If Sponsors Invite Patients To See The Final Draft Protocol, It's Already Too Late

By Kamila Novak, KAN Consulting

In any project, we want to achieve and should plan for success, which requires considering internal and external stakeholders and product end users. It is not any different in drug development. Sponsors wish to launch a successful product, win a good market share, and gain revenue. Meeting the needs of the target patient population is vital to those ends. This implies knowing the patients and their needs very well. Who are they? How old are they? Where do they live? What are their typical comorbidities? What socioeconomic obstacles may stand between them and the product? What other limitations may they have? Without answering these questions, the hoped-for product success may never materialize.

Yet, when we plan and design clinical trials to test the product and gather data for marketing authorization, these questions are not always raised, and the outcome is a greenhouse — a trial in which the patient population does not represent the real-world patients to be treated once the product is marketed, while we try to extrapolate the trial results to all patients at the same time. The average patient in a study is still a young or middle-aged financially stable white male who is relatively healthy and ideally has just the disease being studied. ^1-4 Sponsors, here’s a question: If your revenue depends on real-world patients resembling the typical study patient, how well would you do economically?

Regulators require the sponsors to conduct trials that are inclusive and enroll diverse patient populations.⁵  We talk about bringing trials to patients instead of bringing patients to trials. Going one step further, we can think about clinical trials as part of medical care, one of the options available to patients to choose from. But how do we do it?

Who Are Our Patients, And What’s Important To Them?

The first precondition of success is to learn who our patients are and what matters to them. We must create an environment and forums where we can meet patient representatives and advocates and listen to them, their concerns, and their hopes. We need to foster a dialog with them, answer their questions truthfully and understandably, and demonstrate, not just say, that their voice matters and that we genuinely care about them. Nobody knows the disease symptoms and associated limitations better than our patients. Which symptoms annoy them the most? If they could choose one symptom to get relief from, which one would it be? What would they prefer: to be able to walk 100 meters more in their neighborhood or to climb the staircase in their house? Or do they just want to be more independent in their basic self-care? Do they want to live longer or to have a better quality of life? We can expect diverse answers depending on patients’ age, stage of the disease, family situation, etc.; however, we may be surprised by commonalities in clinical outcomes that are meaningful for them.

What Do Patients Really Want From A Trial Experience?

The second precondition of success is a fit-for-purpose protocol design. If sponsors invite patient representatives just to see the final draft protocol, it is too late. They should be at the table from the early stage of study conception. It is not just about the number of blood draws and related inconveniences; it’s about choosing endpoints that are meaningful for our patients and aligning science with clinical outcomes that matter to them. This means asking the right scientific questions and defining the right trial objectives. We should not be trying to answer as many questions as possible in a single protocol, ending up with seven primary, 10 secondary, and 23 exploratory objectives. Yes, this may be a bit exaggerated, but I have seen a protocol that had 31 objectives in total. Needless to say, the protocol was very complex and difficult for the investigators to implement and follow without deviations, resulting in raising more concerns than hopes for robust outcomes useful for further decision-making. If we include what matters to our patients and makes a difference for them, we could see faster patient recruitment, better compliance, and patient retainage.

What’s Holding Sponsors Back?

All these things are easier said than done. Sponsors face budget constraints that drive their efforts to design trials that answer all possible questions. They handle operational challenges associated with advanced designs, novel endpoints, rare disease trials, new technologies, an increasing number of vendors, and much more. A lack of trust in certain patient populations related to clinical trials, pharmaceutical companies, and the healthcare establishment presents another significant challenge.

Budget And Operations Woes

Understanding those budgetary and operational challenges, what is the way forward? Perhaps developing a new therapy as a solo effort is an outlived model, and the future lies in partnerships and collaborations. We saw some of the first, most successful, examples in the development of COVID-19 vaccines during the pandemic. Collaborations enabled new synergies and new approaches to trial conduct, and all players quickly implemented new technologies. Regulators allowed roll-on submissions and reviewed records on the go, which sped up the development of vaccines in an unprecedented way. Regrettably, after the pandemic ended, we stepped back instead of capitalizing on what we have learned and making it a common practice. Steps for change in this area can be rather fast and help drug development efforts that are beyond the reach of individual sponsors. While mergers and acquisitions need capital and typically lead to massive restructuring that consumes time that can be used for productive work, collaborative drug or device development is within the reach of most companies.

Trust Is Lacking

On the other hand, building trust is a marathon, not a sprint, and resorting to shortcuts disqualifies the runner. How to start? We should keep in mind that individual patients and entire patient populations with low trust in healthcare and the pharmaceutical industry have personal and/or historical reasons for that tenuous trust. Examining the reasons may help us pave ways for change.

Individual reasons for low trust can come from a bad experience, either personal or within close circles of one’s family and friends. Such a bad experience itself may have dozens of reasons, ranging from negligence or malpractice by healthcare professionals to unrealistic expectations and misunderstandings. As an industry, we can hardly deal with these cases. They happened, are happening, and will happen. Some power is in the hands of those teaching and educating the healthcare professionals since teaching and training should include not only medical knowledge and professional skills, but also ethics, respect for patients and their rights, professional responsibility and accountability, communication, etc. Another reason can be the influence of various activists, such as the antivaxxers, or the spread of mis-/disinformation on social media. I do not support overregulation, but sound rules for dealing with hate speech, spreading fake news, and news that can create panic are healthy.

Collective reasons for low trust specifically affect certain ethnic or social groups of people. Many cases that resulted in a lasting lack of trust have been documented and published. Recall the Tuskegee trial, cases of ethics dumping, and the Theranos case — all from recent history. People involved in and even witness these events feel betrayed, abused, fooled, manipulated, patronized, and so on. Another set of causes is socioeconomic, resulting in being and feeling deprived of options those more fortunate ones have, disempowered, disadvantaged, and disrespected. The economic barriers are real and the industry, hand in hand with other stakeholders, has the power to improve the situation step by step.

Research-Naïve HCPs Need Guidance

A promising way to reach groups of people who have little exposure to clinical research is through their healthcare providers (HCPs), usually members of their own communities. We should keep in mind that these HCPS often work in resource-limited settings. If we reach out to them to conduct complex trials, the response will be negative as these trials are not feasible for them. At one FDA-organized public event held earlier this year, I heard an interesting proposal: to create lists of studies, including surveys, registries, epidemiology and observational studies, and more simple trials for HCPs working in resource-limited settings. Let us provide opportunities to start small and grow step by step. I call it capacity building, something I have seen in sub-Saharan Africa, where regulators mandate capacity-building plans to be part of clinical trial submissions for approvals. Capacity building in my and your country may be different, tackling different needs and challenges, but overall, it’s an approach that is likely to succeed. The transformation and fruit of this change will take time and there will be always some work to be done, but this is fine. A way forward does not end on the horizon; the journey goes beyond.

As with any change, it requires a change management method. We need to design a sound and realistic plan to implement the change, work with various stakeholders, find proponents and champions of change and support them, meet opponents and learn about their concerns to address them, and generally understand each other better, identify the low-hanging fruit that will boost morale and interest to keep going.

The envisioned outcome — accessible trials with diverse patient populations, therapies meeting the needs of real-world patients, and studies offered as a treatment option — is worth the effort. Anyone can become a patient tomorrow, and everyone wishes to walk their patient journey with dignity and the ability to make choices.

References:

1. Saphner T, Marek A, Homa JK, Robinson L, Glandt N. Clinical trial participation assessed by age, sex, race, ethnicity, and socioeconomic status. Contemp Clin Trials. 2021 Apr;103:106315. doi: 10.1016/j.cct.2021.106315. Epub 2021 Feb 21. PMID: 33626412; PMCID: PMC8089053.
2. Camidge, D. R., Park, H., Smoyer, K. E., Jacobs, I., Lee, L. J., Askerova, Z., … Zakharia, Y. (2021). Race and Ethnicity Representation in Clinical Trials: Findings from a Literature Review of Phase I Oncology Trials. Future Oncology, 17(24), 3271–3280. https://doi.org/10.2217/fon-2020-1262
3. Giusti K, Hamermesh R. G., Krasnow M. Addressing Demographic Disparities in Clinical Trials. Harvard Business Review, June 2021, https://hbr.org/2021/06/addressing-demographic-disparities-in-clinical-trials
4. Hlavka J. P. Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups. Appendix B. National Academies of Sciences, Engineering, and Medicine; Policy and Global Affairs; Committee on Women in Science, Engineering, and Medicine; Committee on Improving the Representation of Women and Underrepresented Minorities in Clinical Trials and Research; Bibbins-Domingo K, Helman A, editors. Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups. Washington (DC): National Academies Press (US); 2022 May 17. Appendix B, Key Trends in Demographic Diversity in Clinical Trials. Available from: https://www.ncbi.nlm.nih.gov/books/NBK584392/
5. Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies, FDA, June 2024

About The Author:

Kamila Novak, MSc, has been involved in clinical research since 1995, having worked in various positions in pharma and CROs. Since 2010, she has run her consulting company, focusing mostly on GXP auditing. She has first-hand experience with countries in Europe, the Middle East, Africa, and North America. Kamila chairs the DIA Clinical Research Community and the SQA Beyond Compliance Specialty Section, leads the DIA Working Group on System Validation, serves as a mentor at the SQA and the DIA MW Community. In addition, Kamila is a member of the CDISC, the European Medical Writers’ Association, the Florence Healthcare Site Enablement League, the Continuing Professional Development UK, the Association for GXP Excellence, and the Rare Disease Foundation. She publishes articles and speaks at webinars and conferences. She received the SQA Distinguished Speaker Award in 2023 and 2024, and the DIA Global Inspire Award for Community Engagement in 2024. She and her company actively support capacity-building programs in Africa.