Is there a reason for concern or is it just hype? – A systematic literature review of the clinical consequences of switching from originator biologics to biosimilars

Introduction: While prescribing biosimilars to patients naive to a biologic treatment is a well-accepted practice, switching clinically stable patients from an originator to a biosimilar is an issue for clinicians. Well-designed clinical trials and real-world data which study the consequences of switching from an originator biologic treatment to its biosimilar alternative are limited, especially for monoclonal antibodies.

Areas covered: A systematic literature review was conducted on PubMed to identify evidence of the consequences of switching from original biologics to biosimilars. References of included papers were also scrutinized. After a title-, abstract- and full text screening, out of the 153 original hits and 77 additional ones from screening the references, 58 papers (12 empirical papers, 5 systematic reviews and 41 non-empirical papers) were included.

Expert opinion: Preventing patients on biologic medicines from switching to biosimilars due to anticipated risks seems to be disproportional compared to the expected cost savings and/or improved patient access. Indeed, it is the opinion of the authors that the concern of switching to biosimilars is overhyped.     

Uptake of rheumatology biosimilars in the absence of forced switching

Background: To describe the uptake and system-level effects of the introduction of biosimilars in a setting without forced switching.

Research design and methods: We used data from the Swedish Rheumatology Quality register from start of marketing of infliximab (Remsima® and Inflectra®) and etanercept (Benepali®) biosimilars until 31 December 2016. We compared users of each originator-product and its biosimilar(s) by line of treatment: bDMARD-naïve patients, non-medical switchers (vs. matched patients remaining on originator), and patients switching from a previous bDMARD of another type.

Results: From the start of marketing 1343 patients started an infliximab biosimilar (22 months) and 2691 started etanercept (9 months). Overall, the introduction of these biosimilars resulted in an increase of the total number of ongoing infliximab and etanercept treatments (originator + biosimilar) . At the end of the study period, biosimilars accounted for 31% of all infliximab treatments and 31% of all etanercept-treated patients. For each line of therapy, we noted only small differences in patient characteristics between those starting the originator product vs. its biosimilar(s).

Conclusions: Introduction of biosimilars have effects beyond replacement of the originator product, in terms of an increased rate of bDMARD initiation. Selection to non-medical switching displayed no particular disease- or patient-characteristics.     

A double-blind placebo-controlled clinical investigation into pain reduction effect of placing the pain spot outside the intersection area of the two currents of interferential therapy compared to traditional method

Background: Interferential therapy (IFT) is applied to intersect in the painful area but no confirmed effect with this method. Experimentally, the highest voltage of IFT is induced outside the intersection of the two currents. Placing the painful area outside the intersection point (external application) would reveal a better effect.

Objectives: To examine the effect of external application in pain compared to traditional method.

Design: A double-blind placebo-controlled clinical investigation.

Setting: A public hospital.

Participants: 168 LBP subjects.

Interventions: Assignment: (1) external IFT, (2) placebo external IFT, (3) traditional IFT and (4) placebo traditional IFT. Groups 1 and 3 received 20 min of IFT at 100 Hz and groups 2 and 4 received sham IFT.

Main outcome measures: Before and after IFT session, pain severity (VAS), pressure threshold (PPT), pain distribution and ROM were assessed.

Results: IFT changed all outcomes similarly. VAS and ROM improved statistically, P < 0.03. A trend of better VAS reduced with active IFTs.

Conclusions: No therapeutic difference between the two methods.     

Quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections in general practice: a RAND Appropriateness Method

Objective: To develop quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections, tailored to the Danish general practice setting.

Design: A RAND/UCLA Appropriateness Method was used.

Setting: General practice.

Subjects: A panel of nine experts, mainly general practitioners, was asked to rate the relevance of 64 quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections based on guidelines. Subsequently, a face-to-face meeting was held to resolve misinterpretations and to achieve consensus.

Main outcome measures: The experts were asked to rate the indicators on a nine-point Likert scale. Consensus of appropriateness for a quality indicator was reached if the overall panel median rating was 7–9 with agreement.

Results: A total of 50 of the 64 proposed quality indicators attained consensus. Consensus was achieved for 12 indicators focusing on the diagnostic process and 19 indicators focusing on the decision about antibiotic treatment and choice of antibiotics, respectively.

Conclusion: These newly developed quality indicators may be used to strengthen Danish general practitioners’ focus on their management of patients with acute respiratory tract infections and to identify where there is a need for future quality improvements.     

Pharmacokinetic and pharmacodynamic changes in older adults and implications for palliative care

Background: As the population of older adults continues to increase, there will be an increase in the number of older patients requiring pain and symptom management in the setting of advanced, serious illness.

Objectives: To review age-related changes in pharmacokinetics and pharmacodynamics, and to put these changes in the context of providing palliative care to geriatric patients.

Method: Review of literature relevant to age-related changes in physiology, pharmacokinetics, and pharmacodynamics; and the practice of palliative care for geriatric patients.

Results: Multiple age related changes occur which affect the choice and dosing of medications, including those used for pain and symptom management.

Conclusion: The safe and effective management of symptoms in advanced illness for older adults depends on having a clear understanding of physical and metabolic changes and their impact of selection of drug therapy.     

The effect on the patient flow in a local health care after implementing reverse triage in a primary care emergency department: a longitudinal follow-up study

Objective: Reverse triage means that patients who are not considered to be in need of medical services are not placed on the doctor’s list in an emergency department (ED) but are sent, after face-to-face evaluation by a triage nurse, to a more appropriate health care unit. It is not known how an abrupt application of such reverse triage in a combined primary care ED alters the demand for doctors’ services in collaborative parts of the health care system.

Design: An observational study.

Setting: Register-based retrospective quasi-experimental longitudinal follow-up study based on a before–after setting in a Finnish city.

Subjects: Patients who consulted different doctors in a local health care unit.

Main outcome measures: Numbers of monthly visits to different doctor groups in public and private primary care, and numbers of monthly referrals to secondary care ED from different sources of primary care were recorded before and after abrupt implementation of the reverse triage.

Results: The beginning of reverse triage decreased the number of patient visits to a primary ED doctor without increasing mortality. Simultaneously, there was an increase in doctor visits in the adjacent secondary care ED and local private sector. The number of patients who came to secondary care ED without a referral or with a referral from the private sector increased.

Conclusions: The data suggested that the reverse triage causes redistribution of the use of doctors’ services rather than a true decrease in the use of these services.     

A systematic review to determine the optimal type and dosage of land-based exercises for treating knee osteoarthritis

Background: Exercise has been acknowledged as an effective non-pharmacological intervention for osteoarthritis. Consensus regarding the type of exercise i.e., aerobic or resistance, weight bearing or non-weight bearing, and dosage i.e., frequency, loading, duration, or intensity, is yet to be reached.

Objective: The purpose of this review was to address two questions: (1) is there a difference in clinical outcomes between different exercise programmes; and (2) what is the optimal dosage of exercises for people with knee osteoarthritis.

Methods: A systematic review was conducted. A study of published (AMED, CINAHL, MEDLINE, EMBASE, PubMed, and the Cochrane Library) and unpublished literature (WHO International Clinical Trials Registry Platform, current controlled trials and the United States National Institute of Health Trials Registry, and Open Grey) was undertaken in January 2013. Studies assessing the clinical outcomes of different types and dosages of exercise for people with osteoarthritis of the knee were included. Methodological quality was assessed using the critical appraisal skills programme (CASP) randomized controlled trial (RCT) appraisal tool.

Results: Ten studies assessing 958 knees from 916 participants were included. Exercise significantly improved pain and function for people with knee osteoarthritis. There was no significant difference in outcomes for different types of exercise i.e., aerobic versus resistance, weight bearing versus non-weight bearing. There was no significant difference in respect to the intensity of exercise i.e., high- versus lower-intensity resistance or aerobic exercises. The quality of the literature was moderate to high.

Conclusions: While exercise appears to improve symptoms and optimize function for people with knee osteoarthritis, the optimal form and dosage of exercise remains unknown.

Funding: None.

PROSPERO Registration Number: CRD42012002811.     

Factors associated with self-rated health in primary care

Background: Self-rated health (SRH) measures one’s current general health and is a widely used health indicator. Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships are suspected to influence SRH, but studies in primary health care settings are sparse.

Objective: To examine the associations between patients’ self-rated health and their sleep problems, somatic health complaints, and unmet needs in interpersonal relationships.

Design: We collected data via questionnaires for this cross-sectional study from general practice.

Setting: Primary health care in Norway.

Subjects: 1302 consecutive patients participated.

Main outcome measures: The questionnaire included a single question about SRH, the Bergen Insomnia Scale (BIS), five questions on somatic health complaints, and three questions from the Basic Psychological Needs Scale (BPNS) pertaining to the relationships domain. We analyzed our data using ordinal logistic regression models.

Results: Our response rate was 74%. The prevalence of fair/poor SRH was 26%, with no gender differences. We revealed a significant association between increasing age and reduced SRH. The study showed that sleep problems and somatic health complaints were strongly associated with SRH, and unmet needs in relationships were also significantly and independently associated with reduced SRH in a full model analysis.

Conclusion: Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH. These factors are all modifiable and could be managed both within and outside a primary care setting in order to improve SRH.

• Key Points

• There was a high prevalence of reduced SRH in clinical general practice

• Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH

• These predictors are all modifiable with a potential to improve SRH

     

The toxicity of picaridin containing insect repellent reported to the National Poison Data System

Context: While low toxicity is reported, there are sparse data on the safety of acute picaridin (icaridin) exposures in humans.

Objective: The purpose of this study was to review National Poison Data System (NPDS) data regarding ingestion of insect repellents containing picaridin and compare those to insect repellents containing DEET and other insect repellents not containing DEET.

Methods: NPDS was queried for single agent human insect repellent ingestions reported between 1 January 2000 and 31 May 2015 using the American Association of Poison Control Center generic categories 201048 (Insect Repellents with DEET) and 201049 (Insect Repellents without DEET). Picaridin-containing product exposures were assessed using Poisindex^® product ID 6744589. Insect repellents of unknown type were not included.

Results: 68,429 exposures occurred; 24% were non-DEET-containing products, of which 2% were picaridin-containing products. Among picaridin exposures, 92.9% were managed outside of a health-care facility; there were no reported cases of major effect or death, and only one case of moderate effect. Primary symptoms across all insect repellent exposures included ocular irritation/pain, vomiting, red eye/conjunctivitis, and oral irritation. Treatment primarily included dilution/irrigation/wash.

Conclusion: Unintentional ingestion of picaridin-containing and other insect repellents was associated only with minor toxicity and was generally managed outside of a health-care facility.     

Serum osmolal gap in clinical practice: usefulness and limitations

Background: Although serum osmolal gap can be a useful diagnostic tool, clinicians are not familiar with its use in clinical practice.

Objectives: The review presents in a series of questions-answers and under a clinical point of view the current data regarding the use of osmolal gap.

Discussion: The definition and the best formula used for the calculation of osmolal gap, the main causes of increased osmolal gap with or without increased anion gap metabolic acidosis, as well as the role of concurrent lactic acidosis or ketoacidosis are presented under a clinical point of view.

Conclusions: The calculation of osmolal gap is crucial in the differential diagnosis of many patients presenting in emergency departments with possible drug or substance overdose as well as in comatose hospitalized patients.     

Learning to navigate the healthcare system in a new country: a qualitative study

Objective: Learning to navigate a healthcare system in a new country is a barrier to health care. Understanding more about the specific navigation challenges immigrants experience may be the first step towards improving health information and thus access to care. This study considers the challenges that Thai and Filipino immigrant women encounter when learning to navigate the Norwegian primary healthcare system and the strategies they use.

Design: A qualitative interview study using thematic analysis.

Setting: Norway.

Participants: Fifteen Thai and 15 Filipino immigrant women over the age of 18 who had been living in Norway at least one year.

Results: The women took time to understand the role of the general practitioner and some were unaware of their right to an interpreter during consultations. In addition to reliance on family members and friends in their social networks, voluntary and cultural organisations provided valuable tips and advice on how to navigate the Norwegian health system. While some women actively engaged in learning more about the system, they noted a lack of information available in multiple languages.

Conclusions: Informal sources play an important role in learning about the health care system. Formal information should be available in different languages in order to better empower immigrant women.     

Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series

Background: Cannabinoid hyperemesis syndrome (CHS) is characterized by symptoms of cyclic abdominal pain, nausea, and vomiting in the setting of prolonged cannabis use. The transient receptor potential vanilloid 1 (TRPV1) receptor may be involved in this syndrome. Topical capsaicin is a proposed treatment for CHS; it binds TRPV1 with high specificity, impairing substance P signaling in the area postrema and nucleus tractus solitarius via overstimulation of TRPV1. This may explain its apparent antiemetic effect in this syndrome.

Purpose: We describe a series of thirteen cases of suspected cannabis hyperemesis syndrome treated with capsaicin in the emergency departments of two academic medical centers.

Methods: A query of the electronic health record at both centers identified thirteen patients with documented daily cannabis use and symptoms consistent with CHS who were administered topical capsaicin cream for symptom management.

Results: All 13 patients experienced symptom relief after administration of capsaicin cream.

Conclusion: Topical capsaicin was associated with improvement in symptoms of CHS after other treatments failed.     

Yoga for pain and sleep quality in rheumatoid arthritis: study protocol for a pilot randomized controlled trial

Background:

Yoga is a popular complementary and alternative medicine (CAM) therapy among people with rheumatoid arthritis (RA), perceived as offering self-management options for physical and psychosocial symptoms associated with RA.

Objectives:

The primary aims of the current pilot study are (1) to assess the feasibility and safety of a relaxation-focused yoga intervention tailored for people with RA and (2) to estimate the effect of yoga on RA-related pain, sleep quality, functional disability, disease activity, quality of life, anxiety, depression, and fatigue.

Method:

Twenty-eight participants with at least minimum levels of RA-related pain and sleep disturbance will be recruited from a local public hospital database. Participants meeting inclusion criteria will be randomized into either a yoga group (receiving an 8-week program of once-weekly 75-minute relaxation-based yoga classes and thrice-weekly home practice), or a usual care control group. Outcomes will be assessed at baseline, 9, and 12 weeks. Feasibility is operationalized as acceptability (recruitment, adherence, participant retention, and participant satisfaction) and safety of the yoga intervention. Effect sizes for changes in pain, sleep quality, functional disability, disease activity, quality of life, mental health, and fatigue will be estimated.

Discussion:

Results of this pilot study will provide empirical data to determine if a larger, statistically powered main trial is feasible and safe in a national RA population. Additionally, participant feedback will provide information regarding further adaption and tailoring of the study protocol to a clinical RA population.

Trial registration:

Australian New Zealand Clinical Trials Registry ACTRN12612001019897 (registered 20/09/2012).     

Effect of changing from first- to second-line antiretroviral therapy on renal function: a retrospective study based on data from a single health facility in Namibia

Background: Tenofovir disoproxil fumarate (TDF) and lopinavir/ritonavir (LPV/r) can cause renal impairment with this combination co-administered during second-line combination antiretroviral therapy (cART) potentially associated with greater risk of nephrotoxicity. As a result, the aim of this study is to assess effects of second-line cART on renal function.

Methods: Retrospective longitudinal study in patients receiving cART.

Results: 71 patients received TDF, zidovudine or stavudine, each combined with 3TC/NVP or 3TC/EFV. Before second-line cART, 46.5% had abnormal kidney function. First-line cART had no relationship with calculated creatinine clearance (CrCl). During second-line cART, more males than females had abnormal renal function and more females experienced increases in CrCl. Calculated CrCl during second-line cART related strongly with CrCl during first-line cART. Time spent on cART weak had a week relationship with CrCl.

Conclusion: Patients on first-line cART for several years without renal impairment may experience new onset impairment during second line cART. Patients with pre-existing renal impairment just before switching to second-line cART may experience a further decline.     

The effectiveness of cervical versus thoracic thrust manipulation for the improvement of pain,disability, and range of motion in patients with mechanical neck pain

Background:

Many patients present to physical therapy with mechanical neck pain. Cervical and thoracic manipulations are being utilized in treating this impairment, but minimal evidence as to which technique is superior exists in the literature.

Objective:

The purpose of this systematic review is to identify whether cervical or thoracic manipulation is more effective at improving pain, range of motion (ROM), and disability in patients with mechanical neck pain.

Methods:

A comprehensive search of published literature from seven search engines (PubMed, ProQuest, PEDro, CINAHL, Healthsource, Cochrane Library, SPORTDiscus) yielded 13 studies that examined the effectiveness of either cervical manipulations, thoracic manipulations, or cervical and thoracic manipulations to relieve the effects of mechanical neck pain. Eleven of the studies included were randomized controlled trials (RCTs), while two were secondary analyses of RCTs. Each study was assessed using the PEDro scale and found to be of fair to high research quality.

Results:

The studies included in this systematic review produced both positive clinical and statistical differences in pain, disability, and ROM following manipulations of the cervical or thoracic spine.

Conclusion:

There is limited high-quality research directly comparing the two interventions, so determining whether cervical or thoracic thrust manipulation is superior cannot be concluded from this systematic review alone. However, based on the results found in this review, cervical and thoracic thrust manipulations are equally valuable in relieving pain, disability, and improving ROM for a patient with mechanical neck pain in the short term.     

What advice is given to palliative care patients about driving?

Background: The primary aim when providing advice to patients on fitness to drive is the safety of the patient and the general public. Within the current Australian guidelines there is little specific information in regards to providing advice to palliative care patients about driving.

Method: Online survey.

Objective: To investigate the current practice of doctors and the advice provided to palliative care patients about their fitness to drive.

Discussion: When advising a patient with a medical condition that could affect fitness to drive, most respondents were not in consensus with the driving guidelines with only 38% following the recommended procedure. It found some disparity in the advice provided and differences to the Australian driving guidelines.     

Effects of numerical information on intention to participate in cervical screening among women offered HPV vaccination: a randomised study

Objectives: To investigate the effects of different types of information about benefits and harms of cervical screening on intention to participate in screening among women in the first cohorts offered human papilloma virus (HPV) vaccination.

Design: Randomised survey study.

Setting: Denmark.

Subjects: A random sample of women from the birth cohorts 1993, 1994 and 1995 drawn from the general population.

Interventions: A web-based questionnaire and information intervention. We randomised potential respondents to one of the following four different information modules about benefits and harms of cervical screening: no information; non-numerical information; and two numerical information modules. Moreover, we provided HPV-vaccinated women in one of the arms with numerical information about benefits and harms in two steps: firstly, information without consideration of HPV vaccination and subsequently information conditional on HPV vaccination.

Main outcome measure: Self-reported intention to participate in cervical screening.

Results: A significantly lower proportion intended to participate in screening in the two groups of women receiving numerical information compared to controls with absolute differences of 10.5 (95% CI: 3.3–17.6) and 7.7 (95% CI: 0.4–14.9) percentage points, respectively. Among HPV-vaccinated women, we found a significantly lower intention to participate in screening after numerical information specific to vaccinated women (OR of 0.38).

Conclusions: Women are sensitive to numerical information about the benefits and harms of cervical screening. Specifically, our results suggest that HPV-vaccinated women are sensitive to information about the expected changes in benefits and harms of cervical screening after implementation of HPV vaccination.

• KEY POINTS

• Women were less likely to participate in cervical screening when they received numerical information about benefits and harms compared to non-numerical or no information.

• Specifically, numerical information about the potential impact of the reduced risk of cervical cancer among HPV-vaccinated women reduced the intention to participate among vaccinated women.