Science and art of Clinical Research: â?”Role of clinical
Researcher & Monitor
Kranti Sikha Tripathy
ABSTRACT : Clinical research, though essentially a subset of applied science in so far as the involved aspects of the science of medicine and relevant aspects of life sciences in general are concerned, the design, conduct, interpretation and inferences are intimately associated with human elements like value judgment, ethical considerations, human rights,trust,sympathy,pain scores, feeling of wellbeing and social performance etc.Hence the science of medicine which is the mother of clinical research though traditionally considered to be based on experimental evidence, the art of clinical research is more inclined towards modern quality of life assessment, addressing general feeling of wellbeing, physical activity domain tempered with milk of human kindness, human right considerations and humane discretion. In this context, the role of a clinical researcher and the monitor becomes rather onerous who in their roles of pursuing the essentiality of scientific ends have to balance scientific efficiency with human considerations like subject protection. Successful discharge of their duties does not lie only being text book-driven and rule & regulations-oriented but on value judgment and ethically sound discretion. These difficult roles are to be enacted right from the inception starting from designing the clinical trial protocol through the conduct of the actual trial involving human volunteers and finally ending in inferences and final presentation of the clinical trial results for approval of the regulatory authorities. It is proposed to revisit clinical trial in all its aspects indicating the subtle scientific and art elements involved in each stage and the actions of the researcher and the monitor desired there on based on value judgment and ethical considerations.
Debate still continues as to whether â?oClinical Researchâ?ť is an exact science or an art form .In real practical terms this can be termed a hybrid between, applied science and art. This duality makes the job of a clinical researcher extremely challenging balancing the scientific activities with more demanding aspects of social engineering ,human rights, human kindness, sympathy and value judgements.Clinical research is the very backbone of modern medicines and health care making them the mother of medical innovation and scientific breakthroughs. Clinical research brings the latest therapies and pharmaceuticals from the laboratory to the bed side of human patients. It blends the two worlds, the lab and the clinic and translates basic discoveries into treatment for human disease. Since it begins with participation of human volunteers and the ultimate beneficiaries are human beings, human aspects play a vital role in everything connected with the process. We shall revisit different stages of clinical research and bring out the subtleties of science and art involved in each stage with the onerous responsibilities thrust on clinical researchers and monitors to address them effectively.
2.0 CLINICAL RESEARCH REVISITED:
Although â?oClinical trialsâ?ť was reportedly first introduced in 1025 A.D ,the first clinical trial was infact documented in 1753 A.D for treatment of the then dreaded disease â?oscurvyâ?ť. It begins with the innovator or clinical trial sponsor and ends with research participants which are volunteering humans. Along the continuum are CROs, site management organization, clinical trial sites, investigators, clinical research coordinators and CRAs.
2.1 PRE-CLINICAL TRIAL:
Before the actual human clinical trail begins, it is imperative morally and legally to zero in on an, â?oactive lead compoundâ?ť selected out of several â?opotential candidate drugsâ?ť perhaps through an elaborate mechanism involving,â?ť lead compound committeeâ?ť and â?oproduct development representativeâ?ť. These trials involve in-vitro( test tube or lab) studies and in-vivo ( trials on animals ) studies so that chances of precious human lives at risk are minimized and required preliminary efficacy, toxicity and pharmacokinetic data merits to go in for human trials.Pre-clinical testing from initial synthesis to animal testing takes from 1 to 3 years. Documentation of the experimental data is required to obtain the IND number (Investigational new drug number) from FDA (USA) to go in for human trials which starts from Phase-0 and ends in Phase-IV( Five phases, the last one being post-marketing surveillance test).
2.2 COST-EFFECTIVE ANALYSIS:
Developing a new drug product or device takes a very long time and also involves huge lot of money. It has been estimated that the average time between submission of application for new drug approval (ANDA) to obtaining approval from FDA is 8.5 years and involves an expense of $802 millions for a new prescription drug. Hence before committing such cost-intensive proposition, in-depth analysis need be made by sponsors prior to go in for human trials. Such analyses comprise the expected benefits, harms, cost of adopting and translating a clinical finding in to practice. One such method is called,â?ťCost-effective analysis (CEA)â?ť and the methodology is depicted here below:
C1-C2 Net Costs
CEA =????? or ??????
O1- O2 Net health outcomes
â?oCâ?ť, stands for cost associated with an intervention and suffixes 1 and 2 are alternatives
â?oOâ?ť, stands for outcome of the interventions (1 and 2 are two alternatives)
Net costs is the sum of cost of the intervention and cost of treating the side effects minus the costs averted because of the intervention (i.e. costs of care for the prevented disease condition)
Outcomes in case of CEAs are measured in different ways. One such method is measured in terms of â?oLife years saved (LYS)â?ť.This method accounts for how an intervention strategy affects mortality. However it does not take into account â?othe quality of lifeâ?ť associated with different health outcomes. To capture both the effects of life years saved and QOL (quality of life ),the number of years with illness or injury can be multiplied by a weightage factor varying from 0 ( death ) to 1 ( full health ) to generate, â?oquality adjusted life years (QALYS )â?ť.CEA that uses QALYS in the denominator of their cost effectiveness ratios are often referred as â?ocost utility analyses ( CUAs )â?ťbecause they incorporate peopleâ?Ts preferences or utilities for different status of health, illness and injury ( CUAs are subset of CEA ).Economic analyses other than CEAs serve as cost-minimization analyses and â?o cost-benefit analyses(CBAs)â?ť also provide information about potential value of the intended clinical research/trial.
2.3 CONSEQUENTIALIST ETHICAL THEORY:
This theory which stipulates that rightness or goodness of the action in taking up the clinical research work is based on the potential consequences. The most ethically praiseworthy action according to this theory are those that maximize the good for the greatest number amongst humanity. It is essentially a balancing act between scientific efficiency and protection of research subjects and forms the rationale for taking up the study through clinical research.
2.4 CLINICAL TRIAL PROTOCOL:
The next step is to formulate an action plan of the impending trials which is popularly known as â?oClinical trial protocolâ?ť. The plan describes, what will be done in the study, how will it be conducted and why each part of the study is necessary and each study has its own rules about who can participate. This document should be a well thought of and scientifically based coming out of theâ?ť thinking hatâ?ť which needs to be innovative and need-based although standard templates are available for overall guidance. The most common elements include background and significance, specific aims or endpoints, inclusion and exclusion criteria, study procedure and statistical designs with an overall sound rationale for a clinical trial. Here science and art are judiciously integrated to make it scientifically attractive and innovative.
2.5 RECRUITMENT OF TRIAL VOLUNTEERS:
This is perhaps the first field action taken in the pursuit where ethical and scientific considerations are interwined.There are networks of regulations in different countries but the common thread arose in response to abuse of human research participants. There are several international guidelines and codifications ,the main guidelines being, The Nuremburg code, The Declaration of Helsinki, The Belmont Report (USA), International Conference on Harmonization Guidelines for good clinical practice(ICH GCP) setting standards at the international level for the rights, fairness ,respect,beneficence,justice and privacy of human trial subjects.Traditionally,the science aspect of the clinical trial is considered to be based on experimental evidence while art aspect of the trial is based on trust,sympathy,the threatened patient and other human aspects like pain scores, feeling of wellbeing and social performance that transcend mere statistics. The art of medicine is more and more turned into science i.e. with modern quality of life assessments addressing general feelings of wellbeing; physical activity domain etc.Each study component has an ethical aspect. These ethical aspects can not be separated from the scientific objectives as ethical and scientific aspects jointly make a successful clinical trial. The researcher should focus on,â?ť what ought to be doneâ?ť in research involving human subjects. At this stage, the aspect of,â?ť informed and voluntary consentâ?ť of the human subject coupled with inclusion and exclusion criteria occupies center stage in respect of subject selection without any bias. The statement,â?ť Bad science is bad ethicsâ?ť is true here and the intersections of scientific goals and ethical concerns should be properly addressed by the clinical investigator and his/her team together with the monitor and coordinator. The clinical researcher should ask some very valid questions to himself/herself and should proceed ahead only on the basis of appropriate answers:
? How much risk of harming a study volunteer is too much risk?
? What protection ought to be built into a protocol that involves cognitively or socio-economically vulnerable research subjects?
? How should it be determined whether the benefits of the new knowledge to be gained through the instant research for the society is sufficiently important to place research subjects at risk of harm or even at risk of more inconvenience?
? If a study does not promise potential direct benefits for subjects, will the studyâ?Ts result be significant or important enough for society to counterbalance the risks or inconvenience a subject may experience during the trial?
? While designing consent forms, how much information is the â?oright amountâ?ť?
Understandably, the ethical tension inherent in the relationship between the goals of a clinical medicine or device and those of clinical research is necessary to develop excellence in research involving human participation. The clinical investigator must understand the subtle distinction between clinical care in research and standard clinical care. Being a successful clinical researcher, means being a master at achieving two goals concurrently â?”the goal of achieving scientific advancement and due protection of human subjects.
2.6 CLINICAL HUMAN TRIALS:
These trials may be of five types namely,â?ť prevention trialsâ?ť,â?ť screening trialsâ?ť,â?ť diagnostic trialsâ?ť,â?ť treatment trialsâ?ť and â?oquality of life (QOL) trialsâ?ť. Conventionally, the different phases in sequence begins with Phase-0 and ends in Phase-III on successful completion of which drug approval for the new drug is accorded by FDA (USA).The subsequent phase is Phase-IV which is a post-marketing surveillance trial to collect comprehensive data on safety. efficacy, dosage requirements and adverse side effects after long use of the invented drug candidate. In all such human trials, the fundamental design rests on aspects of randomization, blind or double blind and placebo effect controlled trials in contrast to the usual purely evidence-based trials.
Randomization means that each subject is assigned a random number (based on statistical random numbers) so that each subject either receives the study treatment or a placebo treatment (fake treatment) but without his knowledge.
Blind means, the subject does not know which treatment he is receiving. Double-blind means both the investigator and the subject are not aware of which treatment is being given by him/her and which treatment is being received by him/her respectively. The main underlying principle is to isolate the effect of the drug being studied and to prevent human bias in study. The other important parameter is the number of subjects involved in the trial which has a large bearing on the degree of reliability of the research at hand. This is described as, â?opowerâ?ť of the trial.
3 .0 Roles of Researcher and Monitor:
Most monitors and investigators start their job in confusion as to whether they should treat the subject as pure science or a form of an art.Unfotunately,the job is difficult to clearly delineate since it is more art than science, more luck than skill and more experience-driven than textbook-driven. For example, a monitorâ?Ts responsibility is toâ?ť monitor the conduct of a research trialâ?ť and this is what we observe while looking to the code of Federal Rules (CFR).There are no guidelines or rules that outlines the tasks appropriate for a site visit and there are no rules to specify the frequency of such visits. Hence to monitor trials effectively value judgment more than specified rules are necessary. It is also important that monitors and researchers anticipate study-related hurdles and necessary regulatory filings to enable the research team to meet the challenges both at the qualitative and quantitative front. Proper â?obenchmarkingâ?ť should be incorporated: (a) to increase credibility of research studies (b) to identify key opinion leaders and investigators for protocol design input and clinical trials (c) to evaluate commitment, skill and qualification of the research team particularly the investigator (d) to create effective structures for both internal and external accountabilities (e) partner to leverage CRO expertise amongst other things. Beyond reviewing patient records, a good monitor needs to take a global â?osnapshotâ?ť of how each patient is progressing during the trial. This snap shot is useful for confirming that a patient is receiving adequate care, the collected data is coherent and the trial is progressing satisfactorily. If any of the elements of a snap shot seem questionable, it becomes the responsibility of the monitor to discuss those concerns threadbare with investigator, coordinator and even the sponsors. In those circumstances, it is difficult to know whether the treatment is having a favorable effect, no effect or even adverse effect. The best way to answer the real- life scenario is to meticulously scrutinize whether the subject(s) have really gone through random, double-blind controlled clinical trial procedures. Being a good monitor means being a good manager also, leading from the front, fostering team spirit and building up synergy in the organization. The ethical and scientific aspects of the trial must be in sync and no compartmentalization should be allowed. Ethically sound clinical research understands the implications of how, when, why and where there are conflicts between meeting scientific research goals and protecting research participants. The goals of science also conflict with the goals of clinical care when a physician recruits his/her own patient into a trial in which the physician happens to be an investigator.Here.at risk is a physicianâ?Ts objectivity in decision making since the difference between the goals of a clinical medicine and the goals of a clinical research is not the same thing. Although separation of the roles of an investigator and a clinician may neither be practical nor desirable, the clinical researcher should be alert to these differences and the potential conflicts. The other aspect that comes to my mind is the â?oquality managementâ?ť of research. This should mean both quality assurance and quality improvement.
While submitting the final report of the clinical research, it is necessary to take a dispassionate view of the entire pursuit rather than finding out alibis to be able to project an attractive and rosy picture to satisfy both tangible (may be economic gains) and intangible benefits ( may be ego or image considerations).
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