Recent Advancement in Clinical Trials and Drug Development in Pharmaceutical Industry

Dr Vivek Dave
Assistant Professor, Department of Pharmacy
Banasthali University

Dr Sachdev Yadav
Associate Professor (Pharmacology), Department of Pharmacy
Banasthali University
Ms Smita Kumari
Research Scholar, Department of Pharmacy
Banasthali University

This article focus on the different phases and recent advancement in clinical trials and drug development of new drugs. There is also a different guidelines if different countries for clinical trials and their descriptions . Many organization and agencies are responsible for the approval of new drugs. In this article also describe some important points of benefits of clinical trials and drug development, advance technique and clinical research organization structure and its importance. Most important and new topic regarding health and clinical trials is declaration of Helenski.

India has the maximum number of FDA approved plants outside the US. Clinical trials are imminent bio medical or behavioral investigate study of groups of people that is designed to answer specific questions about bio medical or behavioral interventions. Clinical trials are many times used to find out whether new medical treatment or behavioral interventions are safe, and effective for specific diseases. Clinical trials contain behavioral human subject's research involving an intervention to modify behavior (growing the use of an intervention, eagerness to pay for an intervention, etc). Human subject researches are to develop or evaluate clinical laboratory tests might be considered to be a clinical trial if the test will be used for medical decision making for the subject or the test itself imposes more than minimal risk for subjects. Clinical trials are medical research to check whether different treatments which are given to different subjects in different diseases are safe or not and method of their working. Trials having types of groups of people in which one is of healthy members of the community, and others involve patients who may be offered the option of being a part of a trial during their care and treatment. Clinical trials having purpose to find the best ways to decrease disease and the conditions which makes people ill, improved disease state of ill people, increase survival rates or increase the number of people cured, improve or providing good conditions for people living with illness, including reducing problems like side effects of treatments, such as chemotherapy, and diagnose diseases and health troubles. Clinical trials are not all the time method of testing effectiveness and safety of medicines it also an important roles in improving the behavior and standard of living of people. It is also well known methods which embrace educational programmed to increase person’s understanding of their medical situation so they can easily deal with it more effectively, or a psychological treatment, such as cognitive therapy, to treat anxiety or depression.[1] The clinical trials phases and drug development in pharmaceutical industry is shown in [Figure 1].

Figure 1 Clinical trial phases and drug development in pharmaceutical industry.

Phase 0

The FDA has recently approved "micro dosing," or the "Phase 0 trial," which permits researchers to test a small drug dose in some human volunteers to rapidly weed out drug candidates that are metabolically or biologically ineffective or not. The phase 0 studies are done in humans; it is different from other phase studies. This phase small amount of dose of drug is given to all patients. This study includes more scans and blood samples for the studies. Because drug doses are low, there was also less risk to the patient in phase 0 studies compared to phase I studies. Phase 0 studies help researchers to check the results of drugs in matching to their predicted ones. Problems of absorbance and actions of drug in a body can be easily come out in this phase study. Phase 0 may help avoid the interruption and expense of finding out years later in phase II or even phase III clinical trials that the drug does not act as it was expected to base on lab studies. Phase 0 studies are not yet being used widely, and there are some drugs for which they would not be helpful. It can be performed with the few people like 20 people. Although they are not a required part of testing a new drug, but are part of an effort to get faster and simplify the process. [2]

Phase I

Phase I is performed initial human testing in a small group of healthy volunteers. It includes about 20 to 100 healthy volunteers for conducting a study. The main objective of a Phase 1 trial is to find out if the drug is safe in humans or not. Researchers look at the pharmacokinetics of a drug: method of absorbance, method of metabolism and elimination from the body. They also study the drug's pharmacodynamics: chances of side effects, chances of desired effects, this trials helps researchers to find out the safe dose range or effective range of safety and if it is move further it helps in making initially safety of new drugs. An attempt is made to establish the dose range tolerated by volunteers for single and for multiple doses. Phase I trials are sometimes conducted in severely ill patients or in less ill patients when pharmacokinetic issues are addressed. Pharmacokinetic trials are usually measured Phase I trials regardless of when they are conducted during a medicine's development.

Phase II

It is studied in a small group of patients Phase II trials gives researchers to evaluate the candidate drug's effectiveness in about 100 to 500 patients with the disease or situation under study, and examine the possible short term side effects and risks related with the drug. They also make every effort to answer some questions like drug is working on desired mechanism or not, Does it improve the condition in question? Researchers also analyze optimal dose strength and schedules for using the drug. In Phase II trials, the studies have been conducted in vast groups (100-300) and are designed to analyze working of drug along with Phase I assessment of safety in the larger participants. Genetic testing is very much common if there is enough proof of variation in metabolic rate. the part of phase II is II a whose purpose is to determine the effective dose of drug and how often the drug needs to be taken and the second part II b having purpose of determining the efficacy of drugs. Phase II b trials look at how well the selected dose, or doses, of a drug work (called efficacy). Of course, safety is always closely monitored. Moreover, there have been some trials which are performed in the combined form for both efficacy and toxicity. Drugs that are reasonably safe in phase I can advance to phase II. About two-thirds of drugs make it to phase II trials. In fact, phase II trials are usually the make-or-break point for a new drug; development is stopped if it becomes clear that the drug does not work or is too toxic. Sometimes combination of a Phase I trial, a Phase II a trial is meant not only at understanding the safety of a potential drug, but also getting an early read on efficacy and dosage in a small group of patients. The resulting Phase 2b trial would be planned to build on these results in a larger group of patients for the sake of designing a rigorous and focused Phase III trial. [3-4]

Phase III

Phase III trials researchers includes study the drug candidate in a larger number of patients to generate statistically significant data about safety, efficacy and the overall benefit risk association of the drug. Also helped in the gives information for labeling purposes by which many patients compliance are reduced and increase the proper use of drugs. It is both the costliest and longest trials. Phase III trial, also includes conduction of many other critical studies, including plans for full scale production and preparation of the complex application required for FDA approval. Phase III trials (also called registration trials) are the last step before drug approval. Phase III trials are randomized and controlled they are often international, so that different groups of patients can be studied. Phase III trials look at safety, monitor side effects, and test how well the drug works (usually in comparison to the current standard of care or best treatment available) in a large group (hundreds to thousands of people). They also study the best ways to use a drug, so that the drug’s risks and benefits can be seen in, and applied to, a larger and more diverse group of people. Information from phase III trials goes into the labeling of approved drugs, so that doctors and patients can understand more about how to use them. Phase III clinical trials have been suggested to be designed in order to analyze the efficacy of new drug and its therapeutic effect in clinical practices. [5-7] Phase III trials have been conducted randomly on large number of patients (300-3000 or more), having the target to complete the definite assessment of the new drug, by relationship with the standard drug treatment. Also, due to their longer duration and size, some disadvantages of phase III are as the most expensive, time consuming and difficult to design and run. In phase III trials, the chronic diseases having a period of evaluation related to the time period of the intervention can be used in practice. [8-9] In common practice, some trials of Phase III are continued until the regulatory submission is depended at the appropriate regulatory agency. Moreover, the collected information are submitted to the "regulatory submission" so that the hope transpires to the sponsor in order to get the approval of marketing the drug. These clinical trials are conducted in patient populations for which the medicine is in the end proposed. Phase IIIa clinical trials generate additional data on both safety and efficacy in relatively large numbers of patients in both controlled and uncontrolled trials. Some clinical trials are also conducted in special groups of patients under which special conditions dictated by the nature of the medicines and diseases. In case of Phase IIIb clinical trials conducted after regulatory submission of an NDA or other dossier, but prior to the medicine's approval and launch. These trials may supplement earlier trials, complete earlier trials, or may be directed toward new types of trials or Phase IV evaluations. This is the period between submission and approval of a regulatory dossier for marketing authorization. [10-12]

Phase IV

Phase IV, also referred to as Post marketing surveillance, and includes the technical support of the drug after the selling permission of the drug is achieved. The Phase IV studies can be performed with the help of regulatory authority or by sponsoring company for finding a new market of the drug. Such trails have been designed to find out if any long term adverse effect over a much large population of patients for a longer period of time, that were not possible during Phase II and phase III trials, has been noted. However, the whole process of the drug from the lab to this point takes about 12-18 years approximately. After medicines are marketed then this trials are taken place for the determination of the safety and efficacy of the drug dosages. Comparison of different formulations, dosages, and duration of treatment, medicine interactions, and other medicine may be evaluated. It also includes new age groups, races, and other types of patients can be study. Some important aspects of this phase study are discovery and meaning of previously unknown or ineffectually quantified adverse reactions and related risk factors. Regulatory authorities may ask for longer follow up or for more information about drug safety and efficacy, in groups that were disqualified for, or underrepresented in, earlier trials . Often Post marketing trials look at women and children, people with advanced liver disease, people from certain racial and ethnic groups, or people with other illnesses. Sometimes post marketing trials look at different doses and durations of treatment to see if there is a better way to use a drug or a combination of drugs. [10-12]

Phase V

Phase V is also termed as "translational research" to refer the effectiveness and group of people based research studies. It is new to find the interrogation of a new clinical treatment into a large number of public health practices. Generally, the Phase V trials have been considered as the field research and it is particularly designed to test generalization of the mechanism to a large sample. [12]

Guidelines for Clinical Trials in Different Countries

As we know that different countries having different guidelines and rules for their works, same for clinical trials having different guidelines in different countries like for united state having USFDA, for INDIA having CDSCO, South Africa having MCC etc guidelines. Some countries their organization, guidelines and descriptions are showed in Table 1.

Table 1: Guidelines for Clinical Trials in Different Countries

Benefits of clinical trials

Clinical trials offer distinct economic benefits to large pharmaceutical companies who are looking to decrease their time to market on new products and save at the same time. They makes strong development skills as demonstrated in the international market APIs and dosage forms, decrease R & D cost, Cost of industrialized is 40-50 percent decreases as compared to western countries, Large patient population providing a diverse pool for clinical trials for NCEs, High quality telecom and IT infrastructure, Most excellently, Indian companies have adapted to international regulatory, norms & respect IPR.

Organization Structure of CRO

CRO project manager supervises investigator initiated, multicenter clinical studies. The role of project manager to associate and monitors a specific multicenter clinical study by conducting site initiation qualification visits, monitoring clinical trials to guarantee protocol adherence and compliance, conducting study initiation, monitoring close out site visits. Control investigation sites and project team. The CRO coordinator organizes clinical research activity such as recruitment, enrollments, informed consent processes, site initiation visit, the research coordinator is also responsible for hosting monitor visit and is knowledgeable in all regulatory guidelines. Trainer facilitates orientation training programs for all new CRO employees, ensures that training for all staff is up to date, and act as resource for CRO staff. Clinical research supervisor manages a CRO team. Who conduct clinical trials in adult and involve pharmacokinetics, pharmacodynamics, medical devices, or observation studies. Regulatory specialist assumes a central and key supportive role for all studies conducted under the auspices of CRO. A regulatory specialist also assist the study coordinators with the preparation, review and submission of all protocols, amendments, informed consent document, annual review, and safety report, submitted to the institutional review board. Business manager provide administrative and financial management services for CRO. Ensuring that business operations are meeting the needs of the study coordinators and its clients. The organization structure is shown in [Figure 2].

Figure 2 Organization structure of CRO.


Biomarkers/surrogate markers

A surrogate end point is defined as a marker intended to substitute for a clinically significant end point that measures directly how a patient feels, functions, or survives. Biomarkers and surrogate outcomes are used throughout the development, testing, and ongoing positioning of medical therapeutics. The term surrogate literally means a substitute for, replacement, proxy, so some additional outcome is expressed or implied. The relationship between prognostic factors and surrogate markers may also be a source of confusion. This heterogeneity of nomenclature, content, and inference in surrogate therapeutics obscures the meaning of what is being measured and its genuine influence on patient. [13-14]

Adaptive design

An adaptive design is defined as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data from subjects in the study. Changes are based on pre-specified decision rules that supported the notion that. However, the FDA defined adaptive design more generally by interpreting as 'prospective' any adaptations designed 'before data were examined in an unblended manner by any personnel involved in planning the revision' Making planned, well defined changes in key clinical trial design parameters, during trial execution based on data from that trial, to achieve goals of validity, scientific efficiency, and safety, [15] An adaptation may carry out one of the following categories a) allotment rule, b) example rule , c) Stopping, d) Starting, e) long-lasting rule, f) conclusion rule, g) flawless designs.[16]

Bayesian adaptive designs

A Bayesian adaptive design includes a study of comparison of two-armed clinical trial using decision speculative approaches. A loss function is special to consider the cost for each patient, and the costs of making incorrect decisions at the end of a trial. It helps in analysis and decision to continue or eliminate the method of trials which based on the currently safety, efficacy and costs. The maximum numbers of interim analyses are not pre-fixed but can be decided adaptively by the experimental data. We derive explicit connections between the loss function and the frequentist error rates, so that the desired frequents properties can be maintained for regulatory settings. The operating characteristics of the design are able to be evaluated on frequentist grounds. Comparisons of the proposed design with existing ones are carried out by Extensive simulations. The design is general sufficient to accommodate both continuous and discrete types of data.

Data mining in crucial path of research

It includes research advocates are gradually more playing a main role in designing clinical trials that are patient focused and likely to lead to important changes in clinical practice. The purpose of studies is to be sure that clinical trials are designed in a way that will lead to unambiguous results (i.e., are effective at answering research questions). We also want to be sure that the trails should be succeeding as fast as in an affluently as possible and that the patients also get the best possible treatment who volunteers to be in trials (i.e., the trials achieve the highest ethical standards). These goals are often at cross aim; thus, clinical trial designs generally represent a compromise

Micro dosing study

Micro dosing (phase-0) studies help by condensing the time periods of to phase-I studies by earlier evaluation of human pharmacology of a new test substance, they also help in the early selection of hopeful compounds for further increase before the traditional phase 1 trials, they help in overall speeding up in the process of drug development by focusing only on the promising compounds, they decrease the unnecessary exposure of the participants in the trial to the not so hopeful compounds, they decrease risk of human toxicity owing to the low dose of the test substance and less duration of administration/exposure to the drug. In traditional phase I trials having dose rapidly study whereas in such trials single dose administration is involved Also, such trials mostly involve they also having lesser risks, decreased preclinical safety package than the traditional phase 1 studies, less number of animals is used, overall time of drug development is reduced, this methodology helps in early selection of the smarter and more promising lead molecules hence, the more effective drugs reach to the market earlier, small amount of the test drug is needed ,the test drug may be prepared as per the principles of the Good Laboratory Practices (GLP) unlike Good Manufacturing Practices (GMP) compliance as required for the traditional phase-I studies any route of administration is possible, the drug can be tested in the sensitive population like women in their reproductive age, patients with renal impairment, cancer patients, etc, this approach can help in studying the test drug for its modulator effects on the targets in a tumor, in the discovery of endogenous biomarkers for evaluating the quantitative effects of the test drug, by this study the not so promising molecules can be eliminated earlier, by which also help in saving costs, in establishing the likely pharmacological dose and by which also helped determining the first dose for the subsequent phase-1 study ,the PK data for initial dose selection can be obtained in nearly six months as compared to nearly 18 months in case of straight phase-1 studies, and they may help in selecting the best animal species for the long term toxicological studies based on the inference drawn from the micro dose metabolite profiling data.[17-19]

Declaration of Helsinki

1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be applied without consideration of all other relevant paragraphs.
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants in medical research involving human subjects to adopt these principles.
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are involved in medical research. The physician's knowledge and conscience are dedicated to the fulfillment of this duty.
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act in the patient's best interest when providing medical care."
5. Medical progress is based on research that ultimately must include studies involving human subjects. Populations that are underrepresented in medical research should be provided appropriate access to participation in research.
6. In medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests .
7. The primary purpose of medical research involving human subjects is to understand the causes, development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and treatments). Even the best current interventions must be evaluated continually through research for their safety, effectiveness, efficiency, accessibility and quality.
8. In medical practice and in medical research, most interventions involve risks and burdens.
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect their health and rights. Some research populations are particularly vulnerable and need special protection. These include those who cannot give or refuse consent for themselves and those who may be vulnerable to coercion or undue influence.
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration. [20]
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