Definition/Introduction

Pharmaceutics is the overall process of developing a new chemical entity into an approved therapy that is safe and effective in treating or preventing disease. It is a complex process requiring multiple scientific, medical, legal, commercial, and regulatory expertise. On average, it typically takes at least ten years for a new drug to complete the process from initial discovery to the retail marketplace, with clinical trials alone taking six to seven years on average. The Tufts Center for the Study of Drug Development announced that it calculated that it costs pharmaceutical companies $2.6 billion to develop a new drug.[1] This figure has been subject to question, as the raw numbers on which they base the analysis have not been made available. The driving factor of this estimate is the cost of failed drug development attempts, with 80% of new compounds discontinued during their development. The steps involved in bringing a new chemical entity to the market as a drug involve the stages of discovery, chemical optimization and production, preclinical testing, pharmacology, and toxicology testing, early clinical trials establishing proof of concept, registration or pivotal clinical trials showing safety and efficacy in the target patient population and finally regulatory approval.

Pharmaceutical companies are also bringing technology into the picture to speed up the process, using computational methods and artificial intelligence (AI) to determine whether a molecule is likely to produce a viable drug.[2]

Issues of Concern

The discovery phase of the pharmaceutics process involves establishing a receptor, enzyme, protein, RNA, DNA, or protein that modulates a biochemical process as a potential contributor to the pathophysiology of a disease process. They often base this on literature reviews of basic science investigating disease mechanisms. For example, the immune regulating receptor PD-1 and its ligand PD-L1 were implicated in reducing the immune system's response to cancer.[3] The next stage in the development of PD-1 therapy was then to develop monoclonal antibodies targeted against an area of those proteins that would assure good binding and inhibition of effect. They established in-vitro and in-vivo models to show antibody binding and reactivation of the immune system towards a cancer model. A similar process occurs for traditional small molecules but usually with a screening of activity against a target (typically a receptor or enzyme) against a library of compounds. Enzyme inhibitors such as kinase inhibitors against  BCR-ABL1 in chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia with the Philadelphia chromosome are both examples.[4]

The chemical optimization and production phases focus on improving the drugs' drug and manufacturing characteristics found in the discovery phase. For example, with antibodies, this would include selecting the proper subtype of antibody to prolong its half-life in the body and enhance or suppress complement fixation or antibody-dependent cell cytotoxicity (ADCC).[5] This would also be the step to determine what type of cell and bio-incubator should be used to produce the product. Chemical optimization for small molecules involves changing the chemical structure to enhance the therapeutic effect while minimizing the interaction of the drug with CYP450s and transporter protein and HERG or sodium channels involved in cardiac conduction. At this stage, screening for interactions across a large panel of receptors and transporters takes place and when patents get submitted. An important issue regarding the use of excipients is they are often considered inert, but these have caused problems both in the pediatric and adult populations.

Preclinical testing, pharmacology, and toxicology testing involve using models of the disease tested. These animal models often harbor close approximations of human diseases, such as human tumor implants in immune-incompetent mice (xenograft tumor models), or are a relatively poor approximation of human pathologies as the forced swimming test. Standard pharmacology models involving testing for cardiovascular, CNS, and renal effects are performed in in-vitro and in-vivo models such as I(Kr) potassium channel antagonism, and prolongation of the QT interval is assessed in telemetered dogs. These are often not required for targeted drugs such as antibodies. Toxicology testing involves standard protocols with doses and duration that extend beyond the expected human dosing (in animal lifetimes). These are often used to determine the first dose used in human trials and determine any particular toxicity concerns that will require monitoring in the early clinical trials. 

Clinical Significance

Initiating early clinical trials after establishing proof of a concept commence after an Investigational New Drug Application (IND) has been reviewed and approved by the FDA. Similar procedures are used in the EMA, Japan, and other countries, although some nations limit new drug testing for the first time. The initial studies in humans can be in actual patients if the drug's toxicity or target would not be appropriate for volunteers. Increasing doses of the drug are used to establish the drugs' safety and determine the drugs' pharmacokinetics (the duration and extent of the drug in the body) as well as to measure the drugs' effect on biomarkers (serum or tissue enzymes, histology, or any other measure of drug effect such as glucose in diabetes). This data will be used to select doses to be brought into a proof of concept or phase 2 studies in a select patient population. Clinical trials like the TeGenero disaster are fortunately the exception and not the rule. In this study, the first volunteers received a 500 times lower dose than the safe dose as established in animal studies. However, all six human volunteers faced life-threatening conditions involving multiorgan failure, which required transfer to the intensive care unit. As a result, the implementation of new precautions and toxicity calculations became standard since that 2006 incident.[6]

Registration or pivotal clinical trials demonstrate safety and efficacy in the target patient population. These trials may encompass thousands of patients or only a small number (as in ultra-rare diseases). The outcomes vary between pathologies and range from overall survival (in oncology indications) to reducing the incidence of asthma exacerbations requiring hospitalizations to effects on a biomarker like HbA1C in patients with diabetes. Patient selection is crucial to match the drug effects with the target patient population, but the data from the studies must also be extrapolated to the broader patient population. Endpoint selection is crucial because it must reflect a meaningful alteration in patient outcomes and be statistically achievable with the study design. These studies often take several years to complete and analyze.

Once the entire drug development package is complete with reports from discovery, preclinical, chemistry, manufacturing, and clinical, a regulatory submission integrates all of this data in a standard format. The submission can be many terabytes of data. Regulatory approval can take around a year, often through an outside review by experts (FDA Advisory Board) and a public hearing. If all goes well, the drug receives marketing approval and becomes available for patients.

Nursing, Allied Health, and Interprofessional Team Interventions

Obviously, among allied health practitioners, pharmacists need to be subject matter experts regarding pharmaceuticals, providing guidance on appropriate therapy selection, dosing, interactions, and the latest developments in pharmaceutical therapy. Nursing is also expected to possess knowledge on the topic, so they can alert clinicians or the pharmacist of any potential red flags and head off potential adverse outcomes from improper or inadequate pharmaceutical care. Optimal use of pharmaceuticals requires an interprofessional team approach with open communication, where all members are empowered to offer their observations to drive better patient care and prevent adverse patient outcomes. [Level 5]