PPIE Beyond Ethics: A Business Case for ATMP Developers

Patient and public involvement and engagement (PPIE) in drug development is most often framed in ethical terms, particularly in supporting patient rights, inclusion, transparency, and fairness in health research. These arguments remain important. However, PPIE also offers strategic and commercial value.  

PPIE refers to the active involvement of patients, carers, and members of the public in shaping research and development, rather than only participating as study subjects. Its distinctive contribution is the lived-experience expertise it brings into decision-making alongside scientific, clinical, and operational knowledge. Patients can offer unique insight into the realities of living with a condition, navigating care, judging treatment burden, and deciding whether research participation is acceptable and worthwhile. These perspectives can help identify risks, barriers, and opportunities that might otherwise be overlooked, improving study feasibility, participant acceptability, and operational delivery before problems become costly. 

The case for early PPIE is especially strong in drug development, where programmes are costly, uncertain, and highly sensitive to delays. When embedded early and meaningfully, especially in protocol design and study planning, PPIE can improve study feasibility, strengthen participant acceptability, and support more efficient trial delivery. It should therefore be understood not only as an ethical commitment, but also as a practical de-risking measure that improves decision-making under uncertainty and helps protect investment.

PPIE is of particular strategic value in the development of advanced therapy medicinal products (ATMPs). While much of the available evidence comes from drug development more broadly, the implications are clear for ATMP programmes, which often target rare conditions, involve small and hard-to-reach patient populations, and depend on novel mechanisms, limited evidence bases, and demanding trial procedures. In these settings, seemingly minor design flaws or recruitment barriers can create outsized effects on timelines, costs, and programme viability. The two accompanying case studies in this series further illustrate these themes, showing how PPIE creates value in practice through shaping participant-facing materials, protocol design, and trial delivery.

Clinical development is the longest and most expensive part of drug development, typically taking 10–15 years (Paul et al., 2010) and costing hundreds of millions to billions of US dollars (Sertkaya et al., 2024; DiMasi, Grabowski and Hansen, 2016). In such a high-cost and high-risk environment, inefficiency has direct commercial consequences. 

Delays and protocol amendments—referred to hereafter as “modifications” in line with HRA terminology—are major drivers of inefficiency in this process. Recruitment delays are particularly common: over 80% of trials fail to recruit on time, and around 30% never reach target sample size (Huang et al., 2018; Sully, Julious and Nicholl, 2013; McDonald et al., 2006; Treweek et al., 2013; Bower et al., 2014). Protocol modifications also cause substantial delays, particularly where substantial changes are needed to address impractical visit schedules, design flaws, or other barriers to recruitment and delivery that could potentially have been identified earlier. In the UK, a substantial modification can take up to 112 calendar days from submission to final regulatory decision under the standard MHRA/HRA Route A process, excluding extensions or resubmissions (Health Research Authority, 2026). In the United States, mean implementation time for protocol modifications has been reported at around 260 days (Getz et al., 2024). 

The financial implications are substantial. The Tufts Center for the Study of Drug Development (Tufts CSDD) estimates the direct cost of running a phase II or III trial at approximately US$40,000 (£30,000; €35,000) per day, with lost prescription drug or biologic sales averaging around US$500,000 (£370,000; €432,000) per day (Smith, DiMasi and Getz, 2024). These figures are significant but likely represent only a lower-bound estimate, as they do not fully capture indirect costs such as staff time, infrastructure, operational disruption, or the opportunity cost of delayed regulatory approval and delayed patient access. If a phase II or III trial is delayed by three months, the combined effect of daily trial costs and foregone sales can run into tens to hundreds of millions of US dollars, even before accounting for indirect operational and opportunity costs. 

Protocol modifications also carry substantial direct costs, and they are increasingly common. Tufts CSDD reported in 2016 that 57% of protocols required at least one substantial modification, with median direct implementation costs of approximately US$141,000 (£105,000; €122,000) for phase II studies and US$535,000 (£397,000; €462,000) for phase III studies (Getz et al., 2016). By 2024, 76% of protocols required at least one modification, averaging 3.3 modifications per protocol (Getz et al., 2024). These protocol changes were associated with longer recruitment periods, longer study duration, and poorer alignment between planned and actual enrolment. They may also create less visible but important site-level costs, including rework, retraining, re-consenting, paused recruitment, and operational uncertainty. Over time, these pressures can lead to site fatigue and reduced engagement, impacting recruitment, retention, protocol compliance, and data quality, further increasing the risk of delay and avoidable cost. Depending on the study, around one quarter to nearly one half of modifications may be avoidable.  

Taken together, these data show that early decisions around study design have major consequences for cost, timelines, and study performance.  

Improving recruitment and retention 

Early and meaningful patient input can improve recruitment and retention, two of the most common causes of delay. Evidence from a systematic review and meta-analysis found that PPIE improves both enrolment and retention, especially when contributors have lived experience of the condition (Crocker et al., 2018).  

PPIE can improve recruitment and retention by helping trial teams identify barriers before a study opens. Patients and carers may improve the clarity and tone of recruitment materials, highlight concerns that could deter participation, explain what would make participation worthwhile, and identify practical burdens likely to lead to drop-out. For example, they may flag clinic visit schedules that are unrealistic for people balancing work, caring responsibilities, fatigue, or travel limitations.  

Developers can then use this input to refine participant-facing materials, recruitment approaches, visit schedules, and support arrangements. Even modest improvements in recruitment and retention can shorten timelines, reduce the risk of under-enrolment, and improve delivery predictability. This matters especially for ATMP programmes, which often face tighter operational dependencies and smaller eligible patient populations. 

Reducing avoidable protocol modifications 

PPIE can also help identify design problems before they become modification issues. Patients may highlight burdensome procedures, unrealistic visit schedules, unclear information, barriers to participation, or broader concerns about protocol feasibility that developers might otherwise overlook (Boote, Baird and Sutton, 2011; Edwards et al., 2011).  

Addressing such issues early can improve study acceptability, support smoother trial delivery, and reduce the likelihood of costly downstream changes.  

Reducing avoidable protocol modifications lowers direct implementation costs, stabilises timelines, and reduces operational disruption, which may be especially important for ATMP programmes with small patient populations and narrow launch windows. 

Strengthening ethics and regulatory readiness 

PPIE may also reduce regulatory delays by improving participant-facing documents, consent materials, and the clarity and relevance of trial design before submission. In the UK, this is particularly relevant under the combined review process (Health Research Authority, 2026), where the Medicines and Healthcare products Regulatory Agency (MHRA) and a Research Ethics Committee (REC) review applications in parallel and issue requests for further information jointly. Although PPIE is not a formal requirement, issues raised during REC reviews can nonetheless delay overall approval. Beyond REC reviews, sponsors are generally expected to incorporate patient perspectives into trial design and, where PPIE has not been undertaken, provide a clear justification to the HRA. The recently updated ICH E6(R3) guidelines (ICH, 2025) also included the requirement for sponsors to consider participant perspectives in the design and conduct clinical trials. 

Effective PPIE—particularly in the design of participant-facing materials—can help ensure that the condition, treatment rationale, potential benefits, risks, and practical implications of participation are communicated clearly and meaningfully. It can support informed consent, demonstrate a patient-centred approach to development, reduce avoidable misunderstandings and clarification requests, and make the trial and intervention easier for ethics committees to evaluate. For ATMPs, which are often scientifically complex and unfamiliar to non-specialists, this may be particularly valuable. 

Building trust and long-term engagement 

PPIE can help build trust with patient communities. That trust can strengthen recruitment, retention, and engagement, especially among underserved groups (Crocker et al., 2018), while also supporting company reputation and future relationships with patient organisations and communities. 

In the ATMP context, this value may extend beyond trial delivery. Patient communities can help articulate unmet need, treatment burden, meaningful outcomes, carer impact, and benefits that are not always fully captured in clinical endpoints or economic models. Early PPIE can therefore support the development of patient-centred evidence and narratives that may later strengthen discussions with health technology assessment (HTA) bodies, payers, and reimbursement decision-makers. Seen in this way, PPIE is not only a trial-delivery tool but also a longer-term access asset. 

PPIE should be recognised not only for its ethical value, but as an upstream strategic investment in better decision-making under uncertainty. Introduced early and used meaningfully, it can improve protocol quality, strengthen recruitment and retention, support more realistic participant-centred trial designs, and reduce avoidable protocol modifications, delays, and operational inefficiencies. 

The financial value of PPIE is difficult to quantify precisely, but published estimates suggest that it may be substantial. A CTTI model suggested that an investment of US$100,000 (£74,000; €86,400) in patient engagement could generate a return exceeding 500-fold, equivalent to accelerating a pre-phase 2 product launch by 2.5 years, or a pre-phase 3 launch by 1.5 years (Levitan et al., 2018). While these estimates are based on assumptions and should be interpreted with caution, they underline a broader point: earlier, better-informed decisions on trial design can create major downstream value. 

That logic is particularly compelling in a development environment where delays may cost around US$40,000 (£30,000; €35,000) per day in direct trial costs and US$500,000 (£370,000; €432,000) per day in lost commercial sales. Against this, the cost of meaningful PPIE is usually negligible within the overall trial budget. Even modest improvements in feasibility, enrolment, retention, or protocol design can therefore produce significant returns.  

PPIE should be recognised not only as an ethical commitment, but also as a cost-effective upstream strategic investment in better decision-making, stronger study design, more efficient trial delivery, and the mitigation of avoidable risks across clinical development. For ATMP developers, the commercial logic is clear: when implemented early and meaningfully, PPIE can help reduce avoidable inefficiencies and protect the value of development programmes.