From pre-clinical research to post-marketing studies, and all phases in between, Statistics Collaborative has been involved with hundreds of trials across many therapeutic areas for nearly 30 years. Each therapeutic area has its own set of analytical complexities, whether they pertain to endpoint selection, trial design, missing data, or assessing risk versus benefit.
SCI has built on its experiences with these statistical complexities from various clinical trials and has been able to apply this knowledge to other indications that deal with the same types of issues.
SCI has many years of experience in cardiovascular disease. At the time the company was founded in 1990, Dr. Wittes had many years of experience designing, monitoring, analyzing, and reporting on cardiovascular clinical trials, including seven years as Branch Chief of the Biometrics Research Branch at the National, Heart, Lung, and Blood Institute.
Since the founding of SCI, we have served as the independent statistical group on the DMCs for scores of industry-sponsored trials studying cardiovascular interventions, ranging from stem cell therapy to cardiac devices. We have worked on trials with patients who are post–coronary artery bypass graft surgery and at high risk of myocardial infarction and death; who have congestive heart failure, acute coronary syndrome, atrial fibrillation, hyperlipidemia, and pulmonary arterial hypertension; and who are at increased risk of stroke. We are familiar with study endpoints involving major adverse cardiovascular events. We know the challenges associated with summarizing clinical events committee data and the concordance between assessments by investigators and those by the clinical events committee concerning outcome events, such as bleeds, strokes, and myocardial infarctions.
With the growing worldwide epidemic of Type 2 diabetes, and the high prevalence of Type 1 diabetes, the pharmaceutical industry is developing a variety of new drugs for prevention and treatment. We at SCI, and especially our senior staff, have been involved in trials of diabetes since our founding in 1990. SCI has been involved in numerous of studies comparing different types of insulins for both Type 1 and Type 2 diabetes. The trials have compared insulins with respect to their effect on HbA1c and other outcomes that measure efficacy, as well as safety as measured by frequency of hypoglycemic episodes associated with their use. SCI has worked with companies that are developing biologics for treatment of Type 1 diabetes and companies that are studying possible cardiovascular sequelae of treatments for Type 2 diabetes. Drawing on our experience in ophthalmology, we have prepared interim safety reports for trials investigating interventions for the ophthalmologic sequelae of diabetes.
We have worked with pharmaceutical companies to summarize epidemiologic data on the emergence of complications. Senior staff members have served on the DMCs for some major randomized trials of interventions to prevent diabetes conducted by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). We have also served on review teams established by the NIDDK to evaluate statistical centers for diabetes networks and to discuss which direction the Institute should take in allocating its resources for diabetes research.
SCI has provided support to a variety of biotech and pharmaceutical companies designing and conducting trials in patients with genetic conditions. In the context of genetic condition studies, SCI most often collaborates on trials of patients with rare or orphan diseases. Orphan diseases are those affecting fewer than 200,000 persons in the United States.
Very rare diseases are challenging to study because the affected populations are small and often scattered over major geographic areas. The natural history of orphan diseases is often not well known. SCI has experience working with the specific statistical challenges affecting orphan disease trials. Because of the many unknowns involved in the study of rare diseases, in doing this work we collaborate closely with experts in the subject matter. We show sensitivity to the issues presented by small sample size, which can lead to baseline imbalance, failure of distributional assumptions, large variability, and low power.
We have collaborated on trials involving a wide variety of genetic and rare conditions, including phenylketonuria, several mucopolysaccharidosis types, Niemann-Pick disease, Friedreich’s ataxia, Duchenne muscular dystrophy, Lafora disease, Pompe disease, and recessive dystrophic epidermolysis bullosa. SCI is proud to have worked on the statistical design and analysis of the pivotal trial for Luxturna™, the first directly administered gene therapy approved by the FDA that targets a disease caused by genetic mutation.
SCI has experience in a wide variety of infectious disease indications, both in prevention and treatment. We have worked on diseases caused by bacteria, viruses, retroviruses, and parasites, in adult and pediatric populations. Some of the trials have investigated antibacterials or antivirals, while others have studied vaccines. Still others have studied methodologies for early detection of disease. Our experience in infectious disease studies includes investigational therapies for seasonal and pandemic influenza, sepsis, hepatitis C, respiratory syncytial virus, clostridium difficile infection, vancomycin-resistant enterococci infection, pneumonia, herpes zoster, malaria, and HIV/AIDS.
In addition to our work with industry and with the FDA, we have collaborated with nonprofit groups that develop vaccines or treatments for malaria, tuberculosis, and HIV/AIDS.
SCI has worked on many trials in a diverse group of neurological conditions. We have reported to the DMCs for numerous studies investigating novel therapies for Alzheimer’s and other neurodegenerative diseases. We have collaborated on trials involving patients with stroke, Huntington’s Disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, familial amyloid polyneuropathy, neuromyelitis optica, Parkinson’s disease, and rare neuromusculoskeletal disorders, among others.
Efficacy outcomes pose special problems in neurology studies because many of the outcomes are scales. SCI has expertise in developing and implementing appropriate methods, such as multiple imputation, for handling the missing data that is common with scale instruments and other patient reported outcomes. SCI has developed various methods of plotting patient reported outcomes to show their temporal relationship with receipt of investigational agent. We have experience analyzing repeated measure data on many common neurology endpoints, including ADAS‑Cog, MMSE, ADCS-ADL, NPI, NIHSS, C-SSRS, HAM-D, and CDR-SB.
SCI has been involved with hundreds of clinical trials studying various types of solid and hematologic cancers. Our experience with solid tumors includes trials of cancers of the bladder, brain, breast, cervix, colon, endometrium, head and neck, lung, ovary, pancreas, prostate, kidney, rectum, skin, and thyroid. Hematologic cancers we have been involved with include leukemia, lymphoma, and multiple myeloma.
The investigational therapies aim to treat the underlying primary cancers, as well as the metastases. Some trials study treatments for sequelae of the primary therapies, such as oral mucositis and anemia. The therapies include immunotherapy, chemotherapies, radiation therapies, biological therapies, and vaccines.
SCI’s role in this arena has been primarily to support DMCs that monitor the safety of subjects in Phase 1 through Phase 3 cancer trials in various disease settings, including neoadjuvant treatment, adjuvant treatment, and treatment of unresectable disease. We have extensive experience preparing interim analyses of efficacy and futility based on oncology endpoints of interest.
In addition to supporting DMCs, SCI assists clients both in designing oncology trials and in preparing statistical analysis plans. We frequently review and edit protocols or write their statistical sections. SCI provides input in defining or choosing the primary outcomes and proposes methods of analysis. We are knowledgeable about commonly applied response criteria such as RECIST, IMWG, and immune-related response criteria. We also conduct analyses on final, locked databases for inclusion in reports to regulatory agencies and for use in the design of confirmatory trials.
Ophthalmological disorders present unique statistical challenges because of their many outcomes and the paired nature of the data (with each subject having two eyes). SCI has designed unique graphical presentations to summarize changes over time in these multivariate data.
SCI has considerable experience working with clinical trials involving ophthalmological disorders. These underlying diseases have included diabetes, age-related disorders such as age-related macular degeneration, and genetic diseases. For clinical trials in ophthalmology, SCI has served as the statistical organization reporting to DMCs as well as the statistical member of the boards.
Psychiatric disorders present unique challenges to statistical design. Issues include high rates of noncompliance by subjects and outcomes that are difficult to measure quantitatively. Our clients seek our expertise in design and the careful thought we give to statistical approaches for the analysis of these complex psychiatric outcomes. We recognize the complexity of scale and self-report measurements; we employ defensive programming techniques to handle interim data and we consider various methods to address missing data.
SCI has collaborated on trials in the settings of depression, suicide ideation, schizophrenia, bipolar disorder, and cognitive disability. Additionally, we have worked with psychiatric outcomes that are secondary outcomes of other treatments under investigation. These may range from neuropsychological functioning, to adverse events such as the development of depression or suicidality while on study, to changes in quality of life while a subject is on an investigational treatment. SCI has also consulted on the design and analysis for clinical trials evaluating interventions for mental health conditions for the National Institute of Mental Health.
SCI has played an integral role in the development and design of numerous studies of tropical diseases, including malaria, dengue fever, leishmaniasis, and leprosy. Malaria, dengue fever, and leishmaniasis are unusual among illnesses in the world of clinical trials for being parasitic infections introduced into the body by insects rather than by viruses or bacteria.
SCI assisted with the design and analysis for several randomized Phase 1 and 2 clinical and field trials evaluating the safety, immunogenicity, and efficacy of single and multivalent vaccines and prophylactic treatments. We have also designed and analyzed observational, epidemiological studies in malaria.
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