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Acorda's Novel Primary Endpoint For Ampyra Was Made Possible By A Supporting Scaffolding Of Secondary Analyses

This article was originally published in Pharmaceutical Approvals Monthly

Executive Summary

Secondary analyses in the pivotal trials of Acorda’s Ampyra (dalfampridine) were of front-line interest to FDA as the agency grappled with the first indication for improving walking ability in multiple sclerosis patients and an untested primary endpoint.

Secondary analyses in the pivotal trials of Acorda's Ampyra (dalfampridine) were of front-line interest to FDA as the agency grappled with the first indication for improving walking ability in multiple sclerosis patients and an untested primary endpoint.

"The claim sought for dalfampridine is a novel one for multiple sclerosis," Office of Drug Evaluation I Director Robert Temple wrote in a decision memo signed Jan. 22, 2010, the day of the approval. "Past MS claims have been primarily reductions in exacerbations and, in some cases, decreased disability."

Because improvement of walking ability was untried as a basis of approval in MS, Acorda's primary efficacy endpoint could not be as simple as finding shorter walk times for dalfampridine-treated patients.

FDA required that any difference in walk times must be not only statistically significant, but also clinically meaningful - a measurement that was difficult to quantify for a novel area of treatment.

For its part, Acorda added another layer of complexity with its unusual choice to analyze the primary outcome measure based on responder analysis of the 25-foot Timed Walk Test.

But FDA's openness to validating the novel primary endpoint using the internal data from the NDA package - and suggestions of efficacy from the secondary endpoints - eased the way past the obstacle of the first-of-its-kind primary efficacy measure (see chart: "1 How To Validate A Novel Primary Endpoint: Ampyra's Lineup Of Pivotal Trial Endpoints & Analyses' ).

Novel And Nonobvious

Though it was ultimately accepted, Acorda's walking endpoint was not what FDA had in mind. The primary endpoint in Ampyra's Phase III trials "is plainly not the most obvious measure of improved walking speed," Temple observed in his memo.

"Average walking speed in the drug and placebo groups or increase from baseline on drug vs. increase on placebo would be more typical," he commented. Acorda did use a variety of secondary analyses to look at those more typical endpoints.

Less than typical was Acorda's approach to analyzing the Phase III walk time data, which Temple referred to as "a somewhat different and unusual approach ... to address the meaningfulness of the endpoint." The final protocol required a three-component sequential analysis of the timed walk test data to validate and confirm walking speed as a meaningful outcome.

"In order to determine if the difference in proportion of responders on this novel endpoint measured a clinically meaningful outcome, the protocol also required that responders had to have done significantly better on the MSWS-12 score," Division of Neurology Products Director Russell Katz explained in a Jan. 18, 2010, decision memo. The MSWS-12, or Multiple Sclerosis Walking Scale, is an already existing patient-reported outcome instrument that asks patients to rate their recent level of disability.

The assessment of MSWS-12 results to see if responders had significantly more improvement than non-responders "was considered a requirement for a successful study," Temple said. "That is, it was almost a study endpoint." He admitted being "somewhat troubled" by the use of the MSWS-12 results, but said that "it may deserve more thought."

"Although this assessment does indeed appear to add to the 'plausibility' of the meaningfulness of the 25 [foot] walking responder analysis, it is not really a study endpoint, as there is no drug vs. placebo comparison," Temple explained. "What it does show is that walking time results correlate with MSWS-12 results."

The third step in the sequential analysis was "to assure that any treatment effect was not waning over time," Katz's memo explains. "Responders would still have to show a significant improvement in walking speed at the last double-blind visit."

"Typical" endpoints like measurements of leg strength and spasticity were used to build an analytic structure that supported and validated the clinical meaningfulness of the primary endpoint. Secondary outcome measures also served as additional support in the validation of the responder criteria.

Novelty Is No Guarantee Of Meaningfulness

"There was considerable discussion of the meaningfulness of the study endpoint," Temple reported. There was also some disagreement. The primary clinical reviewer, Kachikwu Illoh, urged a "complete response" letter instead of the first-cycle approval dalfampridine received.

The reviewer's concerns hinged on the novelty of the primary endpoint. Illoh's Dec. 10, 2009 review states that "Problems exist with the use of the sponsor's primary endpoint. It has not been frequently used as a primary endpoint in MS clinical trials of other drugs."

"In general, useful endpoints in trials include a clinically significant measure of quality of life or disability reduction," Illoh observed. "In MS patients, it is not clear what degree of improvement in walking speed improves walking ability or quality of life."

The "primary endpoint ... is a response (or intermediate) variable," Illoh said, rather than a direct assessment of a clinically significant measure. Further, Illoh noted that in the primary analysis. "statistical significance can be achieved without clear clinical significance."

"The responder variable ignores the importance of the extent of improvement in walking speed," Illoh said. That meant that a small benefit in a relatively large number of patients on the active drug "will result in a positive trial, even when the benefit is not clinically significant or meaningful for the patient."

Illoh agreed that the MSWS-12 analysis of the primary endpoint data "suggested the responders had greater improvements in their ability to walk, run and climb." But the clinical reviewer was troubled by a magnitude of improvement "so small that the walking speed in that [dalfampridine] group is not significantly different from that of placebo."

"Dr. Illoh was not convinced that this effect represented a clinically meaningful effect, and indeed speed differences were numerically small," Temple said. Indeed, FDA brought the question of the meaningfulness of the effect to the Peripheral and Central Nervous System Advisory Committee for interpretation by experts in the field. Led by the MS practitioners on the panel, the committee determined, on an overwhelming 12-1 vote, that dalfampridine was effective at improving mobility and voted 10-2 (with 1 absention) that the drug could be used safely (2 (Also see "Acorda's Risks With Fampridine Development Look Likely To Pay Off" - Pink Sheet, 26 Oct, 2009.)).

CDER topsiders ultimately concurred with the advisory committee. Temple, Division Director Russell Katz and Cross Disciplinary Team Leader Eric Bastings all disagreed with Illoh's recommendation of a "complete response" action in favor of approval with a Risk Evaluation and Management Strategy and required post-marketing trials.

The Level Of Difference Made The Difference

The responder rate findings were a key element in FDA's decision that the dalfampridine trials had sufficient clinically meaningful findings for approval. Unlike the speed differences, "the responder rate difference was not small (35-43 percent vs 8-9 percent)," Temple stressed.

"In some ways a more clearly impressive result ... is shown in the analysis of the cumulative distribution of results shown in labeling," Temple added. He highlighted an analysis by team leader Bastings showing that "significantly more patients given dalfampridine had a 30 percent increase in walking speed (about 15-20 percent vs about 3 percent on placebo)."

"That is a minority of patients, of course, but it would seem to be an obvious benefit," Temple stated.

Furthermore, Temple said, "the sponsor did show that the MSWS-12 response, an unequivocally clinical measure, was greater in people who were 25-foot walk responders and also showed an effect on the MSWS-12 in direct comparison."

Responder Analysis Drew Cool Response

While Acorda's gamble on using a primary endpoint based on responder analysis was ultimately successful, the idea's reception at FDA suggests that a responder analysis-based strategy is not a good bet - especially in a less debilitating disease or a condition with less unmet medical need than MS.

FDA was decidedly cool to the idea of applying a responder definition to the already novel use of walking as a primary endpoint in MS.

"The division had no precedent for use of such a responder definition," Bastings observed. The trials defined a responder as a patient who had a faster walking speed for at least 3 visits in the double-blind treatment period (visits 3 to 6) as compared to the patient's maximum speed for any of the four pre-treatment visits.

"One of the major problems of the responder analysis is the inability to predict response before treatment," Illoh declared. "If this were possible, a trial in such a population will help determine the real benefits of fampridine treatment."

"The sponsor showed that the fampridine-responders performed better on the secondary outcome variables," Illoh said, "yet comparison of the overall treatment groups irrespective of responder status showed no remarkable benefits for fampridine."

Illoh preferred "a different approach" toward the pooled analyses of the Phase III trials: without differentiation by responder status.

The sponsor's analysis relied on comparing three groups - fampridine responders, non-responders and placebo. However, "since the responders were not identified a priori, such responder groups based on the results of the trials are prone to having related variables trend in the same manner. Such a bias can limit the usefulness of the results of the different variable," Illoh noted.

Temple highlighted the potential, based on previous clinicians' observations, for a subset of MS patients to have a pathology favorable to dalfampridine's effect on potassium channels - a setting conducive to responder analyses. "Responder analyses may be particularly useful where response is confined to a subset," Temple explained.

That's a topic Temple has returned to at recent events. During a March 2 meeting on clinical trials for pulmonary hypertension, Temple discussed how the distribution of positive results for individual patients can be helpful in discerning a drug's effect, especially when there isn't a mean benefit across the population - such as when there is a small subset of patients who have a strong response. He pointed to Ampyra as an example where the distribution of results supported efficacy in the absence of an average benefit (3 (Also see "FDA's Temple Discusses Measuring Efficacy When Mean Effect Is Limited" - Pink Sheet, 1 Mar, 2010.)).

Agency Seeks Outcomes With "Evident" Meaning

Acorda adjusted its analysis plan to add the responder criteria after extensive examination of Phase II data, which identified a distribution of strong responses in certain patients.

It was FDA's willingness to consider the unique methods to assess Amypra's efficacy - and the sponsor's creative adjustments of the analysis plan - that allowed them to appreciate the drug's effect.

Going into the Ampyra review, the responder endpoint was not FDA's preferred option.

During a Dec. 20, 2004, teleconference regarding Acorda's proposed Phase III protocol using responder analysis, Katz described what FDA was looking for in a primary endpoint. "The Division wants the definition of an outcome to be such that when it is positive, the meaning will be evident," he told the sponsor. "What the division would like to see is a prospectively designated global measure and a measure of walking, and would expect a 'win' on both," Katz explained, according to meeting minutes.

"One approach could be to identify those patients who are responders, then look at the global measure in these patients," Katz advised. The meeting minutes observe that "ideally, his preference is defining a responder on the basis of both measures, but he acknowledged that this definition of response would be somewhat arbitrary."

"The Division is willing to consider a responder criterion for a pivotal trial based on walking speed, plus a global measure, used as a two-prong definition," Katz concluded. "No specific magnitude of change would be required, only that the global measure be statistically significant in a positive direction."

Acorda had proposed change from baseline in walking speed on the Timed 25 Foot Walk as the primary endpoint in Phase III during an August 2004 end-of-Phase II meeting, and then returned to FDA with a proposal to add a responder criterion for the endpoint based on new post hoc analyses of its Phase II data. The company's post hoc analyses "suggested that patients who met a responder criteria for a consistent response ... experienced a >25 percent average increase in walking speed," Bastings explained.

Acorda then added the concept of sequential analysis of the primary endpoint data in response to FDA's concerns about the clinical meaningfulness of the walk test responder endpoint. In its first Special Protocol Assessment request for the pivotal program, submitted March 2005, Acorda "addressed some of [the] FDA concerns with the responder criterion" with the second step of the proposed three-part sequential analysis, a comparison of responders and non-responders on MSWS-12, "to validate the clinical meaningfulness of the responder criterion," Bastings reported.

FDA Is Convinced - But Indication Is Limited

Fortunately for Acorda, the combination of the walk test responder analysis, validated by the MSWS-12 data and buttressed by the multiple secondary analyses, convinced CDER decision-makers that Ampyra had a place in the MS armamentarium - even though, as Katz observed, "changes were small, on average."

Katz' decision to break with clinical reviewer Illoh on the question of Ampyra approval boiled down to whether the clinical meaningfulness of the small changes had been supported. Illoh "is unconvinced about the clinical meaning of the changes seen on the primary study outcomes," Katz stated. But the division director added, "I believe that the sponsor has provided evidence that the changes seen were clinically meaningful."

Though Katz acknowledged the mean absolute increase in walking speed was small, "ancillary evidence suggests that these changes were useful to the patients, including changes in the MSWS-12 (as evidenced by large differences between responders and non-responders, and nominally significant, or near-significant differences between fampridine and placebo responders ...), LEMMT, and Ashworth scores," other objective secondary analyses.

Illustrating how FDA tries to take into account a wide range of analyses and explanations, Katz continued: "Further, an examination of the percent of patients with various percentages of improvement (compared to baseline) on walking speeds show significant differences between dalfampridine and placebo patients for differences up to 30 percent change from baseline."

But while open to considering a range of analyses, Katz also shows that FDA is strict in how indications can be worded, based directly on the primary endpoints. Ampyra is approved "to improve walking, as demonstrated in walking speed, in individuals with multiple sclerosis."

Acorda had sought a broader claim "to indicate dalfampridine to improve walking generally," Katz reported. "Exactly what aspect of walking has been shown to have been improved, however, is not entirely obvious," he stated.

Indeed, at an Oct. 27, 2008, pre-NDA meeting, Acorda had set forth an even more expansive indication for "treatment of walking disability in people with multiple sclerosis to improve mobility and leg strength and related activities of daily living," Bastings reported.

FDA reminded Acorda of one of the agency's most fundamental stands, Bastings recalled: "Any claim must be supported by independent substantiation of an effect on a relevant and vital endpoint."

- Bridget Silverman ( 4 [email protected] )

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