Approaches to Design an Efficient, Predictable Global Post-approval Change Management System that Facilitates Continual Improvement and Drug Product Availability.

The complexity and inter-connectedness of operating in a global world for drug product supply has become an undeniable reality, further underscored by the COVID-19 pandemic. For Post-Approval Changes (PACs) that are an inevitable part of a product's commercial life, the impact of the growing global regulatory complexity and related drug shortages has brought the Global PAC Management System to an inflection point in particular for companies that have their products marketed in many countries.This paper illustrates through data analyzed for the first time from 145,000 + PACs for 156 countries, collected by 18 global pharma companies over a 3-year period (2019-2021), how severe the problem of global regulatory complexity is. Only PACs requiring national regulatory agency (NRA) approval prior to implementation were included in the data set. 1 of the 156 country NRAs approved all submitted PACs within a period of 6 months. The 6-month timeline was chosen because it is the recommended review timeline for major changes in the WHO guidance for vaccines and biotherapeutic products. 10 out of the 156 (6%) countries had no more than 10% of the PACs reviewed and approved in > 6 months. In 33 (22%) countries more than half of the PACs took > 6 months for approval. It is rare that the same PAC is approved globally within 6 months as individual NRAs take from a few months to years (in some cases > 5 years) for their review.The global PAC management complexity has steadily grown over the past 20 years. Attempts thus far to solve this problem have not made any meaningful difference. Senior leaders and decision-makers across the interdependent components of the complex Global PAC Management System (industry and regulators) must come together and collaboratively manage the problem holistically with the objective of ensuring global drug product availability instead of continuing with distinct stakeholder or country-focused solutions, which can tend to worsen the problem.In this paper, the Chief Quality Officers (CQOs) from 18 of the largest innovator pharma companies (see Acknowledgements) are speaking with One-Voice-of-Quality for PACs (1VQ for PACs Initiative). They are recommending a set of 8 approaches to activate a holistic transformation of the Global PAC Management System. This article presents their view on the problem of global regulatory complexity for managing PACs, it's impact on continual improvement and the risk to drug product supply, as well as approaches that can help alleviate the problem.

Treating low back pain in athletes: a systematic review with meta-analysis.

OBJECTIVE: To summarise the evidence for non-pharmacological management of low back pain (LBP) in athletes, a common problem in sport that can negatively impact performance and contribute to early retirement. DATA SOURCES: Five databases (EMBASE, Medline, CINAHL, Web of Science, Scopus) were searched from inception to September 2020. The main outcomes of interest were pain, disability and return to sport (RTS). RESULTS: Among 1629 references, 14 randomised controlled trials (RCTs) involving 541 athletes were included. The trials had biases across multiple domains including performance, attrition and reporting. Treatments included exercise, biomechanical modifications and manual therapy. There were no trials evaluating the efficacy of surgery or injections. Exercise was the most frequently investigated treatment; no RTS data were reported for any exercise intervention. There was a reduction in pain and disability reported after all treatments. CONCLUSIONS: While several treatments for LBP in athletes improved pain and function, it was unclear what the most effective treatments were, and for whom. Exercise approaches generally reduced pain and improved function in athletes with LBP, but the effect on RTS is unknown. No conclusions regarding the value of manual therapy (massage, spinal manipulation) or biomechanical modifications alone could be drawn because of insufficient evidence. High-quality RCTs are urgently needed to determine the effect of commonly used interventions in treating LBP in athletes.

Protein supplementation combined with low-intensity resistance training in geriatric medical patients during and after hospitalisation: a randomised, double-blind, multicentre trial.

Sarcopenia (loss of muscle mass/strength) burdens many older adults - hospitalised older adults being particularly vulnerable. Treating the condition, protein supplementation (PrS) and resistance training (RT) may act synergistically. Therefore, this block-randomised, double-blind, multicentre intervention study, recruiting geriatric patients > 70 years from three medical departments, investigated the effect of PrS combined with RT during hospitalisation and 12 weeks after discharge. Participants were randomly allocated (1:1) to receive PrS (totally 27·5 g whey protein/d, about 2000 kJ/d) or isoenergetic placebo-products (< 1·5 g protein/d) divided into two servings per d to supplement the habitual diet. Both groups were engaged in a standardised, progressive low-intensity RT programme for the lower extremities (hospital: supervised daily/after discharge: self-training 4×/week). From April 2016 to September 2017, 2351 patients were screened, 462 were eligible, and 165 included. Fourteen were excluded and ten dropped out, leaving 141 participants in the intention-to-treat analysis. The average total protein intake during hospitalisation/after discharge was 1·0 (interquartile range (IQR) 0·8, 1·3)/1·1 (IQR 0·9, 1·3) g/kg per d (protein-group) and 0·6 (IQR 0·5, 0·8)/0·9 (IQR 0·6, 1·0) g/kg per d (placebo group). Both groups improved significantly for the primary and secondary endpoints of muscle mass/strength, functional measurements and quality of life, but no additional effect of PrS was seen for the primary endpoint (30-s chair stand test, repetitions, median changes from baseline: (standard test: 0 (IQR 0, 5) (protein group) v. 2 (IQR 0, 6) (placebo group) and modified test: 2 (IQR 0, 5) (protein group) v. 2 (IQR -1, 5) (placebo group)) or any secondary endpoints (Mann-Whitney U tests, P > 0·05). In conclusion, PrS increasing the total protein intake by 0·4 and 0·2 g/kg per d during hospitalisation and after discharge, respectively, does not seem to increase the adaptive response to low-intensity RT in geriatric medical patients.

Protein-enriched, milk-based supplement to counteract sarcopenia in acutely ill geriatric patients offered resistance exercise training during and after hospitalisation: study protocol for a randomised, double-blind, multicentre trial.

INTRODUCTION: Age-related loss of muscle mass and strength, sarcopaenia, burdens many older adults. The process is accelerated with bed rest, protein intakes below requirements and the catabolic effect of certain illnesses. Thus, acutely ill, hospitalised older adults are particularly vulnerable. Protein supplementation can preserve muscle mass and/or strength and, combining this with resistance exercise training (RT), may have additional benefits. Therefore, this study investigates the effect of protein supplementation as an addition to offering RT among older adults while admitted to the geriatric ward and after discharge. This has not previously been investigated. METHODS AND ANALYSIS: In a block-randomised, double-blind, multicentre intervention study, 165 older adults above 70 years, fulfilling the eligibility criteria, will be included consecutively from three medical departments (blocks of n=20, stratified by recruitment site). After inclusion, participants will be randomly allocated (1:1) to receive either ready-to-drink, protein-enriched, milk-based supplements (a total of 27.5 g whey protein/day) or isoenergetic placebo products (<1.5 g protein/day), twice daily as a supplement to their habitual diet. Both groups will be offered a standardised RT programme for lower extremity muscle strength (daily while hospitalised and 4×/week after discharge). The study period starts during their hospital stay and continues 12 weeks after discharge. The primary endpoint is lower extremity muscle strength and function (30 s chair-stand-test). Secondary endpoints include muscle mass, measures of physical function and measures related to cost-effectiveness. ETHICS AND DISSEMINATION: Approval is given by the Research Ethic Committee of the Capital Region of Denmark (reference no. H-16018240) and the Danish Data Protection Agency (reference no. HGH-2016-050). There are no expected risks associated with participation, and each participant is expected to benefit from the RT. Results will be published in peer-reviewed international journals and presented at national and international congresses and symposiums. TRIAL REGISTRATION NUMBER: NCT02717819 (9 March 2016).