IV.2	Translational Pathway for Drug Development

A. Introduction

In a NEJM Editorial in 2005, Elias Zerhouni started his manuscript by stating “It is the responsibility of those of us involved in today’s biomedical research enterprise to translate the remarkable scientific innovations we are witnessing into health gains for the nation” (23). It is indeed an ideal, and probably a highly desired objective, for each clinician or biomedical researcher to see the results of his/her work being developed into a product that will eventually be made available for a broad range of patients. One must admit, however, that the stream that starts with an idea, a project initially developed and studied in a standard academic framework, and leads to a registered drug is traditionally understood by most academicians as complex, lengthy and expensive, and is thus often not met with enthusiasm. In addition, the progressive and increasing involvement of various specialized partners throughout this development confine, with time, the importance of the clinician-inventor to a second role (5).

Typically, clinicians and bio-researchers lack education and guidance in strategies and management of biomedical innovation. Also, regulatory aspects of drug development are excluded from their training. Understanding and interest regarding the hurdles encountered by sponsors in assembling a drug registration dossier for market approval is therefore limited. Indeed, it is true that the primary interests of academicians are radically opposed to those of pharmaceutical and biomedical companies; the former are encouraged to rapidly publish results and generate scientific impact factors, while the latter are keen to obtain patents, licenses and other rights to further develop and commercialize one or several products. Entrepreneurship remains excluded from traditional academic biomedical training, and aspects such as patents and start-up creations, for example, are usually not considered in institutional, national or international ranking systems. It is therefore understandable that most clinicians and academic researchers may be reluctant to invest their efforts in the development of new compounds. Nevertheless, the obvious complementarities between academy and industry are key for further pharmaceutical and biomedical development. The role of translational medicine is to link all parties with the aim of increasing the rate of successful development.

B. The Translational Way of Thinking: “Make it Happen!”

In the past, pioneer cardiologists and cardiac surgeons took advantage of their own laboratory platforms, not only for training purposes, but also to evaluate new ideas, approaches and hypotheses that could improve the quality of their daily activities. They eventually returned to the clinic or operation theater with possible solutions. This is how the concept of cardiopulmonary bypass was developed, as the instrumentation was found to be necessary for better surgical access to the heart. Similarly, this is also how Hans Juergen Bretschneider, David Hearse and Gerald Buckberg described their cardioplegic solutions, respectively the Bretschneider solution in 1975 (also called HTK, Custodiol®), the St-Thomas solution in 1976 (Plegisol™) and the Buckberg solution in 1978 (blood cardioplegia). Interestingly, more than 35 years later, these 3 cardioplegic solutions are still used, with only slight modifications or adaptations, by most cardiac surgeons worldwide (13). The situation has changed over time for several reasons including regulatory and financial constraints. In essence, clinicians’ freedom to operate is now critically reduced. For instance, our clinical and research group in Berne has developed a new cardioplegic solution (Cardioplexol™, Bichsel AG, Interlaken, Switzerland), which has shown, in clinical settings, several advantages over existing solutions. A low dose single-shot (100 mL directly injected by the surgeon into the aortic root) is accompanied by an immediate cardiac arrest (typically <8 seconds) and prolonged myocardial protection (45 minutes), making this simple solution very attractive. Although most other widely used cardioplegic solutions are not registered in the majority of countries worldwide, this new solution must be evaluated and pass through the entire regulatory process before possibly becoming available to the international cardiac surgery community. Given commercialization of such a solution is not the direct interest of our institution we opted to create a start-up company (Swiss Cardio Technologies AG) for the further development of this solution; making it compatible with regulatory norms defined for this category of medication.

Today, with only rare exceptions, physicians and clinical scientists seem to have forgotten about their possible roles as innovators and their opportunity to lead creative developments. In fact, the roles of academic and industrial partners have been reversed with time, as ideas are now largely generated by the industry, with a limited number of academic centers acting as consultants during development phases, or testing products in preclinical and/or clinical studies.

Reasons why Translation is Met with Reluctance

Several reasons, including cultural and possibly generational aspects, may explain the persistent, or even widening gap between academy and industry in terms of innovation. It is indeed interesting to notice that translating a scientific idea into a commercial product is not part of the typical medical culture (anymore). Despite large governmental and institutional efforts in several countries are offering management or business introduction courses free of charge, the number of participants from the medical field remains very limited. Conversely, students following technical and engineering classes seem more motivated to incorporate the entrepreneurial culture early in their curriculum. It is true that physicians devote numerous, intensive years, first for their studies and later for their training, in order to become an effective practitioner. In addition, it is rare that physicians fail to find a position after their training and once established, pecuniary conditions generally remain attractive. There is, therefore, no critical need for innovation as a practicing physician. It is also true, that only few physicians will find conditions, such as dedicated time and financial support, allowing them to initiate and develop their own research and development project. As a consequence, they rapidly lose the opportunity to develop their curiosity and creativity and, therefore, their potential for innovation.

Most academic institutions have introduced well-organized technology transfer offices (TTO), which are supposed to assist academicians in protecting and developing their ideas. However, these structures tend to passively wait for opportunities instead of actively checking within their institution for ideas and projects with good potential for further industrial development. Importantly, with their deep involvement over long time periods, most specialists do not even see their idea or concept as a potentially successful translational product. It should thus be the role of TTO to actively screen their institution for ideas with commercialization potential.

Physicians and researchers also tend to understand translation as a complex, long and expensive process during which their role, of inventor, will decrease progressively but rapidly. Intellectual property and regulatory processes, for instance, are aspects that require the support of external specialists with whom their ideas must be shared. However, not only does formulating ideas or results in forms other than scientific publications represent something for which academicians are not trained, but in addition, initial IP costs may need to be covered by the institution, most probably from the research budget. In addition, obtaining patents and creating start-ups are criteria that are normally not taken into account for ranking calculations.

The number and variety of persons involved along the translational pathway have dramatically increased over the years, so that a direct link between the academician, who initiated an innovation, and the businessperson, who will eventually make it a financial success does not exist anymore. Pure clinicians tend to lose their access to research facilities because of a lack of time or more specifically due to the increasing time demands of clinical training and duties. In other words, over time, every link, particularly physicians, has become more specialized, and, therefore, more removed from the big picture. The time when pioneers tested their own laboratory discoveries in their patients is obviously over.

Critical Role of Academicians in Translational Medicine

It is critical to remember that clinicians play critical and privileged roles in both generating and testing new ideas. First of all, with their constant patient interaction, i.e. where the demand for a therapy meets its application, clinicians are in the best position to make an analytic synthesis of the patient’s needs, taking into account not only technical and ethical, but also economic and political considerations. Most clinics also run registries, which represent large collections of data that can be used for retrospective statistics and quality analysis, but also for the planning and design of prospective studies. Clinicians are in the position to reliably identify current and coming needs, and to critically influence decisions regarding future development (3,20).

Clinicians and researchers are also actively needed during preclinical and clinical studies. Whereas preclinical studies may well be outsourced, albeit with much higher costs, for clinical studies, there is obviously no alternative to collaborations with clinicians. Surprisingly, very few clinics that participate in such trials receive sufficient financial support from the industrial partner to cover their related internal costs. The possible competition among clinical centers for selection as clinical investigators appears to prompt many clinics to cover a substantial part of the costs related to their own participation.

Once a product has been launched, scientific publications and communications that have been produced during the translational phase are usually used for marketing purposes. Similarly, the high competence and expertise of some clinicians may lead to their consideration as opinion leaders, which, in turn, can constitute an asset for the company owning the product.

Therefore clinics and clinicians are partners necessary in product development. Clinicians must recognize this value and make better use of it.

Translational Research Units

Translational research thus starts with a new way of thinking. It now needs an organization that facilitates its application and eventually its success. Nowadays, since innovation mostly results from the right combination of technologies (nano- and bio-technologies for example), or the adaptation of one technology for another purpose, it is important to establish a structure that will facilitate these types of interactions; that will encourage people to meet their peers, interact with each other and share their knowledge and competence. Taking advantage of someone else’s know-how is certainly motivating and, conversely, assisting someone else with his/her own experience may be rewarding. Our research and development unit in Berne is organized as described in Fig. 1 and allows the involvement of persons from various backgrounds (surgeons, non-surgeons, biologists, engineers, data-managers, study nurses and statisticians), (7). This approach allows us also to rapidly integrate new collaborators, even for short periods, and permit them to actively contribute to an ongoing project with a tangible finality, in other words, a project in which the new participant can identify him/herself. This platform and the flexibility it allows is not easy to establish as it requires the strong commitment of each collaborator to transparency, honesty and team spirit (www.cardiovascular-research.ch). Obviously, it is essential that each member has a clear understanding of others’ critical roles in the development of the project, and that each contributor is thus recognized as a necessary element that will eventually allow successful completion of this phase in development. This culture of sharing the ups and downs of early phase of development may help to prepare our researchers to accept that successfully bringing the project to the next step may require that further specialists take control, and so on.

C. The long Road Towards Successful Translation

It is commonly recognized that approximately 12 to 15 years of development and regulatory processes are required for a compound to receive approval and eventually reach patients (Fig. 2). The typical developmental story of a drug reaching the market can be separated into a series of sequential steps. These consecutive phases are critical for the good management and execution of a project, but also to keep track of results and document and maintain good laboratory and clinical practices.

Drug Discovery Phase

The drug discovery phase is an initial phase that includes the identification and validation of a molecule or compound possessing a specific activity against a precise target, such as a protein that is seen as critical in the development of a particular disease. The drug discovery phase is mostly undertaken in academic institutions. This phase includes a detailed understanding of the disease mechanism, identification of a target that is specific for this particular disease, and running of series of experiments both in vitro and in vivo that demonstrate the biological activity of the drug candidate via its target.

Preclinical Phase

Once identified as a potential drug candidate, the compound enters a preclinical phase aimed at providing baseline evidence of its safety. A careful analysis of the available literature together with a series of standardized tests in vitro and in vivo from GLP (good laboratory practice) certified laboratories is required by regulatory authorities for evaluation of the compound’s primary and secondary pharmacologic effects, as well as possible toxicity. GLP is defined as a set of principles providing a framework that a laboratory rigorously follows for planning, performing, monitoring, recording, publishing and archiving data. A laboratory must pass a series of tests to achieve “GLP” certification. In this way, regulatory agencies gain assurance that scientific principles, experiments, and data are carefully obtained and monitored. Not only does the primary mechanism of action on the target organ or tissue need to be clearly documented (efficacy), but the pharmacokinetic aspects of the compound, including its absorption, distribution, metabolism and excretion must also be evaluated. The toxicity analysis represents a critical part of this evaluation stage, comprising descriptions of carcinogenicity, genotoxicity and reproductive toxicity risks. Finally, the interaction of the compound with other drugs must be examined.

Investigational New Drug Application (IND)

IND approval by the regulatory authority is necessary before commencing clinical trials. Submission of an IND is therefore obligatory and represents the first step of regulatory authority evaluation of the compound, its structure, production and effects. The IND is a document that recapitulates the information and investigations collected by a sponsor regarding the drug candidate. The IND confirms the absence of known issues that could compromise patient safety. The process provides an opportunity for the sponsor to meet with the authorities, as part of a scientific advisory meeting, in order to discuss the design of further clinical trials.

Clinical Trials Phase I

Phase I clinical trials evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of the drug candidate in healthy adult volunteers. Phase I clinical trials are usually conducted in a limited number of persons (typically between 20 and 80).

Clinical Trials Phase II

Phase II clinical trials are primarily aimed at determining the optimal dose that should be administered. Short-term side effects are also evaluated. Studies are conducted in volunteer patients and typically include a larger number of persons (typically between 100 and 300).

Clinical Trials Phase III

Phase III clinical trials may be considered as the most critical. Phase III clinical trials demonstrate statistical evidence for the safety and efficacy of the drug candidate in a larger and more heterogeneous patient population. Usually, several thousands of patients are enrolled and several recruiting centers (multicenter trials) are involved. Phase III clinical trials last longer and require large financial investments. The failure rate during this last clinical phase is estimated to be around 50% (16).

New Drug Application (NDA)

The NDA is a large document submitted by the sponsor to the regulatory authority, which groups all technical, scientific and clinical information as well as evidence regarding the drug candidate’s safety and efficacy. Once approved, the drug receives market authorization in a country or region pre-specified in the NDA, and becomes available for patients.

Clinical Trial Phase IV

In some situations regulatory authorities may require post-marketing (Phase IV) clinical studies, which are aimed at monitoring possible long-term safety issues as a condition for approval. In any case, companies are compelled to provide the authorities with periodic reports that include quality control data and the descriptions of further adverse events.

D. Innovation and its Protection

Patent protection should be initiated at a very early stage, ideally shortly after the drug discovery phase, but must be in place before making the invention available to the public, i.e. before publication of an article or oral presentation at a meeting.

In most jurisdictions, public disclosure of the invention before the filing of the related patent application constitutes sufficient grounds for rejection, i.e. lack of novelty. Some countries, such as the USA, provide a grace period, for instance of one year, which may avoid the otherwise inevitable rejection of the patent application. But such a remedy should not be viewed as adequate. The general rule is that fast patent filing must be respected.

Generally, patents will be granted for an invention, in any field of technology, provided that it is new, not obvious, and suitable for industrial application. There are however some exceptions to patentability. In Europe for instance, Article 53 of the European Patent Convention states that patents “shall not be granted in respect of methods of treatment of the human or animal body by surgery or therapy and diagnostic methods practiced on the human or animal body” (www.epo.org). However, this provision does not apply to products, in particular substances or composition or medical instruments, for use in any of these applications.

In general, patents covering a physical entity (NME, composition, etc.) are stronger than patents covering a physical activity (method of use, manufacturing process, etc.). New molecular entities (NMEs) are certainly the most valuable objects to patent because they may cover a molecule taken as such, without limiting the scope of protection to a specific therapy. Nonetheless patents claiming a drug for a specific use or a pharmaceutical composition may also constitute a strong strategic asset. The same may also apply to a pharmaceutical formulation, for instance a slow-release formulation.

Manufacturing processes may also be patented, but in some circumstances it might be more appropriate to maintain confidentiality. Indeed, one should not forget that a patent document is a publication and, as a consequence, the possibilities for patent protection may be compromised if processes are disclosed.

Other forms of protection may be used, in addition to or without patent protection. Supplemental Protection Certificate (SPC), Data exclusivity on a New Drug Application, and orphan drug status are all possibilities that can be leveraged.

The patent term is usually 20 years, starting from the filing date. In some cases, this protection may be extended. For instance, SPC protection may be obtained for a pharmaceutical product for which a substantial amount of time, usually at least 5 years, is required between patent application filing and market approval. The patented product, which is commercialized, may benefit.

Data exclusivity is a protection, which is not directed to the product itself but to data contained in the NDA file. Access to these data by parties other than the sponsor and regulatory offices is usually protected for a period of 10 years and therefore, data contained in such a file cannot be exploited by a third party. This kind of protection is certainly one of the strongest against generics companies.

The orphan drug status may apply to drugs that are under development for treatment of rare diseases. This status provides tax reductions and exclusive rights to the cure for a specific condition for a period of several years (seven years in the USA).

E. Financial Aspects (from a start-up to a large company)

According to recent pharmaceutical company analyses, only 5-10 out of approximately 10,000 compounds reach the clinical trial phase and only one or two of them eventually receive market approval (Fig. 2). According to Deloitte Consulting and Thomson Reuters research, costs associated with these developments are typically in the range of several hundreds of millions of dollars, and it is estimated that only 2 out of 10 approved drugs will generate revenues that cover or surpass investments of its R&D (4). There are high financial risks in pharma development, but it is more likely the rather pessimistic evolution over the last two decades that makes current perspectives of venturing into new pharmacologic development less than encouraging (Fig. 3). For instance, a recent report confirmed the trend towards a slow decrease in the number of yearly NME approvals, while global costs invested in pharmacologic development approximately doubled over a 10-year period. This problem has been recognized by governmental and registration authorities (5,17,22). Sub-optimized management strategies of R&D units may have contributed to this evolution (4). Earlier decisions to stop further development of a substance would certainly have spared a lot of money for industry through the years.

Practically, several sources of financial support or participation exist and can be called upon at various stages of development. Typically, research grants from national or international research organizations, as well as private foundations, may support projects at the drug discovery phase, and are aimed more at the development of science, rather than the development of compounds. At a later step, substances that demonstrate potential for preclinical development may benefit from other kinds of governmental support, which are aimed towards stimulating entrepreneurship, and therefore transferring knowledge and prototypes to industrial structures. Indeed, costs rapidly increase when entering the further phases of drug development and it becomes impossible for academic or other small institutional structures to financially support such developments. Other investors are needed, typically as part of a start-up or spin-off company and may be part of a close circle of relationships, or may involve other persons or groups of persons with more professional experience. These can be business-angels, usually persons who besides investing also contribute with their entrepreneurial experience and network, or real professional investors such as venture capitalists. Each situation and its associated conditions must, however, be individually and carefully evaluated since the interests, competence and expectations of the various groups of investors may largely vary.

F. The Preclinical Phase in Cardiovascular Drug Development

Ideally, animal and in vitro models provide results that allow direct correlations with human results. In reality none of the evaluation tests for cardiovascular drug candidates at preclinical stages can fully replace information obtained in patients. Nonetheless, data collected during this early phase of development provide unique opportunities to identify possible safety risks and adapt the general developmental strategy, including discontinuation of further investigations. Generally, designing an intelligent preclinical strategy may thus contribute to reducing the time and costs required to reach clinical trials, in the best-case scenario, or limiting financial losses in case of early failure. For this, it is critical to realize that “more information does not necessarily mean better information” (18), but rather to keep in mind that the ultimate objective of the whole regulatory process is to demonstrate efficacy and safety of the drug candidate in a reliable manner (4).

Pharmacodynamics, kinetics and toxicity of NMEs are the major aspects that must be addressed and presented in the IND at the end of the preclinical phase. The pharmacodynamics of the proposed drug or each individual element of its composition must be detailed. Similarly, the dynamic interactions of these elements, and each element with other substances typically administered to the target patient population must be addressed. Similarly, the pharmacokinetics of the drug candidate and its metabolites, as well as the metabolism of the compound or its elements, including its absorption, distribution and elimination, must be evaluated and reported.

Toxicity of the compound is a critical aspect of preclinical drug evaluation. This obviously includes descriptions of the lethal doses (LD 50), and various organ cytotoxicities following determination in multiple animal models after varied administration routes and single versus repeated administrations, but also involves the evaluation of potential genotoxicity, carcinogenicity and reproductive toxicity.

Practically, a careful and up-to-date analysis of the literature is mandatory and usually provides critical information regarding possible risks. This step may guide the investigator and sponsor toward critical tests, in vitro or in vivo, which would thus need to be performed in order to confirm or refute a specific risk (18). As compared to traditional toxicity studies commonly used for the evaluation of new chemical compounds, new guidelines such as those provided by the International Conference of Harmonization (10,11) include tests aimed at providing a broader evaluation of the new drug in terms of function, pharmacodynamics and electrophysiology (8). Among the typical cardiovascular preclinical tests, one can mention the gold standard in vitro hERG tests by which the proarrhythmic potential of a new compound will be evaluated (8) and Thorough QT (TQT) studies (12) which evaluate possible QT prolongation (12), assuming that this marker could predict much larger prolongation in patients (21). However, the observation of a QT prolongation in the early stage of development implies that large collections of ECGs and their careful interpretation will be required in future clinical studies. A positive TQT test for a specific compound is thus frequently considered as a sign of failure, and many drug companies would base the decision to discontinue this compound’s development on results of this early assessment (14), although recent studies question the cost-effectiveness of such an approach (2).

Studies in animals may be performed in small and large models and in anesthetized or conscious subjects. Each approach having advantages and specificities. Typically, the arrhythmogenic, inotropic (positive and negative), and vasoactive pharmacologic effects are studied. Importantly, one must remember that all preclinical tests must be performed in GLP certified laboratories

G. Clinical Trials in Cardiovascular Drug Development

The clinical phase, and especially Phase III clinical trials, are certainly the most critical part of the entire drug development process. Phase III is typically the longest and requires the highest financial investment. Phase III is also the time in which approximately 80% of the drug candidates will fail, even though these candidates have successfully passed through the severe preclinical selection process. In order to understand this high failure rate, it is important to remember the role of the regulatory authority. This entity is indeed a representative of a country or regional that evaluates each new drug candidate and decides whether it may be brought to market. And by doing so, this authority determines that a particular drug is safe to be administered to its population. Therefore, one must see the regulatory evaluation as a process during which the responsibility regarding the safety of a new compound is transmitted, at least partially, to the regulatory authority.

Preparing a clinical study therefore requires a perfect design and a perfect organization in order to convince the authorities that the results

• accurately represent a large population,
• have been obtained in proper manner, and
• have been analyzed adequately.

As opposed to investigator-initiated clinical studies, which are typically managed by the principal investigator’s own and local team, a clinical study as part of a registration process necessitates a much more complex organization that will coordinate and control every single detail of the study (Fig. 4).

One difficulty in designing a clinical trial is defining the right endpoints. Endpoints are parameters to characterize the clinical efficacy and safety of the new compound (15). Ideally, endpoints are easy to detect and unambiguous, and are directly related to the drug that is tested. Mortality is such an endpoint. However, medicine has vastly improved over the last decades and mortality after a standard cardiovascular intervention has dramatically fallen. For example mortality after coronary artery bypass grafting is currently typically less than 1% in most centers. As a consequence, it would take a very large number of patients to demonstrate a significant advantage of a new therapy if mortality was chosen as the primary endpoint. Other clinically relevant endpoints, such as incidence of post-interventional myocardial infarct, NYHA status, quality of life or incidence of arrhythmia etc., may be considered, but may also represent events that today do not radically differ in treated versus comparison groups. Composite endpoints that include a conglomerate of events can be proposed. MACE (Major Adverse Cardiovascular Events) or MACCE (Major Adverse Cardiac and Cerebrovascular Events), for instance, are typically used in reports on new devices. Cardiac imaging and ECG modifications can also be used to monitor direct changes on the heart or its activity. More recently, biomarkers have been proposed to replace clinical endpoints, as they may directly reflect the drug’s effect on a specific target organ. If a biomarker correlates with a clinical endpoint, then this target may be considered a surrogate for the clinically relevant event. This is the case for troponin, a direct marker of myocardial cytotoxicity, which also correlates with mid- and long-term survival (1,19), and which can thus represent an attractive marker for the evaluation of new compounds (9).

H. Conclusions

Over the years, bringing a new cardiovascular drug to market has evolved from a challenge to a highly risky process that less and less groups are willing to tackle. Among several aspects that must be improved to establish a new, reasonable drug translational pathway, is the involvement of committed clinical scientists. Clinical scientists could be encouraged to either initiate their own new projects and/or to participate in their development. A motivating and supportive structure must be made available with additional training opportunities (or at least an initiation to the field of drug development). Finally, an understanding of the role of other complementary stakeholders must be integrated. In other words, a new culture of translational drug research must be established (15)

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