Beyond the Blockbuster: The Strategic Flex of Niche & Orphan Drug Development

The Pivot Point: Why the Blockbuster Playbook Fails in Niche Markets

For decades, the blockbuster model defined pharmaceutical ambition: massive R&D bets aimed at conditions affecting tens of millions, supported by billion-dollar marketing engines designed to capture broad prescriber mindshare. This playbook, however, is increasingly strained by payer scrutiny, generic erosion, and crowded therapeutic landscapes. The strategic pivot to niche and orphan development isn't merely a retreat to smaller markets; it's a fundamental recalibration of the entire value chain. Success here demands a different kind of flexibility—what we might call strategic flex—where agility, precision, and deep stakeholder intimacy replace scale and brute-force promotion. Teams accustomed to the blockbuster rhythm often stumble not on the science, but on the operational and commercial shift required. This guide is for those ready to master that shift, moving from a volume-centric to a value-centric paradigm, where success is measured by impact and sustainability in carefully chosen, underserved spaces.

Recognizing the Inherent Friction in Model Transition

The first challenge is internal. Organizations built for blockbusters have muscle memory for large, parallel Phase III trials, massive sales forces, and messaging crafted for generalists. Applying this machinery to a niche indication is like using a satellite phone to call your neighbor—overpowered, inefficient, and tone-deaf. The friction appears in budgeting cycles that demand premature blockbuster-scale forecasts, in clinical operations teams that default to large CRO partnerships ill-suited for patient-finding in rare diseases, and in commercial leaders who instinctively plan for a 500-person sales team. Recognizing this institutional inertia is the first step toward building the necessary strategic flex.

Defining the New Success Metrics

In a niche strategy, traditional metrics like peak sales volume and market share percentage become less informative, even misleading. Success is better gauged by different indicators: depth of penetration within a defined, high-need patient population (e.g., >80% of diagnosed patients), speed to peak adoption (which can be faster due to concentrated prescriber bases), sustainability of price premium based on demonstrated value, and the strength of advocacy group partnerships. A product achieving $300 million in annual sales by reaching 90% of a 10,000-patient population is a monumental success, whereas the same revenue figure would be a failure in a broad primary care market. Teams must socialize these new metrics early to align internal expectations.

Building the Case for Strategic Reallocation

Justifying resource allocation for a niche program requires a different narrative. The business case hinges not on total addressable market size, but on the probability of technical and regulatory success (often higher with clear biomarkers and unmet need), the capital efficiency of smaller, focused trials, and the potential for durable pricing and market exclusivity. It's about return on investment, not absolute revenue. Framing the opportunity in terms of capital efficiency and risk-adjusted net present value helps secure buy-in from leadership still thinking in blockbuster terms. This re-framing is a core component of establishing strategic flex within the organization.

Ultimately, the pivot is a conscious trade-off: you exchange the lottery-ticket potential of a multi-billion dollar blockbuster for a portfolio of programs with higher predictability, better capital efficiency, and potentially more defensible commercial positions. It's a shift from hoping for a home run to consistently hitting doubles and triples, building a robust and resilient enterprise. This overview reflects widely shared professional practices as of April 2026; verify critical details against current official guidance where applicable.

De-risking the Hunt: A Framework for Identifying Viable Niche Opportunities

Selecting the right niche is not about finding the smallest disease; it's about finding the smartest intersection of unmet medical need, tractable science, and a viable ecosystem. A common mistake is to pursue a niche solely because it's "orphan" or has a tiny prevalence, without assessing the feasibility of development and commercialization. The goal is de-risked opportunity, not just novelty. This requires a multi-layered filtration process that goes beyond epidemiology reports. Teams must develop the flex to assess opportunities through clinical, regulatory, commercial, and patient-access lenses simultaneously, often with limited pre-existing data. The following framework provides a structured approach to separate truly viable niches from scientifically interesting but commercially perilous pursuits.

Layer 1: Clinical and Scientific Tractability

Begin with the foundational question: Can we develop a drug for this? This involves assessing the strength of the biological hypothesis, the availability of predictive preclinical models (which are often limited in rare diseases), and the feasibility of clinical trial design. Key considerations include: Is there a clear, measurable biomarker or clinical endpoint acceptable to regulators? Can you identify and recruit patients within a realistic timeline, given the geographic dispersion? Is the natural history of the disease sufficiently understood to design a trial? A niche with a well-defined genetic cause, a validated animal model, and a small number of expert treatment centers is inherently more tractable than one with heterogeneous presentation and no consensus endpoints.

Layer 2: Regulatory Pathway Clarity

The regulatory flex offered by orphan drug designation is a key advantage, but it's not automatic. You must map the specific pathway. Will the program qualify for breakthrough therapy or PRIME designation based on preliminary data? What is the precedent for accelerated approval based on surrogate endpoints in this disease? Engaging with regulators early through pre-IND meetings is critical, but that engagement must be informed. Teams should meticulously review relevant guidance documents and previous approval letters in analogous disease areas to understand the agency's current thinking and evidence expectations.

Layer 3: The Commercial and Access Ecosystem

This is where many technically sound programs falter. You must map the stakeholder ecosystem. Who are the 50-100 key opinion leaders globally? How organized and influential are the patient advocacy groups? What is the payer landscape—are there specialized managed care organizations or national health service pathways for ultra-rare diseases? Critically, you must model the value story early. What burden of illness can your drug address (hospitalizations, surgeries, caregiver time)? Building a robust health economics and outcomes research (HEOR) plan from Phase II is not optional; it's the core of your future pricing and reimbursement strategy.

Layer 4: Competitive Intelligence and White Space

Niche does not mean devoid of competition. You must analyze the pipeline meticulously. Are there other companies in Phase I/II with similar mechanisms? More importantly, what is the standard of care, even if supportive? Displacing an entrenched, albeit imperfect, standard of care requires a substantial efficacy or safety delta. Look for "white space" where there is clear patient need, some scientific validation, but where larger companies may be deterred by the market size, creating an opportunity for a focused player.

Applying this layered framework forces disciplined thinking. It turns an intuitive "this seems like a good area" into a scored, comparable assessment. In a typical project, a team might evaluate three potential niches using this framework, scoring each layer on a feasibility scale. The "winner" is often not the rarest disease, but the one with the clearest path to a pivotal trial, the most engaged patient community, and the most straightforward value demonstration to payers. This systematic approach is the bedrock of strategic flex in portfolio planning.

Designing for Efficiency: The Lean Development Playbook

Once a viable niche is identified, the development strategy must embody operational flex. The blockbuster model of large, lengthy, and expensive Phase III programs is antithetical to capital efficiency in niche markets. Instead, the playbook shifts to lean, adaptive, and highly focused development. This isn't about cutting corners; it's about intelligent design—removing waste, leveraging every data point, and building regulatory agreement on a streamlined path. The core principle is to "learn fast and confirm efficiently." This requires a mindset comfortable with smaller patient numbers, innovative trial designs, and deep collaboration with a concentrated community of investigators and patients. The goal is to generate the minimum sufficient evidence for approval and market access, maximizing return on development investment.

Adopting Adaptive and Basket Trial Designs

Traditional fixed-design trials can be prohibitively slow and large for rare populations. Adaptive designs allow for modifications (like sample size re-estimation or dose selection) based on interim data without compromising trial integrity. Basket trials, which test a single therapeutic agent across multiple disease subtypes defined by a common biomarker, are particularly powerful in oncology niches. These designs require sophisticated statistical planning and early regulator buy-in, but they can compress years of sequential development into a single, efficient protocol. They represent a high degree of methodological flex.

Leveraging Real-World Evidence and Natural History Studies

In diseases where randomized placebo-controlled trials are ethically or practically challenging, well-designed natural history studies become a critical tool. By meticulously documenting the course of the disease in an untreated or standard-of-care cohort, you can create an external control arm. When combined with prospective data from your treated patients, this can support regulatory submissions. Investing in such studies early, often in partnership with patient registries, builds invaluable infrastructure and demonstrates commitment to the community, while also de-risking the later regulatory conversation.

Implementing a Patient-Finding and Recruitment Engine

Recruitment is the single greatest operational risk in niche development. A lean playbook demands a proactive, technology-enabled approach. This goes beyond site selection; it involves digital outreach through advocacy groups, social media listening for patient conversations, genetic testing initiatives to identify undiagnosed individuals, and potentially direct-to-patient recruitment campaigns. Building a small, dedicated patient recruitment function, rather than outsourcing it entirely to a CRO's generic processes, is often a worthwhile investment that pays dividends in trial timelines.

Integrating Endpoint and Biomarker Development

In many niche areas, validated endpoints don't exist. Part of the development work may involve co-developing a novel endpoint with regulators and the patient community. This could be a novel digital wearable metric, a patient-reported outcome tool, or a novel imaging biomarker. Starting this dialogue in Phase I, and collecting data on the endpoint throughout development, is essential. It turns a potential roadblock into a strategic asset, as you help define the standard of measurement for the disease.

The lean development playbook is a symphony of these elements working in concert. One team we read about, developing a therapy for an ultra-rare metabolic disorder, combined a small natural history registry, a single-arm trial with an adaptive primary endpoint analysis, and an aggressive patient-finding campaign centered on a specific genetic diagnostic. This integrated approach allowed them to move from first-in-human to marketing authorization submission in under five years, a timeline unthinkable for a common disease. Their flex was in designing the trial around the constraints of the disease, rather than forcing the disease into a conventional trial template.

The Commercial Engine Reimagined: From Mass Promotion to Precision Engagement

If development requires operational flex, commercialization demands relational and strategic flex. The traditional mass-promotion model—deploying hundreds of sales representatives to detail tens of thousands of physicians—is not just overkill for a niche drug; it is actively destructive. It wastes capital and, more importantly, alienates the concentrated ecosystem of experts and patients who value specialized knowledge and partnership. The reimagined commercial engine is built on precision, education, and service. Its goal is not to create broad awareness, but to achieve deep adoption within a defined community by demonstrating unequivocal value and integrating seamlessly into the care pathway. This model flips the script: instead of selling, you are enabling.

Mapping the Micro-Ecosystem of Care

The first step is a granular stakeholder map. For a niche drug, the relevant universe may be 200 specialists globally, 50 key treatment centers, 20 payer medical directors specializing in rare disease, and a handful of influential patient advocacy groups. Commercial planning starts with understanding the specific challenges each stakeholder faces: the diagnostic odyssey for patients, the treatment logistics for clinic coordinators, the budget impact concerns for hospital administrators, and the evidence needs for payers. This map informs every subsequent activity, from medical science liaison (MSL) deployment to patient support program design.

The Central Role of Medical Affairs and MSLs

In niche commercialization, Medical Affairs often leads, with Commercial supporting. MSLs become the primary external face of the company, engaging key opinion leaders in peer-to-peer scientific dialogue long before launch. Their role is to educate on the disease mechanism, clinical data, and appropriate patient identification—not to promote. This builds scientific credibility and trust. The commercial team, often very small and highly specialized, then focuses on ensuring access, reimbursement, and supporting the practicalities of treatment initiation once the scientific value is established.

Building a High-Touch Patient Services Hub

For complex therapies, especially those requiring infusion or specialized monitoring, the patient support program (or "hub") is a critical component of the value proposition. A well-designed hub assists with benefits verification, prior authorization, co-pay assistance, nursing support, and drug shipment logistics. In niche markets, this service can be the difference between a script written and a script filled and administered. The hub must be seamless, responsive, and designed in consultation with patients and providers to address real-world barriers.

Constructing the Value Story and Payer Engagement

Payer negotiations for niche drugs are less about discounting and more about demonstrating holistic value. The dossier must go beyond clinical efficacy to include detailed HEOR data: reductions in hospitalizations, emergency room visits, or need for invasive procedures; improvements in quality of life and productivity; and potential savings in other parts of the healthcare budget. Engagement starts years before launch, with payer advisory boards to understand evidence requirements. The final agreement may involve outcomes-based contracts or innovative financing models tailored to small populations.

This reimagined engine is inherently flexible and resource-efficient. One composite scenario involves a company launching a drug for a rare neurological condition. They deployed a team of eight MSLs globally to engage the top 40 treatment centers, developed a diagnostic algorithm in partnership with key labs, and established a hub that handled everything from genetic test reimbursement to home infusion coordination. Their "salesforce" was essentially their medical and patient services team. This model achieved over 90% penetration in diagnosed patients within 18 months, not through promotion, but through solving the systemic problems that prevented treatment. Their strategic flex was recognizing that commercialization is a service delivery challenge, not a persuasion challenge.

Portfolio Strategy: Balancing Niche Focus with Scalable Platforms

A single niche product can be a successful venture, but long-term enterprise value is built through a portfolio. The strategic question becomes how to balance focused development in discrete indications with the pursuit of scalable platforms that can address multiple niches. This is the pinnacle of strategic flex: managing a pipeline that has both depth in specific diseases and breadth across a therapeutic modality or target class. The goal is to create a pipeline where successes are not one-off events but stepping stones to expanded utility, building cumulative knowledge, regulatory familiarity, and commercial leverage. This approach mitigates the "all your eggs in one basket" risk inherent in ultra-rare diseases while maintaining capital efficiency.

The "Lead and Expand" Model

This is a common and prudent approach. You develop your asset first in the most tractable, high-unmet-need niche where the path to approval is clearest (your "lead" indication). This de-risks the core asset and generates initial revenue and regulatory validation. Concurrently, you invest in exploratory studies in mechanistically related but larger adjacent indications. Success in the lead indication provides proof-of-concept, making development in the adjacent areas less risky and less costly. For example, a monoclonal antibody proven in one rare autoimmune disease can be efficiently tested in another with a similar pathogenic pathway.

The Platform-Based Strategy

This is a more ambitious, infrastructure-heavy model. Here, the company invests in a core technology platform—such as gene therapy, RNA-targeting, or a specific antibody format—and then applies it to a series of genetic or niche diseases. The flex here is in the platform's reproducibility. While each new disease requires its own clinical program, much of the manufacturing process, toxicology understanding, and regulatory dialogue around the platform itself is reusable, creating economies of scale and speed in development. The risk is higher upfront (platform validation), but the long-term potential for a pipeline of products is significant.

The Hybrid "Pipeline in a Product" Approach

Some assets have inherent multi-indication potential. A "pipeline in a product" strategy involves aggressively pursuing multiple niche indications in parallel from mid-stage development, often using basket trial designs or rapid sequential studies. This requires significant capital and operational dexterity but can maximize the asset's value and create a commercial presence across several specialty communities. The key is to ensure the clinical and commercial organizations have the flex to manage multiple, simultaneous small launches without losing focus.

Resource Allocation and Portfolio Trade-Offs

Managing such a portfolio requires disciplined decision gates. Resources (cash, talent, management attention) are always finite. Teams must constantly evaluate trade-offs: Do we invest more in commercializing our first launch or in Phase II studies for our second indication? Do we partner our platform for a new disease area or keep it in-house? A clear prioritization framework is essential, one that weighs factors like probability of success, development cost, time to market, strategic fit with existing capabilities, and the potential to create optionality for the future.

The most resilient niche-focused companies often evolve from a pure "lead and expand" model toward a hybrid or platform strategy over time. Early success provides the capital and credibility to invest in a broader technology base. The strategic flex lies in knowing when to pivot from being a "one-drug company" to a "one-platform company." This transition is fraught but necessary for scaling value. It requires building teams that can both execute deeply in a specific disease and think abstractly about platform applications, a non-trivial organizational development challenge.

Navigating the Unique Risk Landscape: From Regulatory to Reimbursement

Niche and orphan drug development, while de-risked in some areas (e.g., competition), introduces a distinct and often underestimated set of risks. Strategic flex requires not just optimism about incentives but a clear-eyed plan to navigate these unique pitfalls. These risks are interconnected; a regulatory delay can trigger a reimbursement problem, which can crater commercial viability. Proactive risk management, therefore, must be integrated across functions. It's about anticipating points of failure in the ecosystem you're entering and building contingency plans. This section outlines the major risk categories and mitigation strategies, moving beyond the generic "regulatory risk" to the specific challenges of small markets.

The Diagnostic Bottleneck Risk

Many niche diseases are under-diagnosed or misdiagnosed. Your drug's market is not the prevalence number from a textbook; it's the number of correctly identified patients. If the diagnostic pathway is obscure, slow, or expensive, adoption will stall. Mitigation: Invest early in diagnostic development or collaboration. This could mean funding genetic testing programs, creating diagnostic algorithms for specialists, or partnering with diagnostic companies to improve access to key tests. Treat patient identification as a core part of the development program, not a commercial afterthought.

The "Small Data" Regulatory Risk

While regulators are flexible, approvals based on small, single-arm trials carry a different kind of risk: post-marketing requirements (PMRs) can be substantial and costly. You may be required to run a confirmatory trial or a large registry study after launch. If the post-marketing study fails to confirm the initial signal, the approval could be withdrawn. Mitigation: Engage regulators in a candid dialogue about evidence expectations and the design of post-approval commitments. Budget for these studies upfront and design them to be as robust as possible within the constraints of the patient population. Be conservative in your initial efficacy claims.

The Pricing and Access Backlash Risk

High prices for niche drugs, while justified by R&D costs and small volumes, attract intense scrutiny from payers, policymakers, and the media. A backlash can lead to restrictive reimbursement, mandatory price negotiations, or damage to the company's reputation. Mitigation: Build your value story with rigorous, transparent HEOR data from the start. Consider innovative pricing models like outcomes-based agreements or installment payments tied to long-term benefit. Engage with payers and health technology assessment bodies early and often, educating them on the disease burden and the drug's holistic impact.

The Commercial Execution Risk in a Concentrated Market

In a tiny ecosystem, a single misstep can have outsized consequences. Alienating a key opinion leader, providing poor support to a major treatment center, or making an error in a payer contract can block a significant portion of your market. Mitigation: Hire commercial personnel with deep specialty experience and relationship skills. Empower your field teams to provide exceptional service. Implement a "key account management" approach for your top treatment centers, treating them as partners. Have a robust issue-management process to resolve problems quickly before they escalate.

Navigating this landscape requires a team that is humble, agile, and deeply embedded in the disease community. The risks are not abstract; they are the daily realities of working in small, high-stakes environments. The strategic flex is in anticipating these risks during the opportunity assessment phase and building the organizational capabilities to manage them long before launch. It's a mindset of proactive problem-solving, where risk mitigation is a core competency, not a compliance exercise.

Building the Agile Organization: Cultivating Strategic Flex as a Core Competency

Ultimately, the success of a niche-focused strategy hinges not on a single drug or a clever trial design, but on the organization's inherent capability for strategic flex. This is the meta-skill: the ability to sense shifts in the ecosystem, reallocate resources swiftly, make decisions with imperfect information, and execute with precision in constrained environments. It's an organizational phenotype that contrasts sharply with the often bureaucratic, process-heavy structures of large pharma. Cultivating this flex requires intentional design across talent, processes, and culture. It means building a company that is comfortable with focus, thrives on external collaboration, and measures progress by impact rather than activity.

Talent Strategy: Hiring for "Versatile Specialists"

You need people who are deeply knowledgeable in their domain (e.g., regulatory affairs for rare diseases) but who also possess the versatility to operate outside strict silos. A clinical lead may need to engage directly with patient advocates. A market access manager may need to understand the nuances of clinical endpoint selection. Look for individuals with a "builder" mentality, experience in small companies or cross-functional project teams, and comfort with ambiguity. Avoid hiring specialists who can only operate within a large, well-defined corporate machine.

Process Design: Lightweight and Empowered Governance

Decision-making must be rapid and close to the ground. Traditional stage-gate processes with numerous committee reviews can suffocate a niche program. Implement lightweight governance: small, empowered cross-functional teams with clear accountability and authority to make most day-to-day decisions. Escalation paths should be clear but rarely used. Information systems should provide real-time visibility into key metrics (e.g., patient recruitment, trial site activation) to enable quick course correction.

Cultural Pillars: Patient-Centricity, External Orientation, and Learning

The culture must be anchored in patient-centricity, not as a slogan but as a decision-making filter ("How does this choice affect patient access?"). It must be externally oriented, valuing deep relationships with the medical community, payers, and advocates over internal politics. Perhaps most critically, it must be a learning culture. In niche development, you will frequently operate without a playbook. Teams must be encouraged to experiment, to analyze failures without blame, and to rapidly integrate new insights. Psychological safety is a competitive advantage.

Technology Enablement: Tools for the Small and Focused

Leverage technology not to create bureaucracy, but to enable agility. This includes collaborative platforms for engaging with external experts, CRM systems designed for key account management (not mass sales), data analytics tools to monitor real-world evidence post-launch, and modular clinical trial platforms that can be adapted for different studies. The goal is to give small teams the capabilities of a large organization without the overhead.

Building this agile organization is a continuous journey, not a one-time initiative. It starts with leadership modeling the desired behaviors: decisiveness, openness to feedback, and a willingness to pivot. One team we read about instituted a simple rule: any team member could call a "flex check" meeting if they felt processes were becoming too rigid or a decision was taking too long. This empowered everyone to be a guardian of organizational agility. In the end, strategic flex is the sustainable competitive advantage in niche and orphan drug development. It allows you to move faster, learn quicker, partner more effectively, and ultimately deliver life-changing therapies to patients who have been waiting. The information provided in this guide is for general strategic understanding; specific development and commercial decisions require consultation with qualified regulatory, medical, and legal professionals.

Common Questions on Niche & Orphan Drug Strategy

This section addresses frequent, nuanced questions from experienced professionals considering or executing a niche-focused strategy. The answers aim to provide practical judgment, not just textbook definitions.

How do we truly assess "unmet need" beyond the obvious?

Look beyond mortality rates. Engage with patients and clinicians to understand the daily burden: diagnostic odyssey length, frequency of hospitalizations, impact on quality of life and caregiver time, and the limitations of current treatments (e.g., are they palliative, toxic, or difficult to administer?). A high unmet need exists when current care is significantly burdensome, ineffective, or non-existent. Quantitative surveys of patient-reported outcomes and qualitative interviews are essential tools.

Is an orphan designation always advantageous?

Generally yes, for the incentives (tax credits, fee waivers, market exclusivity). However, it can be a double-edged sword. It may limit the initial label and, in some payer systems, trigger complex ultra-orphan funding pathways that can delay access. For a drug with potential in both a rare and a larger condition, sometimes pursuing the larger indication first (if feasible) can be more strategically sound, using the data to later support a label expansion into the niche.

How small is too small for a viable market?

There's no universal threshold. Viability is a function of price, development cost, and operational efficiency. A disease affecting 500 patients globally can be viable if the drug commands a very high price (justified by immense value) and development is exceptionally lean (e.g., leveraging natural history data for control). The key is the net present value (NPV) calculation. If the cost to develop, manufacture, and support the drug exceeds its likely lifetime revenue, it's too small, unless it serves a critical strategic purpose (e.g., a platform proof-of-concept).

What are the biggest pitfalls in partnering niche assets?

The major pitfall is misaligned expectations on commercialization. A large partner may undervalue the asset, under-resource the specialized commercial effort, or try to force it into their standard commercial model, which will fail. In partnership discussions, scrutinize the proposed commercial plan, the experience of the assigned team, and the partner's track record with other niche products. Ensure the agreement includes clear, milestone-based commitments to market-building activities (like diagnostic development) beyond just sales targets.

How do we defend against competitors in such a small space?

Defense is built on multiple layers: regulatory exclusivity (orphan drug, patent), deep ecosystem entrenchment (strong KOL relationships, integrated patient services, diagnostic partnerships), and continuous evidence generation. By the time a competitor arrives, you should be the undisputed expert, with years of real-world data, established treatment protocols, and loyal advocacy group support. Sometimes, the best defense in an ultra-niche market is to make the market less attractive for a second entrant by fully saturating it with a superior service model.

When should we consider a direct-to-patient distribution model?

This is a high-flex, high-complexity model suitable for ultra-rare oral therapies where the patient population is geographically dispersed and traditional pharmacy channels are inefficient. It requires a robust hub service, sophisticated logistics, and deep compliance with state and federal regulations (like the DSCSA). It should be considered when it significantly improves patient access, adherence, and data collection, and when the cost of building the infrastructure is justified by the value of control over the patient experience and data.

How do we manage the tension between rapid development and robust evidence generation?

This is the core tension. The balance is struck through smart trial design and early regulator alignment. Use adaptive designs to make the trial itself more efficient. Invest in high-quality biomarkers and endpoints. Be transparent with regulators about your development strategy and what post-marketing evidence you will provide. The goal is not the fastest possible approval, but the fastest sustainable approval—one that will be accepted by payers and the medical community and not overturned by future data.

What is the single most important factor for commercial success in a niche launch?

While many factors matter, the most critical is unambiguous, clinically meaningful efficacy in the eyes of the treating specialists. In small communities, word travels fast. If the first few treated patients show transformative results, adoption will accelerate. If the effect is marginal or ambiguous, no amount of marketing or service support will drive uptake. Therefore, everything in development should be geared toward proving a clear, meaningful benefit, even if on a novel endpoint.