Challenges and opportunities to include patient‐centric product design in industrial medicines development to improve therapeutic goals

Abstract

In the past, drug developers in industry chose approaches mainly focusing on the drug product's efficacy, safety and quality according to the level required by regulatory expectations stipulated in guidelines, pharmacopoeia and other regulatory provisions. By putting more focus on the patient perspective, regulatory authorities are currently raising their requirements regarding successful product submissions. The increasing involvement of patients in the product development process (e.g. conduction of human factor use tests, integration of feedback from patient and patient advisory groups into clinical programmes) requires adaptations to the existing and established industrial drug development processes without compromising fast patient access to innovative therapies. This review provides an expert opinion on the emerging challenges and opportunities to implement a patient‐centric approach into new drug development programmes. The aim is to better understand the challenge of finding the right balance between bringing innovative drugs fast to the patients and to develop these in parallel in a patient‐centric product form as well as why this is an opportunity and how stakeholder parties (e.g. patients, clinicians, pharmacists, caregivers, regulators) can provide support to achieve desired outcomes.

What is already known about the subject

• Pharmaceutical drug product development is a highly regulated and structured process

• Patient involvement is increasingly required for drug product development

What this study adds

• Provides insights into the industrial challenges and complexity of integrating patient centricity into drug development

• Points out the issues with implementing additional requirements into the complex development matrix and its potential consequences for patient access

1. INTRODUCTION

Bringing new drug substances to the market is a long‐term investment starting in drug discovery and passing through various clinical and drug (product) development phases, with a high risk to fail at any of these steps. Afterwards, the final drug product must pass an intensive regulatory process until the drug product becomes a tangible prescription medicine. ¹ , ² , ³ Safety and efficacy are also further monitored when the product is being commercialized. The dynamics of advances in medical and pharmaceutical sciences, changing demographics, increasingly complex clinical targets towards unmet medical needs, emerging regulations and the tense economic environment represent additional challenges. ⁴ , ⁵ Within this ecosystem, pharmaceutical companies must find the right level of risk mitigation as well as balance between traditional and innovative development approaches or business strategies.

The increasing number of older and multimorbid patients as well as the availability of different medicinal interventions have substantially increased the clinical and therapeutic complexity which affects both, patients and healthcare professionals. ⁶ , ⁷ To ensure that medicines can be used by these patients as intended even within complex therapeutic situations, patient‐centric drug product design has emerged as an additional quality criterion in pharmaceutical drug development. Since there is now globally an increasing awareness of the patient as an important stakeholder to achieve the therapeutic outcomes, regulatory requirements for special patient populations are being raised worldwide.

This expert opinion provides insight into the challenges and opportunities to implement patient‐centric drug product design into the established industrial development processes without compromising on the fast access of patients to innovative treatment with appropriate benefit‐to‐risk profiles. Moreover, the importance of collaborative efforts is elaborated and how stakeholder parties can collaborate to achieve commonly desired outcomes.

2. STAGES OF INDUSTRIAL DRUG DEVELOPMENT

Drug development is generally defined in the pharmaceutical companies as the process of taking a new chemical lead substance resulting from drug discovery and an intensive preclinical development phase through the necessary stages that finally allow drug products with this substance to be tested in the 3 different human clinical trial phases. In other words, drug development refers to the entire process of drug discovery and clinical testing of novel drug substance candidates and development, testing as well as up‐scaling of the drug formulation in its final product presentation. ⁹ The attrition rates of new drug substances during the clinical phases are estimated to be 89% meaning that only 1 out of 10 of new drug substance candidates entering the clinical phase will finally be launched in the market. ¹⁰ Resistance to include older patients ¹¹ , ¹² in clinical trials will have to be justified and approved by an ethical committee to assure proper protection of the participating patient. Predictive, data‐driven and novel clinical trial designs are being increasingly considered to increase and accelerate clinical evidence for new drug in development. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ Figure 1 (modified after ² ), gives an overview about the clinical development phases, efforts (= costs) and timelines from drug discovery to product launch on the EU market. ²

FIGURE 1.

Classical drug development phases regarding clinical and Chemistry Manufacture Control requirements (BCS, biopharmaceutical classification system; TPP, target product profile; QTPP, quality target product profile; CSF, clinical service formulation; QbD, quality by design; CPP, critical process parameter; CQA, critical quality attribute; BE, bioequivalence)

The pharmaceutical drug product development process and the required chemistry manufacture control work is starting already in the preclinical phase. While for the phase 1, a clinical service formulation is used, the commercial formulation has to be developed after the clinical proof‐of‐concept has been established in phase 2b and before the product enters into the phase 3 clinical study programme. This already includes all the quality criteria of internal (e.g. manufacturing, regulatory) as well as external (e.g. patients, medical doctors) stakeholders. Changes to the drug products after starting the phase 3 are no longer possible without substantial additional clinical trials (e.g. bioequivalence studies to bridge formulations).

One of the major challenges is to navigate through the complex and in parallel ongoing clinical and nonclinical development activities with the multiple decisions that have to be taken across the different development activities. As these decisions highly depend on each other standard procedures and matrices are being used to assure regulatory compliance according to the guidelines and hence fast access of innovative medicine to patients. ¹⁷

To assure that drug development is focusing on the right aspects, the Food and Drug Administration (FDA) has recently developed a series of 4 methodological patient‐focused drug development guidance documents to address, in a stepwise manner, how stakeholders can collect and submit patient experience data and other relevant information from patients and caregivers for medical product development and regulatory decision making. With their direct involvement and engagement, patients will influence drug development by early determination and inclusion of their needs beyond the modification of the clinical parameter.

Another example of how patient needs and involvement of caregiver groups can further impact and stimulate drug development is a new FDA draft guidance published in December 2019 to foster oncology product development for paediatric populations. ¹⁸ Development of new oncology drugs for children were extrapolated from adult clinical experiences often due to the limited number of children with the same tumour types. With the new focus on efficacious oncology drugs clinical testing in paediatric populations considering the target at molecular level is the same are facilitated.

Emerging challenges of complex therapeutic targets and patient involvement

The pharmaceutical industry focused over decades on the typical chronic diseases, which affect large patient populations (e.g. key discoveries in the 1920s as insulin, 1930s penicillin, and 1960s diazepam). Since these medicines have converted former life‐threatening chronic diseases into manageable conditions, the focus of the pharmaceutical industry has shifted to unmet medical needs and complex diseases affecting only very small patient populations enabled by geno‐ and phenotyping leading increasingly to the personalization of medicines. For rare diseases affecting not more than 5 in 10 000 in Europe and less than 200 000 in the USA, an orphan drug development status can be designated to enable adequate return on investment budgets by specific legal measures, ¹⁹ not compromising on the required entire drug development stages and processes. In the USA, The Orphan Drug Act of 1983, has helped to get more than 600 drug substances approved by the FDA for orphan drug indications. Especially in case of treatment of orphan diseases, the patient needs to be strongly involved throughout all stages for a successful drug development. Over recent decades, the regulatory authorities have put forward additional pathways such as priority reviews, breakthrough therapy, accelerated approval and fast track designation for innovative therapies to expedite patient access innovative therapies. ²⁰

3. INDUSTRIAL CHALLENGE TO INCORPORATE PATIENT‐CENTRIC DRUG PRODUCT DESIGN INTO DEVELOPMENT AND MANUFACTURING

The efficacy, safety and quality aspects of a pharmaceutical drug product is based on scientific evidence derived from commonly agreed standards of the clinical and pharmaceutical development. Regulatory guidelines assure that these standards are being met and the pharmaceutical drug product can be marketed after a thorough review of the documents supporting relevant evidence for the product claims. As science and medical progress evolves, the regulatory framework does too and also needs to be incorporated into ongoing drug development programmes. The rational drug development matrix plan builds on the data constantly generated throughout the process with several clinical and pharmaceutical milestone decisions that serve each other and are mainly frozen from the time onwards such decisions had to be taken. This also accounts for the market formulation which should be finalized prior to start of phase 3 clinical trials. Emerging regulations cannot be dealt with through just an add‐on study or data set to be generated. Every new requirement has to be incorporated and fit into the development matrix with potentially important implications for milestone decisions, development timelines and finally the access of innovative medicines for patients.

The growing awareness of and demand for the patients as a critical factor in achieving the therapeutic outcomes, led to the development of different regulatory documents, directly related to patient populations (e.g. paediatric, geriatric and frail patients) or indirectly by addressing product attributes (e.g. beads size ²¹ and liquid or soft foods for sprinkle application ²² over the past decade. While these documents provide important guidance on the expected data required, their implementation into the ongoing development could be quite challenging.

To design an efficacious and patient‐centric medication portfolio by including aspects such as altered physiology, physical functioning, psychology, behaviours and practical user aspects ²³ , ²⁴ have to be considered within phase 1 and phase 2 of drug development whereby neither the specific indication nor its clinical proof of concept have already been established. In addition, especially older and multimorbid patients are very heterogeneous populations for which specific needs might need to be prioritized as not all could be covered. ²⁵ , ²⁶ In such cases, clinical as well as pharmaceutical priorities must be defined by multidisciplinary teams early on, balancing the desirable against the feasible, from a scientific, industrial as well as patient perspective. ⁸

In 2005, the quality by design concept was introduced through the ICH Q8 guideline which was adopted in Europe, Japan and USA. ²⁷ The baseline for quality by design is a clearly defined target product profile (TPP), which serves as a commonly agreed, internal document of the planned final product targets with regard to indications and usage, dosage strengths, dosage forms, route of administration, the use in specific populations, supply modes including storage and handling and patient counselling information. ²⁸ The TPP is the guiding document for discussions between a pharmaceutical company (sponsor) and the regulatory authorities that can be used throughout the drug development process as well as to pursue new indications or other substantial changes in the approved indications (labelling).

According to the ICH Q8 annex published in 2008 the patients` needs and requirements have to be considered by stating that “…in all cases, the product should be designed to meet patients' needs and the intended product performance”. ²⁷ This has been adopted by the pharmaceutical industry as shown in Table 1, representing an example of a hypothetical TPP and a proposal by the authors trying to connect these attributes to a few more patient‐centric aspects.

TABLE 1.

Patient centricity aspects in a target product profile

Product attribute	Patient centricity	Comments
Indication	Disease focus	Age‐specific requirements in terms of dose flexibility
Route of administration/dosing frequency	e.g. oral, parenteral	Can be associated with age or patient specific requirements, e.g. swallowability/palatability
		Sticking to a complex dosing regimen could be difficult for certain populations (e.g. patients with dementia
Dosage form	e.g. film‐coated tablet, softgel, hard capsule, pen for autoinjection	Could be critical with regards to size of dosage form, complexity (e.g. autoinjector)
Dosage strength/assay	Efficacy related (pharmacokinetic/ pharmacodynamic relationship)	Based upon clinical efficacy studies
		Dose levels are rarely monitored in older populations with reduced drug metabolism and pharmacokinetic functionalities (safety in terms of over‐/under‐dosing)
Appearance	Product identification and quality aspects	Should help to support compliance, avoid medication errors (colour, shape, size, imprinting)
Size	Size	Critical in case of too large dosage forms (swallowability)
Excipients	Safety of patients	Drug product quality aspects in relation to patient safety and efficacy
Mechanical strength	Acceptability (mechanical integrity during usage)	e.g. tablets should have sufficient mechanical stability to remove from blisters, breakability of tablets with score
Container closure system	Sufficient stability at patients’ homes, acceptability (suitability for compliance)	Strong impact on acceptance (e.g. senior friendliness of primary packaging) and drug product storage
Degradants and impurities	Safety of patients	e.g. genotoxic impurities
Shelf life	Sufficient stability at patients’ homes	Drug product storage at patients’ homes including in‐use stability

The TPP, however, is a document that will have to be adapted constantly during the development process as new clinical and pharmaceutical data become available. For example, during the clinical trials, the disease targets might shift, or new indications might come up that either require different dosing regimens or change the targeted patient population.

Similarly, during the pharmaceutical development drug stability or solubility issues might occur for a particularly desired formulation or dosage form that cannot be solved. While pharmaceutical sciences have focused substantially on predictive models and simulation to reduce the such failures, the evidence still need to be created during drug development requiring a certain level of development work including long‐term stability testing. As consequence, adding or changing drug product formulation and/or dosage forms during ongoing clinical trials or at later stages of development (e.g. phase 3), will have a substantial impact on the entire development programme requiring additional clinical trials (e.g. bioequivalence), pharmaceutical work (e.g. analytical development, stability trials), and further investigations and documentation, which delays product submission, patient access to new drug therapies and increase development costs.

The pharmaceutical industry is trying to mitigate the risk by standard operation procedures to assure that all relevant clinical and pharmaceutical information are captured and modifications to the drug development matrix are dealt with in a concerted manner. The adoption of new guidelines, requirements or procedures into the development practice are true challenges due to a lack of experience and/or confidence within the very tight and controlled development matrix plans. Since the regulatory authorities put forward their Reflection Paper: Formulations of choice for the paediatric population in 2005 ²⁹ and respective guidelines in the following years, the pharmaceutical industry, academia as well as regulatory bodies had to work closely together to develop meaningful approaches for paediatric versions of new drug products. It took 9 more years until P. Kozarewicz (European Medicines Agency [EMA]) published a paper about criteria to better define the age‐appropriateness of paediatric pharmaceutical dosage forms helping to develop the right strategy regarding drug product development by applicants. ³⁰ The paper represented the outcome of discussions pending in the EMA's Pediatric Committee of the Quality Working Party on the development of the guideline for paediatric pharmaceutical development. ³¹ The author concluded that acceptability is driven by the characteristics of the user (age, ability, disease type and state) and by the characteristics of a medicinal product such as palatability, swallowability, appearance, complexity of modification prior to administration (e.g. tablet splitting), required dose, required dosing frequency and duration of treatment, and the actual mode of administration. ³⁰ , ³² To cope with these new guidelines, the pharmaceutical industry has formed internal paediatric expert groups to develop paediatric formulations in parallel to the drug development programmes for the adult population as the major target population.

With the Reflection Paper on the pharmaceutical development of medicines for use in the older population, ³³ the EMA has taken an additional step forward towards patient‐centric drug product design and development as a general requirement. Focusing on the older population as a vulnerable population with special needs, some important considerations and expectations have been stated. Since the knowledge is sparse, the document is intended to bring forward multidisciplinary discussions and collaboration in order to address the needs of the real‐world population beyond the pure clinical needs by patient‐centric drug product development programmes. The implementation of these considerations into industrial practice and development matrix will have to be done in a concerted way in interdisciplinary teams in the industry and a better cross‐functional communication. The objective is to maintain enough risk mitigation as well as create room for process enhancement and address several challenges but also opportunities of which some of those predicted are summarized in Table 2.

TABLE 2.

Predicted challenges and opportunities to implement patient‐centric product design for older patients

Predicted challenges	Reason
Reluctance to focus on smaller sub‐populations within the overall patient population	Not the primary business driver, potential cost increase, not inside the knowledge space (exotic)
Heterogeneity of the patient populations	• how to define the patient and population specific priority characteristics
	• how to estimate an adequate representation of special populations in clinical trails
	• how to address potential issue in multimorbid patient populations regarding pharmacokinetic differences, drug–drug interactions, drug–disease interactions etc.
Drug development organization not prepared for changes	Compliance to defined development matrix mitigates risk and secure successful product launches
Lack of overview about drug delivery and packaging technologies or unwillingness to outsource to specialists	Focus on standardized mature existing technology platforms available internally rather than external technology, concern about loss of freedom to operate (intellectual properties)
Disconnect between different functions within the pharma company (e.g. clinical, pharmaceutical, regulatory)	Lack of communication between multiple disciplines, focus on the disciplinary deliverables according to the development matrix
Lack of experiences/track records/methodology, e.g. how to conduct patient‐centred acceptability studies	Slow capacity building of newly required skills and their inclusion in development programmes (e.g. optimization of packaging design to meet patient needs)
Limited change management	Primary focus is on the development projects and much less on continuous education and human capacity building
Concerns about re‐imbursement and prescribing	Lack of health insurance company involvement and collaboration on drug product value instead of costs
Supply chain complexity	Limited flexibility to manage highly differentiated products in complex clinical and commercial supply chains
Predicted opportunities	Reason
Intensify collaboration between clinicians and pharmaceutical sciences	• collect characteristics and needs from the patient populations
	• include identification of needs into the clinical trial programme
Systematically collect feedback from healthcare professionals and patients	• qualify and quantify the real‐world problems with drug products and patient needs from doctors, pharmacists, patients and care givers
	• understand users problem solving approaches
Initiate noncompetitive research to develop scientific evidence and guidance	• expand the knowledge on real‐world target patient population characteristics
	• identify appropriate methodology to evaluate the product‐user interface (e.g. human factor design)
	• quantification of the impact on drug product safety and effectiveness
Multi‐ and transdisciplinary working groups	• development of a meaningful roadmap for patient‐centric product design

Prior knowledge and existing expertise stemming from the implementation of the paediatric formulation development experience can be leveraged and eventually transferred to patient‐ centric drug product design (Table 3).

TABLE 3.

Commercially available drug delivery technology for special patient populations

Acceptability topic	Approach (technical solution)	Comments/references
Palatability/swallowability	Multiparticulate dosage forms (mini‐tablets, pellets)	Size reduction of dosage forms, e.g. 34
	Orodispersible or dispersible tablets	Transformation of solid forms into suspensions with orodispersible or dispersible tablets
	Films 35
	Jellies
	Soft‐food 36
	Drinking straws 35
	Enteral tubings
Pill burden	Fixed dosed combinations	Reduce number of dose units (might cause size increase as drawback) 37
	Long acting actives
	Sustained release products	Management of chronic pain, e.g. transdermal patches 38
Handling of packaging components and leaflet	Acceptability studies	Testing senior friendliness of packaging components, e.g. 39

4. THE RELEVANCE OF PATIENT‐CENTRIC PRODUCT DESIGN FOR CLINICAL PRACTICE

Pharmaceutical drug products achieve their therapeutic outcomes when used as tested in the clinical trials and described in the drug product information leaflets. To assure the intended use and administration of the prescribed medicine, the drug product needs to be based on a patient‐centric drug product design to optimize tight adherence to the prescribed medication/therapy. Pharmaceutical products that cannot be administered in its existing form will be modified e.g. by tablet crushing independent of the instructions or omitted without communication to the healthcare professional. ⁴⁰ Patients, as well as professional caregivers, might handle a product based on prior learning or perception with the best intent and will not recognize any wrongdoing or even consider having problems with the administration of the drug product. This will leave the prescriber under the impression that the patient is not responding to a therapy with the consequence that the therapy with the best benefit‐to‐risk will not be pursued.

The impact of patient‐centric product design has recently been investigated and demonstrated in rheumatoid arthritis patients. Rheumatoid arthritis patients suffer from deformation and pain affecting hand functions such as severely limiting their grip and pinch forces. Tp allow the patients to administer a new drug by self‐injection a patient‐centric syringe system was developed by considering the capabilities of these patient population across all age groups. A comparative study with a conventional syringe investigated differences in performance, physical aspects, preference, confidence, willingness to inject and sex. The study revealed that the new syringe enabled patients to achieve higher injection forces, shorter injection times and hence more control over the injection, which led to a clear preference for the new syringe. ⁴¹ This example demonstrates the importance to include patients in the drug development to gain insights into their capabilities and needs as well as utilize their input to co‐create better drug products.

Another example how to significantly improve quality of life of patients is Parkinson's disease (PD), a neurodegenerative disorder that is characterized by progressive, disabling motor symptoms, such as bradykinesia, rigidity and resting tremor. While at earlier stages of PD some nonmotor symptoms, including depression, REM sleep behaviour disorder, and olfactive impairment can be part of the starting progression of the disease, at later stages apathy, impulse control disorder, neuropsychiatric disturbances and cognitive impairment can be present which are often heavy burdens for both patients and caregivers. ⁴²

The classical PD treatment is replacement of L‐dopamine as neurotransmitter. As an example, for the treatment of dyskinesia and on–off symptoms continuous L‐dopamine infusion via pumps has proven to significantly reduce the dyskinesia severity and duration of off‐times. ⁴³

A couple of further innovative drug administration approaches for L‐dopamine administration using other application routes is also under development (intestinal infusion, transcutaneous, or inhaled L‐dopa): as 1 example from patient‐centric development activities, levodopa–carbidopa intestinal gel is an approved therapy consisting of a suspension of levodopa and carbidopa infused directly into the proximal jejunum via a percutaneous endoscopic gastrojejunostomy tube through a portable infusion pump.

Another approach that has been evaluated was a gatroretentive system, known as accordion pill. ⁴⁴

Acknowledging the importance of patient involvement and patient‐centric drug product development, the development of new therapies will remain focused on the fast access of safe and effective innovative medicines. At the same time increasing involvement of patients, doctors, pharmacists and care givers will lead to scientific evidence on the most important needs of patient populations that can be incorporated early on in a new development programme or its life cycle management later on. These efforts need to be accompanied by close collaboration and alignment between all stakeholder that patient‐centric drug products finally reach the patients and care givers.

5. CONCLUSION

Drug product development is a long‐term investment with several uncertainties and risk for failure. The drug development follows a defined yet complex development matrix within a highly regulated process to provide evidence for the desired benefit‐to‐risk ratio of a new drug. The increasing acknowledgment of the heterogeneity and complexity of the patient populations and development of treatments for unmet medical needs (e.g. orphan populations), create additional requirements that needs to be incorporated into the drug development matrix for future treatments. The challenge is to achieve this without impacting the access of innovative treatments to patients due to longer development times or increasing development, manufacturing and hence treatment costs. To avoid unnecessary delays, a rational and systematic approach towards patient‐centric drug development is required that provides a balanced roadmap including product and patient needs. An industrial academic group has recently been founded with the focus on patient centricity (PaCeMe In) to develop a general roadmap.

The pharmaceutical companies take their share of the responsibility and try to adapt their development programmes to the new and emerging regulations. However, this also requires close cooperation and mutual understanding between all participants involved in new drug development and patient treatment. Learnings from the paediatric regulations can facilitate the incorporation of patient‐centric drug development and should start very early with the definition of the TPP. The demographic change in terms of a constantly growing older and multimorbid patient population is a challenge for all stakeholders in healthcare provision and as such represent an opportunity to re‐focus the existing healthcare business models. In this context, patient‐centric drug products can lead to improved therapeutic outcomes, maintain independent living and improve quality of life, reducing the overall healthcare costs. The collaboration between clinicians, pharmacists, industry, regulators and healthcare providers is necessary to ensure that patient‐centric products reach the patients and especially the older and multimorbid patient population. Such collaborations may be promoted by understanding working practices in other domains like the pharmaceutical industry, which was 1 of the aims of this article.

Timpe C, Stegemann S, Barrett A, Mujumdar S. Challenges and opportunities to include patient‐centric product design in industrial medicines development to improve therapeutic goals. Br J Clin Pharmacol. 2020;86:2020–2027. 10.1111/bcp.14388