A comprehensive evaluation of the safety of ipilimumab, nivolumab and their combination therapy: A systematic review and network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the landscape of management of advanced cancers. It is imperative to evaluate the safety of nivolumab and ipilimumab based therapies. This study was aimed to assess the comparative safety profiles of ipilimumab, nivolumab and their combinations. MATERIALS AND METHODS: We searched PubMed, Embase, and the CENTRAL for randomised controlled trials of ipilimumab and nivolumab. The outcome measures were treatment-related adverse events [TRAEs], TRAEs of grade 3-5, treatment discontinuation due to TRAEs [TDTRAEs], TDTRAEs of grade 3-5, serious adverse events [SAEs] and SAEs of grades 3-5. We performed a network meta-analysis using the Bayesian approach in R version 4.0.3. RESULTS: We identified 42 RCTs for final analysis. The treatment ranking for TRAEs revealed that nivolumab 240 mg/week and nivolumab 3 mg/kg/week were safer (0.84 and 0.81 in SUCRA); for TRAEs of grade 3-5, nivolumab 3 mg/kg/week and nivolumab 240 mg/week were safer (0.83 and 0.75 in SUCRA); for TDTRAEs nivolumab 3 mg/kg/week and ipilimumab in combination with other drugs were safer (0.87 and 0.64 in SUCRA) and for TDTRAEs of grade 3-5, nivolumab 3 mg/kg/week was safer (0.85 in SUCRA). Nivolumab 3 mg/kg/week and nivolumab 240 mg/week were safer (0.79 and 0.76 in SUCRA) for SAEs and nivolumab 3 mg/kg/week was safer for SAEs of grade 3-5 (0.78 in SUCRA). CONCLUSION: Nivolumab 3 mg/kg biweekly, nivolumab 240 mg weekly and nivolumab 3 mg/kg plus ipilimumab 1 mg/kg triweekly could be preferred due to the relatively low risk of TRAEs, TDAEs and SAEs.

Efficacy and Safety of Liraglutide 3.0 mg in Patients with Overweight and Obese with or without Diabetes: A Systematic Review and Meta-Analysis.

Background: Liraglutide in a 3.0 mg subcutaneous dose daily is approved for weight reduction. Objectives: Objectives are to evaluate the efficacy and safety of liraglutide 3.0 mg in patients with overweight and obesity irrespective of diabetic status. Methods: We conducted an electronic database search in PubMed, Embase, and https://ClinicalTrial.gov to identify all randomized control trials (RCTs) that evaluated the efficacy and safety of liraglutide 3.0 mg dose compared to placebo in overweight (≥27 kg/m2) and obese (≥30 kg/m2) patients above 18 years of age. Results: We compared the pooled estimate of the study results between liraglutide 3.0 mg groups and placebo groups both in diabetic and nondiabetic patients. The efficacy outcomes that were found to be significant among respective studies involving nondiabetic patients vs. diabetic patients were mean change in body weight from baseline: 12 studies [MD = -5.04 kg (95% CI = -5.60, -4.49), P < 0.001, I 2 = 92.95%] vs. 2 studies [MD = -4.14 kg (95% CI = -4.95, -3.32), P < 0.001, I 2 = 0%], reduction in waist circumference from baseline: 8 studies [MD = -3.64 cm (95% CI = -4.43, -2.85), P < 0.001, I 2 = 96.5%] vs. 2 studies [MD = -3.11 cm (95% CI = -3.88, -2.34), P < 0.001, I 2 = 0%], BMI reduction from baseline: 5 studies [MD = -1.95 kg/m2 (95% CI = -2.22, -1.68) vs. 1 study [MD = -1.86 kg/m2 (95% CI = -2.14, -1.57), P < 0.001, I 2 = 0%, P < 0.001, I 2 = 95.6%], proportion of patients losing more than 5% of weight loss from baseline: 8 studies [RR = 2.21, (95% CI = 1.89, 2.58), P=0.03, I 2 = 59.02%] vs. 2 studies [RR = 2.34, (95% CI = 1.93, 2.85), P=0.39, I 2 = 0.00%], and 10% weight loss from baseline: 7 studies [RR = 3.36, (95% CI = 1.92, 5.91), P=0.00, I 2 = 87.03%] vs. 2 studies [RR = 3.64, (95% CI = 2.46, 5.40), P=0.81, I 2 = 0.00%]. Safety outcome assessment with use of liraglutide 3.0 mg compared with placebo in respective nondiabetic vs. diabetic patients revealed significant proportion of patients experiencing the adverse events: 9 studies [RR = 1.11, (95% CI = 1.04, 1.18), P=0.00I 2 = 79.15%] vs. 2 studies [RR = 1.06, (95% CI = 1.01, 1.11), P=0.42, I 2 = 0.03%] but similar risk of serious adverse events: 9 studies [RR = 1.03, (95% CI = 0.70, 1.51), P=0.26, I 2 = 18.54%] vs. 2 studies [RR = 1.11, (95% CI = 0.67, 1.84), P=0.25, I 2 = 23.77%] and TDAEs: 4 studies [RR = 0.89, (95% CI = 0.35, 2.28), P=0.03, I 2 = 61.89%] vs. 1 study [RR = 2.53, (95% CI = 1.00, 6.37)]. However, the pooled estimates irrespective of the glycaemic status were mean change in body weight from baseline: 14 RCT [MD = -4.91 kg (95% CI = -5.43, -4.39), P < 0.001, I 2 = 92.35%], reduction in waist circumference from baseline: 10 studies [MD = -3.55 cm, (95% CI = -4.21, -2.89), P < 0.001, I 2 = 94.99%], BMI reduction from baseline: 6 studies [MD = -1.86 kg/m2, (95% CI = -2.14, -1.57), P < 0.001, I 2 = 96.14%], and proportion of patients losing more than 5% and 10% of weight from baseline: [RR = 2.23, (95% CI = 1.98, 2.52), P < 0.001, I 2 = 48.87%] and [RR = 3.28, (95% CI = 2.23, 4.83), P < 0.001, I 2 = 78.98%], respectively. Also, the proportion of patients experiencing the adverse event was more with liraglutide 3.0 mg compared with placebo 11 study [RR = 1.09, (95% CI = 1.04, 1.15), P < 0.01, I 2 = 76.60%] and similar risk for both serious adverse events: 11 studies [RR = 1.09, (95% CI = 1.04, 1.15), P < 0.01, I 2 = 76.60%] and TDAEs: 5 studies [RR = 1.14, (95% CI = 0.50, 2.60), P < 0.01, I 2 = 64.93%] with liraglutide compared with placebo. Conclusions: Liraglutide in 3.0 mg subcutaneous dose demonstrated significant weight reduction with a reasonable safety profile for patients with overweight or obesity regardless of diabetic status compared to placebo.

Impact of sodium-glucose co-transporter 2 inhibitors on renal outcomes in patients of diabetes mellitus: A meta-analysis of landmark renal and cardiovascular outcome trials.

Sodium-glucose co-transporter 2 inhibitors (SGLT2is) are recommended as the next step therapy for the management of diabetes mellitus. The large clinical trials of SGLT2is demonstrated benefits on various renal endpoints. We conducted this meta-analysis of large trials on cardiovascular and renal safety trials to explore the renoprotective effect of this group of drugs. PubMed, Cochrane CENTRAL, and EMBASE databases were searched with specific keywords till January 19, 2021. Randomized trials of SGLT2is that evaluated the cardiovascular or renal composite outcome as a primary outcome measure were eligible. Random-effects model was used to calculate the overall risk ratios. The search yielded 716 studies and 10 studies were included. The SGLT2is reduced the risk of composite renal outcome (risk ratio [RR] = 0.64, 95% confidence interval [CI] = 0.58-0.72), decline in estimated glomerular filtration rate (eGFR) (RR = 0.62, 95% CI = 0.50-0.77), doubling of serum creatinine (RR = 0.67, 95% CI = 0.56-0.81), dialysis or renal replacement therapy (RR = 0.71, 95% CI = 0.59-0.86), sustained eGFR of <15 ml per min per 1.73 m2 for at least 30 days or more (RR = 0.66, 95% CI = 0.55-0.81), end-stage renal disease (RR = 0.70, 95% CI = 0.56-0.87), and acute kidney injury (RR = 0.79, 95% CI = 0.71-0.89). This analysis establishes the renoprotective effect of SGLT2is. This benefit is noted in patients who had eGFR of more or <60 ml per min per 1.73 m2. This benefit was uniform across all the SGLT2 inhibitors except ertugliflozin and sotagliflozin.

Vitamin D deficiency in rheumatoid arthritis patients of India - a single-arm meta-analysis.

Background: Vitamin D deficiency is commonly seen in patients with rheumatoid arthritis (RA). Objectives: This meta-analysis is aimed to determine the prevalence of Vitamin D deficiency in RA patients in India and also to evaluate the association between vitamin D level and disease activity. Methods: The relevant works of literature were identified through multiple databases and data was extracted from eligible studies independently. A single-arm meta-analysis was performed to estimate the prevalence of Vitamin D deficiency in RA patients in an Indian setup and its association with disease activity. A total of 15 studies was included in the analyses. Results: The mean serum vitamin D level was 19.99 ng/ml [95% CI 16.49-24.23]. The proportion of patients with low vitamin D level was 0.80 [95% CI 0.65- 0.90], Vitamin D deficiency was 0.56 [95% CI 0.31-0.77] and vitamin D insufficiency was 0.20 [95% CI 0.12- 0.32]. A negative relationship was seen with serum vitamin D and disease activity score. Conclusions: The results demonstrate significant low levels of serum vitamin D levels in patients with RA and established a negative correlation of Vitamin D with RA disease activity. The current evidence suggests a rationale for Vitamin D supplementation in the management of RA.

Evaluation of clinical trials done for orphan drugs versus nonorphan drugs in infectious diseasesan eleven year analysis [2010-2020].

Background: The 1983 US Orphan Drug Act provided impetus for the development of new therapies for rare diseases. Several studies focused on the number of orphan designations over time. However, very few focused on clinical trials that lead to their approval, particularly for infectious diseases. Materials and Methods: All new drug approvals (orphan and non-orphan) by the US Food and Drug Administration (FDA) from January 2010 to December 31, 2020, were identified and details of approvals were taken from the US-FDA labels and summary reports for each drug. The pivotal trials for each were characterized based on their design. We tested the association of the type of drug approval with respect to the characteristics of trial using Chi-square test and generated crude odds ratios with 95% confidence intervals. Results: From the total 1122 drugs approved, 84 were for infectious diseases, of which 18 were orphan drugs and 66 were nonorphan. A total of 35 pivotal trials supported 18 orphan drug approvals, while 115 pivotal trials supported 66 nonorphan drugs. The median number of participants enrolled/trial for orphan drugs was 89, while for nonorphan drugs, it was 452 (P < 0.0001). Blinding was done for 13/35 (37%) orphan drugs versus 69/115 (60%) nonorphan drugs (P = 0.029); randomization was done for 15/35 (42%) orphan drugs versus 100/115 (87%) nonorphan drugs (P < 0.0001) and 20/35 (57%) of the orphan drugs got approval in phase II versus 8/115 (6%) of nonorphan drugs (P < 0.00001). Conclusion: A significant number of orphan drugs get approval based on early phase, nonrandomized, and unblinded with a smaller sample size as compared to nonorphan drugs.

Analysis of Robustness of the Landmark Cardiovascular Outcome Trials of Antidiabetic Drugs - A Systematic Review.

BACKGROUND: It is essential for randomized controlled trials (RCTs) to report results in a comprehensive manner. Hence, it is necessary to assess the robustness of the trials with statistically significant and as well as non-significant results. Robustness can be evaluated using fragility index (FI), while reverse fragility index (RFI) can be used for trials with statistically significant as well as non-significant results. The primary aim of this study was to calculate FI and RFI for cardiovascular outcome trials (CVOT). MATERIALS AND METHODS: PubMed/MEDLINE was searched to identify all RCTs of antidiabetic drugs where the primary objective was to evaluate the cardiovascular outcomes. We recorded the trial characteristics of each CVOT trial. The FI, RFI, fragility quotient (FQ), and reverse fragility quotient (RFQ) were calculated to evaluate the robustness of the trials. Spearman rank correlation test was used for correlation. FINDINGS: A total of 889 studies were identified and 24 RCTs were included. Among the 24 trials, 12 (50%) trials achieved statistical significance. The median FI and RFI were 29 (4-12) and 22.5 (1-37) for trials with statistically significant and non-significant results. The median FQ and RFQ were 0.0075 (0.002-0.013) and 0.0003 (0.0001-0.004) for trials with statistically significant and non-significant results. The hazard ratio, p-value, and NNT-B had a strong negative relationship with FI. INTERPRETATION: Our study showed that half of the trials showing the superiority of cardioprotective benefits have favourable FI. The trials that failed to show superiority also have a reasonable RFI indicating the robustness of these trials. However, the results of the trials where patients lost to follow- up exceed the FI of that trial demands caution during interpretation.

A Meta-Analysis of Safety of Different Regimens of Remdesivir in COVID-19 Patients.

Remdesivir is an adenosine analogue drug that targets RNA-dependent RNA polymerase enzyme and inhibits viral replication. As of 22nd October, 2020, US FDA fully approved the drug Remdesivir for the treatment of COVID-19 patients who requires hospitalisation. Many clinical studies reported the derangement in hepatic and renal function tests, which is alarming considering the health conditions of the COVID-19 patients. In view of these results, the present study was envisaged to review the safety of Remdesivir in COVID-19 patients. The PubMed, Embase, and Cochrane databases were searched using the terms 'Remdesivir,' 'veklury,' 'SARS' and 'COVID' till 1st December, 2020. The studies included in this meta-analysis were either randomised or nonrandomised studies that evaluated Remdesivir for the treatment of COVID-19 against Placebo [standard of care]. The Adverse events [AEs], Serious adverse events [SAEs] and Treatment Discontinuation due to Adverse Events (TDAE) were used as primary outcome measures. The quality of studies was evaluated by using the Cochrane Collaboration's tool for the assessment of RoB. Data analysis was performed by two authors (MK & DB) using statistical software Review manager [Revman] version 5.3. The pooled Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated by using a random-effects model for both primary and secondary outcomes. A total of four RCTs were included for the meta-analysis. Out of the four included clinical trials accepted for its methodological quality, three were of excellent quality and one study was of moderate quality. The pooled estimates of the three studies showed that Remdesivir had a 24% lower risk of SAEs compared to the placebo arm. However, the pooled estimates of two studies showed that 10 days of Remdesivir had 56% higher risk of SAEs compared to 5 days of Remdesivir regimen. Similarly, the 10 days of Remdesivir had two times higher risk of TDAEs compared to 5 days Remdesivir regimen. In conclusion, our meta-analysis demonstrated that Remdesivir is a safe therapeutic option. Our metanalysis revealed 5 days' regimen have better safety profile than 10 days' regimen of drug Remdesivir with respect to SAEs and TDAEs. For hospitalized patients, a 5-day course could be preferable with fewer safety concerns and lower drug costs. PROSPERO Registration ID: CRD 42020224272.

An Audit of Black Box Warnings (BBWs) in the United States Food and Drug Administration (US-FDA) Database - A Five-Year Analysis.

BACKGROUND: The Black-Box Warning (BBW) is the most serious warning that US-FDA can ask for on a drug's labelling. BBWs represent key safety concerns uncovered either during dossier review or post-approval. We have conducted the present study with the primary objective of assessing BBWs issued by the US-FDA. METHODS: BBWs were identified on US-FDA's website from 1st January 2015 to 31st December, 2019. Prescribing information was used to identify and characterize BBWs into new and minor/major updates on a previous BBW. The therapeutic class of the drug, nature [Biological/New Molecular entity (NME)], formulation type, expected duration of use, along with the year of first approval of the molecule with BBWs were evaluated. RESULTS: A total of n = 167 BBWs were issued by the FDA of which 53 (31.7%) had major updates, 57(34.1%) had minor updates and 57(34.1%) were new BBWs. A total of 137(82%) of BBWs were with NME's whereas 30(18%) were with biologics. Drugs for neurology 40(25.5%)had the highest number of BBWs, followed by oncology 38(24.2%). Among the type of BBWs, cardiovascular risk 31 (15%) were the highest. CONCLUSION: Practicing physicians need to understand that benefit-risk of a drug is dynamic and keep abreast of new data related to it.

Impact of disease-modifying therapies on MRI outcomes in patients with relapsing -remitting multiple sclerosis: A systematic review and network meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disorder of the central nervous system. The clinical presentation supported by characteristic findings on MRI forms the backbone of the current diagnostic criteria. This study was aimed to investigate the efficacy based on MRI outcomes of FDA approved disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS). MATERIALS AND METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs) of DMTs. The outcome measures were the mean number of T2 [new/enlarging lesions], new T1 [gadolinium-enhancing (Gd+) T1 and hypointense T1] lesions in brain MRI performed at 12 months or 24 months. We performed a network meta-analysis using the frequentist approach in STATA version 16.0. RESULTS: We identified 26 RCTs for final analysis. Interferon ß-1a and placebo were the most common comparison treatment. Ocrelizumab was more effective in reducing the number of Gd+T1 lesions. Dimethyl fumarate 480 mg was relatively better in reducing the number of new T2 lesions. The treatment ranking showed that ocrelizumab and dimethyl fumarate 480 mg were more efficacious (1 and 0.9 in SUCRA, respectively) for reducing the number of new Gd+T1/hypointense lesions; dimethyl fumarate 480 mg/720 mg and natalizumab were more efficacious (1.0, 0.9 and 0.8 in SUCRA, respectively) to reduce the number of new T2 lesions. CONCLUSION: Ocrelizumab, dimethyl fumarate 480/720 mg and natalizumab demonstrated favourable MRI outcomes in patients with the RRMS.

Evaluation of efficacy and safety of fosfomycin versus nitrofurantoin for the treatment of uncomplicated lower urinary tract infection (UTI) in women - A systematic review and meta-analysis.

Urinary tract infections (UTI) are among the most frequent medical conditions requiring outpatient treatment. Single dose oral fosfomycin (300 mg) and the older nitrofurantoin (100 mg for 5 days) have been found to be more effective than other first-line drugs in multiple studies. This systematic review and meta-analysis were carried out with the objective of evaluating their comparative efficacy and safety in the management of uncomplicated UTI. Two authors independently searched PubMed, Cochrane Central, Embase, and Google Scholar till Nov 2020 using MeSH terms and free text. Randomized controlled trials (RCTs) comparing both drugs for efficacy and safety in uncomplicated UTI in adult women were included. The primary outcome measures were microbiological and clinical cure rates. The search resulted in n = 663 studies out of which only four studies (three for treatment of uncomplicated UTI in women and one for asymptomatic bacteriuria in pregnancy) satisfied the selection criteria. No significant differences in clinical, (RR 0.95, 95% CI - 0.81, 1.12) and microbiological cure, (RR 0.96, 95% CI - 0.84, 1.08) were found within 4 weeks of treatment. The incidence of adverse events was found to be more in fosfomycin relative to the nitrofurantoin group (RR 1.05, 95% CI - 0.59, 1.87). Hence, single-dose fosfomycin presents a potentially useful and safe treatment option for the treatment of uncomplicated UTI in women and asymptomatic bacteriuria in pregnancy.

A Systematic Review and Meta-Analysis of the Safety of Hydroxychloroquine in a Randomized Controlled Trial and Observational Studies.

INTRODUCTION: Hydroxychloroquine (HCQ) has recently become the focus of attention in the current COVID-19 pandemic. With an increase in the off-label use of HCQ, concern for the safety of HCQ has been raised. We, therefore, performed this systematic review to analyze the safety data of HCQ against placebo and active treatment in various disease conditions. METHODS: We searched PubMed, Embase, and Cochrane for Randomized Controlled Trials (RCTs) and Observational Studies (OSs) that evaluated HCQ for the treatment of any disease other than COVID19 in adult patients up to May 2020. We assessed the quality of the included studies using Risk of Bias 2 (for RCTs) and Newcastle-Ottawa Scale (for OSs). Data were analyzed with randomeffect meta-analysis. Sensitivity and subgroup analyses were performed to identify heterogeneity. RESULTS: A total of 6641 studies were screened, and 49 studies (40 RCTs and 9 OSs) with a total sample size of 35044 patients were included. The use of HCQ was associated with higher risks of TDAEs as compared to placebo/no active treatment [RR 1.47, 95%CI 1.03-2.08]. When HCQ was compared with active treatments, the risks of AEs [RR 0.74, 95% CI 0.63-0.86] and TDAEs were less in the HCQ arm [RR 0.57, 95% CI 0.39-0.81]. The outcomes did not differ in the sensitivity analysis. CONCLUSION: The results suggest that the use of HCQ was associated with a lower risk of AEs and TDAEs as compared to active treatment, whereas posing higher risk of TDAEs as compared to placebo.

An evaluation of drug lag for new drugs approved by the Indian regulator relative to the United States, European Union, and Japanese regulatory agencies: A 15-year analysis (2004-2018).

BACKGROUND: The approval process of every drug regulatory agency differs, and hence, the time required for the approval of a new drug varies. This results in a drug lag and India is no exception to this phenomenon. A drug lag precludes Indian patients from accessing new medicines at the same time as they are approved elsewhere. Against this backdrop, we assessed the absolute and relative drug lags of the Indian regulator relative to three regulators in mature markets, namely United States (US), European Union (EU), and Japan. METHODS: International nonproprietary names were used to identify new drugs. Their dates of approval (2004-2018) from the online database of four regulatory agencies were identified. Both absolute and relative drug lags were calculated for India as compared to US, EU, and Japan as well for all the agencies relative to the Indian regulator. RESULTS: We identified a total of 453, 473, 424, and 472 new drugs approved over the study period in India, US, EU, and Japan, respectively. The absolute drug lag of Central Drugs Standard Control Organization (CDSCO) was 19 and 18 relative to the US Food and Drug Administration (FDA) and Japan Pharmaceuticals and Medical Devices Agency (PMDA), respectively. The relative drug lag for the CDSCO vis-a-vis the US FDA, European Medicines Agency, and PMDA was 43.2 (2.1-1287.8), 25.6 (0.03-1310.5), and 30.3 (1.2-1242) months, respectively. CONCLUSION: Our study shows a significant drug lag between India and other three developed nations (US, EU, and Japan). However, in some therapeutic areas, Indian regulator has proactively approved new drugs much before other agencies. The New Drugs and Clinical Trials Rule of 2019 has brought hope for reduction in drug lag in the near future.

The global initiative for asthma guidelines (2019): change in the recommendation for the management of mild asthma based on the SYGMA-2 trial - A critical appraisal.

The Global Initiative for Asthma (GINA) recently released their updated Global Strategy for Asthma Management and Prevention Guide (2019). The pocket guide for practicing clinicians states that "the 2019 GINA strategy report represents the most important change in asthma management in 30 years." An important recommendation is the change in treatment strategy for the management of mild asthma where the guideline recommends that" all adults and adolescents with asthma should receive either symptom driven (in mild asthma) or daily low dose inhaled corticosteroid (ICS) containing controller treatment to reduce the risk of serious exacerbations." Our study critically appraises the SYGMA-2 trial, a key trial that largely formed the basis of this recommendation and discusses the potential consequences of using only long-acting beta-2-agonist + ICS as needed as against regular, daily low-dose ICS with as-needed short-acting beta-2-agonist. Our critique covers airway inflammation, disease heterogeneity, understanding the noninferiority margin and its consequences, the Hawthorne effect, and conflict of interest. It is our view that statement of this magnitude will have far-reaching implications for clinical practice which will be in the interests of some patients but also against the interests of others.

Investigator-initiated studies: Challenges and solutions.

Investigator-initiated studies (IISs) help by generating data on effectiveness and safety of a drug in the real-world setting and attempt to answer questions that clinicians face in their day-to-day practice. These are studies that are initiated and managed by a nonpharmaceutical company researcher/s who could be an individual investigator, an institution or a group of institutions, and a collaborative study group or a cooperative group. They are largely driven by questions that arise beyond the completion of Phase III studies that have not been studied during Phases I-III of drug development. The benefits of doing IISs are often offset by the myriad challenges posed by an IIS. These include finances, regulatory submissions, continuous oversight, training of study personnel, lack of expertise in statistics, data management, and medical writing Nonetheless, doing an IIS is extremely rewarding for the investigator and has the capacity to contribute to evidence and eventually impact policy. The present article presents both a brief literature review of IISs and a personal narrative of experience gained during the conduct several IISs in the last two decades. Challenges and potential solutions are described.