Safety and Tolerability and Response Duration are Most Common Secondary Endpoints for Phase III Pipeline Molecules of Acute Myelocytic Leukemia (AML)

Monday 20 February 2012, Amsterdam

The report examines different aspects of clinical trial endpoints in orphan diseases, such as analysis of major marketed orphan drugs with an emphasis on safety and efficacy details, Phase II and Phase III clinical trial analysis for both completed and ongoing clinical trials, the most promising orphan drugs and their safety, efficacy and clinical trial details, and terminated trial analysis. The company profiles details the orphan drugs of different companies. These rare diseases have a low rate of prevalence in the existing population and a physician rarely gets to see patients with these conditions. Most of the orphan diseases are often genetic and hence they persist throughout a person’s life. It is estimated that 80% of orphan diseases have genetic origins. The remaining diseases occur due to allergies, degenerative and proliferative causes and as a result of infection. The symptoms for these diseases are not immediate and it appear later for most of the conditions. The definition of orphan diseases varies with geography and is primarily dependent upon the prevalence of a disease. This report “Endpoints- Clinical Trials in Orphan Diseases” highlights the seven major orphan diseases: Huntington’s disease, acute myeloid leukemia, amyotrophic lateral sclerosis, Hodgkin’s lymphoma, multiple myeloma, ovarian cancer and pancreatic cancer. The term endpoint refers to an outcome or measure of a clinical trial. Endpoints can include all kinds of aspects, those related to the effectiveness of treatment and others. However, endpoint selection must take into account the need to obtain the most information of therapeutic interest with the least risk and discomfort for the individual. Also, the endpoints must be in line with the objective of the study and represent the most effective way of assessing a pharmacological response.

Safety and Tolerability and Response Duration are Most Common Secondary Endpoints for Phase III Pipeline Molecules of Acute Myelocytic Leukemia (AML)

In general, multiple factors are considered for secondary endpoints. Most commonly seen secondary endpoints in Phase III molecules of Acute Myelocytic Leukemia include Safety and tolerability, Duration of Response and Complete remission rate, each of which account for 13% of secondary endpoints. Overall survival, used as a secondary endpoint in 12% of AML trials, is the next most common endpoint. Efficacy, EFS (Event-free survival,), DFS (Disease free survival), PFS (Progression free survival), QOL (Quality of life), Remission duration, and Toxicity each contribute 7% of secondary endpoints.

See figure: Acute Myelocytic Leukemia, Global, Clinical Pipeline Phase III by Secondary Endpoints, 2010

Clinical Trial Design - Need for Adaptive Trial Designs in Orphan Diseases

It is often difficult to design clinical trials of any type for a rare disease, due to the low incidence of such diseases. A rare disease is defined as a condition or disease affecting fewer than 200,000 individuals in the US. While considering treatment options, comparative studies play a key role in evaluating the therapy and due to an insufficient number of patients available to conduct trials, the efficacy of any intervention for a rare disease may be difficult to establish. Moreover, the small number of patients available makes conducting trial more difficult as a large majority of the patients will not be eligible for trials due to concomitant illness or conflicting pre-existing treatment regimes.

In orphan diseases, clinical trials are often designed where patients serve as their own controls. In this scenario, crossover studies are commonly used in clinical settings as patients are scarce, and these have been shown to achieve the same outcomes as the traditionally designed studies. In a two-group crossover study, each patient receives two different study molecules sequentially and is evaluated for a response after each treatment. If there are no carryover effects and no dropouts, studies with a crossover design can have fewer patients to achieve the same reliability as traditionally designed studies. In traditionally designed studies each patient is randomly assigned to receive only one of the treatments.

In the case of fewer patient numbers another method of achieving success in the trial is a threestage clinical trial design. This is also a more effective design than the traditional randomized trial for detecting clinical benefits. A three-stage clinical trial design consists of an initial randomized placebo-controlled stage, a randomized withdrawal stage for subjects who responded well to the treatment, and a third randomized stage for placebo non-responders who subsequently respond to treatment.

Multiple Myeloma Trials Account for the Highest Number of Terminated Trials among the Orphan Diseases

There are 23 terminated trials in multiple myeloma which is two to three times more than in other orphan disease indications studied in this report. Of these terminated molecules, four were terminated in the Phase III and 19 molecules were terminated during Phase II of clinical trials. Novartis and Cephalon had more than two studies each in these terminated multiple myeloma trials.