Collaborating disciplines

Collaborating disciplines

New drug discovery and development is a long, complex process that involves multidisciplinary scientists working together in diverse, intercon-nected, and interdependent teams that coordinate their activities and where decision by each team potentially affects every other team working on a given project. A consistent feature of new drug discovery research is the cross-disciplinary progress and collaboration. This interdisciplinary col-laboration is partly accomplished by scientists working together in different departments within a pharmaceutical or a biopharmaceutical company. Each of these disciplines is responsible for one or more aspects of the drug discov-ery and development process as it moves along the pipeline. These functions are usually known by different names in different organizations but have common underlying themes, such as discovery chemistry, discovery biology, preclinical development, toxicology, pharmaceutical development, clinical development, analytical and bioanalytical sciences, regulatory sciences, man-ufacturing operations, quality operations, and commercialization functions.

This chapter will briefly highlight the roles and responsibilities of each of these functions, the key methodologies that are adopted in fulfilling those responsibilities, and the underlying scientific disciplines of study that con-tribute to drug discovery.

Various scientific disciplines that work within this paradigm are briefly discussed in the following subsections.

Biology

The scientists in this function are responsible for the identification of drug targets for chosen disease indications and assessment of efficacy of com-pounds against those targets. The efficacy may be tested in assays that may be conducted in vitro, ex vivo, or in vivo. These assays, for example, could be target-binding assays for isolated receptors, cellular response assays in cell culture models, or animal studies. Dose–response curves are gener-ated in cell culture models (Figure 1.3) that help rank different compounds

Figure 1.3 An illustration of the dose–response curves generated during cell culture prescreening. This example illustrates the dose-dependent cytotoxic effect of drugs on cells cultured in vitro in cell culture dishes. Cell cultures that are not exposed to the drug (I) grow to a hypothetical 3-fold, or 300%, of their initial numbers on culturing in a growth-promoting media for a fixed amount of time. Thus, these cells show 200 % growth, or 200% increase in viable cell count. However, the cells exposed to the drug (II) have less number of viable cells on culture under similar conditions for the same amount of time. The number of viable cells in the drug-exposed culture dish depends on the drug concentra-tion in a manner illustrated by curve II. The drug concentration, at which the viable cell count after culture remains the same as the initial, that is, at 100%, is defined as the total growth inhibitory (TGI) concentration. Drug concentra-tion that halves the growth of cells in culture, that is, increase in cell number to half of the levels seen without drug (which was 200%), is defined as the GI₅₀ (growth inhibition to 50% level). Similarly, the concentration of drug that halves the viable cell count from its initial level (which is 100%) is defined as LC₅₀ (lethal concentration to 50% level). (With kind permission from Springer Science+Business Media: Pharmaceutical Perspectives of Cancer Therapeutics, Anticancer drug development, 2009, 49–92, Narang A.S. and Desai, D.S.)

in the development pipeline through various metrics of their effectiveness. New drug discovery research should meet multiple criteria, such as clini-cal novelty, commercial opportunities, meeting unmet clinical need, and to build intellectual property.

This group also gets involved in identifying biomarkers and indicators of efficacy and toxicity in preclinical species, for potential utilization as surrogates for efficacy and toxicity assessment in the clinical studies. The discovery biology group works closely with bioanalytical scientists, who get involved in developing assays for compounds and physiological markers. The data generated by these functions are critically analyzed by pharmaco-kineticists and toxicologists to differentiate compounds for prioritization for advancement to the next stages of the drug discovery and development process.

Chemistry

Working closely with the discovery biology function, the discovery chemists provide an array of purified compounds for investigation. Discovery chemists, typically synthetic organic chemists who are involved in chemical synthesis, purification, and characterization of new chemical entities (NCEs), form the bulk of this function. This function is involved in identifying chemical compounds that may have drug-like properties and would respond in desirable ways (such as agonist or antagonist) on chosen enzymes, receptors, or other targets. The drug design roles of these sci-entists frequently involve molecular modeling of the target receptor and in silico assessments of receptor binding of potential chemical structures and structural modifications.

This group gets closely involved in the identification of potential mea-sures of efficacy, as well as in the pharmaceutical developability assess-ment of new drug candidates to identify lead compounds that potentially maximize efficacy and minimize potential developability risks and toxicity. Developing structure–activity and structure–toxicity relationships is a key function of this group of scientists. High-throughput synthesis and purifi-cation technologies are commonplace in modern-day discovery chemistry laboratories.

The discovery chemistry function works closely with analytical scientists to assess the purity and identify of their compounds and with the discovery biology function to assess the efficacy of animal, cell culture, or in vitro models. Working coherently, discovery chemistry and discovery biology functions shortlist a few candidates that enter preclinical assessment and optimization.

Pharmaceutics

Preclinical pharmaceutical development involves optimization of potential drug candidates for drug-like properties. Development of pharmaceuticals comprises diverse group of scientists that assess both pharmaceutical dosage form developability through a series of assessments of solubility as a func-tion of pH and in various biorelevant fluids, chemical stability of the com-pound to various stresses such as temperature and humidity, and polymorph stability. This function also undertakes pharmacokinetic and toxicokinetic assessment, in close collaboration with discovery biology colleagues, in one or more species, in an effort to identify potential starting dose and effica-cious dose range for the FIH administration and dose escalation clinical studies. Pharmaceutical development scientists work closely with all func-tions involved in drug characterization and administration to address three key aspects of any new drug: stability, bioavailability, and manufacturability.

Preclinical optimization, discovery chemistry, and discovery biol-ogy functions work together as a team and may identify several molecules that go through developability assessments and are compared against each other for an array of desirable physicochemical and biological properties. The outcome of this exercise is the identification of one lead candidate that provides optimum balance of desirable attributes, while avoiding the unde-sirable ones. Often, one or more backup candidates are identified in case any significant undesirable observation (such as toxicity) is observed with the lead candidate.

Animal toxicology

As drug candidates advance toward FIH, formal toxicological evaluation in animal species is initiated. These studies are guided by the compound characteristics, target therapeutic area and biological receptor, as well as regulations that govern toxicity assessment in the animal species. Typically, toxicity is studied in two species, one rodent and one nonrodent, with an intent to identify target organs and organ systems that may exhibit toxicities at higher doses. These studies involve increasing drug dosing and exposures in the animal species until toxicity is observed and carefully documented. These studies frequently combine plasma concentration assessment and biomarker studies, if a biomarker has already been identified.

Toxicologists, working with diverse teams of professionals, are involved in the design and conduct of animal studies, as well as in the interpretation of observations. The goal of toxicological assessments is to rule out any significant toxicities, identify a starting dose for the clinical studies, and outline a monitoring strategy for potential toxicities during clinical studies. Toxicology studies seek to identify a maximum tolerated dose (MTD) that

Figure 1.4 Hypothetical dose–effect and dose–toxicity curves for cytotoxic (a) and noncytotoxic, molecularly targeted anticancer (b) agents. The cytotoxic agents are known for their dose-dependent toxicity, which closely follows the dose–effect curve. Noncytotoxic agents, on the other hand, could have a linear dose–toxicity relationship similar to the cytotoxic agents (I) or a nonlinear profile with dose–toxicity curve lower than the dose–effect curve (II). MTD represents the maximum tolerated dose for the cytotoxic agent. (With kind permission from Springer Science+Business Media: Pharmaceutical Perspectives of Cancer Therapeutics, Anticancer drug development, 2009, 49–92, Narang A.S. and Desai, D.S.)

presents an acceptable balance of desired therapeutic effect and toxicity. Dose–effect and dose–toxicity relationships are delineated to identify the balance of effect and toxicity as a function of dose. As exemplified in Figure 1.4, these can be different for different compounds, based on their mechanism of action and target specificity.

Clinical pharmacology

Although no clinical studies are carried out with test candidates during drug discovery stages, clinical pharmacologists get involved in understand-ing the emerging profile of new drug candidates being screened. Aspects of drug discovery that can impact later stages of drug development, such as the relevance of animal models to human disease state and projected clini-cal doses or administration profile (e.g., route or frequency of administra-tion), are critically assessed.

Analytical and bioanalytical sciences

Analytical and bioanalytical sciences form the core indispensable compo-nent of all functions involved in drug discovery and development. Analyses of drug content, purity, and any changes during storage are an essential part of identification of new chemical candidates through all stages of drug development, including commercialization. All drugs are required by federal regulations to have specification controls to ensure their identity, purity, and quality. The analytical methodologies utilized for ensuring these attributes could be spectroscopic or wet analytical techniques such as titrations and chromatography. For example, an oral solid dosage form must be tested for drug content, purity, water content, and drug release. A parenteral biologic drug product must be tested for drug content, purity by different methods (charge or size-based separation techniques), recep-tor binding, bioactivity, pH, osmolality, and structure/isoforms. In addi-tion, all the starting (raw) materials, intermediates for synthesis, and excipients used in formulations must be rigorously tested to ensure these attributes and consistent quality across different batches. The assurance of maintenance of all quality attributes of the drug substance and drug product over the duration of storage (stability testing) utilizes analytical testing at various time points under different storage conditions (such as temperature, humidity, and light exposure). These functions are carried out by analytical scientists.

Bioanalytical sciences focus on analyses of drug content, metabolites, and any drug-related substances (such as both the parent compound and prodrug in the case of prodrug administration) in both animal and human studies. Bioanalytical sciences present significant and unique challenges due to complex, multicomponent nature of the biological fluids in which specific compounds must be tested—often without rigorous separation— and the very low concentrations of the target compounds (often in micro-molar quantities). These analyses are typically carried out using highly sensitive analytical methods such as high-performance or ultra-high per-formance liquid chromatography (HPLC/UPLC), followed by tandem mass spectrometry (MS/MS).

All analytical methods are required to be qualified and validated for a host of criteria that ensure their robust and reproducible performance across potentially multiple testing sites, laboratories, and personnel.

Regulatory sciences

All drug products developed in modern biopharmaceutical settings are designed for global patient populations. Government regulatory agencies that monitor and control (regulate) the commercialization and utilization of drug products vary by each country and as do their requirements for the testing and commercialization of new drug products. As much harmoniza-tion of international regulations is being advocated and implemented (e.g., by the International Council on Harmonisation [ICH]), each country thus maintains its sovereign control over access to its markets and the require-ments, which are often embedded in historical idiosyncrasies and scientific elements that may be unique to each region or subpopulation. The govern-ment regulatory agencies include, for example, the federal Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) for several countries in the European Union; each of these countries do have their own drug regulatory agencies.

To ensure access of new drug products to patient populations globally, regulatory scientists work in the biopharmaceutical industry to proactively understand the regulations of the targeted markets. The regulatory sciences have evolved into a complex field that addresses not only the diversity of regulatory requirements but also the variations in scientific perspectives and understanding of different regions and countries. With ever-evolving analytical methodologies, drug development paradigms, and accelerating scientific growth in multiple disciplines involved in drug discovery and development, the regulatory scientists also form the interface of biophar-maceutical companies with the regulatory agencies and seek to educate and influence regulatory policy to evolve with the times.