Abstract The implementation of a pharmacovigilance service compliant with the legal and regulatory responsibilities of clinical trial sponsors presents particular challenges for sponsors in a non-commercial setting. In this paper we examine these challenges in detail. We identify and discuss the key steps in the development of a pharmacovigilance service within a public health service and university setting in the United Kingdom. We describe how we have established a central Pharmacovigilance Office with dedicated staff and resources within our organisation. This office is supported by an electronic pharmacovigilance reporting infrastructure developed to facilitate the receipt and processing of safety information, the onward reporting in compliance with legislation and the provision of sponsor institution oversight of clinical trial participant safety. An education and training programme has also been set up to ensure that all relevant staff in the organisation are fully aware of the pharmacovigilance service and are appropriately trained in its use. We discuss possible alternatives to this approach and why we consider our solution to be the most appropriate to ensure that a non-commercial sponsor organisation and investigators are operating in a fully compliant way.
Background The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. Methods We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). Results The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. Conclusions Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).
In: Stott , D J , Rodondi , N , Kearney , P M , Ford , I , Westendorp , R G J , Mooijaart , S P , Sattar , N , Aubert , C E , Aujesky , D , Bauer , D C , Baumgartner , C , Blum , M R , Browne , J P , Byrne , S L , Collet , T-H , Dekkers , O M , den Elzen , W P J , Du Puy , R S , Ellis , G , Feller , M , Floriani , C , Hendry , K , Hurley , C , Jukema , J W , Kean , S , Kelly , M , Krebs , D , Langhorne , P , McCarthy , G , McCarthy , V , McConnachie , A , McDade , M , Messow , M , O'Flynn , A , O'Riordan , D , Poortvliet , R K E , Quinn , T J , Russell , A , Sinnott , C , Smit , J W A , Van Dorland , H A , Walsh , K A , Walsh , E K , Watt , T , Wilson , R , Gussekloo , J & the TRUST Study Group 2017 , ' Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism ' , New England Journal of Medicine , vol. 376 , no. 26 , pp. 2534-2544 . https://doi.org/10.1056/NEJMoa1603825
BACKGROUND: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older personswith this condition. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to thethyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptomsscore and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). RESULTS: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women.The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year,this level had decreased to 5.48 mIU per liter in the placebo group, as compared with3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptomsscore (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], −2.0 to 2.1) or the Tirednessscore (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI,−2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. CONCLUSIONS: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.govnumber, NCT01660126.)