Improving clinical trial design in acute pain
Dr. Lucy Lu of Avenue Therapeutics
Designing clinical trials in acute pain is challenging, primarily due to the well-known placebo effect. While certain pain conditions such as chronic low back pain are known for high placebo response rates in clinical trials, placebo response is also often present in acute pain trials, which are generally done in postoperative settings.
Based on current guidance, to obtain a general post-operative pain label, an acute pain drug seeking U.S. Food and Drug Administration (FDA) approval must demonstrate efficacy and safety compared to placebo in an orthopedic model and a soft tissue model. While there has been significant effort to better understand how to demonstrate therapeutic benefit, success does not necessarily mean a positive trial outcome, but rather a clean dataset that clearly exhibits the presence or lack of a therapy’s efficacy.
A successful acute pain trial is dependent on controlling experimental variables, including: patient qualification; trial enrollment and procedures; and surgical and anesthesia techniques—as well as ensuring that staff are adequately trained on study protocol and that rescue and concomitant medications are used consistently. These are among the many factors that biopharma companies must consider when designing a trial that will enable a truly efficacious medication to show significant treatment effect compared to placebo.
Controlling variables in orthopedic models
Many biopharma companies elect to use a dental pain model for early clinical trials, as dental pain models provide a reliable benchmark for demonstrating initial proof of concept and enable the selection of an efficacious dose for later-stage multidose and multiday trials. In addition, clinical trials involving dental pain models are often quickly enrolled, have standardized procedures and produce predictable pain levels.
Total joint replacement surgery, such as total knee replacement and total hip replacement, has been customarily used in pivotal orthopedic model trials. However, the standard of care for U.S. patients requiring total joint replacement has significantly changed over the past several years, as many institutions mandate multimodal protocols with nerve blocks and/or continuous epidural infusions for pain treatment and management. While these techniques can be effective in reducing patient pain, they introduce variables into clinical trials, which decrease assay sensitivity and can make it more difficult to demonstrate the efficacy of an experimental therapy versus placebo.
Importantly, protocols vary from hospital to hospital, which can make it challenging to enroll patients who have undergone joint replacement surgery and to maintain consistency across hospital-based trial sites. For example, to ensure a homogeneous patient population and predictable pain levels, a trial testing the efficacy and safety of a new drug in patients undergoing joint replacement surgery generally does not allow nerve blocks for pain management, which contradicts the standard of care at most U.S.-based hospitals. In turn, this can make the approval of clinical trial protocol through the institutional review board more difficult and patient recruitment challenging.
Given the changing landscape of joint replacement surgery, many biopharma companies are now electing to use bunionectomy surgery as the orthopedic model in their pivotal Phase 3 programs. Bunionectomy surgery is known to be an acutely uncomfortable procedure, with pain that can be consistent for three to five days following the surgery. A significant benefit that is characteristic of bunionectomy models is the ability to efficiently enroll trials, which can lead to fewer trial sites, investigators and support staff and, therefore, more control and oversight at trial sites as well as an increased familiarity with the study protocol. As such, bunionectomy trials, when reasonably sized, can demonstrate a consistently accurate treatment effect of a new therapy. Data demonstrated in bunionectomy trials have provided the basis for FDA approval of several postoperative pain drugs, including Exparel (Pacira Pharmaceuticals).
Controlling variables in soft tissue models
In soft tissue surgery, open or laparoscopic abdominal surgery or pelvic surgery have been the historical standard for clinical study. However, the failure rate for these surgeries is high, due to the variability of the procedure and patients’ recovery process in postsurgical settings. Moreover, many failed trials are not published, making it difficult to ascertain an accurate failure rate. As a result, more recently, biopharma companies have opted instead to use hemorrhoidectomy, hernia repair or abdominoplasty as their soft tissue models in pivotal trials.
Based on predicted pain levels following these models, abdominoplasty surgery, or “tummy tuck,” offers the consistency desirable for a pivotal Phase 3 trial. Like bunionectomy surgery, abdominoplasty patients can be rapidly recruited into trials, and surgical techniques and study procedures can be mandated at the research site, as the sponsor pays for the procedure. Abdominoplasty trials typically require a small support staff, which can make training on study protocol more efficient. Unlike hernia repair models, where the majority of patients are male, most abdominoplasty patients are expected to be female. In general, an effective drug should demonstrate efficacy in both genders. Likewise, the FDA prefers that new therapies be studied in both genders prior to granting approval. Therefore, a sponsor must consider this issue before choosing a soft tissue model.
Incorporating an active comparator
While an active comparator arm is not required for FDA approval, it has been recommended, as demonstrated in a recent FDA Anesthetic and Analgesic Drug Products Advisory Committee meeting on Exparel. An active comparator arm provides assay sensitivity on efficacy because it is generally a standard-of-care therapy approved in the same setting, and context for interpreting a drug candidate’s tolerability and potential for adverse side effects. Moreover, if the drug candidate fails to demonstrate efficacy versus placebo, the active comparator arm can provide valuable insight into the outcome of the trial. For example, if both the drug candidate and the active comparator do not separate from placebo, it indicates that the trial has failed to provide useful information and it will not be possible to tell if the drug candidate is effective. On the other hand, if the active comparator demonstrates efficacy versus placebo and the drug candidate does not, the interpretation may be that the study was successful but the drug candidate was not effective. Importantly, the addition of an active comparator can also help position a drug candidate in the competitive landscape of available treatments.
Challenges ahead
While the selection of appropriate trial models and an active comparator arm are critical pieces in designing meaningful acute pain trials, biopharma companies still face the challenge of translating clinical data generated for regulatory approval into reliable, real-world situations that are relevant in broad medical practice. For example, orthopedic surgeons are interested in how a new drug performs in patients undergoing joint replacement surgery, while general surgeons may be more concerned with the effectiveness of a therapy in treating pain from bowel surgery. Emergency room physicians want to understand how a new drug performs in their patient population, as the acute pain patients they treat may be different from those in postsurgical settings. In addition, pharmacy directors responsible for establishing formularies within hospital networks must establish a rationale for putting a costly new drug on the formulary when there is an available generic medication. Many physicians are not convinced that placebo is a fair comparator in acute pain trials, but rather favor the positioning of a drug candidate against a therapy currently used in practice. It is important that these concerns are addressed in post-marketing studies.
Lucy Lu, M.D., is president and CEO of Avenue Therapeutics Inc.
