The long road of biopharmaceutical drug development: from inception to marketing.

The development of therapeutics is costly, time-consuming and has high attrition rates. Biopharmaceutical medications differ from traditional agents in their discovery, design, structure and formulation. Prior to marketing a drug must show efficacy and acceptable toxicity in both preclinical and clinical trials. Regulatory bodies have a pivotal role in the licensing, naming and marketing of an agent.

Assessment of anti-TNF-alpha efficacy in rheumatoid arthritis: is 3 months sufficient?

OBJECTIVES: The optimal therapeutic trial duration of anti-TNF-alpha therapy is currently unknown. The British Society for Rheumatology (BSR) guidance states that non-response at 3 months warrants re-evaluation of treatment and recommends not to persist beyond 6 months. The National Institute for Health and Clinical Excellence (NICE) specifies treatment continuation if response is achieved by 6 months, yet the European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR) maintain a 3 month cut-off. No evidence exists to support a 6 month therapeutic trial over 3 months. Thus, we undertook a study to evaluate the proportion of patients who failed to meet NICE response criteria at 3 months but obtained this by 6 months, and to identify predictive factors for this. METHODS: Patients who commenced anti-TNF-alpha therapy for RA were studied, counting those who switched to a second or third agent separately for each instigation of therapy (n = 244). Response at 3 and 6 months was defined according to NICE criteria as a >or=1.2 reduction in Disease Activity Score (DAS28). RESULTS: Of the 189 patients with available 3 month DAS28 responses, 149 fulfilled response criteria. Of the 40 who failed, 27 continued treatment, of whom 21 were available for follow-up at 6 months. Out of the 21 patients, 12 (57%; 95% CI 36, 78) achieved a response at this time. This data set was too small to investigate predictors of response at 6 months. CONCLUSIONS: A substantial proportion of patients who fail NICE response criteria at 3 months and continue on treatment to 6 months achieve a response. These results support a 6 month therapeutic trial over 3 months.

Hypovitaminosis D among rheumatology outpatients in clinical practice.

OBJECTIVES: A role for vitamin D in the pathogenesis of autoimmune and inflammatory diseases is emerging. We undertook an audit of 25-hydroxyvitamin D (25OHD) investigation and treatment in rheumatology outpatients. METHODS: Serum 25OHD requests were matched to electronic medical records from rheumatology and metabolic bone clinics (April 2006-March 2007). Data were analysed separately for two groups, 'Documented osteoporosis/osteopaenia' (Group 1) and 'General rheumatology outpatients' (Group 2, sub-divided by diagnosis). Hypovitaminosis D was defined by 25OHD levels <50 nmol/l. Values were compared with healthy adults to calculate geometric z-scores. RESULTS: A total of 263 patients were included (Group 1, n = 122; Group 2, n = 141) with an overall median 25OHD of 44 nmol/l. The 25OHD level among general rheumatology patients (median 39 nmol/l, mean z score -1.2, was statistically significantly lower than among osteoporotic/osteopaenic patients (median 49 nmol/l, mean z score of -0.9, p < 0.05 for the difference). 25OHD was lower in inflammatory arthritis and chronic pain/fibromyalgia than in other groups. Prescribing was recorded in 100 in Group 1 (of whom 95% were prescribed calcium/800 IU cholecalciferol) and 83 in Group 2 (91% calcium/800 IU). Only 31% of the patients with 25OHD <50 nmol/l would have been identified using general guidelines for screening patients at 'high risk' of hypovitaminosis D. CONCLUSIONS: Improved guidelines for managing hypovitaminosis D in rheumatology patients are needed. We found a high prevalence of hypovitaminosis D among secondary care patients in rheumatology and widespread supplementation with 800 IU cholecalciferol. Substantially reduced levels of serum 25OHD were identified among patients with inflammatory arthritis and chronic pain.

Pulsed low-intensity ultrasound therapy for chronic lateral epicondylitis: a randomized controlled trial.

OBJECTIVES: Pulsed low-intensity ultrasound therapy (LIUS) has been found to be beneficial in accelerating fracture healing and has produced positive results in animal tendon repair. In the light of this we undertook a randomized, double-blind, placebo controlled trial to assess the effectiveness of LIUS vs placebo therapy daily for 12 weeks in patients with chronic lateral epicondylitis (LE). METHODS: Patients with LE of at least 6 weeks' duration were recruited from general practice, physiotherapy and rheumatology clinics, and had to have failed at least one first-line treatment including non steroidal anti-inflammatory drugs (NSAIDs) and corticosteroid injection. Participants were assigned either active LIUS or placebo. Treatment was self-administered daily for 20 min over a 12-week period. The primary end-point was a 50% improvement from baseline in elbow pain measured at 12 weeks using a patient-completed visual analogue scale. RESULTS: Fifty-five subjects aged 18-80 were recruited over a 9-month period. In the active group 64% (16/25) achieved at least 50% improvement from baseline in elbow pain at 12 weeks compared with 57% (13/23) in the placebo group (difference of 7%; 95% confidence interval -20 to 35%). However, this was not statistically significant (chi(2) = 0.28, P = 0.60). CONCLUSION: In this study LIUS was no more effective for a large treatment effect than placebo for recalcitrant LE. This is in keeping with other interventional studies for the condition.

Diagnosis and relation to general health of shoulder disorders presenting to primary care.

OBJECTIVES: To prospectively evaluate the incidence, spectrum of disease and relation to general health of shoulder disorders in primary care. METHODS: Patients presenting with shoulder pain to two large general practices in the Cambridge area over a 1-month period were invited to participate. After consulting their general practitioner, patients were administered a demographic information questionnaire, a shoulder pain and disability index (SPADI) and a short form 36 (SF-36) health survey. Subsequent review in a clinic held by a rheumatology registrar every 2 weeks was undertaken. RESULTS: The sex- and age-standardized incidence of shoulder pain was 9.5 per 1000 (95% confidence interval 7.9 to 11.2 per 1000). Rotator cuff tendinopathy was found in 85%, signs of impingement in 74%, acromioclavicular joint disease in 24%, adhesive capsulitis in 15% and referred pain in 7%. On the SPADI the mean disability subscale score was 45 (95% confidence interval 41 to 50) and the mean pain score was 58 (95% confidence interval 53 to 62) (range 0 to 100). Evaluation of general health status using the SF-36 showed the difference between population norms and those with shoulder pain was significant in six of the eight domains, being especially marked (greater than 20 point reduction) for emotional role, physical function and physical role. CONCLUSION: Shoulder pain, most commonly due to rotator cuff tendinopathy, is associated with significantly reduced health when measured by both specific and generic means. Effort towards prevention and early intervention in these complaints is warranted.

Interrater reproducibility of clinical tests for rotator cuff lesions.

BACKGROUND: Rotator cuff lesions are common in the community but reproducibility of tests for shoulder assessment has not been adequately appraised and there is no uniform approach to their use. OBJECTIVE: To study interrater reproducibility of standard tests for shoulder evaluation among a rheumatology specialist, rheumatology trainee, and research nurse. METHODS: 136 patients were reviewed over 12 months at a major teaching hospital. The three assessors examined each patient in random order and were unaware of each other's evaluation. Each shoulder was examined in a standard manner by recognised tests for specific lesions and a diagnostic algorithm was used. Between-observer agreement was determined by calculating Cohen's kappa coefficients (measuring agreement beyond that expected by chance). RESULTS: Fair to substantial agreement was obtained for the observations of tenderness, painful arc, and external rotation. Tests for supraspinatus and subscapularis also showed at least fair agreement between observers. 40/55 (73%) kappa coefficient assessments were rated at >0.2, indicating at least fair concordance between observers; 21/55 (38%) were rated at >0.4, indicating at least moderate concordance between observers. CONCLUSION: The reproducibility of certain tests, employed by observers of varying experience, in the assessment of the rotator cuff and general shoulder disease was determined. This has implications for delegation of shoulder assessment to nurse specialists, the development of a simplified evaluation schedule for general practitioners, and uniformity in epidemiological research studies.