Novel COPD Exercise Claims Eluded Boehringer In Bid to Differentiate Striverdi

Sponsor’s claimed impact on exercise tolerance was not adequately supported and should not serve as a marketing advantage for the chronic obstructive pulmonary disease drug, FDA review staff said. However, Boehringer Ingelheim’s failed attempt for the exercise-related labeling language spurred the agency to clarify the types of studies and endpoints that potentially could support such claims.

Boehringer Ingelheim GMBH failed to get the novel exercise tolerance claims it sought to distinguish Striverdi Respimat (olodaterol) in the crowded chronic obstructive pulmonary disease market. Nevertheless, the company’s attempt may have laid the groundwork for others and forced FDA’s hand to try to further elucidate the evidence needed to support such claims.

BI sought the inclusion of exercise endurance claims in the Clinical Trials section of labeling for olodaterol, its long-acting beta-adrenergic agonist for COPD. However, no other COPD treatment has these claims, and no sponsor had ever sought them in this therapeutic category.

The company found itself in the challenging position of trying to pursue a novel claim that lacked any precedent or final guidance document. However, BI may have compounded its difficulties by not first discussing with FDA the data likely needed to support such a claim.

Boehringer Ingelheim conducted two studies in support of the proposed exercise claims, but FDA called the results modest and questioned their clinical significance.

Relying upon a 2007 FDA draft guidance that envisioned the use of exercise capacity assessments as a potential endpoint in COPD drug trials, BI designed two studies in support of the proposed exercise claims. While the primary endpoint of increased exercise endurance time in both studies was met, FDA called the results modest and questioned their clinical significance.

Among the agency’s concerns were lack of an established minimum clinically important difference (MCID) for exercise endurance in COPD drug trials; there also was no demonstration of a relationship between the magnitude of effect seen with olodaterol and improvement in activities of daily living.

Furthermore, Striverdi may offer nothing different with regard to the exercise endurance measures used in the BI studies than other LABAs, agency reviewers said, suggesting the claimed impact on exercise improvement was not a unique benefit worthy of differentiation but rather a mere “marketing tool” sought by the sponsor.

Despite finding that BI fell short on the evidence needed to support the novel exercise claims, FDA did provide some unofficial guidance for future sponsors who may be considering this route.

Specifically, senior reviewers cited the need for a “clinical anchor” for exercise endpoints to demonstrate a meaningful benefit. Improvements in exercise capacity also should be demonstrated at various times of the day and in longer-term trials than those conducted by BI.

Coming Late To A Crowded Market

FDA approved the 5 mcg dose of olodaterol (two actuations of 2.5 mcg) for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema, on July 31 (Also see "Boehringer’s Striverdi Respimat Approved For COPD, But Without Exercise Claim" - Pink Sheet, 1 Aug, 2014.).

Approval came more than a year later than expected; the delay was solely the result of current Good Manufacturing Practice violations at Boehringer’s manufacturing facility in Germany.

The GMP issues led to an FDA “complete response” for olodaterol in March 2013; the BI facility was cited in a May 2013 warning letter (see timeline, (Also see "Striverdi Respimat Clinical Development" - Pink Sheet, 22 Jan, 2015.)).

Upon approval, Striverdi became part of a wave of new COPD drugs that have cleared the agency in the past three years.

The COPD market has long been dominated by two major players: GlaxoSmithKline PLC’s LABA/corticosteroid combination Advair (salmeterol/fluticasone) and BI/Pfizer Inc.’s long-acting muscarinic antagonist Spiriva (tiotropium).

Since 2011 there has been a slew of new COPD drugs approved. These include Novartis AG’s LABA Arcapta (indacaterol), Forest Laboratories Inc.’s (now Allergan PLC) phosphodiesterase inhibitor Daliresp (roflumilast) and LAMA Tudorza Pressair (aclidinium), and two new GSK combination products containing the LABA vilanterol – Breo Ellipta (with fluticasone) and Anoro Ellipta (with the LAMA umeclidinium).

Boehringer’s GMP woes meant that both of GSK’s Ellipta products got to market before Striverdi, despite arriving later in the regulatory queue (Also see "GSK’s Breo Ellipta Approved With COPD Airflow Obstruction, Exacerbation Claims" - Pink Sheet, 10 May, 2013.).

The increasingly crowded therapeutic category has made product differentiation based upon efficacy benefits, dosing schedule or safety advantages all the more important, particularly in the eyes of payers (Also see "COPD Market Snapshot: New Products, Limited Differentiation" - Pink Sheet, 6 May, 2013.).

While Striverdi’s approved indication is typical for COPD treatments, the exercise-related labeling statements sought by BI were not.

In addition to the standard COPD indication, BI initially sought claims for increased exercise tolerance, increased inspiratory capacity at rest and during exercise, and reduced lung hyperinflation based on decreased functional residual capacity, review team leader Theresa Michele reported in a Jan. 31, 2013 first-cycle review. The company also sought claims for improved quality of life as measured by the St. George’s Respiratory Questionnaire.

However, Michele said BI subsequently withdrew the claims for increased inspiratory capacity at rest, decreased functional residual capacity and the SGRQ in light of FDA comments in the 74-day letter confirming the NDA filing and the agency’s briefing document prepared for the Jan. 29, 2013 meeting of the Pulmonary-Allergy Drugs Advisory Committee on the olodaterol NDA.

In Pursuit Of A Novel Claim

In 2007, FDA issued draft guidance on COPD drug development that envisions the potential use of exercise capacity as an objective physiological assessment of efficacy. Yet, prior to the olodaterol application no sponsor had sought to incorporate exercise testing results as a labeling claim.

An exercise endurance benefit “would be a novel claim for COPD that has not been presented to, or considered by, the agency previously,” Office of Drug Evaluation II Director Curtis Rosebraugh said in a March 14, 2013 memo written during the first review cycle.

“Regulatory policy regarding the development pathway required for such claim is still evolving,” Michele noted.

Support for the exercise-related claims came from two randomized, double-blind, crossover trials. Studies 1222.37 and 1222.38 were conducted in a total of 300 patients with moderate-to-severe COPD. Three six-week treatment arms included placebo, olodaterol 5 mcg and 10 mcg. Between each treatment period there was a two-week washout.

“The primary endpoint was exercise endurance time during constant rate cycle ergometry to symptom limitation at 75% maximal work capacity after six weeks of treatment,” Michele explained. “Key secondary endpoints were inspiratory capacity at isotime (defined as the endurance time of constant work rate exercise of shortest duration) at 75% maximal work capacity and intensity of breathing discomfort” as measured by the Borg Category Ratio Scale at isotime.

In a briefing document prepared for the January 2013 advisory committee meeting, BI said it included the two studies in the Phase III program “to extend the relevance of olodaterol clinical efficacy by describing it in the context of improved exercise tolerance. Such an assessment is particularly relevant in COPD, because an improvement in FEV₁ should translate into improved exercise capacity when tested in an appropriate exercise setting.”

FEV₁, or forced expiratory volume in one second, is commonly used as an efficacy endpoint in COPD trials because it reflects the extent of airway obstruction.

At the advisory committee, Michele said that FDA offered no guidance to BI on the exercise trials or their design because the company never talked about them during meetings with agency staff (Also see "Boehringer’s Novel Exercise Claims In COPD May Spur FDA Action To Clarify Requirements" - Pink Sheet, 4 Feb, 2013.).

Given the novelty of the claims, “there are many questions regarding appropriate design of the trials and interpretation of results,” Michele said in her cross-discipline review (see related story, (Also see "Striverdi Exercise Trials Tried, But Failed, To Control For Non-Disease Impacts" - Pink Sheet, 22 Jan, 2015.)).

Improvements, But What Do They Mean?

While the two studies demonstrated statistically significant benefits, questions about the meaningfulness of these benefits troubled FDA.

“The results of the exercise trials show that olodaterol 5 mcg increased cycle ergometry exercise endurance time after six weeks of treatment from 42-52 seconds (12%-14%),” Michele said.

Olodaterol treatment also resulted in a statistically significant increase in inspiratory capacity at isotime compared with placebo. Olodaterol was associated with increased inspiratory capacity ranging from 84-182 mL over placebo after six weeks of treatment.

There was a decrease in functional residual capacity – an exploratory, secondary endpoint – compared to placebo for both treatment groups at one hour after dosing. However, this effect did not appear to be durable over the 24-hour dosing interval, clinical reviewer Robert Lim said in a Jan. 17, 2013 review. “As olodaterol is meant to be used as a daily maintenance COPD medication, transient non-durable effects may not be relevant,” he said.

Statistically significant differences for breathing discomfort as measured by the Borg Category Ratio Scale were reported in trial 1222.37 but not trial 1222.38, Lim said, adding, “this lack of replication implies that olodaterol does not improve breathing discomfort.”

In addition to the lack of replication across studies, Lim also raised questions about use of the Borg instrument, which is a 10-point scale that assesses the intensity of breathing discomfort.

“The scale was not specifically developed for use in clinical trials and its attributes in the longitudinal interventional setting have not been fully elucidated,” Lim said. “The lack of concordance between trials may indicate lack of efficacy with respect to this endpoint, or limitations of the instrument, or both. Regardless of the reason, given the lack of concordance between trials, this endpoint is not supportive of efficacy.”

While acknowledging that the two trials demonstrated a statistically significant benefit on exercise duration and inspiratory capacity, Michele said “it is unclear if this represents a true clinical benefit.”

For starters, FDA reviews point out that the MCID for exercise endurance in COPD drug trials is not known.

Michele’s memo references two studies that evaluated the effects of pulmonary rehabilitation. While these studies suggested that the MCID in this setting may be in the range of 101-153 seconds, “these results are not universally accepted or validated, and it is unclear if the results in pulmonary rehabilitation would also pertain to drug trials,” she said.

Notably, the 2007 draft guidance’s discussion of secondary endpoints states that for some efficacy measures, “the threshold that defines a clinically meaningful improvement may not be well defined for use in clinical studies that test new drugs. Having such a benchmark of effect would be important in interpreting the meaning of differences shown in the clinical trials. Therefore, the study protocol should define minimal clinically important difference with appropriate reasoning and justification.”

The MCID for inspiratory capacity also is unknown, Michele said.

Lim said the clinical significance of an 84-182 mL increase in inspiratory capacity is unclear, and he questioned whether “this effect would have been maintained for a longer duration over time or over the entire dosing interval.”

In addition to the lack of MCIDs, various reviews noted the timing of the testing used in the exercise trials was problematic, as was the duration of the studies themselves.

“Exercise testing was performed approximately two hours post-dose, which correspond to the time at which the bronchodilator effect of olodaterol has reached its peak,” Division of Pulmonary, Allergy and Rheumatology Director Badrul Chowdhury said in a March 13, 2013 first-cycle review memo. “It is not known if the benefit with olodaterol would persist later in the dosing period.”

Furthermore, studies lasting for just six weeks are not adequate to show sustainability of effect. “For comparison, studies to show bronchodilator efficacy are at least 12 weeks in duration, and studies to show exacerbation efficacy are six to 12 months in duration,” Chowdhury said.

ODE Director Scoffs At ‘Marketing Tool’

The reviewers also felt it is unlikely that olodaterol produces a pharmacological effect on exercise that other LABAs do not.

“The mechanism of action of olodaterol is the same as other beta-agonists used in COPD and one might predict the other agents to have the same effect,” Rosebraugh said.

“The effect of olodaterol in this regard is probably not unique compared to other LABAs, which may be seen as efforts to find a marketing tool instead of a unique benefit worthy of differentiation,” ODE II Director Rosebraugh said.

Rosebraugh was critical of how BI went about pursuing exercise-related claims for olodaterol, and he drew a line between a clinical claim and marketing benefit.

“It does seem that the sponsor is proposing a new, novel claim, without developing the supporting evidence of what should be expected as the criteria to support such an indication or with any idea if this is something novel for their product that really warrants identification in labeling,” Rosebraugh said.

“Also, the effect of olodaterol in this regard is probably not unique compared to other LABAs, which may be seen as efforts to find a marketing tool instead of a unique benefit worthy of differentiation. In any event, I do not feel they have demonstrated a unique and clinically important difference worthy of labeling.”

Evidentiary Requirements For An Exercise Claim

At the advisory committee meeting, panelists overwhelmingly endorsed olodaterol’s approval but were not asked to vote on exercise endurance because BI was not seeking an indication for this. However, they questioned the clinical meaningfulness of the exercise tolerability findings and whether the effects seen were actually due to the drug (Also see "Boehringer’s Novel Exercise Claims In COPD May Spur FDA Action To Clarify Requirements" - Pink Sheet, 4 Feb, 2013.).

“The committee observed that exercise tolerance is an important endpoint for patients, and many members expressed support for inclusion of exercise endpoints in pharmaceutical trials in COPD,” Chowdhury said. Panelists also said that more information is needed to understand the optimal design of exercise trials in COPD and the MCID of exercise endpoints, he noted.

Panelists suggested the agency convene a scientific meeting to discuss the issues (Also see "Boehringer’s Novel Exercise Claims In COPD May Spur FDA Action To Clarify Requirements" - Pink Sheet, 4 Feb, 2013.).

FDA has not announced plans for a scientific meeting or formal guidance on exercise-related claims in COPD trials. However, the Striverdi review did provide an opening for senior review division staff to lay out their view on a threshold level of evidence needed to support such labeling claims – at least in the context of the olodaterol application.

Chowdhury said that BI’s proposed wording for exercise claims in the Clinical Trials section of labeling is not supported by the submitted data.

Exercise endurance measures require a linkage with activities of daily living in COPD patients to support a labeling claim.

“To support such labeling claim, reasonable expectation would be that olodaterol treatment demonstrates a benefit in some exercise-related activity of daily living in COPD patients, or a benefit in exercise endurance test-based measures with effect sizes that cross accepted MCIDs,” Chowdhury said.

“In either scenario, the benefit will need to be demonstrated at various relevant time points of the day after dosing, and over at least six months of treatment. Lack of accepted MCIDs for exercise endurance test-based measures makes studies challenging. Development of MCIDs for such measure[s] will likely need linking the measures to some exercise-related activity of daily living in COPD patients.”

Michele said additional data demonstrating long-term benefit and benefit across the dosing interval will likely be necessary for a claim, “although this remains under discussion by the project team.”

“In addition, since the MCID for these endpoints is unknown, a clinical anchor associating the degree of benefit on exercise with some other clinically meaningful endpoint would also be helpful in interpretation,” she said.