Power to the People: Why person-generated health data is important for pharmacoepidemiology.

Person-generated health data (PGHD) are valuable to study outcomes relevant to everyday living, to obtain information not otherwise available, for long-term follow-up and in situations where decisions cannot wait for traditional clinical research to be completed. While there is no dispute that these data are subject to bias, insights gained may be better than an information void, provided the biases are understood and acknowledged. People will share information known uniquely to them about exposures that may affect drug tolerance, safety and effectiveness, e.g., using non-prescription and complementary medications, alcohol, tobacco, illicit drugs, exercise, etc. Patients may be the best source of safety information when long-term follow-up is needed, e.g., the 5-15-year follow-up required for some gene therapies. Validation studies must be performed to evaluate what people can accurately report and when supplementary confirmation information is needed. But PGHD has already proven valuable in quantifying and contrasting COVID-19 vaccine benefits and risks, and for evaluating disease transmission and the accuracy of COVID-19 testing. Going forward, PGHD will be used for patient-measured and patient-relevant outcomes, including regulatory purposes, and will be linked to broader health data networks using tokenization, becoming a mainstay for signals about risks and benefits for diverse populations.

Demonstrating Benefit-Risk Profiles of Novel Therapeutic Strategies in Kidney Transplantation: Opportunities and Challenges of Real-World Evidence.

While great progress has been made in transplantation medicine, long-term graft failure and serious side effects still pose a challenge in kidney transplantation. Effective and safe long-term treatments are needed. Therefore, evidence of the lasting benefit-risk of novel therapies is required. Demonstrating superiority of novel therapies is unlikely via conventional randomized controlled trials, as long-term follow-up in large sample sizes pose statistical and operational challenges. Furthermore, endpoints generally accepted in short-term clinical trials need to be translated to real-world (RW) care settings, enabling robust assessments of novel treatments. Hence, there is an evidence gap that calls for innovative clinical trial designs, with RW evidence (RWE) providing an opportunity to facilitate longitudinal transplant research with timely translation to clinical practice. Nonetheless, the current RWE landscape shows considerable heterogeneity, with few registries capturing detailed data to support the establishment of new endpoints. The main recommendations by leading scientists in the field are increased collaboration between registries for data harmonization and leveraging the development of technology innovations for data sharing under high privacy standards. This will aid the development of clinically meaningful endpoints and data models, enabling future long-term research and ultimately establish optimal long-term outcomes for transplant patients.

COVID-19 Vaccinations in Pregnancy: Comparative Evaluation of Acute Side Effects and Self-Reported Impact on Quality of Life between Pregnant and Nonpregnant Women in the United States.

OBJECTIVE: The objective of this study was to describe the acute side effects experienced by pregnant women who received a coronavirus disease 2019 (COVID-19) vaccine in the United States and to compare their experience to nonpregnant women of similar age. STUDY DESIGN: Adults who received a COVID-19 vaccine in the United States were invited via social media to enroll in an online, longitudinal, community-based registry ( www.helpstopCOVID19.com ). Participants self-reported pregnancy status, vaccination dates, manufacturer, acute side effects, impact on work and self-care, medical consultation, and hospitalization. This analysis was restricted to women aged 20 to 39 at the time of vaccination. Side effects reported by pregnant women were compared to those reported by nonpregnant women. RESULTS: This analysis included 946 pregnant women, with 572 (60%) receiving at least one dose of Pfizer, 321 (34%) Moderna, and 53 (6%) J&J, and 1,178 nonpregnant women. Demographic and medical history were similar across manufacturers for both cohorts.Overall, pregnant women reported similar side effects as nonpregnant women, with the most common being injection site reactions (83 vs. 87%), fatigue (72 vs.78%), and headache (45 vs. 59%). Pregnant women reported fewer side effects (median: 3 vs. 4, respectively). In both cohorts, very few reported seeking medical care (<5%) or being hospitalized (<0.3%) after vaccination. Fewer pregnant women reported working less after vaccination than nonpregnant women (32 vs. 40%) or trouble with self-care (32 vs. 46%), respectively. CONCLUSION: Pregnant women reported similar COVID-19 vaccine side effects as nonpregnant women, although fewer total side effects; pregnant women judged these side effects to have less impact on work and self-care. While these results do not address pregnancy outcomes or long-term effects, findings about acute side effects and impact offer reassurance for all three vaccines in terms of tolerability. KEY POINTS: · COVID vaccines were well tolerated by pregnant women.. · Pregnant women reported fewer total side effects.. · Pregnant women reported less impact on work and self-care..

Real-world evidence to support regulatory decision making: New or expanded medical product indications.

There is increasing interest in utilizing real-world data (RWD) to produce real-world evidence (RWE) on the benefits and risks of medical products that could support regulatory approval decisions. The field of pharmacoepidemiology has a long history of focusing on data and evidence that would now be termed "real-world," including evidence from healthcare claims, registries, and electronic health records. However, several emerging trends over the past decade are converging to support the use of these and other RWD sources for approval decisions, and there are several recent examples and ongoing research that demonstrate how RWE may be used to support regulatory approval of new or expanded indications. The goal of this article is to review the current landscape and future directions of the use of RWE in this context. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE).

Trial designs using real-world data: The changing landscape of the regulatory approval process.

PURPOSE: There is a need to develop hybrid trial methodology combining the best parts of traditional randomized controlled trials (RCTs) and observational study designs to produce real-world evidence (RWE) that provides adequate scientific evidence for regulatory decision-making. METHODS: This review explores how hybrid study designs that include features of RCTs and studies with real-world data (RWD) can combine the advantages of both to generate RWE that is fit for regulatory purposes. RESULTS: Some hybrid designs include randomization and use pragmatic outcomes; other designs use single-arm trial data supplemented with external comparators derived from RWD or leverage novel data collection approaches to capture long-term outcomes in a real-world setting. Some of these approaches have already been successfully used in regulatory decisions, raising the possibility that studies using RWD could increasingly be used to augment or replace traditional RCTs for the demonstration of drug effectiveness in certain contexts. These changes come against a background of long reliance on RCTs for regulatory decision-making, which are labor-intensive, costly, and produce data that can have limited applicability in real-world clinical practice. CONCLUSIONS: While RWE from observational studies is well accepted for satisfying postapproval safety monitoring requirements, it has not commonly been used to demonstrate drug effectiveness for regulatory purposes. However, this position is changing as regulatory opinions, guidance frameworks, and RWD methodologies are evolving, with growing recognition of the value of using RWE that is acceptable for regulatory decision-making.

Real-world evidence to support regulatory decision-making for medicines: Considerations for external control arms.

Randomized clinical trials (RCTs) are the gold standard in producing clinical evidence of efficacy and safety of medical interventions. More recently, a new paradigm is emerging-specifically within the context of preauthorization regulatory decision-making-for some novel uses of real-world evidence (RWE) from a variety of real-world data (RWD) sources to answer certain clinical questions. Traditionally reserved for rare diseases and other special circumstances, external controls (eg, historical controls) are recognized as a possible type of control arm for single-arm trials. However, creating and analyzing an external control arm using RWD can be challenging since design and analytics may not fully control for all systematic differences (biases). Nonetheless, certain biases can be attenuated using appropriate design and analytical approaches. The main objective of this paper is to improve the scientific rigor in the generation of external control arms using RWD. Here we (a) discuss the rationale and regulatory circumstances appropriate for external control arms, (b) define different types of external control arms, and (c) describe study design elements and approaches to mitigate certain biases in external control arms. This manuscript received endorsement from the International Society for Pharmacoepidemiology (ISPE).

Methods for external control groups for single arm trials or long-term uncontrolled extensions to randomized clinical trials.

PURPOSE: Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long-term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness. METHODS: We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps. RESULTS: Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences. CONCLUSION: This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.

Lessons learned on the design and the conduct of Post-Authorization Safety Studies: review of 3 years of PRAC oversight.

AIMS: To describe and characterize the first cohort of Post-Authorization Safety Study (PASS) protocols reviewed under the recent European pharmacovigilance legislation. METHODS: A systematic approach was used to compile all publicly available information on PASS protocols and assessments submitted from July 2012 to July 2015 from Pharmacovigilance Risk Assessment Committee (PRAC) minutes, European Medicines Agency (EMA) and European Network of Pharmacovigilance and Pharmacoepidemiology (ENCePP) webpages. RESULTS: During the study period, 189 different PASS protocols were submitted to the PRAC, half of which were entered in the ENCePP electronic register of post-authorization studies (EU-PAS) by July 2015. Those protocols were assessed during 353 PRAC reviews. The EMA published only 31% of the PRAC feedback, of which the main concerns were study design (37%) and feasibility (30%). Among the 189 PASS, slightly more involved primary data capture (58%). PASS assessing drug utilization mainly leveraged secondary data sources (58%). The majority of the PASS did not include a comparator (65%) and 35% of PASS also evaluated clinical effectiveness endpoints. CONCLUSIONS: To the best of our knowledge this is the first comprehensive review of three years of PASS protocols submitted under the new pharmacovigilance legislation. Our results show that both EMA and PASS sponsors could respectively increase the availability of protocol assessments and documents in the EU-PAS. Protocol content review and the high number of PRAC comments related to methodological issues and feasibility concerns should raise awareness among PASS stakeholders to design more thoughtful studies according to pharmacoepidemiological principles and existing guidelines.

Bridge the gap: The need for harmonized regulatory and ethical standards for postmarketing observational studies.

Drug safety issues do not respect national borders. Hence, addressing a safety question may necessitate globally coordinated efforts between regulatory authorities and market authorization holders (MAHs) to draw reliable conclusions. Regulatory authorities have shared responsibility with MAHs sponsoring postmarketing nonintervention studies in determining study goals and design. Their shared accountabilities include what will be investigated and how the data will be retrieved to ensure appropriate study quality required for regulatory decision making. The need for a harmonized framework and ethical standards for postmarketing observational studies is well recognized but has been lacking even among the United States, European Union, and Japan, which are so-called International Conference on Harmonisation (ICH) regions. A recent update of the Council for International Organizations of Medical Sciences International Ethical Guidelines for Health-Related Research Involving Humans provides further clarification on provisions for informed consent and the role of research ethics committees. However, without incorporation into legislative structures, the future impact of these guidelines is uncertain. This lack of harmonization leads to a complex and uncertain framework for ethical review and for participant informed consent, resulting in numerous inefficiencies in the regulatory postmarketing observational studies. The regulatory frameworks for postmarketing observational studies conducted under the auspices of regulatory agencies in the 3 regions are reviewed, with a focus on ethical requirements and opportunities for efficiencies.

COVID-19 Vaccination Reactions and Risk of Breakthrough Infections Among People With Diabetes: Cohort Study Derived From Community Reporters.

BACKGROUND: This exploratory study compares self-reported COVID-19 vaccine side effects and breakthrough infections in people who described themselves as having diabetes with those who did not identify as having diabetes. OBJECTIVE: The study uses person-reported data to evaluate differences in the perception of COVID-19 vaccine side effects between adults with diabetes and those who did not report having diabetes. METHODS: This is a retrospective cohort study conducted using data provided online by adults aged 18 years and older residing in the United States. The participants who voluntarily self-enrolled between March 19, 2021, and July 16, 2022, in the IQVIA COVID-19 Active Research Experience project reported clinical and demographic information, COVID-19 vaccination, whether they had experienced any side effects, test-confirmed infections, and consented to linkage with prescription claims. No distinction was made for this study to differentiate prediabetes or type 1 and type 2 diabetes nor to verify reports of positive COVID-19 tests. Person-reported medication use was validated using pharmacy claims and a subset of the linked data was used for a sensitivity analysis of medication effects. Multivariate logistic regression was used to estimate the adjusted odds ratios of vaccine side effects or breakthrough infections by diabetic status, adjusting for age, gender, education, race, ethnicity (Hispanic or Latino), BMI, smoker, receipt of an influenza vaccine, vaccine manufacturer, and all medical conditions. Evaluations of diabetes medication-specific vaccine side effects are illustrated graphically to support the examination of the magnitude of side effect differences for various medications and combinations of medications used to manage diabetes. RESULTS: People with diabetes (n=724) reported experiencing fewer side effects within 2 weeks of vaccination for COVID-19 than those without diabetes (n=6417; mean 2.7, SD 2.0 vs mean 3.1, SD 2.0). The adjusted risk of having a specific side effect or any side effect was lower among those with diabetes, with significant reductions in fatigue and headache but no differences in breakthrough infections over participants' maximum follow-up time. Diabetes medication use did not consistently affect the risk of specific side effects, either using self-reported medication use or using only diabetes medications that were confirmed by pharmacy health insurance claims for people who also reported having diabetes. CONCLUSIONS: People with diabetes reported fewer vaccine side effects than participants not reporting having diabetes, with a similar risk of breakthrough infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT04368065; https://clinicaltrials.gov/study/NCT04368065.

Longitudinal Molecular and Serological Evidence of SARS-CoV-2 Infections and Vaccination Status: Community-Based Surveillance Study (CONTACT).

INTRODUCTION: This prospective, longitudinal, community-based study, EpidemiologiCal POpulatioN STudy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Lake CounTy, Illinois (CONTACT), investigated coronavirus disease 2019 (COVID-19) immunity, occupational risks related to SARS-CoV-2 exposure, and long-term immunoglobulin G (IgG) seroconversion kinetics. METHODS: At baseline and follow up (3, 6, and 9 months), non-hospitalized adult participants provided nasal and blood serum specimens for molecular [reverse transcription polymerase chain reaction (RT-PCR)] and serological (IgG) testing (4 November 2020-30 October 2021). RESULTS: At baseline, 6.4% (65/1008) had evidence of current/prior SARS-CoV-2 infection. At 3, 6, and 9 months, positive PCR tests were obtained from 0.4% (3/781), 0.4% (3/733), and 0% (0/673) of participants, respectively. Positive IgG occurred at baseline and 3, 6, and 9 months in 4.5% (45/1008), 6.0% (48/799), 5.4% (39/733), and 2.8% (19/673) of participants, respectively. Of participants positive for IgG at baseline, 28 had a negative IgG test at a follow-up visit; of those 28, 21 had their first negative IgG test within 6 months. Participants were more likely to retain positive IgG if they were 18-29 years of age, were male, or had medium-high/high-risk occupations. A high vaccination rate (70% received ≥ 1 dose by 9 months) was observed. Influence of occupational status or characteristics on transmission and IgG, and COVID-19 vaccination trends, are shown. CONCLUSIONS: This study expands on prior studies assessing COVID-19 immunity and IgG seroconversion by including both RT-PCR and serologic testing and longitudinal follow-up of study participants. We observed decreased infection rates over the 9 month follow-up period as well as a decline in IgG persistency after 6 months. The findings from this community-based study regarding vaccinate rates, infection rates by PCR, and IgG persistency over time can help improve our understanding of COVID-19 immunity, occupational risks related to SARS-CoV-2 exposure, and the kinetics of long-term IgG seroconversion, which is important to help guide local and national mitigation strategies. CLINICAL TRIAL REGISTRATION: NCT04611230.

Human influenza A H5N1 in Indonesia: health care service-associated delays in treatment initiation.

BACKGROUND: Indonesia has had more recorded human cases of influenza A H5N1 than any other country, with one of the world's highest case fatality rates. Understanding barriers to treatment may help ensure life-saving influenza-specific treatment is provided early enough to meaningfully improve clinical outcomes. METHODS: Data for this observational study of humans infected with influenza A H5N1 were obtained primarily from Ministry of Health, Provincial and District Health Office clinical records. Data included time from symptom onset to presentation for medical care, source of medical care provided, influenza virology, time to initiation of influenza-specific treatment with antiviral drugs, and survival. RESULTS: Data on 124 human cases of virologically confirmed avian influenza were collected between September 2005 and December 2010, representing 73% of all reported Indonesia cases. The median time from health service presentation to antiviral drug initiation was 7.0 days. Time to viral testing was highly correlated with starting antiviral treatment (p < 0.0001). We found substantial variability in the time to viral testing (p = 0.04) by type of medical care provider. Antivirals were started promptly after diagnosis (median 0 days). CONCLUSIONS: Delays in the delivery of appropriate care to human cases of avian influenza H5N1 in Indonesia appear related to delays in diagnosis rather than presentation to health care settings. Either cases are not suspected of being H5N1 cases until nearly one week after presenting for medical care, or viral testing and/or antiviral treatment is not available where patients are presenting for care. Health system delays have increased since 2007.

Determinants of antiviral effectiveness in influenza virus A subtype H5N1.

BACKGROUND: Oseltamivir is widely used as treatment for influenza virus A subtype H5N1 (hereafter, "H5N1") infection but, like any intervention, is not always effective. METHODS: We used Avian Influenza Registry data from 10 countries to examine the risk of death in 215 patients with confirmed H5N1 infection who were treated with oseltamivir, according to viral clade, age, respiratory failure, and adjunctive treatment with corticosteroids or antibiotics. RESULTS: The median age of infected individuals was 18 years, and 50% were male. The highest fatality rate occurred in a country with clade 2.1 virus circulation, and the lowest occurred in countries with clade 2.2 virus circulation (P < .001). In univariate analyses, age of ≤5 years and treatment ≤2 days after symptom onset were protective against fatality. When accounting for all risk factors, early initiation of oseltamivir was found to be particularly effective in individuals without respiratory failure (odds ratio, 0.17; P = .04). Patients who had advanced respiratory failure requiring ventilatory support at the time of oseltamivir initiation were more likely to die from the episode of H5N1 infection than patients who did not (P < .001). Adjunctive therapy did not improve the likelihood of surviving the episode. CONCLUSIONS: Oseltamivir is especially effective for treating H5N1 infection when given early and before onset of respiratory failure. The effect of viral clade on fatality and treatment response deserves further investigation.

Tactical Considerations for Designing Real-World Studies: Fit-for-Purpose Designs That Bridge Research and Practice.

Real-world evidence (RWE) is being used to provide information on diverse groups of patients who may be highly impacted by disease but are not typically studied in traditional randomized clinical trials (RCT) and to obtain insights from everyday care settings and real-world adherence to inform clinical practice. RWE is derived from so-called real-world data (RWD), ie, information generated by clinicians in the course of everyday patient care, and is sometimes coupled with systematic input from patients in the form of patient-reported outcomes or from wearable biosensors. Studies using RWD are conducted to evaluate how well medical interventions, services, and diagnostics perform under conditions of real-world use, and may include long-term follow-up. Here, we describe the main types of studies used to generate RWE and offer pointers for clinicians interested in study design and execution. Our tactical guidance addresses (1) opportunistic study designs, (2) considerations about representativeness of study participants, (3) expectations for transparency about data provenance, handling and quality assessments, and (4) considerations for strengthening studies using record linkage and/or randomization in pragmatic clinical trials. We also discuss likely sources of bias and suggest mitigation strategies. We see a future where clinical records - patient-generated data and other RWD - are brought together and harnessed by robust study design with efficient data capture and strong data curation. Traditional RCT will remain the mainstay of drug development, but RWE will play a growing role in clinical, regulatory, and payer decision-making. The most meaningful RWE will come from collaboration with astute clinicians with deep practice experience and questioning minds working closely with patients and researchers experienced in the development of RWE.

Cognitive and other neuropsychiatric symptoms in COVID-19: analysis of person-generated longitudinal health data from a community-based registry.

OBJECTIVE: To describe cognitive symptoms in people not hospitalised at study enrolment for SARS-CoV-2 infection and associated demographics, medical history, other neuropsychiatric symptoms and SARS-CoV-2 vaccination. DESIGN: Longitudinal observational study. SETTING: Direct-to-participant registry with community-based recruitment via email and social media including Google, Facebook and Reddit, targeting adult US residents. Demographics, medical history, COVID-19-like symptoms, tests and vaccinations were collected through enrolment and follow-up surveys. PARTICIPANTS: Participants who reported positive COVID-19 test results between 15 December 2020 and 13 December 2021. Those with cognitive symptoms were compared with those not reporting such symptoms. MAIN OUTCOME MEASURE: Self-reported cognitive symptoms (defined as 'feeling disoriented or having trouble thinking' from listed options or related written-in symptoms) RESULTS: Of 3908 participants with a positive COVID-19 test result, 1014 (25.9%) reported cognitive symptoms at any time point during enrolment or follow-up, with approximately half reporting moderate/severe symptoms. Cognitive symptoms were associated with other neuropsychiatric symptoms, including dysgeusia, anosmia, trouble waking up, insomnia, headache, anxiety and depression. In multivariate analyses, female sex (OR, 95% CI): 1.7 (1.3 to 2.2), age (40-49 years (OR: 1.5 (1.2-1.9) compared with 18-29 years), history of autoimmune disease (OR: 1.5 (1.2-2.1)), lung disease (OR: 1.7 (1.3-2.2)) and depression (OR: 1.4 (1.1-1.7)) were associated with cognitive symptoms. Conversely, black race (OR: 0.6 (0.5-0.9)) and COVID-19 vaccination before infection (OR: 0.6 (0.4-0.7)) were associated with reduced occurrence of cognitive symptoms. CONCLUSIONS: In this study, cognitive symptoms among COVID-19-positive participants were associated with female gender, age, autoimmune disorders, lung disease and depression. Vaccination and black race were associated with lower occurrence of cognitive symptoms. A constellation of neuropsychiatric and psychological symptoms occurred with cognitive symptoms. Our findings suggest COVID-19's full health and economic burden may be underestimated. TRIAL REGISTRATION NUMBER: NCT04368065.

Daily COVID-19 symptom assessment over 28 days - findings from a daily direct-to-patient registry of COVID-19 positive patients.

In January 2021, 999 COVID-19 positive adults in the US enrolled in an online, direct-to-patient registry to describe daily symptom severity and progression over 28 days. The most commonly reported and persistent symptoms were fatigue, headache, decreased sense of taste, decreased sense of smell, and cough. Fast resolving symptoms included gastrointestinal symptoms (nausea, vomiting, diarrhea) and those related to fever and chills. While more than half (56%) of patients reported overall symptom improvement during the 28-day study period, 60% of patients were still reporting at least 1 COVID-19 symptom at the end of 28 days. Risk factors for experiencing symptoms for longer duration included at least one of the following: older age (> 60 years), higher BMI, lung disease, and receiving medication for hypertension. The study demonstrates the value of patient-reported data to provide important and timely insights to COVID-19 disease and symptom progression and the potential of using real-world data to inform clinical trial design and endpoints.

H5N1 avian influenza in children.

BACKGROUND: Avian influenza continues to pose a threat to humans and maintains the potential for greater transmissibility. Understanding the clinical presentation and prognosis in children will help guide effective diagnosis and treatment. METHODS: A global patient registry was created to enable systematic collection of clinical, exposure, treatment, and outcomes data on confirmed cases of H5N1. Bivariate and multivariate statistical tools were used to describe clinical presentation and evaluate factors prognostic of survival. RESULTS: Data were available from 13 countries on 193 children <18 years who were confirmed as having been infected with H5N1; 35.2% of cases were from Egypt. The case fatality rate (CFR) for children was 48.7%, with Egypt having a very low pediatric CFR. Overall, children aged ≤5 years had the lowest CFR and were brought to hospitals more quickly and treated sooner than older children. Children who presented for medical care with a complaint of rhinorrhea had a 76% reduction in the likelihood of death compared with those who presented without rhinorrhea, even after statistical adjustment for age, having been infected in Egypt, and oseltamivir treatment (P = .02). Delayed initiation of treatment with oseltamivir increases the likelihood of death, with an overall 75% increase in the adjusted odds ratio for death for each day of delay. CONCLUSIONS: The presence of rhinorrhea appears to indicate a better prognosis for children with H5N1, with most patients surviving regardless of age, country, or treatment. For individuals treated with oseltamivir, early initiation of treatment substantially enhances the chance of survival.