Challenges in inhaled product development and opportunities for open innovation☆
Graphical Abstract
Introduction
This article considers inhaled product development with an emphasis on dosimetry, safety and efficacy. A commentary on current industry practices in these areas is provided based on the experience of the authors together with the consensus views of the APSGB Drugs in the Lungs Workshop on 10 June 2010 where these topics were discussed in a series of structured debates [1]. Furthermore, consideration is given to the scientific developments and collaborative approaches required for industry to move towards a more efficient paradigm for developing inhaled medicines.
The successful integration of novel drugs with devices capable of delivering defined doses to the respiratory tract has resulted in a proven track record for inhalation as a route of administration that limits systemic exposure and provides localised topical delivery. Thus, a number of orally inhaled products have been developed successfully over the last 50 years, providing symptomatic relief to millions of patients with asthma and chronic obstructive pulmonary disease (COPD) [2]. Inhalation is also a proven means of systemic delivery for drugs that have limited bioavailability by other routes or would benefit from rapid onset of action and a variety of products are in development for this purpose [3], [4].
In recent decades, advances in device design and formulation science have addressed the need for more efficient inhalers that are capable of delivering larger doses to the lung with low extra-thoracic deposition [2], [5]. Once deposited in the lungs, drug disposition (dissolution, absorption, distribution, metabolism and elimination) and the influence of pulmonary pharmacokinetics (PK) on drug efficacy and safety are the critical determinants of clinical outcomes. Pulmonary disposition remains poorly understood despite modern capabilities in imaging, analytical and biological science which make measurement of drug disposition and mode of action more accessible. This raises the question, how can the fate of drugs in the lungs be understood better to allow improvements in current therapy and expedite the development of new inhaled medicines?
In the early stages of drug discovery a sound scientific case is built to rationalise and validate a potential biological target. As a whole, the industry is well versed and able to undertake these tasks in an efficient manner. Once a drug target has been accepted as part of a wider portfolio of mechanisms, the intellectual property around know-how and tractability grows. However, the development of new medicines depends not only upon understanding the disease and target, but also how amenable the drug molecule is to pharmaceutical development. Regulatory guidelines dictate well-defined non-clinical and clinical phases of medicine development, but escalating costs, high attrition (failure to reach market) for novel therapies, poor product differentiation for reimbursement and generic competition are increasingly severe challenges to bringing novel medicines to market.
The success stories in inhaled therapy of lung diseases are restricted to a small number of target classes, notably β2 receptor agonists, antimuscarinic drugs and corticosteroids [6] which for β2 receptor agonists and antimuscarinic drugs are associated with the muscular bronchioles and the airways of the proximal lung. In addition, most inhaled therapies do not modify to any great extent the underlying diseases, although steroids may impart some beneficial effects. In this regard, there is considerable scope to develop novel new medicines which seek to modify respiratory disease processes directly and to embrace respiratory disease areas for which therapy is inadequate or non-existent.
The inhaled route of delivery has always been associated with a considerable challenge in getting the drug to its target. The lungs are a highly complex organ designed to filter inspired air with many different cell types contributing to their function. Furthermore, the lungs may change dramatically when afflicted by disease resulting in an internal environment that works against the drug reaching and interacting successfully with the target. For targets in the upper airways this may have lesser significance, but drug delivery to the deep lung may be impeded by changes such as mucus hypersecretion or thickening, airway narrowing or collapse, fibrosis and poor blood circulation. To mitigate the risk of failing to deliver an inhaled molecule to its site of action, a far greater understanding of the impact of disease on lung pathophysiology is required.
The health and economic burden of respiratory disease [7] not only provides a huge market for inhaled therapy, but also invokes a need to evaluate current practices and identify ways to develop new and better inhaled medicines. In contrast to precedented mechanisms, future drug targets in the lung are likely to be novel and necessitate new classes of molecules, engaging unprecedented mechanisms for which limited biological information is available [7], [8], [9]. For example, new approaches to disease modification will require pulmonary delivery of biopharmaceuticals, genes and small interfering RNA. The pharmaceutical portfolio for delivery by inhalation will be increased further by the emergence of drugs for systemic delivery via inhalation [3], [4] and combination therapies (9). This expansion in the number and classes of drugs for delivery to the lungs will bring new challenges in establishing their safety and efficacy. This is likely to require new methods and collaborative approaches to the way that industry currently develops inhaled medicines, as the achievements of the past will be no guarantee of success in the future.
Development of best practice may require new ways of cross company collaboration that break current conventions. Pertinent questions include:
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How consistent is the industry approach to developing inhaled medicines?
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What are the molecular characteristics that make a good respiratory drug?
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Are standardised validated methods used for drug administration in non-clinical settings?
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Do pharmaceutical companies measure similar parameters and at what stage in the discovery and development cycle are safety and efficacy studies conducted?
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Are toxicological data obtained and reported similarly between companies and is inconsistent reporting of pathology creating a more complex picture for the industry and regulators than is necessary?
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Do the endpoints of clinical trials show sufficient commonality across companies to demonstrate the true value of a new medicine?
Given the considerable challenges outlined above, can pharmaceutical companies continue to work in isolation to develop inhaled medicines or is it possible for cross company collaborations in a pre-competitive environment to increase the future chances of success for all? The latter will depend upon what information can aid not only the progression of targets through the drug development pipeline, but also guide regulatory authorities, payers and medical practitioners to a better understanding of the potential of a new drug. If common barriers and bottlenecks to progression are identified it may be possible to find better ways to develop understanding of inhaled medicines through wider collaborations between industry, academia and contract research organisations. This will need to encompass areas of mutual benefit, while maintaining intellectual property rights which so often tend to stifle innovative approaches. While intellectual property is of great importance to each pharmaceutical company, this need not prevent wider collaboration between companies to develop such assets where the nature of the challenges facing the industry is common.
Pre-competitive collaborations in the pharmaceutical sciences are emerging and being advocated, for example, in the bioinformatics field [10]. In inhalation science, initiatives include the recent publication by the Association of Inhalation Toxicologists (AIT) encouraging a harmonised data-driven approach to calculating delivered dose in non-clinical toxicology studies [11] and the recent U-BIOPRED consortium (unbiased markers for the prediction of respiratory disease outcomes; part of the European Innovative Medicines Initiative), which is seeking to improve the diagnosis of asthma to aid better treatment [12], [13]. In addition, the Cross Company Animal Models group (CCAMS; incorporating pharmaceutical companies, academia and CROs) is seeking to unify models for chronic respiratory diseases and methods used during drug discovery by gaining consensus on those techniques best able to predict a drug effect in vivo. Adoption of best practice would allow common models to be used, reduce the number of animals used overall and aid regulatory authorities by providing comparable data across licensing submissions.
At a time when development costs are rising and payers are seeking greater differentiation as well as value for money for new drugs, the time of stand-alone pharmaceutical companies may be coming to an end. Sharing best practice and undertaking pre-competitive approaches may help to reduce the pathways to developing new medicines considerably. In the following sections we identify current practices, consider common challenges regarding drugs in the lungs and suggest opportunities to galvanize inhaled product development.
Section snippets
Dosimetry in inhaled product development
Accurate dosimetry is essential in studies investigating drug safety and efficacy. At the Drugs in the Lungs Workshop the current opinion of the state-of-the-art concerning methods of quantifying the delivery of inhaled molecules was ascertained by considering: (i) How are non-clinical doses calculated or measured and is this consistent across the industry?, and (ii) Is there a scientific basis to support a more informed approach to guidelines on dosimetry in safety studies?
Inhalation safety studies
Current practices in inhalation toxicology, how these might be improved and the challenges that might benefit from a collaborative approach were considered by asking the question, “what measurements can be used consistently across the industry to establish safety or toxicity to allow regulatory bodies to assess new chemical entities (NCE)?” A rational approach to developing inhalation safety science is of importance to industry and regulators, both of whom have an interest in maximising safety
Pulmonary drug disposition
Key questions considered at the Workshop concerning pulmonary drug disposition were what is the relative importance of intrinsic and formulation-driven PK? What methods are available to determine PK and how are these being applied? What is known about the presence and influence of transporters on the fate of drugs in the lung?
The major advantage of using inhaled medicines to target the lungs is the elevated drug concentration that can be achieved locally in the target tissues after
Pharmacodynamics (PD) in the lungs
The previous section considered inhaled medicines with regard to the factors affecting PK; i.e. the quantitative and temporal relationship between administered drug dose and drug concentration measured in a distinct biological matrix. Whereas PK measures the fate of an inhaled drug molecule, it is PD that defines the quantitative relationship between drug concentration and pharmacological response. Linking PK/PD quantitatively affords an understanding of the relationship between drug dose and
Challenges and opportunities
The factors needed to produce oral compounds with more drug-like properties are defined by Lipinski's ‘rule of five’ [189], [190]. While the lung may be a more complex organ, is it possible to pool data on the physical and chemical properties for inhaled delivery and generate a model that similarly reduces the attrition in development for inhaled compounds? Selecting the right molecule is critical and, although formulation plays a part, the chemical structure ultimately determines the fate of
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This article is based upon an international workshop held by the Academy of Pharmaceutical Sciences Great Britain on 10 June 2010 at GlaxoSmithKline, Stevenage, UK, to launch the Drugs in the Lungs Network. The meeting aimed to identify common challenges facing those undertaking inhaled product development. Details of the Workshop participants, presentations, discussions and the consensus achieved are freely available on the APSGB website [1]. This article by the meeting organisers and expert speakers aims to deliver a more detailed perspective on the topics discussed and conclusions reached at the meeting.