Alternative Clinical Trial Designs Research Articles

Perceptions of non-disclosure of results in clinical trial designs for multicancer detection tests.

10546 Background: Multi-cancer detection tests (MCDs) are blood-based tests designed to detect multiple cancers. The National Cancer Institute (NCI) is planning a pilot study to ascertain the feasibility of recruitment and the necessary infrastructure, clinical workflow, and diagnostic pathways for conducting a large clinical trial to assess whether cancer screening using MCDs reduces cancer mortality. In preparation for these activities, the NCI conducted a qualitative focus group study with primary care physicians (PCPs) and laypersons to explore the acceptability of alternative MCD trial designs, including the disclosure vs. non-disclosure of MCD test results to study participants. Methods: Focus groups were conducted with convenience samples of PCPs (6 groups, N=45) and laypersons (4 groups, N=88) by a consumer research firm. Interviews used both open-ended questions and specific prompts to explore participants’ perceptions of alternative clinical trial designs. Interviews were audio-recorded and transcribed, and qualitative thematic analysis of interview transcripts was conducted to identify emergent themes. Results: In general, PCPs and laypersons reported a willingness to refer or participate in an MCD trial regardless of design, with the understanding that clear and transparent information would be provided in the consent process. However, both groups expressed concern with a trial design in which patients in the control arm would not receive their MCD test results—a design that would allow a marked reduction in sample size and time necessary to assess a mortality endpoint. PCPs noted that although this design might be ethically acceptable due to current clinical equipoise about MCD testing, they expressed concern about mistrust among patients and medical-legal liability. Laypersons had difficulty understanding the rationale for non-disclosure of MCD test results during a trial, and concerns about the ethics of non-disclosure. Some participants felt more comfortable if return of value with other information was included as part of routine study procedures. Participants were more comfortable with an alternative design involving delayed testing of stored blood samples from the control group after trial completion. PCPs also expressed concern about increased workloads if their patients enrolled. Conclusions: PCPs and laypersons had generally positive reactions to a trial to investigate diagnostic performance, pathways, and outcomes of MCDs. Concerns about study designs involving non-disclosure of results might be managed through return of value strategies, careful education, and clear communication of the benefits and risks of MCDs.

Estimating HIV Incident Diagnoses Among Men Who Have Sex With Men Eligible for Pre-exposure Prophylaxis but Not Taking It: Protocol and Feasibility Assessment of Data Sources and Methods

HIV incidence estimates are published each year for all Ending the HIV Epidemic (EHE) counties, but they are not stratified by the demographic variables highly associated with risk of infection. Regularly updated estimates of HIV incident diagnoses available at local levels are required to monitor the epidemic in the United States over time and could contribute to background incidence rate estimates for alternative clinical trial designs for new HIV prevention products. We describe methods using existing, robust data sources within areas in the United States to reliably estimate longitudinal HIV incident diagnoses stratified by race and age categories among men who have sex with other men (MSM) eligible for pre-exposure prophylaxis (PrEP) but not taking it. This is a secondary analysis of existing data sources to develop new estimates of incident HIV diagnoses in MSM. We reviewed past methods used to estimate incident diagnoses and explored opportunities to improve these estimates. We will use existing surveillance data sources and population sizes of HIV PrEP-eligible MSM estimated from population-based data sources (eg, US Census data and pharmaceutical prescription databases) to develop metropolitan statistical area-level estimates of new HIV diagnoses among PrEP-eligible MSM. Required parameters are number of new diagnoses among MSM, estimates of MSM with an indication for PrEP, and prevalent PrEP use including median duration of use; these parameters will be stratified by jurisdiction and age group or race or ethnicity. Preliminary outputs will be available in 2023, and updated estimates will be produced annually thereafter. Data to parameterize new HIV diagnoses among PrEP-eligible MSM are available with varying levels of public availability and timeliness. In early 2023, the most recent available data on new HIV diagnoses were from the 2020 HIV surveillance report, which reports 30,689 new HIV infections in 2020, and 24,724 of them occurred in an MSA with a population of ≥500,000. Updated estimates for PrEP coverage based on commercial pharmacy claims data through February 2023 will be generated. The rate of new HIV diagnoses among MSM can be estimated from new diagnoses within each demographic group (numerator) and the total person-time at risk of diagnosis for each group (denominator) by metropolitan statistical area and year. To estimate time at risk, the person-time of individuals on PrEP or person-time after incident HIV infection but before diagnosis should be removed from stratified population size estimates of the total number of person-years with indications for PrEP. Reliable, serial, cross-sectional estimates for rates of new HIV diagnoses for MSM with PrEP indications can serve as benchmark community estimates of failures of HIV prevention and opportunities to improve services and will support public health epidemic monitoring and alternative clinical trial designs. DERR1-10.2196/42267.

Clinical research challenges posed by difficult-to-treat depression.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

Evaluating hearing performance with cochlear implants within the same patient using daily randomization and imaging-based fitting - The ELEPHANT study

BackgroundProspective research in the field of cochlear implants is hampered by methodological issues and small sample sizes. The ELEPHANT study presents an alternative clinical trial design with a daily randomized approach evaluating individualized tonotopical fitting of a cochlear implant (CI).MethodsA single-blinded, daily-randomized clinical trial will be implemented to evaluate a new imaging-based CI mapping strategy. A minimum of 20 participants will be included from the start of the rehabilitation process with a 1-year follow-up period. Based on a post-operative cone beam CT scan (CBCT), mapping of electrical input will be aligned to natural place-pitch arrangement in the individual cochlea. The CI’s frequency allocation table will be adjusted to match the electrical stimulation of frequencies as closely as possible to corresponding acoustic locations in the cochlea. A randomization scheme will be implemented whereby the participant, blinded to the intervention allocation, crosses over between the experimental and standard fitting program on a daily basis, and thus effectively acts as his own control, followed by a period of free choice between both maps to incorporate patient preference. With this new approach the occurrence of a first-order carryover effect and a limited sample size is addressed.DiscussionThe experimental fitting strategy is thought to give rise to a steeper learning curve, result in better performance in challenging listening situations, improve sound quality, better complement residual acoustic hearing in the contralateral ear and be preferred by recipients of a CI. Concurrently, the suitability of the novel trial design will be considered in investigating these hypotheses.Trial registrationClinicalTrials.gov: NCT03892941. Registered 27 March 2019.

A Proposed Framework for Patient-Focused Policy at the U.S. Food and Drug Administration.

Medical product sponsors are encouraged to include the patient perspective in their medical product development strategy to inform product design, augment regulatory submissions, argue for alternative clinical trial designs, or to support indications in specific patient populations. The goal is to create a patient-focused ecosystem that enables industry to integrate the patient voice throughout the medical product lifecycle. To this end, the U. S. Food and Drug Administration (FDA) has published several guidance documents to provide industry with the expectations and opportunities for conducting patient-focused activities. From an industry perspective, the Center for Devices and Radiologic Health (CDRH) and the Center for Drug Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER) patient-focused policies are complementary. The basic tenets promoted in all FDA patient-focused guidance could apply across therapeutic areas. However, there remain differences in these guidance documents across FDA centers, and there is no framework in place to provide industry with consistent recommendations. Without a coordinated patient-focused policy from the FDA, there is the potential for confusion and a lack of consistency among industry and regulatory decision-makers. The objective of this paper was to propose an alternative framework for patient-focused policy at the FDA, which recognizes the potential for different types of patient input to be used across therapeutic areas and medical product types. Further, these policies need to provide greater clarity on how patient input data is used, so that sponsors may navigate the opportunities to use patient input regardless of the FDA center under which their product is regulated. Creating consistent, coherent, and transparent FDA patient-focused policy will encourage sponsors to obtain patient input more often and with greater certainty of the value that these data may have to their medical product strategies.

Design and Endpoints of Clinical Trials, Current and Future.

With the advent of several new systemic agents for the treatment of hepatocellular carcinoma and the prospect of more to come it is expected that many more clinical trials will be undertaken to establish the best treatment paradigm(s). In order to help develop the most efficient and most relevant clinical trials this review concentrates on endpoints that have been used in the past. Survival is the gold standard. None of the surrogate endpoints correspond completely with survival. In addition, alternative clinical trial designs are presented that may be more efficient than the usual phase I, II, and III clinical trial strategy that has been used in the past.

Clinical Trials and the Importance of Biobanks in Rare Diseases

Rare diseases ('orphan diseases') (RDs) count for 5000-8000 diseases with low prevalence and most commonly of genetic origin. Although most of rare diseases are manifested in early childhood, many are diagnosed in adults, even in elderly. Common characteristics, such as severity, debilitating and life-threatening features, with the lack of a specific drugs, make the treatment of RD a significant public-health problem. Even though randomized controlled trials (RCTs) are the most ideal design for evaluating new drugs, the aim of this review was to present the aggravating circumstances that development of so-called orphan drugs faces in context of RD. We searched the PubMed/Medline for publications on studies and ethics in RDs and applying of 'omics' technologies in analysing tissue samples at biobanks published between 2010 and 2017. In this review, we presented the most significant obstacles in conducting clinical trials in RD as well as main alternative clinical trial designs aiming to decrease the number of patients recruited with increased access to innovative medicines as many as possible. Furthermore, we have presented the possibility of accessing innovative drugs outside of clinical trials as well as ethics violations by the involvement of the subject in clinical trial. Modern technologies in molecular biology will enable the development of 'precision medicine' aimed at identifying the best therapeutic goal, depending on the genetic and epigenetic factors in the affected person. That is why RD biobanks have great significance in the preservation and distribution of tissue samples, in the research of diagnostic biomarkers and the drug development.

Experience in the global forum of bioethics in research. Challenges for the ethical review in Chile

The Global Forum on Bioethics in Research annually convenes a number of researchers, bioethicists and stakeholders with a shared interest in the ethics of conducting research in low and middle-income countries (LMIC). It provides a useful platform to discuss ethical issues that affect research practice in different scenarios, promoting ethically conducted research, global development for health research ethics and partnerships between the global north and south. As participant of the last three meetings, in this article the author analyzes the main ethical issues that were discussed in this forum, namely "Emerging epidemic infections and experimental medical treatments" (Annecy, France, 2015); "Ethics of research in pregnancy" (Buenos Aires, Argentina, 2016), and "The ethics of alternative clinical trial designs and methods in LMIC research" (Bangkok, Thailand, 2017). Local research ethics committees are not well prepared to face the new ethical challenges associated with research conducted in emergency situations or in pregnant women, or to evaluate new methods, such as alternative clinical trial designs (cluster randomized trials, adaptive platforms, or controlled human infection models, among others). According to this scenario, research ethics committees should be trained to carefully assess the risks and benefits of approving this type of research. In this context, it is necessary to harmonize local regulations with the new international standards in research ethics.

Alternative designs for clinical trials in rare diseases.

Evidence-based medicine requires strong scientific evidence upon which to base treatment. In rare diseases, study populations are often small, and thus this evidence is difficult to accrue. Investigators, though, should be creative and develop a flexible toolkit of methods to deal with the problems inherent in the study of rare disease. This narrative review presents alternative clinical trial designs for studying treatments of rare diseases, including cross-over and n-of-1 trials, randomized placebo-phase design, enriched enrollment, randomized withdrawal design, and classes of adaptive designs. Examples of applications of these designs are presented along with their advantages and disadvantages. Additional analytical considerations such as Bayesian analysis, internal pilots, and use of biomarkers as surrogate outcomes are further discussed. A framework for selecting appropriate clinical trial design is proposed to guide investigators in the process of selecting alternative designs for rare diseases. © 2016 Wiley Periodicals, Inc.

Hyperbaric oxygen brain injury treatment (HOBIT) trial: a multifactor design with response adaptive randomization and longitudinal modeling.

The goals of phase II clinical trials are to gain important information about the performance of novel treatments and decide whether to conduct a larger phase III trial. This can be complicated in cases when the phase II trial objective is to identify a novel treatment having several factors. Such multifactor treatment scenarios can be explored using fixed sample size trials. However, the alternative design could be response adaptive randomization with interim analyses and additionally, longitudinal modeling whereby more data could be used in the estimation process. This combined approach allows a quicker and more responsive adaptation to early estimates of later endpoints. Such alternative clinical trial designs are potentially more powerful, faster, and smaller than fixed randomized designs. Such designs are particularly challenging, however, because phase II trials tend to be smaller than subsequent confirmatory phase III trials. The phase II trial may need to explore a large number of treatment variations to ensure that the efficacy of optimal clinical conditions is not overlooked. Adaptive trial designs need to be carefully evaluated to understand how they will perform and to take full advantage of their potential benefits. This manuscript discusses a Bayesian response adaptive randomization design with a longitudinal model that uses a multifactor approach for predicting phase III study success via the phase II data. The approach is based on an actual clinical trial design for the hyperbaric oxygen brain injury treatment trial. Specific details of the thought process and the models informing the trial design are provided. Copyright © 2016 John Wiley & Sons, Ltd.

Alternative clinical trial design in neurocritical care.

Neurocritical care involves the care of highly complex patients with combinations of physiologic derangements in the brain and in extracranial organs. The level of evidence underpinning treatment recommendations remains low due to a multitude of reasons including an incomplete understanding of the involved physiology; lack of good quality, prospective, standardized data; and the limited success of conventional randomized controlled trials. Comparative effectiveness research can provide alternative perspectives and methods to enhance knowledge and evidence within the field of neurocritical care; these include large international collaborations for generation and maintenance of high quality data, statistical methods that incorporate heterogeneity and individualize outcome prediction, and finally advanced bioinformatics that integrate large amounts of variable-source data into patient-specific phenotypes and trajectories.

Abstract 4642: Model-based alternative clinical trial designs and evaluations for SGN-CD19A, a novel antibody-drug conjugate

Abstract Background SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin F (MMAF) via a maleimidocaproyl (mc) linker. Upon binding to CD19, SGN-CD19A internalizes and releases cys-mcMMAF, which binds to tubulin and induces G2/M arrest and apoptosis in the targeted cells. CD19 is a B-cell specific marker that is found on B cells as early as the pro-B cell stage and is expressed in the majority of patients with B-lineage leukemia and non-Hodgkin lymphoma (NHL). The objectives of this evaluation were to develop a semi-mechanistic PK-PD model based on the pharmacokinetics (PK) and pharmacodynamics (PD) of SGN-CD19A in patients with leukemia or NHL and to simulate alternative clinical trial designs using this model for the design of future clinical trials. Methods A semi-mechanistic integrated PK-PD model was developed based on the mechanism of action of SGN-CD19A and the clinical PK and PD data from the ongoing first-in-human dose-escalation study in adult and pediatric patients with relapsed or refractory B-cell leukemia or highly aggressive B-cell lymphoma (CT.gov NCT01786096). Plasma SGN-CD19A ADC concentration-time profiles were described by a two-compartment PK model with both linear and nonlinear clearance pathways. The nonlinear clearance was modeled as target-mediated disposition through binding to cell membrane CD19 and internalization of the complex. Anti-tumor effects in the form of reduced bone marrow disease burden were modeled using a cell-kill PK-PD model driven by the internalized cys-mcMMAF concentrations. Both PK and PD data were fitted simultaneously using NONMEM® version 7.1.2. Model simulations were conducted for alternative doses and schedules, including loading dose regimens, and for patients with different baseline disease characteristics. Results The integrated PK-PD model accurately described the SGN-CD19A PK and PD profiles in patients with either leukemia or NHL at multiple dose levels. Intra-patient adjustments in doses, disease status changes over time, and CD19 occupancy on tumor blast cells were well described based on goodness-of-fit evaluations. Using CD19 occupancy as the target engagement biomarker, multiple dosing schedules were evaluated using simulations for patients with different levels of baseline disease burden. Simulations suggested that various schedules can achieve and maintain target saturation, which may result in comparable anti-tumor activity. Conclusions The clinical PK, PD, and PK/PD of SGN-CD19A are well-characterized by a semi-mechanistic integrated model. Multiple dosing schedules were predicted to achieve target saturation. Citation Format: Baiteng Zhao, Tina M. Albertson, Che-Leung Law, Megan M. O'Meara, Ana Kostic, Tae H. Han. Model-based alternative clinical trial designs and evaluations for SGN-CD19A, a novel antibody-drug conjugate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4642. doi:10.1158/1538-7445.AM2014-4642

Pharmacodynamic Biomarkers: Falling Short of the Mark?

In recent years, the clinical development of targeted therapies has been advanced by a greater understanding of tumor biology and genomics. Nonetheless, drug development remains a slow and costly process. An additional challenge is that targeted therapies may benefit only a subset of patients treated-typically those patients whose tumors are dependent on the target of interest. Thus, there is a growing need for the incorporation of both predictive and pharmacodynamic (PD) biomarkers in drug development. Predictive biomarkers are important to help guide patient selection, while PD biomarkers can provide information on the pharmacologic effects of a drug on its target. PD studies may provide insights into proof of mechanism (i.e., Does the agent hit its intended target?) and proof of concept (i.e., Does hitting the drug target result in the desired biologic effect?). PD studies may also provide information on the optimal biologic dosing or scheduling of a targeted agent. Herein, we review PD endpoints in the context of targeted drug development in non-small cell lung cancer, highlighting some of the key challenges encountered to date. In doing so, we discuss recent experiences with repeat tumor biopsies, surrogate tissue analysis, alternative clinical trial designs (e.g., window-of-opportunity trials), circulating biomarkers, and mechanism-based toxicity assessments. The application of such technologies and biomarkers in early clinical trials may facilitate rational drug development, while enhancing our understanding of why certain targeted therapies succeed or fail. See all articles in this CCR focus section, "Progress in pharmacodynamic endpoints."

Advancing Clinical Trial Design in Pulmonary Hypertension

In pulmonary hypertension, as in many other diseases, there is a need for a smarter approach to evaluating new treatments. The traditional randomized controlled trial has served medical science well, but constrains the development of treatments for rare diseases. A workshop was established to consider alternative clinical trial designs in pulmonary hypertension and here discusses their merits, limitations and challenges to implementation of novel approaches.

How to Develop Treatments for Biologically Heterogeneous “Diseases”

The standard paradigm for the design of phase III clinical trials is not suitable for evaluation of molecularly targeted treatments in biologically heterogeneous groups of patients. Here, we comment on alternative clinical trial designs and propose a prospective discovery/evaluation framework for using tumor genomics in the design of phase III trials.

An alternative clinical trial design for early cancer vaccine development to phase 3+3 design.

2578 Background: Traditional phase I, “3+3 dose escalation” design, is conducted to identify the MTD and in some cases the optimal biologic dose. Given their unique mechanism of action and the profile of their clinical outcome, this design may not apply to cancer vaccines. The therapeutic cancer vaccine FDA guidance calls for an alternative early development design. Nevertheless, whether an alternative design should be based on “dose escalation” is still an opened question. Methods: We analyzed the toxicity profile in 241 phase 1, 1/2 and pilot therapeutic cancer vaccine trials conducted between 1990 and 2011. Results: Sixty-two grade 3/4 vaccine related systemic toxicities were reported in 4952 treated patients (1.25 events/100 patients). Interestingly, only 2 out of 127 trials that used dose escalation reported vaccine related DLTs, both trials used bacterial vectors. Furthermore, correlation of immunological response with dose level showed no consistent trend. Conclusions: Our analysis suggests that in cancer vaccines neither toxicity nor cellular immune response correlates with dose levels. Accordingly, dose escalation is not suitable for most cancer vaccine studies. Here, we propose a two-step alternative design for early development of cancer vaccines. The first step is to determine and confirm the minimum Immune-Active Dose (IAD). If a vaccine class has been used in humans, IAD dose is chosen based on previous experience if the class is non-toxic (eg. Peptide), otherwise, a traditional dose escalation will be used. For a vaccine class that has not been tested or has undetermined toxicity we recommend “One Patient Escalation Design” (OPSD): one patient is treated per tested dose until an immune response is induced. To confirm this activity, an expanded cohort of 7 patients will be tested until demonstrating an additional response. This will then be used in phase II combination therapy trial. Alternatively, IAD can be directly tested in combination with an immune modulator in a phase II clinical trial using a two-stage design. The first stage of the phase 2 trial can be set at 4-5 patients for a target response rate of over 50%. If no response is seen, then the immune modulator will be escalated in the second stage.

Orthopaedic Surgeons Prefer to Participate in Expertise-based Randomized Trials

Empiric data and theoretical arguments suggest an alternative randomized clinical trial (RCT) design, called expertise-based RCT, has enhanced validity, applicability, and ethical integrity compared with conventional RCT. Little is known, however, about whether physicians will participate in an expertise-based RCT. In a cross-sectional survey of Canadian orthopaedic surgeons, we evaluated preference for and willingness to participate in an expertise-based versus a conventional RCT if given the opportunity to participate in a trial investigating the effectiveness of high tibial osteotomy versus unicompartmental knee arthroplasty. Using an electronic survey ((c)2005 SurveyMonkey.com), we invited all 767 members of the Canadian Orthopaedic Association (2005) to participate; 276 surgeons completed the questionnaire (37.5% response rate). One hundred two surgeons (53.4%) were willing to participate in an expertise-based RCT compared with 35 surgeons (18.3%) willing to participate in a conventional RCT. Ninety-seven surgeons (52.4%) strongly or moderately preferred the expertise-based design compared with 25 (13.5%) who preferred the conventional design. For the clinical example we presented, the majority of Canadian orthopaedic surgeons were willing to participate in and preferred the expertise-based design. The expertise-based randomized clinical trial design may overcome some of the barriers to conducting clinical trials in orthopaedic surgery and improve the validity of their conclusions.

Regulatory issues facing the development of drug-eluting stents: a US FDA perspective

Coronary drug-eluting stents (DES) are a breakthrough technology that has changed the standard of care for many patients undergoing percutaneous intervention for coronary artery disease. Initial trials of two DES demonstrated significant clinical benefit with respect to the need for reintervention when compared with bare metal stents. However, more recent studies of DES involve in-patients with more complex disease, such as bifurcation lesions, chronic total occlusions and multiple-vessel disease. Additionally, DES are now being evaluated in patients previously only considered for surgical intervention. Assessment of DES in these complicated patient populations can lead to challenges in trial design, but the US FDA is willing to consider alternative clinical trial designs and statistical analysis plans. Other complex issues associated with DES include duration of clinical trials to determine safety, and the appropriate dose and duration of concomitant antiplatelet therapy. Finally, the FDA acknowledges that DES are complex products to produce and we believe that through interaction with the FDA during development, difficulties with test methodologies, animal studies and clinical trial designs can be addressed. The future of DES likely involves new stent and carrier materials, including biodegradable materials and new drugs and biologicals. The FDA anticipates continued collaboration with physicians, manufacturers, academic institutions and professional societies.

Clinical trials in multiple sclerosis: methodological issues

The availability of partially effective immunomodulatory and immunosuppressive treatments for relapsing multiple sclerosis (MS) opens important ethical, methodological and practical issues in the design and conduct of new clinical trials in these patients. The recommendation of the National Health Authorities to prioritize phase III clinical trials using placebo arm raises ethical questions. In addition, patients are reluctant to be involved in such trials. Alternative clinical trial designs will be discussed. Relapses and active lesions are accepted measures of disease activity; new/enlarging T2 lesions and/or enhancing lesions are accepted surrogate markers of disease activity in phase II clinical trials. On the contrary, there are no accepted magnetic resonance imaging (MRI) surrogate markers of disease progression and also the clinical measures to monitor the degenerative aspects of the disease are not without important limitations. New scales of impairment, disability and quality of life will be reviewed extensively. We will also focus on the value of modern and quantitative MRI techniques, which hold substantial promise as tools to estimate the extent of MS-related irreversible tissue loss. The use of an active comparator in a superior clinical-trial design is becoming an attractive option for testing the efficacy of new drugs in relapsing MS. At present there are no fully reliable and sensitive clinical markers of the accumulation of irreversible tissue damage in MS. Although additional extensive application in longitudinal studies is needed, modern MRI techniques are promising tools to monitor the neurodegenerative aspects of MS.

Clinician preferences and the estimation of causal treatment differences

Clinician treatment preferences affect the ability to perform randomized clinical trials and the ability to analyze observational data for treatment effects. In clinical trials, clinician preferences that are based on a subjective analysis of the patient can make it difficult to define eligibility criteria for which clinicians would agree to randomize all patients who satisfy the criteria. In addition, since each clinician typically has some preference for the choice of treatment for a given patient, there are concerns about how strong that preference needs to be before it is inappropriate for him to randomize the choice of treatment. In observational studies, the fact that clinician preferences affect the choice of treatment is a major source of selection bias when estimating treatment effects. In this paper we review alternative designs that have been proposed in the literature for randomized clinical trials that utilize clinician preferences differently than the standard randomized trial design. We also examine the effects of clinician preferences on the ability to estimate causal treatment differences from observational data, and propose an alternative method of analysis for observational data that uses clinician preferences explicitly. We report on our experience to date in using our alternative randomized clinical trial design and our new method of observational analysis to compare two treatments at the orthodontic clinics at the University of California San Francisco and the University of the Pacific, San Francisco.