March is Endometriosis Awareness Month, a reminder of the importance of ensuring that clinical development of novel endometriosis treatments progresses as rapidly as possible. This is an area of significant unmet medical need affecting approximately 10% of women of reproductive age worldwide – approximately 176 million women. While sometimes asymptomatic, endometriosis is often associated with infertility and pelvic pain. Up to 50% of women with endometriosis may also have to deal with infertility. Even more women with endometriosis – 70% – experience pelvic pain and this can be chronic. Other symptoms include dysmenorrhea and dyspareunia. For women experiencing moderate to severe endometriosis pain, currently available treatments are often ineffective. Fortunately, development of new treatments for endometriosis is an area of intense activity. Novel treatments under clinical investigation include GnRH antagonists, selective progesterone receptor modulators and selective dopamine (D2) receptor agonists.
Key Considerations in Endometriosis Studies
Ensuring rapid development of new endometriosis treatments requires understanding the operational and methodological considerations that often come up in these studies. For example, enrollment benefits from the high motivation of women who have not yet found an effective treatment for moderate to severe endometriosis pain. On the other hand, some aspects of these studies may be more demanding than anticipated and discourage participation. Issues that may discourage some eligible women from enrolling in endometriosis studies include the following:
- Studies typically include washout periods for hormonal treatments
- A screening period typically spans two menstrual cycles and includes asking women to change from their accustomed analgesics to those allowed as rescue medications during the study
- Risk of randomization to placebo is a serious consideration for patients with a painful condition like endometriosis
- There are generally monthly visits for six months or more
- There will likely be a requirement to use two methods of nonhormonal contraception to minimize risk of pregnancy for this premenopausal population
- Patients must commit to completing a daily diary about pain and medication use.
Both recruitment and subject retention can present issues in endometriosis trials. Provision for rescue medications may not be enough to allay all concerns about risk of randomization to placebo. There is a risk of discontinuation, especially for patients randomized to placebo or to a possibly less effective lower dose of the investigational drug. Studies may observe discontinuation rates on the order of 25%.
Statistical and Data Quality Considerations
Endometriosis studies require close attention to statistical analysis techniques and data quality. Assessments must address the multiple types of pain associated with endometriosis, both dysmenorrhea and nonmenstrual pelvic pain, and assess pain in multiple ways. There are subjective assessments in these studies and those present the risk of high data variability. In addition to subjective pain assessments, endometriosis studies typically collect data on frequency and quantity of rescue medications used. Trials may involve secondary endpoints for dyspareunia, quality of life, productivity and perhaps other areas. Because patient adherence is another important consideration in data quality, it is important to have patients return unused medication and dispensed medication packages. There must be a decision about the statistical treatment of missing pain-assessment data (e.g. the last-observation-carried-forward method). Still another consideration in studies involving a placebo control is the placebo effect itself.
Addressing a Significant Unmet Medical Need for Millions of Women with Endometriosis
While successful execution of endometriosis studies involves many challenges, there is no question about the importance of ensuring that these studies are conducted with high quality and efficiency. As a CRO committed to improving healthcare outcomes for women worldwide, Health Decisions considers endometriosis a top priority as reflected in everything from high-level therapeutic expertise and patient advocacy to staff therapeutic training and offering sponsors strong capabilities for clinical studies in endometriosis.