1 Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and further notice) This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine Tapentadol Trade names - Nucynta [US] or Palexia Manufacturer - Gruenenthal Document status Reviewed at March 2011 Suffolk D&TC meeting Date of last revision 2 March 2011 Traffic light decision Prescribers rating Blue- Primary Care Judgement reserved- The committee postpones its judgement until better data and a more thorough evaluation of the drug are available Mechanism of action Medicine class Likely indication Dual mode analgesic that inhibits norepinephrine reuptake and has mu opioid receptor agonism. [1] BNF 4.7 opioid analgesic New chemical entity [1] Treatment of moderate to severe acute or chronic pain in patients 18 years of age or older. [1] Tapentadol is available as an immediate release (IR) and extended release (ER) formulation. The IR preparation was launched in the US in June 2009 for treatment of moderate to severe acute pain in patients 18 years of age or older. [2] In October 2010 the US FDA requested data regarding the conversion of the ER formulation used in the clinical efficacy and safety trials to a different ER formulation that is designed to increase mechanical resistance to breaking or crushing. [1] Neither the IR or ER preparations are available yet in the UK. Tapentadol is in schedule II of the Controlled Substances Act in the US because of the potential for abuse. Other schedule II products include morphine, oxycodone and hydromorphone. [1] Tapentadol will also be a controlled drug in the UK. [8] Dosage IR oral tablets: 50 mg, 75 mg, 100 mg [2] Initiate with or without food at a dose of 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending upon pain intensity. On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose. Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability. Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are, therefore, not recommended. [2]

2 The ER formulation will have twice daily dosing, the exact dosage is not known yet. [8] Use is not recommended in patients with severe renal or hepatic impairment. Use with caution in patients with moderate hepatic impairment. [2] Care should be taken when selecting an initial dose in elderly patients. [2] There are no adequate and well controlled studies of tapentadol in pregnant women. Tapentadol should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. [2] Tapentadol is not recommended for use in women during and immediately prior to labor and delivery. Due to the mu-opioid receptor agonist activity of tapentadol, neonates whose mothers have been taking tapentadol should be monitored for respiratory depression. A specific opioid antagonist, such as naloxone, should be available for reversal of opioid induced respiratory depression in the neonate. [2] Tapentadol should not be used during breast-feeding. [2] Treatment alternatives Place in therapy The safety and effectiveness of tapentadol in pediatric patients less than 18 years of age has not been established therefore tapentadol is not recommended in this population. [2] Morphine, oxycodone and hydromorphone Tapentadol IR has been trialled in post bunionectomy, hysterectomy and dental surgery patients with acute pain and therefore may be an option in secondary care. The IR preparation has also been studied in patients with knee osteoarthritis (OA) and low back pain. Tapentadol ER has been trialled in patients with chronic pain due to knee OA and low back pain. Pain relief after surgery should be adjusted for each patient and each situation. Multimodal regimens, using several classes of analgesic, and ideally more than one route, are now generally favoured. Pre-operative evaluation of the patient, and frequent assessment of pain intensity after surgery (both to allow appropriate analgesia, and to detect possible complications) are fundamental. Patients undergoing minor surgery can be adequately managed with oral analgesics, such as paracetamol, NSAIDs, tramadol, and oxycodone. Opioid analgesics, in particular morphine, are the mainstay of treatment for moderate to severe postoperative pain. Opioid dose should be individually titrated. [15] The Clinical Knowledge Summary on osteoarthritis states that regular dosing with paracetamol and topical nonsteroidal antiinflammatory drugs (NSAIDs) to substitute or supplement paracetamol should be used initially. If paracetamol and/or topical NSAIDs are ineffective consider standard oral NSAIDs or coxibs. If an opioid is needed codeine should be tried first, alone or together

3 with paracetamol. Obtain specialist advice before prescribing stronger opioids such as fentanyl or buprenorphine patches, or morphine. [13] The Clinical Knowledge Summary on low back pain states that for first-line analgesia offer paracetamol. If paracetamol is insufficient, offer a standard nonsteroidal anti-inflammatory drug (NSAID), or a coxib. For additional analgesia, consider the following options: paracetamol combined with an NSAID/coxib or adding a weak opioid such as codeine, dihydrocodeine, or tramadol. For chronic pain not responding to first-line analgesics and additional analgesics consider offering a trial of a tricyclic antidepressant such as amitriptyline, nortriptyline, or imipramine. A strong opioid is rarely necessary. If a strong opioid (such as standard-release morphine) is to be used prescribe it for a short period, and step down to a weak opioid when appropriate. [14] Future alternatives Evidence for use Approximately 20% of patients taking opioids discontinue therapy due to adverse effects. [9] Use of tapentadol may be considered if patients can not tolerate currently used strong opioids. None known Details of the published and unpublished clinical trials for the IR and ER formulations are in table 1 and 2 respectively. Tapentadol immediate release and extended release has been compared with oxycodone in most published studies, two studies used morphine and one study used ibuprofen as the comparators. NNT Contraindications / cautions Tapentadol has comparable analgesic efficacy and tolerability to oxycodone. It demonstrates a lower incidence of opioid receptor related side effects such as nausea and vomiting. Not calculated The following information is taken from the US prescribing information [2] Impaired pulmonary function (significant respiratory depression, acute or severe bronchial asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment). Paralytic ileus. Concomitant use with monoamine oxidase inhibitors (MAOI) or use within 14 days due to potential additive effects on norepinephrine levels which may result in adverse cardiovascular events. Respiratory depression: Increased risk in elderly, debilitated patients, those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction. CNS effects: Additive CNS depressive effects when used in conjunction with alcohol, other opioids, or illicit drugs. Elevation of intracranial pressure: May be markedly exaggerated in the presence of head injury, other intracranial lesions. Abuse potential may occur. Monitor patients closely for signs of abuse and addiction. Impaired mental/physical abilities: Caution must be used with potentially hazardous activities.

4 Side effects Seizures: Use with caution in patients with a history of seizures. Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic administration. The most common adverse events (reported by 10% in any tapentadol dose group) in 9 phase 2/3 studies were: nausea, dizziness, vomiting and somnolence. [2] The most common reasons for discontinuation due to adverse events in the studies described above (reported by 1% in any tapentadol dose group) were dizziness (2.6% vs. 0.5%), nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache (0.9% vs. 0.2%) for tapentadol- and placebo-treated patients, respectively. [2] Drug Interactions Cost within PbR tariff? Cost Comparative costs of other medicines 76% of tapentadol-treated patients from the nine studies experienced adverse events. [2] Tapentadol may have a lower potential for drug-drug interactions since its activity does not involve an active metabolite with analgesic activity. [8] Patients receiving other opioid agonist analgesics, general anesthetics, phenothiazines, antiemetics, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with tapentadol may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with tapentadol. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered. [2] Likely to be within tariff Not known as the product is not licensed yet. An American cost effectiveness analysis compared tapentadol immediate release with oxycodone immediate release for treatment of acute post-surgical and non-surgical pain. [7] A Markov model simulated clinical economic outcomes for tapentadol 100mg vs. oxycodone 15mg for 3 days for acute postsurgical pain and tapentadol 50mg vs. oxycodone 10mg for 10 days for acute non-surgical pain. The model simulated changes in pain relief, occurrence of opioid related adverse effects, opioid switching, discontinuation, dose change and number of quality adjusted life days. The cost of medication was higher for tapentadol than oxycodone but there were reduced pharmacy and medical costs associated with treatment of adverse effects, opioid switching and discontinuation with tapentadol. The authors conclude that tapentadol is a cost effective alternative to doses of oxycodone that provide comparable analgesia for the treatment of acute surgical and non-surgical pain. Drug Dose Cost Morphine IR Dose adjusted 56 x 10mg = 5.61 Morphine ER according to response 60 x 100mg = (MST Continus) Oxycodone IR Dose adjusted 56 x 5mg = Oxycodone ER according to response 56 x 40mg =

5 Potential number of patients & usage in Suffolk PCT Prevalence of chronic pain in the UK population is about 13% - back pain and OA pain are the most common causes. Of this population, about 12% are taking strong opioids for pain relief. [1] Points for consideration Is the drug on the WSH or IHT formularies? Decisions from other bodies Comments sought from Decision review date March 2013 Applying these figures to NHS Suffolk (population 600,000) means there are approximately 78,000 people with chronic pain, of whom about 9,360 are currently taking strong opioids. It is difficult to estimate the potential number of patients who may be eligible for tapentadol. In 2008/2009 there were over 9,000,000 procedures in England and Wales which may have required use of opioids. The incidence of severe acute pain has been estimated at 11% of all patients in the first 24 hrs after major surgery. [8] In primary care in 2008, approximately 229 million was spent on opioid analgesics with almost 16 million prescriptions dispensed in England and Wales. [8] Tapentadol immediate release and extended release has been compared with oxycodone in most published studies, two studies used morphine and one study used ibuprofen as the comparators. Tapentadol has comparable analgesic efficacy and tolerability to oxycodone. It demonstrates a lower incidence of opioid receptor related side effects such as nausea and vomiting. Tapentadol will have to compete with currently used generic analgesics used for post-operative pain and will inevitably be more expensive. If the extended release product is launched, this may be promoted for use in chronic OA pain or low back pain which would have wider use in primary care. Tapentadol may be a useful option if reduced gastrointestinal adverse effects are proven and could be used if another analgesic can not be tolerated due to adverse GI effects. Tapentadol is also being investigated for treatment of diabetic peripheral neuropathic pain and cancer pain. [1, 8] No the product is still unlicensed so has not been considered. Cambridgeshire JPG not assessed Norfolk TAG not assessed SMC not assessed as not licensed yet AWMSG not assessed as not licensed yet References 1. New Drugs Online report for Tapentadol. Accessed via on Feb Nucynta prescribing information. Accessed via on Feb Daniels S, Casson E et al. A randomised, double blind, placebo controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Current Medical Research & Opinion 2009; 25 (6): Hartrick C, Van Hove I et al. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery

6 for end stage joint disease: a 10 day, phase III, randomised, double blind, active and placebo controlled study. Clinical Therapeutics 2009; 31 (2): Hale M, Upmalis D et al. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomised, double blind study. Current Medical Research & Opinion 2009; 25 (5): Afilalo M, Etropolski MS et al. Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee. Clinical Drug Investigation 2010; 30 (8): Kwong WJ, Ozer-Stillman I et al. Cost effectiveness analysis of tapentadol immediate release for the treatment of acute pain. Clinical Therapeutics 2010; 32 (10): Tapentadol (Palexia) prolonged release for severe chronic pain / Tapentadol (Palexia) for severe acute pain. National Horizon Scanning Centre December ml 9. Candiotti KA, Gitlin MC. Review of the effect of opioid-related side effects on the undertreatment of moderate to severe chronic non-cancer pain: tapentadol, a step toward a solution? Current Medical Research & Opinion 2010; 26 (7): Daniels SE, Upmalis D, Okamoto A et al. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Current Medical Research and Opinion 25(3) 2009;(3): Kleinert R, Lange C, Steup A et al. Single dose analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study. Anesthesia & Analgesia 2008;107(6): Stegmann J-U, Weber H, Steup A et al. The efficacy and tolerability of multiple-dose tapentadol immediate release for the relief of acute pain following orthopaedic (bunionectomy) surgery. Current Medical Research and Opinion 2008;24(11): Clinical Knowledge Summary Osteoarthritis. Version 1.4, last revised in August Clinical Knowledge Summary Low back pain without radiculopathy. Version 1.3, last revised November Postoperative analgesia (Latest modification: 20-Aug-2010). Martindale - The Complete Drug Reference. 36 th Ed. Accessed via

7 Appendix 1 Summary of published clinical trials with IR tapentadol Ref No 3 Randomised, double blind, active and placebo controlled, parallel group, multicentre, 72 hour, phase 3 study Trial Design Trial Population Treatment Primary Outcomes N=901 Adults aged undergoing primary unilateral first metatarsal bunionectomy. Baseline pain rating of 4 the day after surgery. Tapentadol 50mg, N=275 Tapentadol 75mg, N=278 Oxycodone 10mg, N=279 Placebo, N=69 Study drugs taken every 4-6 hrs for up to 72 hrs Up to 2g paracetamol was allowed as rescue medication. Sum of pain intensity difference (SPID) over the first 48hrs The results were reported as least squares mean differences from placebo Tapentadol 50mg: 62.4 (95% CI: ); P<0.001 Tapentadol 75mg: 84.6 (95% CI: ); P<0.001 Oxycodone 10mg: 81.5 (95% CI: ); P<0.001 Incidence of treatment-emergent adverse events of nausea & vomiting Tapentadol 50mg: N = 93 (34%); V = 34 (12%) Tapentadol 75mg: N = 127 (46%); V = 77 (28%) Oxycodone 10mg: N = 160 (57%); V = 72 (26%) Placebo: N = 12 (17%); V = 0 (0%) 4 Randomised, double blind, active and placebo controlled, parallel group, multicentre, 10 day, phase 3 study N=659 Adults aged who were candidates for primary joint replacement (knee/hip) surgery due to OA with uncontrolled pain. Baseline pain rating of 5 over 3 days before randomisation. Tapentadol 50mg, N=157 Tapentadol 75mg, N=168 Oxycodone 10mg, N=172 Placebo, N=169 Study drugs taken every 4-6 hrs (maximum of 6 doses/day) for 10 days. Patients allowed to continue with previous stable non-opioid analgesic regimen, no rescue medication permitted. Sum of pain intensity difference (SPID) over the first 5 days The results were reported as least squares mean differences from placebo Tapentadol 50mg: (95% CI: ); P<0.001 Tapentadol 75mg: 97.5 (95% CI: ); P<0.001 Oxycodone 10mg: (95% CI: ); P<0.001 Incidence of treatment-emergent adverse events of nausea & vomiting Tapentadol 50mg: N = 29 (18%); V = 11 (7%) Tapentadol 75mg: N = 35 (21%); V = 23 (14%) Oxycodone 10mg: N = 70 (41%); V = 59 (34%) Placebo: N = 9 (5%); V = 7 (4%)

8 Ref No 5 Randomised, double blind, active controlled, parallel group, multicentre, 90 day, phase 3 study Trial Design Trial Population Treatment Primary Outcomes 10 Randomised, double blind, active and placebo controlled, parallel group, multicentre, phase 3 study N=878 Adults aged 18 or older with a clinical diagnosis and at least a 3 month history of lower back pain or OA pain of the knee or hip. Baseline pain rating of 4 before randomisation while taking non-opioid analgesics or 24 hrs after stopping opioid analgesics N=603 Adults aged 18 to 80 with postoperative pain following first metatarsal bunionectomy with osteotomy. Baseline pain moderate to severe; 4-point intensity on 11-point numerical rating scale (NRS). Tapentadol 50 or 100mg, N=679 Oxycodone 10 or 15mg, N=170 Study drugs could be taken flexibly every 4-6 hrs as needed (maximum of 6 doses/day) over 90 days. Patients allowed to continue with previous stable non-opioid analgesic regimen, rescue medication up to 2g paracetamol or 400mg ibuprofen. Tapentadol 50mg, N=119 Tapentadol 75mg, N=120 Tapentadol 100mg, N=118 Oxycodone15mg, N=125 Placebo, N=121 Study drugs taken every 4-6 hrs for 72 hrs. Tolerability evaluations Tapentadol Oxycodone Discontinued early: 42% 49% Discontinued due to adverse events: 21% 31% Treatment emergent adverse effects:76.3% 82.9% Nausea: 18.4% 29.4% Vomiting: 16.9% 30% Medication taken for at least 45 days:67% 61% Mean (standard deviation) length of treatment exposure in days: 63 (36.5) 58 (39.9) Mean total daily dose: 284mg 42mg Tapentadol and oxycodone demonstrated similar efficacy based on pain intensity scores taken throughout the study. Pain improved: 66% 62% Sum of pain intensity difference (SPID) over the first 48hrs Tapentadol 50mg: mean 119.1; SD ; p<0.001 vs. placebo Tapentadol 75mg: (118.93); p<0.001 vs. placebo Tapentadol 100mg: (98.99); p<0.001 vs. placebo Oxycodone 15mg: (110.86); p<0.001 vs. placebo Placebo 24.5 (120.93) 30% reduction in pain intensity at 48 hrs Tapentadol 50mg: 65%; p<0.001 vs. placebo Tapentadol 75mg: 68%; p<0.001 vs. placebo Tapentadol 100mg: 79%; p<0.001 vs. placebo Oxycodone 15mg: 78%; p<0.001 vs. placebo Placebo 40%

9 Ref No 11 Randomised, single dose, double blind, active and placebo controlled, double dummy, multicentre, phase 2 study Trial Design Trial Population Treatment Primary Outcomes N=400 Adults aged 18 or older with postsurgical dental pain. Pain moderate to severe on a visual analogue scale within 6 hours post surgery. Tapentadol 25mg, 50mg, 75mg, 100mg or 200mg Morphine 60mg Ibuprofen 400mg Placebo Single dose of study drug taken Incidence of nausea, vomiting and constipation Tapentadol 50mg & 75mg: 46% Tapentadol 100mg: 59% Oxycodone 15mg: 73% Mean total pain relief score over 8 hrs after drug administration Tapentadol 25mg: 6.3 (standard deviation 8.4) vs. placebo Tapentadol 50mg: 7.9 (8.1) vs. placebo Tapentadol 75mg: 9.7 (8.5) vs. placebo; p 0.05 Tapentadol 100mg: 11.6 (8.2) vs. placebo; p Tapentadol 200mg: 15.3 (7.5) vs. placebo; p Morphine 60mg: 13.8 (10.3) vs. placebo; p Ibuprofen 400mg: 17.9 (9.9) vs. placebo; p Placebo: 4.7 (7.3) 50% pain relief experienced Tapentadol 25mg: 32% Tapentadol 50mg & 75mg: 46% Tapentadol 100mg: 65% Tapentadol 200mg: 88% Morphine 60mg: 65% Ibuprofen 400mg: 77% Placebo: 26% 12 Randomised, double blind, placebo controlled, multicentre, phase 2 study N=269 Adults aged 18 to 65 with postoperative pain following first metatarsal bunionectomy with Tapentadol 50mg, N=67 Tapentadol 100mg, N=68 Oxycodone10mg, N=67 Placebo, N=67 Incidence of adverse effects lower with all doses of tapentadol vs. morphine 60mg (not statistically significant) Sum of pain intensity difference (SPID) over 24hrs on day 3 Tapentadol 50mg: mean 33.6; SD 19.7; p= vs. placebo

10 osteotomy. Pain moderate to severe; 4-point intensity on 11- point NRS. Study drugs taken every 4-6 hrs for 72 hrs. Appendix 2 Summary of published and unpublished clinical trials with ER tapentadol Ref No 6 Randomised, double blind, active and placebo controlled, parallel group, multicentre, 12 week, phase 3 study Trial Design Trial Population Treatment Primary Outcomes N=1030 Adults 40 years old with a diagnosis of OA of the knee (ACR criteria) requiring analgesics equivalent to 160mg oral morphine/day for 3 months before the study. Pain moderate to severe; 5-point intensity on 11-point NRS 3 days before randomisation Tapentadol 100 to 250mg, N=346 Oxycodone 20 to 50mg, N=345 Placebo, N=339 Adjustable doses taken twice daily for 12 weeks (after a 3 week titration period) Tapentadol 100mg: 29.2 (15.2); p= vs. placebo Oxycodone 10mg: 35.7 (17.2); p= vs. placebo Placebo 41.9 (17.7) Nausea: tapentadol = 46.3%; oxycodone = 71.6% Dizziness: 32.8% vs. 17.9% Vomiting: 16.4% vs. 38.8% Constipation: 6% vs. 17.9% Somnolence: 28.4% vs. 26.9% Mean pain intensity change from baseline over 12 weeks The results were reported as least squares mean differences from placebo Tapentadol: -0.7 (95% CI: -1.00, -0.33) Oxycodone: -0.3 (95% CI: -0.67, 0.00) Statistical significance not stated Trial completed by Tapentadol: 57.3% (197/344) Oxycodone: 35.4% (121/342) Placebo: 61.4% (207/337) Discontinuations were due to adverse effects in the tapentadol and oxycodone groups (19.2%, 66/344 and 43%, 147/342 respectively) and lack of efficacy in the placebo group (16.6%, 56/337). Incidence of treatment emergent adverse effects; nausea & vomiting Tapentadol: 75.9%; 21.5%, 5.2% Oxycodone: 87.4%; 36.5%, 17.8%

11 8 Randomised, placebo controlled, multicentre, 12 week, phase III study 8 Randomised, open label, multicentre, 52 week, phase III study N=977 Adults aged 18 or older with chronic, non-malignant back pain requiring analgesics equivalent to 160mg oral morphine/day for 3 months before the study. Pain moderate to severe; 5-point intensity on 11-point NRS. N=1121 Adults aged 18 or older with OA pain of the knee or hip or non-malignant low back pain for 3 months. Baseline pain rating of 4 on 11 point NRS. Tapentadol 100 to 250mg Oxycodone 20 to 50mg Placebo Adjustable doses taken twice daily for 12 weeks (after a 3 week titration period) Tapentadol 50 to 250mg Oxycodone 10 to 50mg Adjustable doses taken twice daily for 51 weeks (after a 1 week titration period) Placebo: 61.1%, 6.8%, 3.3% Mean pain intensity change from baseline The results were reported as least squares mean differences from placebo Tapentadol: -0.7 (95% CI: -1.06, -0.35), p=0.001 Oxycodone: -0.8 (95% CI: -1.16, -0.46), p=0.001 Incidence of treatment emergent adverse effects Tapentadol: 76% Oxycodone: 85% Placebo: 60% Mean pain intensity change from baseline Tapentadol: (standard deviation 2.66) Oxycodone: (2.41) Overall incidence of treatment emergent adverse effects Tapentadol: 86% Oxycodone: 91% Overall treatment discontinuation Tapentadol: 53% Oxycodone: 65%

12 Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this- Rank: Methodology Description 1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews." 2 Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals) Individuals are randomly allocated to a control group and a group who receive a specific intervention. Otherwise the two groups are identical for any significant variables. They are followed up for specific end points. 3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes. 4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to

13 look for differences between the two groups. 5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time 6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series 7 Expert opinion A consensus of experience from the good and the great. 8 Anecdotal Something a bloke told you after a meeting or in the bar. Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008 To Decide if a Medication Is To Be Used In Suffolk Criterion to be measured Tends to poor 2 Medium 4 Tends to good Quality of evidence in the papers reviewed Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Outcomes Clinical usefulness of trial end-points x Known Side Effect Profile High x Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor x Medium Good NNT not calculated High Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Poor x Medium Good Same Condition Severity of Condition to be Treated Trivial Medium x Severe Novel drug or member of existing class Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration maximum and minimum uptake) Is the drug to be used in Suffolk? Novel 5% Prescriber s Rating Definitions

14 Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire) To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green Blue Experience Of The Condition Specific Specific Specific General Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14: Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2