In recent years, the development of follow-on biological products (biosimilars) has received increasing attention. The dissertation covers statistical methods related to three topics of Non-inferiority (NI), Bioequivalence (BE) and Equivalence in demonstrating biosimilarity. For NI, one of the key requirements is constancy assumption, that is, the effect of reference treatment is the same in current NI trials as in historical superiority trials. However if a covariate interacts with the treatment arms, then changes in distribution of this covariate will result in violation of constancy assumption. We propose a modified covariate-adjustment fixed margin method, and recommend it based on its performance characteristics in comparison with other methods. Topic two is related to BE inference for log-normal distributed data. Two drugs are bioequivalent if the difference of a pharmacokinetics (PK) parameter of two products falls within prespecified margins. In the presence of unspecified variances, existing methods like two one-sided tests and Bayesian analysis in BE setting limit our knowledge on the extent that inference of BE is affected by the variability of the PK parameter. We propose a likelihood approach that retains the unspecified variances in the model and partitions the entire likelihood function into two components: F-statistic function for variances and t-statistic function for difference of PK parameter. The advantage of the proposed method over existing methods is it helps identify range of variances where BE is more likely to be achieved. In the third topic, we extend the proposed likelihood method for Equivalence inference, where data is often normal distributed. In this part, we demonstrate an additional advantage of the proposed method over current analysis methods such as likelihood ratio test and Bayesian analysis in Equivalence setting. The proposed likelihood method produces results that are same or comparable to current analysis methods in general case when model parameters are independent. However it yields better results in special cases when model parameters are dependent, for example the ratio of variances is directly proportional to the ratio of means. Our research results suggest the proposed likelihood method serves a better alternative than the current analysis methods to address BE/Equivalence inference.

Master of Science / Department of Statistics / Christopher Vahl / In clinical research, noninferiority trials are becoming an important tool for investigating whether a new treatment is useful. The outcome measured can be either continuous (e.g. blood pressure level), time-to-event (e.g. days until heart attack), or binary (e.g. death). Rather than showing that the new treatment is superior to an active control, i.e. standard drug or treatment already available, one tests whether the new treatment is not meaningfully worse than the active control. Here we consider a binary outcome such as success or failure following an intervention. Evaluation of the treatment relative to control becomes a comparison of two binomial proportions; without loss of generality it will be assumed the larger the probability of success for an intervention the better. Simulation studies under these assumptions were programmed over a variety of different sample sizes and true population proportions to determine the performance between asymptotic noninferiority methods based on calculations of risk differences (with and without a continuity correction), relative risks, and odds ratio from two independent samples. Investigation was done to compare type I error rates, power when true proportions were exactly the same, and power when the true proportion for treatment group was less than the control, but not meaningfully inferior. Simulation results indicate most analysis methods have comparable type I error rates; however, the method based on relative risk has higher power under most circumstances. Due to the ease of interpretation with the relative risk, its use is recommended for establishing noninferiority of a binomial proportion between 0.2 and 0.8.

Humant immunbristvirus (HIV) tillhör gruppen retrovirus. Det finns två typer av HIV, HIV-1 och HIV-2. HIV-1 är den mest spridda typen. Viruset angriper CD4+ T-hjälparceller och använder cellerna för att replikera. När HIV förökar sig minskar antalet CD4+ T-hjälparceller vilket leder till nedsatt immunförsvar och kroppen får svårare att hantera andra infektioner. Obehandlad HIV kan leda till ”acquired immunodeficiency syndrome” (AIDS) som innebär att immunförsvaret är kraftigt nedsatt och kroppen därmed är mycket känslig mot alla sorters infektioner. Globalt uppskattas cirka 38,4 miljoner människor leva med HIV, och 40 miljoner människor har avlidit på grund av AIDS.  Det finns ingen botande behandling mot HIV, men flera olika behandlingsmöjligheter för att minska virusmängden i kroppen. HIV muterar dock frekvent vilket innebär att viruset kan utveckla resistens mot läkemedel. För att minska risken för resistensutveckling behandlas HIV med kombinationsbehandling där läkemedel med olika verkningsmekanism kombineras. Standardbehandlingen mot HIV har under en lång period varit en kombination av tre eller fler olika läkemedel. Det finns dock nackdelar med att kombinera tre eller flera olika läkemedel, till exempel läkemedel-läkemedelsinteraktioner och ökad frekvens av biverkningar. På grund av detta testas nu i olika studier om kombinationer med endast två läkemedel kan fungera lika bra.  Syftet med det här arbetet var att genomföra en litteraturstudie för att beskriva effekt och säkerhet av kombinationsbehandling mot HIV-1 med två antiretrovirala läkemedel där det ena läkemedlet var integrashämmaren dolutegravir, jämfört med tidigare godkända kombinationsbehandlingar med tre eller fyra antiretrovirala läkemedel. Dolutegravir valdes på grund av att läkemedlet har hög resistensbarriär och ingår i två rekommenderade kombinationer med två läkemedel. För att svara på syftet genomfördes sökningar efter relevanta artiklar i PubMed. Artiklarna som inkluderades skulle vara randomiserade kontrollerade studier med noninferiority studiedesign. Artiklar som redovisade sekundära eller uppföljande studier exkluderades. Utifrån inklusion- och exklusionskriterierna inkluderades fyra kliniska studier till resultatet. Resultatet visade att dubbelbehandling mot HIV-1 innehållande dolutegravir och antingen lamivudin eller rilpivirin inte gav sämre effekt än standardbehandling med tre eller fyra antiretrovirala läkemedel hos både virologiskt supprimerade och behandlingsnaiva personer med HIV-1 under 48 veckor. Dubbelbehandling var inte sämre på att behålla HIV-1 RNA <50 kopior/ml vid vecka 48 och gav inte högre risk för virologisk svikt eller resistensmutationer. Biverkningar var fler vid dubbelbehandling än standardbehandling hos redan virologiskt supprimerade personer, men färre vid dubbelbehandling än standradbehandling hos behandlingsnaiva personer under 48 veckor.  Längre studier och fler studier som inkluderar subgrupper, t.ex. gravida, barn och personer med samsjuklighet behövs för att långtidseffekter ska kunna uvärderas och göra det möjligt att använda dubbelbehandling bredare i framtiden. / Human immunodeficiency virus (HIV) belongs to the group of retroviruses. There are two types of HIV, HIV-1 and HIV-2. HIV-1 is the most widespread type. The virus attacks CD4+ helper T cells and uses the cells to replicate. When HIV replicates, the number of CD4+ helper T cells decreases, which leads to a weakened immune system which makes it harder for the body to fight other infections. Untreated HIV can lead to acquired immunodeficiency syndrome (AIDS), which means that the immune system is severely weakened, and the body is, therefore, very susceptible to many kinds of infections. Globally, it is estimated that about 38,4 million people are living with HIV, and 40 million people have died due to AIDS. There are no cure for HIV, but several different treatment options to reduce the viral load in the body. HIV has a high frequency of mutations which can make the virus resistant to a drug. To reduce the risk of resistance, HIV is normally treated with a combination of drugs with different mechanisms of action. The standard treatment for HIV has for a long time been a combination of three or more different drugs. However, there are disadvantages to combining several different drugs, such as drug-drug interactions and increased risk of side effects. Because of this, recent studies have been testing whether combinations with only two drugs can work just as well. The purpose of this study was to review the efficacy and safety of combination therapy for HIV-1 with two antiretroviral drugs, where one drug was the integrase inhibitor dolutegravir, compared to previously approved combination therapies with three or four antiretroviral drugs. Dolutegravir was chosen due to the drug's high resistance barrier and inclusion in two recommended two drug regimens. To answer the purpose,  searches for relevant articles were conducted on PubMed. The articles that were included were randomized controlled trials with a non-inferiority study design, while articles that presented secondary or follow-up studies were excluded. Based on the inclusion and exclusion criteria, four clinical studies were included in the result. The results showed that dual therapy against HIV-1 containing dolutegravir and lamivudine or rilpivirine were non-inferior in efficacy compared to standard treatment with three or four antiretroviral drugs in both virologically suppressed and antiretroviral therapy-naive individuals with HIV-1 for up to 48 weeks. Dual therapy was non-inferior in maintaining HIV-1 RNA <50 copies/mL at week 48 and did not confer a higher risk of virological failure or resistance mutations. Side effects were more frequent with dual therapy than standard treatment in individuals who were already virologically suppressed, but fewer with dual therapy than standard treatment in treatment-naive individuals over 48 weeks. Longer and more studies that include subgroups, such as pregnant women, children, and people with comorbidities, are needed to evaluate long-term effects and make it possible to use two drug regimens more widely in the future.

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