Low hanging fruit in infectious disease drug development
Introduction
Two decades after the advent of the antibiotic era there was a prevailing belief that infectious diseases were soon to be part of a closing chapter in the history of human medicine. It is not clear from where the quote originated, but the statement that “It is time to close the book on infectious diseases, and declare the war against pestilence won [3]” seems to have captured the zeitgeist. Six decades have now passed since the first randomized controlled trial in infectious diseases was initiated [4], and the chapter on infectious diseases has not closed. Rather, infectious diseases remain an ever-present and changing threat to human health, considered the second-leading cause of death globally, directly resulting in approximately fifteen million deaths annually [5].
At least four crucial factors have contributed to the persistent demand for innovative anti-infective products in the global marketplace: (1) consistent development of drug resistance by targeted pathogens, (2) the re-emergence of pathogens previously considered controlled or of declining significance, (3) the identification of new pathogens, and (4) the very real threat of bioterrorism [6, 7, 8, 9, 10]. These factors have resulted in the growth of the global infectious diseases marketplace (anti-bacterials, anti-virals, anti-fungals, and vaccines) to an estimated $48.5 billion in annual sales with projections to exceed $60.6 billion by 2011 [11]. Challenging the growth of this market are obstacles intrinsic to this clinical area [1], including: indications that require short courses of therapy, a marketplace that is highly competitive, and competition from generic drugs that is shrinking revenues for innovator companies [2].
Compounding the specific challenges of anti-infective drug development are the industry-wide difficulties of rising costs and shrinking pipelines. Estimated development costs for a NME are now exceeding $1 billion, pharmaceutical marketplace shareholder value loss is estimated to be in excess of $850 billion and only three of ten drugs that reach the marketplace recouping their respective development costs [12, 13, 14, 15].
There are multiple reasons for the increasing costs, both in time and money, for drug development programs. Most salient is the increased requirement of study participants [12, 16] but other factors have also become more prominent in the past decade, including increased safety requirements, fewer first round approvals, increasing size of submitted new drug applications, increasing complexity of studies, increasing number of advisory committee reviews, declining investigator participation rates, and declining patient participation rates [17, 18, 19]. The ultimate results are costlier trials with longer development timelines [20]. The specific shortfalls in anti-infective drug development have led to a concerted response from the infectious disease community, calling for a change in the business model so that issues such as lower profitability do not hinder the development of life-saving therapies in an era of increasing drug resistance and sponsor divestment [2, 9, 21, 22•].
Section snippets
Stakeholder responses to drug development challenges
There are a number of responses to these shortfalls from concerned professionals in academia, government, and industry. There has been a clarion call from the infectious disease community asking stakeholders to address the growing crisis in antibiotic drug development, with recommendations directed at Congress, the United States Food and Drug Administration, and the National Institute of Allergy and Infectious Diseases [23]. Some changes have indeed occurred. There are new sources of funding, a
Secondary use of health care data in drug development
A clinical trial that is delayed as a consequence of new amendments, is unable to recruit patients, cannot secure the interest from targeted investigators, or has an inappropriate design to meet regulatory requirements can not only result in a large financial burden but can also result in the need for more trials or simply registrational rejection. Opportunities do however exist for identifying and correcting such errors earlier in the development lifecycle and for limiting the likelihood of
Regulatory precedent
Given that more than 50% of New Drug Application (NDA) submissions to the US FDA have received marketing approval from another regulatory agency there is more often than not relevant pre-randomization data that can add substantial value to a US FDA submission [35]. There are multiple examples among recent anti-infective development programs where standard requirements for large trials and development timelines have been curtailed through the use of such data. Tinidazole (Tindamax, Presutti
Study planning
The use of non-confidential data available in the public domain either free or for purchase for the purpose of decision-support in drug development has recently been described as ‘Open Source Intelligence (OSINT)’ [40••]. Such data sources include information related to genomic targets, disease epidemiology, trial design and competitive intelligence. When integrated into planning workflow they can have a dramatic impact on cost and timelines since modeling study variables such as, investigator
Study execution
Evidence-based study planning permits the tailoring of inclusion and exclusion criteria, selection of appropriate countries and sites based on disease prevalence data, and allows drug sponsors to forecast patient recruitment estimates, crucial for budget management. In many ways this can be considered the ‘operational epidemiology’ of a clinical trial, characterizing the patient pools, assessing countries with the most favorable political and economic infrastructure for study conduct as well as
Conclusions
Infectious diseases drug development has changed considerably since Amberson used a coin toss to allocate patients in his pulmonary tuberculosis trial [50]. Although we face the obvious challenges of emerging and re-emerging pathogens, drug resistance, and anti-microbial stewardship to prolong the utility of developed compounds, we also face the rising costs of drug development associated with patient recruitment and data management. There are low hanging fruit available to all stakeholders in
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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