Unknowns That Can Make or Break a Non-Opioid Analgesic Clinical Trial

Commentary
Article

New and renewed approaches to improve chances of success in developing non-addictive drugs for chronic pain.

Image credit: Feng Yu | stock.adobe.com

Image credit: Feng Yu | stock.adobe.com

Many pitfalls are associated with clinical trials of pain therapeutics, accounting for disappointing study results over the past decade. The root cause of these challenges is that there are only a limited number of models for pain, and the ones that do exist have significant limitations.

Based on a presentation at the Pain Therapeutics Summit (San Diego, CA; October 19-20, 2023), this article examines ways to improve pain clinical trials. The summit’s theme was “Identifying and Advancing Novel Pain Drugs Through Preclinical, Clinical Development and Commercialization.”

Pain remains a significant problem for millions of people around the world, with a recent study revealing that 20.9% of American adults (51.6 million individuals) experience chronic pain and 6.9% (17.1 million) have high-impact chronic pain.1 Yet there is a continued shortage of new therapies.2 Excluding migraines, no novel targeting, non-addictive drugs for chronic pain have been approved in the past five years.3

The pain drug pipeline is declining, with the number of active clinical drug programs in this area falling by 44% from 220 in 2017 to 124 in early 2023, according to a February 2023 analysis from the industry group, BIO.4 The analysis also found that only 0.7% of new pain drugs progress from Phase I clinical trials to FDA approval, compared to an average success rate of 6.5% for new drugs across all therapeutic areas.5

Pain Models: An Analysis

Considerations for models used in pain clinical trials involve the following: acute vs. chronic pain, and spontaneous pain models vs. postoperative pain models and their challenges; the evolution of regulatory requirements; and the features of recruited vs. shared-cost clinical studies.

Acute vs. chronic: spontaneous acute pain models

A challenge related to spontaneous pain models—such as sprains, strains, fractures, and headaches—is that their occurrence is unpredictable, and they are typically treated in urgent care facilities rather than at dedicated research centers. In addition, there is significant interpatient variability in the intensity, duration, and quality of pain.

Solutions to these challenges can be provided by acute postoperative pain models, such as third molar excision (the Dental Impaction Pain Model [DIPM]), bunionectomy, open inguinal hernia repair and abdominoplasty. Advantages of these postoperative pain models include:

  • Well-developed approaches to patient recruitment
  • Standardized surgery and anesthesia protocols
  • Standardized recovery environmental conditions
  • Verifiable baseline pain intensity thresholds
  • Accepted and validated outcome measures
  • Documented assay sensitivity with prototype drugs
  • Performed in dedicated research centers
  • Routine acceptance by FDA
  • Act as effective surrogates for other pain states

Challenges with current models include data integrity problems, recruitment issues, site multiplication, and unanticipated adverse events (AEs).

Evolving regulations: “Somatic and visceral” have evolved to “hard and soft tissue”

Past FDA guidance surrounding analgesic research required positive clinical trials in both somatic and visceral pain models. Somatic pain is defined as involving skin, bone, muscles, and soft tissues, with visceral pain affecting internal organs or blood vessels.

Visceral pain indications, in particular those involving the internal organs, have high variability and are hard to enroll. This is recognized in more recent guidance, including draft FDA guidance on Development of Non-Opioid Analgesics for Acute Pain, published in February 2022 (Sidebar 1).6

Sidebar 1

FDA 2022 draft guidance on Development of Non-Opioid Analgesics for Acute Pain7

  • A general acute pain indication would reflect the expectation that the product will be effective for most types of acute pain.
  • It is generally not feasible to study all possible populations that fall within a general acute pain indication.
  • Products with well-established analgesic mechanisms of action may be able to obtain a general acute pain indication when supported by at least two clinical trials, each in a different pain population.
  • For example, a novel nonsteroidal anti-inflammatory drug with two successful clinical trials in postoperative pain—one following bunionectomy and one following herniorrhaphy—may be suitable for a general acute pain indication.

This confirmed that the requirement for somatic and visceral models has evolved to one for hard (bone) and soft tissue models, both of which represent somatic pain.

Problems with bunionectomy

Challenges experienced with the bunionectomy model include the fact that study participants are increasingly hard to enroll, with high no-show and screen failure rates, unfavorable male-to-female ratio (patients are almost all female), and a tendency for multiplication of study sites.

Common to most bunionectomy clinical trials is the popliteal block—a peripheral nerve block utilized to defer initiation of efficacy assessments to postoperative day one. In addition to increased costs associated with an additional day of inpatient confinement, changes in the local anesthetic used for clinical trials have resulted in increased variability and decreased effect size. Creative attention to protocol design can mitigate these challenges.

Problems with inguinal hernia repair

The inguinal hernia repair model is also increasingly hard to enroll, with an unfavorable male-to-female ratio (the majority of patients are male), and a likelihood of multiplication of study sites.

Problems with abdominoplasty

Although abdominoplasty is comparatively easier to enroll—effectively countering increased per-subject costs by eliminating the need for advertising—this model has multiple downsides. These include: higher rates of serious AEs including the competing complication risks of postoperative hemorrhage and deep vein thrombosis/pulmonary embolism and their potential for hidden costs for sponsors; unfavorable male-to-female ratio (with patients being almost all women); and higher intraoperative anesthesia requirements than other indications, potentially confounding efficacy data. These disadvantages can be mitigated by selective recruitment, for example, based on body mass index, and by carefully balancing DVT prophylaxis and hemostasis.

For all models, placebo response can depend on expectations and conditioning, staff and subject training, and differences between healthcare and research settings. Mitigations include standardization and limiting the number of sites to the extent possible. An analysis of opioid trials (Sidebar 2) indicated that a larger number of sites is associated with a lower treatment effect size.

Sidebar 2

Larger number of sites linked to smaller effect size

“In summary, this analysis of opioid clinical trials suggests that the greater the number of sites, the smaller the observed effect size of treatment. This means that more subjects overall, and per site, need to be added to preserve power as the number of sites increases. Sample size calculations from smaller Phase 2 studies may seriously underestimate sample size requirements for larger Phase 3 studies…”

Meske, Vaughn, Kopecky & Katz (2019)8

Considerations for site selection

The two main types of sites—hospitals or surgery centers that do some research as a side activity, and dedicated research sites with surgical capabilities—have various advantages and disadvantages. Hospitals or surgery centers may face regulatory hurdles due to rotating personnel (which can make training and regulatory compliance difficult) and the use of local institutional review boards (IRBs) and Ethics Committees.

The primary focus and profit motive of these centers drive volume and efficiency, with a goal of early discharge. Meeting surgeons’ expectations and gaining their buy-in for study protocols can be challenging. In addition, ancillary providers often have a limited understanding of research and the importance of following protocol requirements closely.

Considerations for multi-site studies using patient care-first facilities include data quality, based on experience and focus; cost (start-up, maintenance, close-out); and regulatory burden, including the need for training, delegation, audits, and medical monitoring.

Standing in contrast, patient care-first facilities are dedicated research facilities capable of providing surgical services in fully accredited on-site surgery centers. These sites typically focus solely on research, thus avoiding many of the regulatory and quality hurdles faced by other sites.

Recruited vs. shared cost models

With recruited clinical trials, the sponsor pays all costs, and has full control over the study. A shared model includes elements that are billed to the participant’s health insurance, reducing sponsor costs.

However, the shared model involves a lack of flexibility around: the duration of the study participant’s stay; the need to deal with insurance company practice mandates that may be incompatible with the protocol; potential enrollment challenges; and the fact that the site may not be linked to the patient’s insurance company. In addition, patients may have high-deductible plans and the insurance company may have a pre-approval process.

Although sharing the costs of surgical care with insurance companies may sound advantageous, delays in enrollment due to the challenges described above can actually make the shared cost model more expensive for sponsors in the long run. Overall, the best value is gained from a recruited model. In addition, generous subject and surgeon stipends and a sufficient advertising budget can speed enrollment significantly and save sponsors money in the end.

Other key elements in the site selection process include the need for the sponsor to be closely involved in this process, assessing each site’s expertise and experience, and reviewing site data on factors such as:

  • Placebo response mitigation
  • Quality metrics (i.e., protocol deviations)
  • Enrollment rates
  • Data surveillance procedures
  • Subject and staff training
  • Peer-review publications by site staff, indicating high-quality data

Don’t Forget The DIPM

The DIPM has historically been the most relied upon acute postoperative pain (APOP) model and is by far the most sensitive acute pain model available. The male-to-female ratio among patients is generally balanced, and the patient population is typically extremely healthy. These are mostly pain-naïve subjects.

Anesthetic effects tend to be minimal, with a significantly lower per-subject cost than other models. Single site enrollment is usually possible, leading to decreased variability. Enrollment is typically 10 times faster than for the bunionectomy or hernia repair models, an important factor because longer enrollment times often lead to reduced study success. (Sidebar 3).

Sidebar 3

Key attributes of the DIPM

The main attributes of the DIPM are as follows:

  • Consistent and very low placebo response (<20%).
  • Substantial upside assay sensitivity, separating control drugs from placebo in 100% of studies and being sensitive to dose-ranging for experimental drugs.
  • Enrollment rate approximately 10X faster than bunionectomy or hernia repair.
  • Relatively lower per subject cost to execute.
  • Can use a single clinical research site.

In addition, the DIPM has an effect size significantly larger than models using surgery for bunions, joint replacement, or soft tissue. The DIPM has several positive implications for study costs. Decreased costs result from: the higher effect size seen with the DIPM, which allows a smaller sample size to be used; the lower per-subject costs; the more rapid enrollment rate, which shortens study duration; and the need for fewer sites, lowering regulatory and oversight burden.

Historically DIPM had been used as an important model in the early Phase II studies for pain therapies. However, recent agency draft guidance has led to sponsors instead using bunionectomy, hernia, or abdominoplasty models—all of which involve relatively high costs and high risks.

Conclusion

Acute pain research is unique, nuanced, and laden with pitfalls. Improvements are needed in study design and in regulatory guidance. Pain clinical trial failures of the past might have been avoided with closer attention to pain model choice and protocol design.

Sponsors should carefully consider the pros and cons of various acute pain models, including costs, and work with regulators to advance the development of much needed nonopioid analgesics. Looking ahead, sponsors might be well served by a renewed emphasis of the DIPM in their studies—with its superior sensitivity, favorable male/female ratio among patients, faster enrollment, lower costs, and ability to be carried out at a single site.

About the Author

Todd M Bertoch, MD, Principal Investigator & CEO, CenExel JBR.

References

1.https://www.cdc.gov/mmwr/volumes/72/wr/mm7215a1.htm#:~:text=During%202021%2C%20an%20estimated%2020.9,Hispanic%20American%20Indian%20or%20Alaska

2. https://www.clinicaltrialsarena.com/features/pain-clinical-trials/?cf-view

3. https://www.bio.org/press-release/new-bio-analysis-reveals-declining-pain-drug-pipeline-and-underinvestment-new

4. https://www.bio.org/press-release/new-bio-analysis-reveals-declining-pain-drug-pipeline-and-underinvestment-new

5. https://go.bio.org/rs/490-EHZ-999/images/BIO_The_State_of_Innovation_in_Pain_and_Addiction_2017_2022.pdf

6. FDA: Development of Non-Opioid Analgesics for Acute Pain: Draft Guidance for Industry, February 2022 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-non-opioid-analgesics-acute-pain-draft-guidance-industry

7. FDA: Development of Non-Opioid Analgesics for Acute Pain: Draft Guidance for Industry, February 2022 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-non-opioid-analgesics-acute-pain-draft-guidance-industry

8. Meske DS, Vaughn BJ, Kopecky EA, Katz N. Number Of Clinical Trial Study Sites Impacts Observed Treatment Effect Size: An Analysis Of Randomized Controlled Trials Of Opioids For Chronic Pain. J Pain Res. 2019 Nov 20;12:3161-3165. doi: 10.2147/JPR.S201751. PMID: 31819600; PMCID: PMC6875508.https://pubmed.ncbi.nlm.nih.gov/31819600/

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