Domenico Merante

	The following article delves into the why, when, and how a patient-centric approach should be adopted for both the benefit of patients and the successful development of novel and innovative medicines. The article relies heavily on Domenico Merante, MD, a pharmaceutical physician specializing in diabetes and endocrinology with over 25 years’ experience in clinical development and clinical practice experiences. His exposure to patient-centric initiatives, such compassionate use, named patient programs, and collaborations with patient groups, led him to a recognition of the vital importance of a patients-first concept and incorporating the patient viewpoint when developing medicines. 

	Historically, drug development has employed an inside-out (1) product development approach (see graphic), that begins from the core molecule itself. As we progress through the pre-clinical and clinical stages, we generate more data about the molecule, and so develop our understanding of its characteristics. Finally, this product development approach may reach out to patients on the outside of the circle.

	The model that we, as the biopharma industry need to follow, should operate the other way around, using an “outside-in”, patient-centric approach. Beyond the obvious regulatory requirements, a truly patient-centric model begins with an understanding of the patient needs, disease area characterized by unmet medical needs, and patient-reported outcomes (2). From that point, working from the outside to the inside we develop appropriate molecules that are focused on the patient’s needs. We know that patients do not all respond in the same way to the same treatment; they might develop different side-effects (or the same side effects with different severity), and the therapeutic profile and responsiveness can differ quite substantially from patient to patient. In some cases, for example, patients need to be clustered into sub-groups  In this new paradigm, a deep understanding of specific patient needs can actually drive the development of the molecule (3-6).

	During recent years, there has been a great deal of discussion across the industry about this new paradigm of patient-centricity. However, in practice, the historical model of “inside-out” drug development is still very much at the fore. Using the traditional approach that has been followed for decades may seem to be the natural option, but without a patient focus, we risk a number of consequences. For instance, a drug may be wrongly discontinued, because we didn’t study the correct segment of patients; we may have used inappropriate patient questionnaires, or we may develop our understanding of the disease or target profile too late in the development cycle. This development of understanding should be done up front and continuously via the implementation of the target product profile. From this point of understanding, we are empowered to search for, and identify new targets.

	The industry is shifting its approach towards this new model, but it is not happening in a systematic way. 

When should the patient view be incorporated?

	When during drug development should sponsors begin engaging with patients? To be most effective, patient engagement should happen as soon as possible, or at least when the molecule enters the clinical stage. In Phase I, the clinical development plan should be in place to engage patients and patient focus groups, and to enable fine-tuning the target product profile of the molecule, to gain a much deeper understanding of the patient’s needs, symptoms, and reported outcomes. Within the design of these early phase studies, we can also include exploratory endpoints that aren’t necessarily driven by the regulatory requirements, but endpoints that reflect the patient’s true interpretation of their symptoms and of the response and tolerability to the treatment (7).

	As we move through to more advanced stages of development, it’s important to establish a disease awareness campaign and consolidate the network of patient associations. Entering Phase III trials, endpoints captured previously, including the exploratory endpoints, that were initiated in Phase II (8).  If the medicine is approved, patient engagement using patient education programs during the lifecycle management period should happen. In addition, continuous monitoring of the side-effects of the medicine in the post-approval, as well as careful listening to what patients are saying about the therapeutic profile of the medicine. This is important because now the medicines are reaching a much larger population than during clinical trials, where side-effects that were unknown or not well understood during the clinical studies could be occurring.

	Since patients talk with one another and with their physicians, sponsors need to capture the feedback about the drug from social media and other sources to understand how the medicine is working in practice and how the patients are reacting and responding to it. This exercise is also immensely helpful in identifying any safety signals that emerge during the course of treatment. 

	In summary, these kinds of interactions characterize the continuous engagement that should be in place from the beginning of Phase I through to Phase III and then onward in Phase IV and a post-marketing environment. By engaging from this early stage, and keeping that relationship with patients open throughout, we can improve our transparency, industry reputation, and recognition as a trusted partner of patients and patient groups. This should be a systematic approach regardless of the ultimate success or failure of the investigational medicine (9).

Where is it particularly important to incorporate the patient view?

	There are conditions where the exercise of incorporating and capturing exploratory endpoints in clinical trial design is particularly relevant. For example, in neuropathic pain conditions like diabetic neuropathic pain or post-herpetic neuralgia, or post-surgical pain conditions such as post-mastectomy. Another example is fibromyalgia, a disease that is characterized by amplified, peripheral pain which is very difficult to treat. These chronic conditions tend to also carry severe co-morbidities such as depression, hypertension, or obesity, because patients’ daily activities are heavily impacted by pain, detrimentally affecting their quality of life. As mentioned earlier, for instance, rheumatoid arthritis, lupus, diabetes, and cancer are similarly associated with pain. In fact, cancer is very much characterized by pain, and for this reason, there is the need to examine multiple endpoints during the course of clinical studies. These are necessary to monitor the treatment and the underlying conditions. This is an element that further complicates the analysis of the data and increases the risk of failure of the study. In all these cases, being close to patients can greatly help us to understand more about the patient profiles and much better tailor the study design, and the endpoints that we need to utilize (10-12).

	Input received from clinicians, patient advocates, and patient groups can be instrumental in guiding discussions with regulatory agencies. Regulatory endpoints need to be achieved in the development of new medicines, but in tandem, endpoints that may not be immediately necessary for regulatory purposes but could become important in the future should also be put in place. Sponsors have an important role to play in healthcare by bringing the discussions with patients to the table when we liaise with regulatory agencies (13).

	When implementing a patient-centric model, it’s important to understand the patient experience in depth. How do we achieve that understanding and complement regulatory endpoints with quality of life endpoints? Listening carefully to what patients say about their symptoms and experiences is critical. Understanding their feelings and experiences will help sponsors to better characterize the change in quality of life and daily functioning, as well as the role of the multiple comorbidities and related medications they have to take and cope with (14,15).

	Developing a deeper understanding of patients’ needs and perspectives helps sponsors better tailor new medicines that can treat different subgroups of patients or clusters. As, for example, in the case of fibromyalgia, patients do not respond in the same way, or at the same level as the particular treatment, whether pharmacological or non-pharmacological. To illustrate, there are fibromyalgia patients who do respond well, for instance, to acupuncture and those who respond less well. Some anti-depression treatments that are approved in the US for fibromyalgia may work for those groups of patients who have features of depression, but obviously less well for those who do not. Within fibromyalgia, patients are distinguished between high catastrophizers, moderate, and low catastrophizers, and develop novel medicines that treat these specific subgroups. To do this, we first need to understand more about the characteristics of each subgroup to address a particular medicine to a certain group rather than to the whole population. Indeed, there may be subgroups of patients where the drug may not work at all, and other groups where there are more side-effects than in other patients taking the same drug at the same doses. The same applies to drug responsiveness. There is a huge need nowadays to genotype and phenotype patient clusters as industry moves towards a personalized medicine healthcare model.

	In addition, and not less importantly, due to study complexity of study designs, number of study visits, pain severity, and pain chronicity, patient enrollment and retention in clinical studies can be a real challenge due to severity of pain from which people with fibromyalgia suffer(17).

	In conclusion, there is still a lot of work to do, at a number of different levels. As an industry, we have a very important role and responsibility to play with all the other healthcare stakeholders, patients first and all others to follow. 

, is the VP Clinical Development Europe for Shionogi Limited. 

 is Senior Director at Cytel. The authors would like to acknowledge 

 at Cytel for the graphics included in this article.

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	16. D. Merante. `Collaborate with patient groups, patient advocates and patient networks to drive forward clinical research`. Patients Centric Clinical Trials Europe. Oral presentation on June 9th, 2015. Eyeforpharma. 

http://www.eyeforpharma.com/patient-clinical-trials-europe/

Hilton Tower Bridge, London - June 8-9th, 2015.

	17. D. Merante. `Patient recruitment and retention strategies in fibromyalgia clinical development`. Oral presentation will be made at the 11th Annual Patient Recruitment and Retention Summit, London, 26-28 February 2019. 

Articles

This article delves into the why, when, and how a patient-centric approach should be adopted for both the benefit of patients and the successful development of novel and innovative medicines.

Domenico Merante

Articles

Outside-In: Why Putting Patients at the Heart of Drug Development Matters