Table 2 –

Comparison of Select Regulator Preferences Based on Precedent-Setting Late Phase Development Programs and Key Considerations to Ensure Successful Future Development Programs as CFTR Modulator Therapy is More Broadly Transitioned into SOC

Past and Current Regulatory Pathways							Future Pathways
	Preferred Pivotal Trial Design1				Label Expansion Approach		Key Considerations to Ensure Success for Future Global Development Programs within the Context of Standard of Care Modulator Therapy
	Comparator & Hypothesis	Blinding	Primary Endpoint	Duration	Pediatric Development	Novel Approval mechanisms
CFTR Modulator Therapies
EMA	Placebo-controlled; Superiority Hypothesis	Blinded	Difference in ppFEV1change	6 months	Placebo controlled study required; Difference in LCI change from baseline primary efficacy endpoint	No current precedent	Feasibility and, if applicable, duration of future placebo-controlled trials once SOC modulator therapy is established must be determined and accepted by regulators. Design will be based on contemporary and ongoing evidence both from survey efforts to assess the willingness of individuals with CF to withdraw from modulator therapy and from safety data from ongoing trials including periods of withdrawal of modulator therapy. Open-label, prescription-based active- comparator trials may be a necessary component for establishing the efficacy of new modulators once SOC modulator therapy is established. Non-inferiority margins in this context must be carefully considered in relation to total clinical benefit rather than simply comparability to the active comparator. Use of historical controls from reliable data sources may become a necessary augmentation to future development plans to bolster efficacy data in the absence of longer-term placebo-controlled trials. Sufficiency of a robust ppFEV1 response supported by clear MOA will be a necessary path to fulfill efficacy criteria as currently defined PEx endpoints will be difficult to assess in populations receiving CFTR modulator therapy associated with substantial clinical benefit due to lower event rates and resulting increased sample size requirements. A streamlined pathway for label expansion for rare mutations including the use of in vitro data will be essential for ensuring access for all who will benefit.
FDA	Placebo-controlled; Superiority Hypothesis	Blinded	Difference in ppFEV1 change from baseline (insufficient if lacking a robust response, which may lead to request for PEx efficacy endpoint)	28 days to 6 months	Safety but not efficacy required for pediatric approval	Approval for rare mutations based on in vitro data contingent on prior regulatory approval for other populations for which clear efficacy and safety demonstrated
Anti-Infective Therapies for Chronic Airway Infection
EMA	Standard of Care Active- Comparator; Non-inferiority hypothesis	Open Label	Difference in ppFEV1 change from baseline	6 months	PIP required including establishment of efficacy in pediatrics	NA	Increased efforts to establish meaningful non-inferiority margins using contemporary data and decreasing the risk of bio-creep (ineffectiveness of the SOC active comparator over time) will be essential for broader acceptance of active- comparator designs across global regulatory agencies. Monitoring for a reduction in the prevalence of chronic anti-infective use across the growing population on CFTR modulators will be important to evaluate the feasibility of placebo-controlled trials across the globe. Acceptance of short-term placebo- controlled pivotal trials (approx. 1 month) demonstrating robust efficacy and MOA represents an essential opportunity to advance new chronic anti-infectives in populations unable to withhold chronic inhaled antibiotics for longer durations for a placebo-control. Sufficiency of a robust clinically meaningful ppFEV1 response supported by clear MOA may be a necessary path to fulfill efficacy criteria as currently defined PEx endpoints will be difficult to assess in populations receiving CFTR modulator therapy associated with substantial clinical benefit due to lower event rates and resulting increased sample size requirements.
FDA	Placebo-controlled; Superiority Hypothesis	Blinded	Time to PEx or need for antibiotics, Difference in ppFEV1 change from baseline alone not generally sufficient	3–6 months (ppFEV1 change endpoint may be measured earlier)	Safety but not efficacy data required for pediatric approval	NA
Anti-Inflammatory Therapies2
EMA	Placebo-controlled;Superiority Hypothesis	Blinded	PEx rate (PEx using a standardized definition)	6 months-1 year	Unknown	NA	A critical understanding of the changing symptomatology of PEx in the presence of CFTR modulators will be necessary to define relevant and clinically meaningful respiratory events coinciding with clinical worsening to serve as sensitive endpoints for these trials, as currently defined PEx endpoints may be diminishing in populations receiving CFTR modulator therapy associated with substantial clinical benefit (resulting in unfeasible sample size requirements for trials using PEx as an endpoint).
FDA	Placebo-controlled; Superiority Hypothesis	Blinded	PEx rate (PEx using a standardized definition)	6 months-1 year	Unknown	NA

¹Pivotal trials for initial indication or CF patient population.

²No regulatory approved anti-inflammatory therapies, extrapolated based on current phase 2b trial designs.

FDA: Food and Drug Administration, EMA: European Medical Agency; NA, not applicable; ppFEV₁, percent predicted forced expiratory volume in 1 sec; Abx, antibiotic;; LCI, lung clearance index; MOA, mechanism of action; SOC, standard of care; PEx, pulmonary exacerbation; PIP, pediatric investigation plan