Drug Development: Drug Delivery Carriers and Clinical Trial
PREM PRAKASH KUSHWAHA, SWAGATA DAS, ATUL KUMAR SINGH, and SHASHANK KUMAR
School of Basic and Applied Sciences, Department of Biochemistry, Central University of Punjab, Bathinda, Punjab-151001, India,
Tel: +91 9335647413,
Engrossment of genomic infonnation to introduce drug discovery and development has announced lots of concepts since last three decades. Though the previously data’s and reports acknowledged various striking new dings against aggressive diseases, but their side effects, cost adjustment and availability provided unsatisfactory outcomes. Various drugs also remained unimpressive in the different clinical trials. These trials stages define the drug phannacology, dose range, ding efficacy, therapeutic effect, and long term effect. Failure of drug delivery to the diseased position also hampered its successiveness in the clinical trials. Later, various ding delivery systems come up with their ability to solve the challenges against the ding delivery in body system. In this chapter, we reviewed the various clinical trial phases and several ding delivery systems with their renounced characteristics.
CLINICAL TRIALS: AN INTRODUCTION
Preclinical improvements begin before clinical trial. This aims to govern the care and efficiency of the intervention. With reference to, the preclinical studies if therapy is safe and operative, clinical trials are initiated. On the basis of clinical trials, the interventions are decided as positive or negative for human subjects. The clinical trial undergo in a stepwise process known as phases О, I, II, III, IV, and V (Figure 12.1).
FIGURE 12.1 Clinical phase trials: The stage of drug development.
CLINICAL TRIALS: PHASE 0
The IND (investigational new drug) is also widely known as Phase 0 analyses it provides information on pharmacokinetics as well as selection of promising product from a certain group of candidates followed by evaluation of their bio-distribution and determination of mode of action.
The motive of analysis is to assess the benefit of go versus no-go outcome of early drug. In this early drug, developmental process human models are considered instead of trusting on animal model data. Investigative IND studies shown in early clinical phase includes a restricted human introduction without diagnostic intent. Doses are sub-therapeutic and patients are observed by the clinical investigator and include about 10 study patients for less than week duration. Pharmacodynamics and pharmacokinetics studies are carried out. These trials are based on earlier traditional dose appreciation, safety, and tolerance studies. It neither replace the phase I clinical trials nor specifies whether the therapy has positive influence on the targeted pathology or not. It also helps in the removal of candidate therapy before Phase I studies (Kummar et al., 2007). These trials were established to minimize the difficulties in drug development, discoveiy of pharmacodynamics and pharmacokinetics profiles of IND, aid in accelerated documentation of auspicious drugs and to lower the input of time and money. The drawbacks of these trials comprise lack of therapeutic commitment, motivation of patients to join, delay, or exclude patients from the other clinical trials having therapeutic commitment, micro-dosing pharmacokinetics, association to a therapeutic dose and obtainability of sensitive analytical methods (Le Tourneau et al., 2009).
CLINICAL TRIAL: PHASE I
A Phase I clinical trial is the finest way to manage occurrence, dose, maximum tolerated dose (MTD), side effects tolerability, pharmacokinetics, and pharmacodynamics of a drug. These studies are regulated with the safe treatment trials on 20 to 100 patients checked by the clinical investigator. Doses are amplified if do not showed severe side effects and the patients are tested for the positive outcome of therapy. These gratitude dose studies are availed to regulate the finest and harmless dose that can be administered. It is fraction of the dose that caused damage during animal testing. Unnecessary introduction of subjects to sub-therapeutic doses sustaining safety and rapid accumulation is the main ami of Phase I trials (Storer, 1989). In most of the cases, healthy volunteers (having a certain disease) are required. In normally contract research societies conduct this type of studies and salaries might be given. Testing is performed consecutively for every patient or a group of patients with proper data study. Dose toxicity and efficacy curves are determined during the phase and involve single-dose trials (Phase IA), multiple arising dose trials (Phase IB), and food effect studies. These are easy to implement and do not need exceptional software.
CLINICAL TRIAL: PHASE II
A Phase I clinical trial study MTD while Phase II study assesses the possible effectiveness, characterize treatment advantage of the disease. These studies are accomplished on massive groups about 100 to 300 subjects and are intended to evaluate the drug's effectiveness and safety evaluations. The therapeutic doses determined in phase I study administered in the patients and monitored by clinical investigator. Trials are frequently accompanied in a multi-institution setting. Phase II is distributed into Phase IIA (preliminary clinical trials to assess effectiveness and care in designated populations with the disease or disorder to be treated diagnosed or baimed) and Phase IIB (the toughest trials designed to validate effectiveness). The Phase II design mainly depends on the excellence and potential of Phase I study. A susceptible feature of both phases includes the type of registered patient. In Phase II trial, elimination of patients involves more criteria than Phase III trial. They are strategized as single and multi-stage clinical trials based upon particular endpoint of the interest. Adaptive clinical trial strategies based on temporarily collected data are used in Phase II clinical trials due to its elasticity and efficacy. This strategy enables the investigator to transfoim or reshape the trial during the study. Adaptive designs are classified by FDA into well-known and less well-known category (Chow, 2014). Well- understood strategies have been used for years with consistent statistical approach. They are well established and FDA approves these study strategies by reviewing the use of submissions. In less well-understood strategies, relative qualities and boundaries are not completely assessed, devoid of valid established statistical methods. FDA also lacks requisite knowledge about submissions using the study strategies.
CLINICAL TRIALS: PHASE III
Phase III trials include full-scale assessment of treatment aimed to obtain the efficiency of the new treatment in the comparison with its standard treatment. It is an extensive and laborious type of technical clinical study of a new treatment in pre-marketing phase of clinical trial. Additionally, they are the most luxurious and time-consuming trials. The trials might be problematic to design and run. Large groups (100 to 3000 subjects) are recruited and trial include strategies such as randomized skillful trial, uncontrolled trial, historical control, no-randomized concurrent trial, factorial design, and group consecutive designs. Patients are checked by clinical investigator and individual physician. Phase III clinical trials are commonly separated into Phase IIIA and Phase IIIB. Phase IIA trial usually carried out after the establishment of efficiency of the therapy and before the regulatory submission of a new drug application (NDA) or any other dossier. On the other hand, Phase IIIB trials are directed after the submission of NDA or other report but earlier than its endorsement and introduction. Randomized phase III trials are the gold standard indication to endorse new drugs. Drug development-related problems includes limited clinical advantage in large RCT's, estimation of a fruitful trial of Phase III based on Phase II data, drug toxicity determination, strategy of drug combination, and cost of the trial.
CLINICAL TRIALS: PHASE IV
Phase IV trials include all the studies achieved after the drug endorsement and related to approved or accepted indications (ElsaBer et al., 2014). These are the post advertising investigation studies. The focus of the trials is how the drug works in a definite world. Anyone looking for treatment from the physician may be cured with the treatment. The physician displays the results of treatment to the subjects. Effectiveness and discovery of rare or long-term side effects over a relatively higher patient population along with longer duration are assessed, healthcare charges and outcomes are determined, and pharmacogenetics is studied in this phase. New clinical suggestions for a drug may be recognized involving a large number of patients and doctors (Bemabe et ah, 2014). The FDA may necessitate a designer to direct a Phase IV trial as a necessity for the drug approval. Few numbers of the study about less than half are finished or even started by designers. It may also lead to the removal of drug from market or controlled to certain signs.
CLINICAL TRIALS: PHASE V
Phase V clinical trials demonstrate relative efficacy and community-based investigation. The investigation is based on the collected data. Patients are not observed but the chief attention is to determine the incorporation of a new therapy into widespread clinical training.
MARKETING OF A DRUG
The estimated extent of the influence of pharmaceutical industry on medical research and patient care can be easily made through an analysis of its marketing strategies. The strategy is mainly organized in five category based on ascending order of potential harm to consumers: targeted promotion of physicians, direct-to-consumer (DTC) advertising, unethical recruitment physicians, conflicts of interest in research, and clinical trial data manipulation.
PHYSICIANS TARGETED PROMOTIONS
The influence of a physician’s prescription pattern is significant as it subconsciously affects the promotion of Drug companies. In 2002, $15.63 billion was expended by phannaceutical industry on promotional activities such as the free office supply, sales representatives, all-expenses-paid events, and gifts given to physicians (Parker and Pettijohn, 2003). According to Dr. Israel, out of the promotional budget, a sum of about $8,000 to $ 13,000 was spent on single physician (Israel, 2003). Likewise, a 10 year reported study by interns of seven university hospitals was published in 1990. The study reported that prescription practice was merely changed by the regular contact with sales representative (Israel, 2003). Parker and Pettijolm reported that the interaction between a doctor and pharmaceutical representative affects the possibility of a drug to be included into an approved and insured list and is increased thirteen times than normal situation (Parker and Pettijolm, 2003). Studies showed that promotion of drugs are distinguished by then- prescription in lieu of probable fact that an ideal physician provides the most suitable therapy and care to the patient, at best economic value. This results in the falsified theory of patients receiving quality care. Actually, these patients are to afford high treatment costs due to biased prescription of potential drug.
DIRECT TO CONSUMER ADVERTISING
Although hefty DTC advertising increased the sale of promoted drugs but it is not a best-suited option in terms of patients in health and cost. The number of patients seeking for medical attention for allergy during 1990 to 1998 rendered about 14 million, raised up to 18 million by 1999. The money corresponds to more than 15% of SI.85 billion was targeted for DTC advertisement of prescribed oral antihistamines. In 1999, sale of top 25 DTC-advertised drugs increased by 43% in comparison to previous year. It was due to their increased prescription raised by 34.2%. This further increased the DTC advertising cost from $2.3 billion (2000) to $7.5 billion (2005). This clearly illustrates that increased expenditures on doing advertisement of a drug give an increased profit due to increased number of prescriptions (Parker and Pettijohn, 2003).