The Who, What, and Why of Drug Discovery and Development

*Correspondence: [email protected] (F.-C. Chen). https://doi.org/10.1016/j.tips.2018.07.004 References 1. General Office of the State Council, China (2018) Opinions of the General Office of the State Council Regarding Improving and Perfecting the Supplies and Policy of Adopting Follow-On Drugs, General Office of the State Council 2. US Department of Commerce (2018) Secretary Ross Announces Activation of ZTE Denial Order in Response to Repeated False Statements to the U.S. Government, US Department of Commerce 3. Statista (2016) The Global Pharmaceutical Industry, Statisita 4. US Treasury (2013) Guidance on the Sale of Food, Agricultural Commodities, Medicine, and Medical Devices by Non-U.S. Persons to Iran, US Treasury 5. Office of the United States Trade Representative (2018) 2018 Special 301 Report, Office of the United States Trade Representative 6. Office of the State Council (2016) Opinions of the General Office of the State Council regarding Deploying Equivalence Evaluation on the Quality and Efficacy of Follow-On Drugs, General Office of the State Council of China 7. ChinaFoodandDrugAdministration(CFDA)(2016)Regulations of Drug Registration and Management, SAIC [in Chinese] 8. China Food and Drug Administration (CFDA) (2015) Technical Guidance for Biosimilar Research & Development and Evaluation (Draft), SAIC [in Chinese] 9. European Medicines Agency (2014) Guideline on Similar Biological Medicinal Products Containing BiotechnologyDerived Proteins as Active Substance: Non-Clinical and Clinical Issues, EMA 10. US Food and Drug Administration (2015) Scientific Considerations in Demonstrating Biosimilarity to a Reference Product—Guidance for Industry, FDA 11. US Department of Commerce International Trade Administration (2016) Top Market Report Pharmaceutical Country Case Study, US Department of Commerce International Trade Administration 12. Unger, B. (2018) An analysis of FDA FY2017 drug GMP warning letters. Pharmaceutical Online January 10 13. International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (2017) Press Release ICH Assembly Meeting in Montreal, Canada, May/June 2017, ICH 14. Graabaek, T. and Kjeldsen, L.J. (2013) Medication reviews by clinical pharmacists at hospitals lead to improved patient outcomes: a systematic review. Basic Clin. Pharmacol. Toxicol. 112, 359–373 15. Jokanovic, N. et al. (2017) Pharmacist-led medication review in community settings: An overview of systematic reviews. Res. Soc. Adm. Pharm. 13, 661–685

Science & Society

The Who, What, and Why of Drug Discovery and Development Glenn Hogan1,2 and Mark Tangney1,2,3,* 848

Inquiry into declining pharmaceutical R&D efficiency has focussed on ‘what’ can be improved, with only brief thought given to ‘who’ can be improved. Here, we argue that enabling people in the idea-toproduct chain to have a more holistic knowledge of the behaviours and incentives of each other can optimise R&D. A New Approach to an Old Problem in Pharmaceutical R&D R&D within the pharmaceutical industry is undergoing a well-catalogued decline. The concept-to-product path for a commercial therapeutic is a long and costly one, with total capitalised expenses approaching US$ 3 billion [1]. Success stories are rare, as the number of marketable medicines that can be found on the hospital trolley or the pharmacy shelf is dwarfed by the sheer volume of products lost along the way in the drug pipeline [2]. The same industry which was once praised for embracing high-quality, disruptive technology (see Glossary) is now criticised for investing its time in developing medicines with marginal benefits over their predecessors [3]. The industry is of course responsible for recently making available important treatments for diseases both rare and common, such as the 2017 approval by the FDA of the first drug treatment for a form of Batten diseasei, as well as the approval of PD-1 and PD-L1 inhibitors that same year for urothelial cancer immunotherapyii. Nevertheless, attrition rates have been steadily increasing across all clinical trial phases over the past two decades, attracting scrutiny of conventional R&D practices in an effort to unearth potential flaws [4]. Resultingly, we are now better informed of the mechanistic elements that could impinge on the economics and functionality of drug discovery and development

Trends in Pharmacological Sciences, October 2018, Vol. 39, No. 10

Glossary Advanced therapy medicinal product: defined by the European Medicines Agency as medicines for human use, which are divided into gene therapy medicines, somatic-cell therapy medicines, and tissue-engineered medicines. Contract research organisation: an institution that is solicited by a biotechnology or pharmaceutical company to perform outsourced research activities on their behalf. Disruptive technology: technology that either establishes a new market or affects an existing market to such a degree that its predecessors become outmoded and their market influence reduced. Marketing authorisation: a document composed by the European Commission for a medicinal product which, when centrally authorised, allows the holder to market that product to patients and health-care professionals in the European Union, provided that the product adheres to certain quality, safety, and efficacy standards. Mergers and acquisitions: business operations in which administrative responsibilities are shared between two companies (merged) or are transferred completely from one company to another (acquired). Monoclonal antibody:: a biological molecule capable of specifically binding to protein targets, allowing it to be used and manipulated for immunotherapeutic applications. Payer: an institution that covers the cost of health care for a patient. Payers can be private (e.g., insurance agencies) or public (e.g., the government). Regulatory authority: a government institution capable of, in the case of medicines, protecting public health by overseeing clinical trials, and ultimately controlling whether medicinal products are accepted or rejected for use in members of the public. Science of Science and Innovation Policy: a project established in the United States to define the ways in which research programmes may best be developed, conducted, supported, and evaluated. Its aims are to determine the most appropriate methods of quantifying and qualifying the impact of scientific research and advise on the development of robust protocols that maximise the worth of R&D programmes. Scientifically novel drug: small-molecule and biopharmaceutical drugs with molecular structures or mechanisms of action not exhibited by other compounds described to date. Small- and medium-sized enterprise: defined by the European Commission as a business with a headcount no greater than 250 employees, and a turnover or balance sheet total no greater than s50 million or s43 million, respectively. Small-molecule drug: a compound comprising chemical functional groups, with a molecular weight normally not exceeding 900 Da.

Box 1. The ‘Who’ of Drug Discovery and Development

Technology transfer office: a constituent of an academic institution that positions itself at the threshold between academia and industry with the aim of commercialising the academic institution’s output. Venture capitalist: an entrepreneur who invests private funds in start-up companies and smalland medium-sized enterprises, with the aim of encouraging growth in the business and acquiring long-term returns on investment.

Health-care products are carried through obstacles, or ‘gates’, from concept to market by individuals or groups who vouch for them (promoters; Figure I). Any actor who takes an active, pioneering role in conveying a medicine from concept to product, by building value into it such that it can oppose whichever forces keep the gate locked, can be considered a promoter (e.g., public-sector research institutions and pharmaceutical companies). Gates are maintained by ‘gatekeepers’ – individuals or groups who deliberate on whether the product makes it past the checkpoint. They can range from public (government) and private (venture capitalist) investors who may approve or disapprove of a product on commercial grounds, to regulatory authorities who hold a product up against strict efficacy and safety criteria. These obstacles necessitate wide-angled expertise on the promoter’s part to permit a smooth transition from one gate to the next. This requires the product to change hands several times between bench research and regulatory approval. Market-approved products are brought closer to the end user (i.e., the patient), where payers weigh up the financial consequences of including the therapy in their budget, and physicians compare the clinical value of the product with the current standard of care. Finally, at the peripheries, but still crucial, are the ‘facilitators’. These are distinguished from promoters in that, while they may be similarly proactive and focussed on product progression, their role is ancillary (e.g., technology transfer offices and contract research organisations).

[5], and while this is integral to appreciating the vulnerabilities of R&D, we question whether we owe more consideration to the human side of the issue. Health-care products are conceived, crafted, and judged by humans, and thus a comprehensive knowledge of drug discovery and its pitfalls is achieved by understanding not only technical aspects of R&D, but also by understanding the people who influence triage from idea through to market. This concept is of increasing importance to scholars who attempt to provide an evidence-based rationale for

advancing public and private scientific policy (e.g., Science of Science and Innovation Policy). To frame our discussion, we illustrate here a people-centric R&D model, populated by ‘actors’ who serve different functions in the idea-toproduct timeline (Box 1).

Putting a Face to the Name: Who Does What, and Why? Big pharmaceutical companies dominate small-molecule drug discovery, and drug discovery in general [6]. However, ‘scientifically novel’ drug discovery

elicits a different trend wherein biotechnology companies come to the fore, while big pharma’s influence becomes less prominent. The readiness of an industry to grapple with the unknown is predictive of its longevity, and the sustainability of the pharmaceutical industry itself relies on investment in creative, high-risk R&D [7]. Although scientifically novel drugs are to some extent unknown, they comprise compounds like small-molecule drugs and monoclonal antibodies, for which we have decades of clinical trial data and long lists of market-approved products. By contrast, advanced therapy medicinal products (ATMPs) have only recently reached the market both in Europe and in the United States. They could therefore be considered ‘historically novel’ agents, and a closer approximation of the unknown within the pharmaceutical industry.

Key: Gatekeeper Promoter

Government

Facilitator Stage (a) basic research

Concept

Grants

Stage (b) preclinical op misa on and clinical trials Phase I/II

Public sector research ins tu on Commercialisa on of life sciences research

Tech transfer offices

Knowledge transfer, enhanced research via industry colabora on & commercial gain via patents

Private investor

Regulatory authority

Investments

Regulatory approval

Small biotechnology company Outsourced research

Big pharma

(Op onal) merger & acquis on

Stage (c) clinical trials phase III

Private investor

Regulatory authority

Payer

Physician

Investments

Regulatory approval

Purchase

Prescrip on

Favourable product characteris cs & availability of capital and qualified personnel

GCP demonstra on of clinical safety and efficacy

Stage (d) end-user benefit

Biotechnology company/ big pharma Favourable product characteris cs & availability of capital and qualified personnel

GMP & GLP demonstra on of preclinical safety and efficacy

Provision of R&D skillset, improved financial stability & enchanced investment opportuni es

Outsourced research

CROs

CROs

Hospitals

Hospitals

Approved product Pa ent need &

cost-effec veness of product

Clinical need for therapy

Pa ent

Figure I. A People-Centric R&D Timeline. A depiction of the array of individuals and organisations involved in bringing a medicinal product from concept to market. The auxiliary role that facilitators provide to promoters is indicated by an arrow pointing from the facilitator. Each stage is divided from the next by gates, each represented by a lock and key. Actions that unlock each gate are indicated by an arrow pointing from each gatekeeper. Conditions that favour the movement of a medicinal product from stage to stage are described underneath each lock and key. CROs, contract research organizations; GLP, good laboratory practices; GMP, good manufacturing practices.


849

Since 2009, the European Medicines Agency (EMA) has granted marketing authorisations for 10 ATMPs, of which three have already been either withdrawn or suspended (ChondroCelect, MACI, and Provenge) and one has expired without renewal (Glybera)iii. Public statements issued by the EMA highlight that commercial factors resulted in the withdrawal of ChondroCelectiv and Provengev, the absence of an authorised manufacturing facility prompted the suspension of MACIvi, and lack of demand resulted in the nonrenewal of Glyberavii. Each of these ATMPs followed a common track in which discovery and development were overseen by small- and medium-sized enterprises (SME) with collaborative input from large firms occurring long after clinical trials commenced, if at all. Glybera, for example, was discovered and developed by the SME Amsterdam Molecular Therapeutics and first trialled in patients in 2005 [8], eight years prior to Chiesi Farmaceutici’s involvement with the productviii. ChondroCelect and Provenge were discovered and developed solely by SMEs (TiGenixix and Dendreon Corporationx, respectively), and MACI (discovered and developed by the SME Verigen AGxi) was acquired by Genzyme in 2005, seven years after the product was made available in several European countries, Australia, and parts of Asiaxii.

company is unfamiliar can signal a disturbance to its viability [10]. In addition, given the austere regulatory environment and considerable financial risk that pervades the pharmaceutical industry, it is understandable that these groups appear reluctant to commit to novel R&D projects in their early stages, however detrimental it may be to R&D productivity.

Each R&D actor is accustomed to asking questions addressing problems pertinent to their immediate circumstances, causing those questions to be answered diffusely across the entire timeline. Ideally, questions that reveal salient information about a therapy should be answered at the beginning of drug development projects. It can be proposed therefore that the sooner that actor coordination occurs, the greater the benefit to R&D productivity. There is evidence that big drug companies already possess a sophisticated approach to R&D in terms of the way they form collaborative networks between themselves and external partners [4]. While we agree that large firms have made progress interfacing with R&D programmes at earlier stages through collaboration, our analysis of market-approved ATMPs (see aboveiii–xii) suggests that this has not translated into critical, early stage collaborations in highrisk, innovative zones of drug discovery. The disconnect between the R&D actors is at its core governed by human attitudes The revocation of ATMP marketing author- towards risk and can only truly be appreisations for primarily commercial reasons, ciated by probing the motivating factors and not due to postmarketing surveillance behind institutional behaviours. detecting safety and efficacy concerns not observed in clinical studies, is revealing. Appreciating Actor Risk Small biotechnology companies are often Preferences and Motivations reliant on larger firms for marketing and We reason that novel R&D projects fail at manufacturing expertise [9], and delayed least in part due to the risk appetites of the evaluation of late-stage issues like these various actors being at odds with one even at the discovery phase could have another, further causing the actors to dramatic effects downstream. However, sequester themselves in different parts big corporations with up-and-running of the R&D timeline (Box 2). Alongside pipelines are often comfortable with stick- this, we believe that there is a tendency ing to what they know best, and the emer- in the literature to prematurely and unjusgence of a new technology with which the tifiably confine the R&D actors to specific 850


roles. We are used to placing the actors of R&D into isolated boxes based on how we expect them to operate, allocating small biotechnology companies and academia to drug discovery, and big pharmaceutical companies to drug development. Big pharma is increasingly being viewed as a generalist with a creativity deficit, and is noted for its predilection for mergers and acquisitions (M&A) that help it profit from the labour of smaller, more inventive companies [11]. Sometimes it is acknowledged that drug discovery can in fact take place in big pharmaceutical corporations, but even in these instances the phrase ‘discovery research’ is omitted from a list of their strengths [12]. Novel therapies are likely to be discovered in a public-sector research institution (PSRI) or small biotechnology company outside of a collaborative context, and are later acquired by larger corporations, primarily because big drug companies are required to cope with the extraordinary costs of late-phase clinical testing [13]. Such sequential transfer of technology creates ‘distance’ between early and latestage actors, resulting in underinformed design of the product and a fragmented knowledge of the technology as it changes hands, ultimately diminishing success rates. Although fledgling biotechnology companies have tremendous flexibility, their futures are uncertain as SMEs sparingly have the occasion to engage multiple unsuccessful projects before they become financially exhausted [14], leaving them with little room to ‘get it wrong’. Incentivising the R&D actors to collaborate before a product’s design is finalised would be supportive in this respect. This, of course, raises the question of how a quid pro quo relationship should be drawn between large drug companies, PSRIs, and SMEs to bring them together at the outset of R&D projects. Large drug companies, being more

Box 2. Teasing Out Actor Compatibility Issues in the R&D Timeline Navigation of the various gatekeepers, an unavoidable reality of drug R&D, can arguably be accomplished only by actors in the later stages of the R&D timeline. However, late-stage actors are risk averse, while early stage actors are risk tolerant. As successful R&D projects are low-probability events (as outcomes are highly uncertain, especially at the concept phase), the early stage actors are arguably better placed to undertake drug discovery projects as their high risk tolerance allows them to initiate and manage R&D projects at critical points. We illustrate such a risk/strength compatibility issue in Figure I. Academic drug discovery is largely directed towards historically novel drugs because they represent a happy hunting ground for breakthrough scientific findings. Similarly, the risk tolerance and agility of young biotechnology companies allow them to carve out a path using disruptive technologies that are relatively inaccessible to conservative, less adaptable larger companies, thereby giving them an entry point into the R&D arena. Public-sector research institutions (PSRIs) and small biotechnology companies could therefore be said to have a duty to incorporate gatekeeper preferences into their activity. Small biotechnology companies, possessing the optimal blend of risk tolerance and gatekeeper navigation skills, may be the best actor to ‘curate’ the drug development cycle.

Approved product

Concept

Risk tolerance

Gatekeeper navigaƟon skills

PSRI

Small biotechnology company

Big pharma and big biotech

R&D actors Figure I. Actor Aptitudes across the R&D Timeline. The degree to which fundamental R&D attributes (gatekeeper familiarity and risk tolerance) are expressed in the R&D timeline by the R&D actors. In being stationed at the extremities, PSRIs and big drug companies have developed a skewed skillset in favour of one attribute over the other. An ideal balance of both attributes coincides with the small biotechnology company, found within the middle ground of the R&D timeline.

intimately at the frontier between regulated and unregulated medicines than any other R&D actor, are ideal counsellors on the selection of appropriate patient cohorts, providing advice on adverse drug reactions and adverse events, and clarifying the existence of a clinical need for the therapy. If industrial companies delay their participation and instead opt to inherit the ill-crafted

produce of academic institutions downstream of the discovery stage, it may be too late for their input to correct any design flaws. Universities are criticised for being out of touch with industrial standards [15]. However, successful universities are adept at both basic research and entrepreneurial activity [16], and the output of a university will have a greater likelihood of being marketable if its

research programmes are market informed. This should encourage academics and big pharma to seek out connections with each other at the earliest opportunity, so these differences can be negated. These partnerships would hugely benefit not only big pharma, but also small biotechnology companies, which depend on universities to create successful products [17].


851

Concluding Remarks

ix

Were the actors at all stages to more fully appreciate each other’s risk preferences and motivations, it may permit more optimal project initiation, design, and progression processes. Prescribing a single standard operating procedure to facilitate such interactions is a naïve aspiration, and optimal success in this context is likely to be derived from a portfolio of approaches appropriately targeted at actors. For example, innovative approaches to bestowing an understanding of actor behaviours on individuals (educational vehicles on ‘human practices’) could play an important role here, in addition to a focus on funding mechanisms that promote outsourcing of industrial research to PSRIs (technical practices).

x

One of the surest ways of tackling declining R&D efficiency may involve reconsidering our own attitudes and instigating a cultural shift in the industry. If the intellectual ideas of humans serve as the raw material for fully formed therapies, these ideas will be optimised if the people from whom they come are likewise optimised. Resources i

https://www.fda.gov/newsevents/newsroom/

pressannouncements/ucm555613.htm ii

https://www.nature.com/articles/

d41586-017-08703-6 iii

http://www.ema.europa.eu/docs/en_GB/

document_library/Presentation/2018/03/ WC500246465.pdf iv


document_library/Public_statement/2016/08/ WC500211564.pdf v


document_library/Public_statement/2015/05/ WC500186950.pdf vi


document_library/Public_statement/2018/07/ WC500251497.pdf vii


document_library/Public_statement/2017/10/ WC500237864.pdf viii

https://www.sec.gov/Archives/edgar/data/

1590560/000104746914000006/a2217855zf-1.htm

852

https://adisinsight.springer.com/drugs/800021407


xi


xii


document_library/ EPAR_-_Public_assessment_report/human/002522/ WC500145888.pdf

Spotlight

Pulmonary Ionocytes Challenge the Paradigm in Cystic Fibrosis

1

SynBioCentre, University College Cork, Cork, Ireland Cancer Research@UCC, University College Cork, Cork, Ireland 3 APC Microbiome Ireland, University College Cork, Cork, 2

Finn J. Hawkins1,2,* and Darrell N. Kotton1,2

Ireland *Correspondence: [email protected] (M. Tangney). https://doi.org/10.1016/j.tips.2018.08.002 References 1. DiMasi, J.A. et al. (2016) Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econ. 47, 20–33 2. Hay, M. et al. (2014) Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40–51 3. Munos, B.H. (2013) Pharmaceutical innovation gets a little help from new friends. Sci. Transl. Med. 5, 168ed1 4. Mignani, S. et al. (2016) Why and how have drug discovery strategies in pharma changed? What are the new mindsets? Drug Discov. Today 21, 239–249 5. Scannell, J.W. et al. (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug Discov. 11, 191–200 6. Kneller, R. (2010) The importance of new companies for drug discovery: origins of a decade of new drugs. Nat. Rev. Drug Discov. 9, 867–882 7. Meier, C. et al. (2013) Can emerging drug classes improve R&D productivity? Drug Discov. Today 18, 607–609 8. Bryant, L.M. et al. (2013) Lessons learned from the clinical development and market authorization of Glybera. Hum. Gene Ther. Clin. Dev. 24, 55–64 9. Yang, H. et al. (2013) Exploration or exploitation? Small firms’ alliance strategies with large firms. Strateg. Manage. J. 35, 146–157 10. McNamee, L.M. and Ledley, F.D. (2012) Patterns of technological innovation in biotech. Nat. Biotechnol. 30, 937– 943 11. Gautam, A. and Pan, X. (2016) The changing model of big pharma: impact of key trends. Drug Discov. Today 21, 379–384 12. Fishburn, C.S. (2013) Translational research: the changing landscape of drug discovery. Drug Discov. Today 18, 487– 494 13. Lipton, S.A. and Nordstedt, C. (2016) Partnering with big pharma—what academics need to know. Cell 165, 512– 515 14. Löfsten, H. (2016) Business and innovation resources: determinants for the survival of new technology-based firms. Manage. Decis. 54, 88–106 15. Whitty, A. (2011) Growing PAINS in academic drug discovery. Future Med. Chem. 3, 797–801 16. D’Este, P. and Perkmann, M. (2011) Why do academics engage with industry? The entrepreneurial university and individual motivations. J. Technol. Transf. 36, 316–339 17. Bstieler, L. et al. (2014) Trust formation in university–industry collaborations in the U.S. biotechnology industry: IP policies, shared governance, and champions. J. Prod. Innov. Manage. 32, 111–121


Two recent studies have identified novel airway cells termed pulmonary ionocytes that express higher levels of CFTR than other airway cells express. These findings raise new questions in the evolving debate about the physiological role of CFTR in lung epithelia and its importance in the pathogenesis of cystic fibrosis (CF). The application of a new technology, single cell RNA-sequencing (scRNAseq), to an old problem, interrogating the heterogeneity of lung cell populations, is expected to alter our understanding of lung epithelial cell biology. Using this new technology, two groups recently identified a novel cell type in the airway epithelium [1,2]. These rare, previously uncharacterized cells, now called pulmonary ionocytes, appear to play a role in airway surface physiology and are implicated as potential players in the pathogenesis of CF. These findings raise fundamental questions about our understanding of CF and are likely to change many aspects of research aimed at therapeutics for this disease. CF, the most common genetic lung disease, affects approximately 70 000 individuals worldwide. This monogenic, recessive disorder is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. CFTR encodes an anion channel that contributes to the hydration and pH of airway secretions.