Preclinical development of therapeutic drug is nonclinical and clinical research to determine primary feasibility of a molecule through qualitative and quantitative testing. Preclinical study involves collection of experimental & statistical data to assess method of drug delivery, safety of therapeutics, quality, strength and extraction of molecules from source.
Laboratory and scale-up procedures help to validate manufacturing standards from regulatory point-of-view. Clinical trials are real-time scientific experiments with prospective biomedical application of preclinical research involving particular disease or target mechanism on study group (focus group). This is carried out in several phases.
Clinical trials on human subjects start once the therapeutic drug, method of delivery and target mechanism is successfully validated in animal trials. Human trials may involve healthy human subject or particular study group affected with certain disease conditions, age group and special disability depending upon the objective of the trial. Often clinical trials are supported by clinical decision support system (CDSS) for treatment as per regulatory protocols for safety, quality and efficacy of the drug compound.
Dietary choices, nutritional supplements, generic pharmacy and healthcare standards for each individual under observation are carefully monitored in clinical trials. Clinical study is vastly affected by preclinical data and development. Any new improvements or preclinical changes must be validated in clinical studies again. This may bring complete turnover in clinical trial management of diagnostic product, nutraceutical or biopharmaceutical compound such as monoclonal antibody, hormone derivative and vaccine.
Clinical trials focus on collection of experimental data regarding the safety and efficacy of new drug or diagnostic device, which is not yet approved for public use by regulatory council (like FDA). Clinical trials measure the patient’s response to a particular treatment/medicine or diagnostic parameters until the research team is satisfied with experimental results and statistical data. Abnormal changes in the patient’s body – anatomy, morphology, physiology and metabolism is monitored for focus group.
Success of a clinical trial links medical observations to therapeutic efficacy of molecule, which shall determine future healthcare choices of people and community. Human clinical trials are accomplished in four phases. Phase I study primarily determines the safety of therapeutics for human use, which is conducted on small number of healthy volunteers (2 – 20). Phase II study determines the efficacy, dosage (amount) and preferred method of delivery to human subjects. This phase involves randomized trials on individual groups (focus group) of different age and health conditions. Focus group receiving standard treatment (placebo) or previously established drug is compared to focus group receiving experimental treatment, which is known as “control group”.
Trials in phase II are often blinded and individual patients receiving placebo may be subjected experimental treatment to varying degrees. This is to determine feasibility of experimental treatment. Phase II clinical trials may last for years and new inventions are carried forward to the next phase only with volumes of experimental & statistical evidence. Phase III trial is an extension of phase II trial that involves randomized testing on several thousand human volunteers to measure long-term success rates and failure (false-positive & false-negative results). Most drugs are approved for marketing by FDA after success of this phase. Phase IV is also known as post-marketing surveillance trial, which determines competition and effectiveness to generic treatment/medicine for capturing particular market or completely replaces ancient procedures.
Participation in clinical trials is not mandatory rather voluntary for patients. This usually depends on patient awareness, type of study and selection criteria for the trial, known as “inclusion criteria”. The volunteer receives experimental treatment under expert supervision of a physician doctor and other research professionals (research team) in hospital settings, as required for the trial. The benefit of trials to participants is active involvement in medical research and access to new treatment/therapies before available in public domain. However, there always remains a risk of unwanted side-effects and even threat-to-life in some instances.
Vast amount patient education resources are available for volunteers to gain their knowledge about clinical trials. It is a usual practice that research team or participating company conducting the trial must obtain ‘informed consent’ of the volunteer to enter into clinical trial. Patient may be paid to enter into trials and may be insured by funding company depending upon level of interaction or depth of investigation.
Demographic and socioeconomic advantages
CRMOs can take advantage of large patient-pool, skilled medical investigators, and technology for cost-effectiveness in development process across the world for establishing a new product but must evaluate preliminary safety and efficacy of drug/therapy through phase I & phase II trials. International norms have made mandatory for participating companies to register phase I trial of new chemical entity in country of origin.
Global pharmaceutical companies have outsourced many projects to India for phase III trials, which is approximately eight per cent of trials conducted across the world. The relevant expertise for conducting trial depends on factors such as presence of skilled professionals (research team) and local availability of drug/treatment. Thus, a number of clinical trials conducted in India meet professional ethics and availability of resources.
Global companies like GSK, Terumo Europe N.V., Biotronik are relocating their clinical research operations to India for phase III because of low-cost skilled professionals, existing technology, infrastructure support and diverse patient pool, which can make their project a financially attractive proposal for this demography. For Example, Biotronik is conducting safety and performance registry for diabetic patients having limus eluting orsiro stent system to measure response in coronary artery disease (CAD) with percutaneous transluminal coronary angioplasty (PTCA). The trial is being currently conducted in three major hospitals in New Delhi and several other locations in India to determine the performance of drug eluting stents (DES) over bare metal stents (BMS) in restenosis after PTCA and symptomatic CAD.
Biotech companies can conduct trials in India either through government mandate, which is regulated by Ministry of Finance or automotive route with 100 per cent FDI inflow. The Government of India (GOI) has set-up regulatory council – Clinical Trials Registry India (CTRI) on July 20, 2007 for registration of clinical trials of participating biotechnology companies. The prime purpose is to bring structural reforms, transparency, accountability and accessibility of clinical information in public domain.
CTRI is supported and jointly funded by Indian Council of Medical Research (ICMR), National Institute of Medical Statistics (NIMS), Department of Science & Technology (DSIR) and World Health Organization (WHO). CTRI does not conduct trials but provides database of clinical trials currently active in India for both communicable and non-communicable diseases. The Drug Controller General of India (DCGI) has made trial registration mandatory with CTRI before enrolment of first participant for any kind of investigation such as therapeutic drug (including herbal drugs in purview of the department of AYUSH), surgical procedure, therapy, nutraceuticals, diagnostic devices, behavior treatment and rehabilitation strategies. ClinicalTrials.gov is a registry and results database of public-private supported clinical studies of human participants conducted across the world, which is maintained by the National Institutes of Health (NIH), USA.
Hospital recruitment process and regulatory policy
The process of recruiting patient for a hospital trial is under debate because drug manufacturing companies prefer to recruit patients through local recruiters/agencies whereas patients for special focus group undergo hospitalization for some disease/illness. Pharmaceutical company planning to collaborate venture for a new region discuss advantage of hospital recruitment through expertise available in form of skilled doctors, nurses, staff, pharmacy, technology and infrastructure support. The type of healthcare facility (public or private healthcare) is the major deciding factor availability of resources and cost of recruitment of physicians and patients in funding clinical trial operations.
A case study shows comparison of two pharmaceutical companies that pay volunteers for single visit in cosmetic treatment. Patients were paid Rs 1000 for private healthcare whereas patients that underwent government healthcare facility were given refreshments to eat for their visit. The study points at unethical practices in clinical trials and risk of sickness, bad health and even death that patients have to face for monetary compensation. However, this varies from trial to trial. In India, prior to 2005 no clinical trials were registered and some studies claim loss of more than 3000 people in new drug trials.
The issue of unethical practices in clinical trials brings controversy of complicated regulatory policies and contradictory norms for patient recruitment. Supreme Court of India orders to implement structured approach for registration of clinical trials & recruitment of physician and patients for focus group study. Court has directed pharmaceutical companies to educate patients entering the trial for ‘inclusion & exclusion criteria’, benefit and risk-factors associated with the trial through audio-video lecture series.
Participating company must obtain ‘informed consent’ from patient and guardian as witness for entering the trial. If necessary, ‘informed consent process’ must be revalidated for additional trial of same treatment/drug. Proper records in form of audio-video recording and signed documents must be maintained by participating company. Preclinical research must be translated to patient for their disease condition to raise bar of consciousness in trial process.
Courts have also directed companies to recruit ‘head physician’ as certified to conduct and manage particular clinical trial. Physician certification can be validated through test/interview or internal mandate such that the research team is aware of medication/treatment process involved in randomization of trials. Hospital research team must give timely feedback to the patient (volunteer) and participating company for experimental investigation and validate ‘informed consent process’. For serious and life-threatening procedures, it is important that patient should be covered under medical management program and medical insurance or life insurance program to avoid unforeseen
circumstances and compensate family members of deceased. To conclude, clinical trials have enormous potential to bring advancement in medical science, improve medicolegal framework and overcome financial problems of public healthcare.
(The author is MD of VMG Biotech Consultants, New Delhi)