Public Awareness
Clinical research literally means research performed in the clinic. By implication, clinical research involves patients and medical practitioners and is essential to diagnosis and treatment of disease. A large part of clinical research is directed towards confirming the effectiveness and safety of new medicines and systematically gathering information that will help maximize the benefits while minimizing the risks associated with the use of medicines to treat disease. Applying this information to medical practice helps us use medicines to our best advantage.
Clinical trials are ethically and scientifically designed studies to confirm or compare the effects of medicines used to treat disease in human patients. Clinical trials are only conducted after laboratory studies and studies of the use of a medicine in animals has indicated that the medicine would be sufficiently safe to use in humans, and is expected to have benefits that are at least as good, if not better than existing therapies.
At a philosophical level, life itself is risky. We are always at risk of accident and injury. What we eat, drink, and inhale, including the air we breathe, carries with it some risk to our well-being, small though it may be. The act of taking a medicine, no matter how extensively tested, or how familiar, carries with it the risk of side effects. However, all effective medicines reduce the risks and discomforts associated with the disease for which the medicine is taken. Regulations across the world do not allow new medicines to be tested in human patients unless the expected benefits associated with taking a medicine are far in excess of the estimated risk of side effects. It is true, however, that some rare side effects of a new medicine may not have come to light at the time a trial is conducted, or that occasionally a new medicine may not turn out, at the end of the clinical research program, to be as effective as current therapy. These risks are usually very small and often more than compensated for by the possibility that the new medicine will turn out to be better, more effective, or have fewer side-effects. Moreover, many trials are conducted with products that are already extensively tested, approved, and marketed to millions of patients. Here, the risks may be no greater than when the same medicine is prescribed in the course of a normal medical consultation.
While all patients who receive effective treatment for their disease will benefit from such treatment, those who participate in clinical trials often receive additional benefits. Trial patients usually receive free treatment. This usually includes a waiver of consultation fee, waiver of fee for investigations included in the trial plan such as blood and urine tests, x-ray, sonography, scanning, etc., and free supply of trial medicine/s. In some trials the patient also receives reimbursement of the cost of travel to the clinic or hospital. Additional payments may sometimes be made to encourage patients to participate. Trial patients are often asked to visit the hospital or clinic at a time different from those for other patients or are seen at a different room or clinic so that they do not have to wait in queue and the doctor can spend more time with the trial patient without holding up other patients. On occasion, trial patients may be the first to receive a revolutionary new medicine and experience dramatic or life-saving benefits unimagined in the past – sometimes years in advance of other patients.
It is usually your doctor who will inform you of ongoing trials and your eligibility to participate. However, more often than not, your doctor may not be aware of trials going on in your city in which he or she is not an investigator. In order to increase patients’ access to clinical trials we, at ISCR, have plans to build a directory of ongoing trials that will be available on this website and will provide patients with information on trials that they may be eligible for. On occasion sponsors of clinical trials publish advertisement in local newspapers to aid recruitment of patients to a clinical trial.
Before enrolling in a clinical trial, it is worthwhile to acquaint oneself with the details of the study. Is the medicine to be used in the trial an investigational product or is it a marketed drug? For investigational products, written permission from the Drugs Controller General of India is required for each trial. In addition, patients have greater assurance of ethical practice if the study plan has been reviewed and approved by an Ethics Committee following Good Clinical Practice guidelines. In studies following such guidelines patients are given detailed information about the trial and potential associated risks and benefits before being asked to decide to participate.
If you are suffering from a disease or health problem for which a clinical trial is currently ongoing in your city, you may be eligible to enroll. Ask your doctor, or call the number provided in a clinical trial advertisement. On your first contact with the trial staff you may be asked a few questions to make a preliminary assessment of your eligibility for the trial. If you are, with your consent, you may be asked to undergo more detailed screening tests to confirm eligibility. Once your eligibility is confirmed, you will be provided with full information on the trial. After fully understanding the information you may decide to participate in the trial. If required, you may request additional information. If you decide to participate, you will have to sign an “Informed Consent Form” and agree to abide by all the trial requirements that would have been explained to you.
You can change your decision to participate and withdraw from a trial at any stage irrespective of whether you have, or have not, signed the “Informed Consent Form”. You need not give any reasons for withdrawing from a study. Your investigator (trial doctor) is required to ensure that you receive the same quality of care irrespective of whether you are participating in a clinical trial or have withdrawn from the study. However, you will not be eligible for any trial-related benefits after you have withdrawn from a study.
If the trial was conducted using a marketed formulation, you should ask your doctor whether it would be appropriate for you to continue to take the medicine. If so, your doctor will give you a prescription which will allow you to buy the medicine from the pharmacy store or chemist shop and continue to use it. For investigational products, you may not be able to continue to receive the medicine after the trial is over. For short-course medicines continuation may not be required. For diseases that require continued treatment, you may have to switch to an alternative marketed medicine till such time that the trial medicine is released for sale. This is so because government regulations do not allow use of investigational product outside of a clinical trial. For life-threatening diseases, there may be an Extension Protocol or a Continued/Compassionate Use Program being run with the permission of regulatory authorities. If so, your trial doctor will be able to tell you how to enroll for such a program and continue to receive the study medicine till the time that it becomes commercially available or the development program is discontinued for whatever reason.
The sponsor of a clinical trial, usually a pharmaceutical company or a research organization, is morally bound to arrange for free treatment of side effects of a study drug, any illness or injury directly resulting from exposure to the study drug, or any injury directly related to procedures undertaken in the course of a clinical trial. While serious trial-related injury requiring major expenditure for treatment is rare, the sponsor has an obligation to ensure that the affected subject/s receive full and appropriate treatment. The cost of such treatment is borne by the sponsor or reimbursed to the patient by the sponsor. In order that this provision is not misused, the opinion of the investigator and, if required, that of experts appointed by the Ethics Committee may be taken to determine whether the injury is trial-related or not.
While we have made great progress in the last 100 years in our fight against disease and premature death from illness, the great majority of diseases still remain to be conquered. Discovering and developing new medicines to fight disease is a collaborative effort requiring contributions from industry, government, the medical community, and patients. Patients are asked to participate in the final stage of drug development – the stage where a few thousand patients volunteer to be the first to take the medicine, thus clearing the way for millions of others to benefit. Observations made during the process of clinical trials are vital to the proper use of the medicine after it is released for general use. Unless patients volunteer to participate in clinical trials, new medicines cannot be brought into the world.
A patient’s participation in a clinical trial is an entirely voluntary act. Your doctor may suggest your participation in a trial if he/she believes it to be in your best interests. Your doctor may be hoping that the trial medicine will be more effective, or that you will be able to tolerate its effects more than your current medication, or simply that you will benefit from the convenience of its mode of administration or from free treatment. However, you must satisfy yourself that you will be able to make the required number of visits to the hospital/clinic for the trial. For most trials, the patient needs to visit the doctor more frequently than in the course of routine treatment. In some trials, when not considered inappropriate or harmful to the patients interests, dummy tablets, called placebo, may be used (see next question). In such cases you must satisfy yourself that you are comfortable with the use of dummy medication, whether or not in conjunction with other medicines. You must read the information sheet/s provided to you, and make your own judgment about participating in the trial. Some patients may find that the benefits of participating in a trial are not attractive enough to compensate for the inconvenience of repeated visits to the clinic or the possible risk of side effects, and that participation boils down to altruism and a willingness to contribute to science and society. If so, you must find out about the scope of the study and decide for yourself whether the value of the study in terms of generating new knowledge makes it worth your participation.
Scientifically designed clinical trials often involve the use of dummy medication called placebo. The use of placebo is important to distinguish the effect of a medicine from the effects of the underlying disease or other factors such as natural changes in the disease process with the passage of time. Placebo is generally used in one of three ways: as run-in, as double dummy, and as a parallel group. In the run-in design, patients who complain of mild symptoms of a disease are given dummy medication to see whether the symptoms go away on their own or really require treatment with a medicine. Although it may seem strange but many patients with mild symptoms will respond to placebo, or report substantial benefit from dummy pills. This is especially true of chest pain, symptoms of anxiety, and mild elevations of blood pressure, sleep disturbances, and so on. Up to a third of all patients with these conditions report relief of symptoms with placebo. It is obvious that placebo responders should be excluded when the true effect of a medicine is being evaluated. The double dummy design has to do with masking the identity of medicines being given to patients – a technique called blinding. When two medicines are being compared in a clinical trial, it is important for patients and their doctors not to know which is which, because this may have a placebo effect on patients besides biasing the doctor in favor of one or the other of the two medicines. To achieve this, the two medicines are made to look the same and distributed to the patients in the trial in a random manner by the pharmacist according to a secret code. However, this is sometimes not possible, as when one of the two medicines is a tablet while the other is a capsule. It is in such circumstances that the double dummy technique is used – some patients receive a medicine tablet and a dummy capsule while other patients receive a medicine capsule and a dummy tablet. Neither patient nor doctor knows which medicine the patient is receiving – the capsule or the tablet. Blinded studies can also be conducted using the parallel group design. Here the aim is to compare a medicine and a look-alike dummy to see whether the medicine is any better than the dummy. Some patients receive the medicine while other patients receive the dummy. This design is only permissible when the disease is not particularly harmful to the patient and patients can afford to go without treatment for some time, for example patients seeking treatment for baldness or forgetfulness, or when the trial medicine is being given on top of other medicines to see whether it has any additional effects. In conclusion, dummy medicines are frequently used in clinical trials, but they are never used to the detriment of patients.
Doctors and other hospital staff conducting a clinical trial for a pharmaceutical company are usually compensated for the time they spend on a clinical trial. Clinical trial patients are usually not required to pay consultation fees to the doctor. Consequently trial doctors lose the consultation fees that would otherwise have been paid to them by the patient. Moreover, trial doctors have to spend more time on a trial patient than on a normal patient, further losing out on earnings. Pharmaceutical sponsors therefore need to compensate the trial doctors for this loss besides reimbursing them for the expenses incurred for conducting the trial.
Almost all modern medicines that we use for treatment and prevention of diseases in our country have been discovered and developed in foreign countries. Patients in our country have benefited enormously from such medicines, be they antibiotics like penicillins or medicines for the heart, without having contributed much to their discovery and development. In recent years, however, the pace of research has increased tremendously. This has led to a relative shortage of eligible patients for clinical trials, and the speed of drug development has sometimes had to slow down because of slow recruitment of patients in clinical trials. India, being one of the worlds most populated nations, has a relatively large patient population, and worldwide patient recruitment in clinical trials can be considerably speeded up if India were to participate in international clinical trials. Some international pharmaceutical companies have therefore started inviting Indian doctors to participate in international clinical trials. This helps speed up the pace of drug development, while at the same time providing Indian doctors with valuable research experience and giving Indian patients the opportunity of early benefit from new medicines if they so desire. Foreign companies also find India attractive for clinical research because of the low cost of research, the presence of well-trained medical professionals, and the ease of communications.
Drug Development
Overview of Drug Development
Medicines are discovered and developed for human use through a long and expensive, failure-prone process that requires cutting edge scientific skills, and collaboration across multiple disciplines within the pharmaceutical industry and among educational institutions, research laboratories, government regulators and healthcare professionals.
Some Lesser-known Facts About Drug Discovery and Development
It takes 8 to 12 years, on average, for a new medicine to be developed for human use, from the time it is discovered to have potential value to the time it is available to the public.
Only about 10 of 10,000 substances identified as potential drugs will make it to the human testing stage. Substances that have been identified to have potential for serious side effects are discarded without human testing.
The challenge of bringing new medicines to market is in discovering and developing them, not so much in manufacturing them. Somewhat like computer software, good chemists can copy, in a matter of a few months, a molecule that has been discovered from among millions of others, and painstakingly developed through years of experimentation to prove that it is safe for human use and effective as a cure for disease.
Patents provide up to 20 years of exclusive marketing rights to the discoverer of a new medicine, during which others are disallowed from marketing the same medicine. Potential new medicines are patented as soon as they are discovered, and the discoverer usually has less than 10 years of exclusive marketing rights remaining by the time regulators approve a medicine for marketing.
Patents do not prevent others from developing a similar medicine with minor differences in chemical structure. However, a medicine even with the slightest difference in chemical structure will have to proved to be safe and effective through a whole series of experiments.
The process begins with a new idea directed at chemically modifying a disease process. Often the idea relates to developing a drug that will react with a new molecular target within the human body. The idea is usually generated from a thorough knowledge and understanding of disease processes and a continuing involvement with research in the specific therapeutic area of interest.
The target molecule, usually a protein, is isolated or sequestered by biological techniques. Tests are devised that can detect interactions of drug molecules with the target. Tens of thousands of potential drug substances, obtained from massive compound libraries, are then tested against the target in a process called high throughput screening (HTS). Robotics is often used to accomplish this task. HTS yields “hits” – compounds that seem to possess the ability to react with the target molecule.
Hits are then studied in detail to determine their exact chemical structure, physical properties, and biological characteristics. Hits that seem suitable from a physical, chemical, and biologic perspective may be termed “leads”. A lead compound is one that will be modified to optimize its properties to one that will be the best suited to develop into a medicine – a drug “candidate”.
The process of modifying a lead compound to obtain one or more drug candidates is called “lead optimization”. It uses a technique called combinatorial chemistry to produce a large number of variants of the lead. The variants are again put through high throughput screening to identify substances with the best target activity profile. Each of the best compounds is studied in detail, and one, two, or perhaps three are chosen for further investigation as drug candidates.
The announcement of a drug candidate is a major milestone in the process of drug discovery and development. It marks the end of the discovery phase and the beginning of early development. The announcement is preceded by a patent search, to ensure that the patent on the candidate drug is not already taken by a rival research group, and by patenting all relevant aspects of the discovery.
Early development involves laboratory and animal studies. Small animals such as albino rats and mice are the most frequently used to ensure that the investigational product is safe for use in humans. The use of animals has diminished over the years as new bench-based techniques have become available. However, animal testing can be eliminated only for a minority of non-clinical studies and animal toxicology tests are still considered essential to drug development, and are required by government regulators before they will allow human testing. A large proportion of candidate compounds fail animal testing, leading to attrition in the pipeline. Sometimes development efforts have to be abandoned and discovery work re-initiated because all concurrent candidates failed non-clinical testing.
Candidates that prove successful in non-clinical testing are prepared for human testing. A drug formulation such as tablets, capsules, or injection, is produced and tested, and an application, known as the Investigational New Drug (IND) application is filed for regulatory approval in anticipation of permission to conduct human studies.
All potentially unsafe molecules are identified early in laboratory and animal studies so that only those molecules that are relatively safe and effective reach the stage of clinical testing. Government regulators thoroughly scrutinize the results of non-clinical testing and approve, for human testing, only those candidates for which experts feel that the potential benefits in patients will be greater than any potential risk of side-effects.
Human testing begins with Phase 1 studies in a small number of healthy volunteers who are given very small doses of the test compounds in specialized Phase 1 laboratories, in the presence of experienced doctors who have expertise in first-in-man studies. Volunteers are told about the study and all its risks. They are paid a participation fee if they decide to participate. The dose of the test compound is slowly increased over a period of several days till the frequency of minor side-effects reaches the upper end of the acceptable range, or the full dose is reached. The nature of any side effects, and the drug concentration in the body are documented. The investigational compound enters Phase 2 studies only if the potential benefits to patients continue to outweigh the risk of side effects in the opinion of government regulators and independent experts.
Phase 2 studies are conducted in a few hundred volunteer patients suffering from the disease for which the investigational compound is being developed. Patients are explained about the study and the investigational medicine, including potential benefits and all potential side effects. Those who wish to participate in the study are enrolled. Patients receive free treatment, and all blood, urine, and other diagnostic tests are paid for by the sponsor company. However, unlike volunteer subjects in Phase 1 studies, patients are usually not paid for participation in the study. The informed consent document and patient recruitment procedures are reviewed by government regulators and the Ethics Committee of the hospital in advance. Patients are free to withdraw consent at any time during the study. Phase 2 studies help in confirming that the medicine works and in determining the exact dose at which it works best. The new medicine is compared with dummy tablets, usually given on top of standard medicines for the disease so that patients are not harmed even if the experimental treatment does not work.
Many investigational drugs do not work well in these studies. Some are shown to have side effects that occur in more patients than is the case with the older medicines. In many cases the overall cost of using the new medicine works out to be too high when compared to the benefits, and therefore may not sell in preference to older, cheaper drugs. Many investigational compounds are dropped from further development for one or the other of these reasons.
Those drugs that are shown to work the best in Phase 2 studies, have the least side effects, and are expected to be the most economically viable, are mass tested in thousands of patients. This phase of drug development is called Phase 3 or full development. The investigational drug is given to many different types of patients – children and the elderly, those with different grades of severity of the disease, those taking other medicines for other diseases, those that need to take the medicine for a long time, and so on. The Phase 3 program is the most expensive part of clinical development. Studies are conducted across multiple patient recruitment sites simultaneously in many countries across continents. All the time, the new medicine is compared with older drugs to confirm that it indeed works better than currently available therapies. The drug may have to be dropped from further development if it is shown that it is only as good as cheaper, older drugs. The sponsor company will want to have such information as early in the development program as possible, so that development can be halted before too much money has been spent.
In the end, only 1 of 10 drug candidates that enter clinical testing at Phase 1 are found to be good enough to justify the high price tag that must be put on the medicine to meet the cost of development. Government regulators review the results of all the studies in great detail and sometimes visit the study sites and cross-question the investigators and sponsor staff. Only when the regulator is fully satisfied with the quality and extent of data is marketing permission given. The investigational drug is then “launched”, and becomes a medicine available at the chemist shop or pharmacy.
Even after regulators have allowed the medicine for general use, a strict vigil is maintained. Doctors are required to report any unexpected side effect or suspected health risk with the new medicine as soon as possible to the regulators and the pharmaceutical company concerned. When millions of people start taking a new medicine, new side effects or health risks sometimes come to light. The frequency and extent of these is closely monitored by regulators. Sometimes, warnings and precautions must be added to the product label, and rarely, a drug may have to be withdrawn from the market.
New medicines are very expensive in the early years of sales to pay for the cost of drug development, publicize the benefits of the new therapeutic option, and provide returns to shareholders of the company. Eight to 10 years after launch the patent period expires and the drug is thrown open for other companies to manufacture and sell at low price. Patients are often not able to afford new medicines and, in most countries, the government pays for them and provides them free or at low cost to patients. Health insurance schemes offer to pay the price if the patient holds an appropriate health insurance policy. While government and pharmaceutical companies are doing their best to minimize the costs involved in drug development, the high price of innovative new medicines worldwide remains an unavoidable necessity without which there would be no new medicines. It the price we pay for medical breakthroughs in the early years of their advent so that millions of patients can enjoy their benefits in later years and live longer and healthier lives.
Clinical Research
The fascinating process of drug discovery and the rigors of pre-clinical testing prepare the drug for its most crucial phase.
Human trials are likely to be initiated if the following circumstances are met:
Pre Clinical data demonstrate that it may be useful in treating a disease.
Pre Clinical trials are adequately designed to provide efficacy and safety data.
The compound appears to be reasonably safe for initial testing in humans.
The proposed clinical trials will not expose subjects to unnecessary risks.
The simple yet not simplistic way of describing a clinical trial is to quote Sir Austin Bradford Hill’s classic, “it is an ethically and scientifically designed experiment with the aim of answering some precisely framed question”.
It is evident that a clinical trial has to be properly designed and planned in order to provide reliable efficacy and safety data. Needless to say a statistician’s input is vital right from the design of a clinical trial protocol through to the data analysis on its completion. As Jerome Cornfield, an American Statistician used to say, “Overinterpretation is an effort to compensate for underplanning”.
A protocol is a document that states the background, rationale and objectives of the clinical trial and describes its design, methodology and organization including statistical considerations, and the conditions under which it is to be performed and managed.
It has to be approved by an Independent Ethics Committee who permit the trial to be conducted at a particular institute. A monitor or clinical research associate, appointed by the pharmaceutical company (whose drug is being tested) is responsible for overseeing the progress of the trial, and of ensuring that it is conducted, recorded and reported in accordance with the protocol, standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
Appropriate selection of these subjects is particularly critical. Inclusion and exclusion criteria are drawn to select the optimum patient population on whom the test drug can be adequately assessed. Women of child bearing age, very small children and the elderly are generally excluded from the majority of phase 2 and 3 clinical trials. The sample size i.e., is calculated based on certain parameters:
  • The expected difference in efficacy between the two treatment groups
  • The standard deviation of that difference i.e., the measure of the way in which the efficacy variables are distributed w.r.t a mean variable. A sample is a statistically determined number of people (on whom the drug is tested) representative of the population at large. Results obtained from such a sample are then extrapolated to a much larger population within certain (95%) confidence limits to predict the drug’s safety and efficacy.
  • The level of change one will accept for the so-called type I (or a) error. This is the error of accepting a result which is apparently significant but is not reflective of the true difference in efficacy. This probability is generally fixed as 5% i.e., a 1/20 (or 0.05) chance that the apparent difference was not a true difference. If the value found on comparing results is less than 0.05, (p<0.05) the difference is regarded as a true difference.
  • The level of chance one will accept for the so-called type II (or b) error. This is the error of not picking up a truly significant difference in efficacy when one really exists. It can happen if too few patients are recruited, because of incorrect trial design. The level of probability for this error is often more liberal e.g., it might be set at 0.8, accepting that there is a 20% chance (1/5) that such an error has been made. This is sometimes called the power of a trial (1-b).
    The smaller the difference between the results of two treatments, the more patients will need to be studied to have a reasonable chance of detecting a significant difference. Thus it is very important to plan carefully on the ‘n’ value i.e., the number of subjects to be enrolled in a clinical trial.
Randomization is a process of including patients at random such that each patient has an equal chance of being assigned to either of the treatment groups. It is a means of minimizing bias in patient selection. Another way of doing this is double blinding where both the subject and investigator are “blind” to the nature of the subject’s treatment. This also reduces the chance that the doctor and patient may allow personal biases to influence their efficacy and safety evaluation.
The test drug is generally compared with the standard drug for the disease/condition and/or a placebo group. The comparator group serves as a control with which the effect of the test drug is compared to evaluate its true efficacy. The placebo group is essential when it is known that the disease/condition can be unduly influenced by the placebo effect- a psychoneuroimmunological effect of the doctor/treatment on the patient, which inexplicably ameliorates the condition and potentially obfuscates the interpretation of the drug’s true pharmacological effect.
In recent years the pharmaceutical & regulatory bodies of USA, Europe, Australia, Canada, the Nordic Countries, Japan and the WHO have mutually agreed upon an international, ethical and scientific quality standard for designing, conducting & reporting trials that involve the participation of human subjects. The objective of this International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guideline is to provide a unified standard for the European Union, Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. Compliance with this standard provides public assurance that the rights, integrity, confidentiality, safety and well-being of trial subjects are protected and that the clinical trial data are credible, valid, accurate, and verifiable from source documents. It also obviates the need for replication of clinical trial data on a product in the individual countries.
Clinical drug development in humans takes place in a series of phases. Phase 1 studies are the first time a new drug compound is tested in human subjects who are generally normal, healthy volunteers. These studies, often referred to as clinical pharmacology studies, are designed to determine tolerance/safety, pharmacokinetic and pharmacodynamic properties, including occasionally early indications of efficacy. The preferred route of administration and a safe dosage range are other parameters tested during this process. A phase 1 trial generally takes from 6 months to a year, and includes fewer than 100 healthy volunteers. Oncology drugs are an exception. Due to their potential for toxicity, such drugs are tested in cancer patients rather than healthy volunteers.
During this early phase exploratory work is begun to determine whether valid quality-of-life (QOL) measures are available for diseases that may be targeted for the new drug compound. If QOL measures are not available instrument development may begin.(e.g., for Viagra in erectile dysfunction, Pfizer scientists developed the International Index of Erectile Function (IIEF) questionnaire which is now used as a standard for assessing quality-of-life in trials of drugs for erectile dysfunction).
As a part of phase 1 trials, bio-availability studies are conducted to determine pharmacokinetic parameters like the rate and extent of absorption, maximum serum concentration (Cmax), and time to Cmax (Tmax) and the area under dose-response curve (AUC) is plotted.
Bio-equivalence trials are done when a branded generic is sought to be marketed within 4 years of introduction of the first (often patented) brand. The imitator’s pharmacokinetic profile (Tmax, Cmax, AUC) has to exactly match/superimpose that of the original drug.
Nowadays clinical trials are structured to assess not just safety and efficacy but also quality-of-life (outcomes research) and cost-effectiveness (pharmacoeconomics). Pharmacogenomics, i.e., the study of the way drugs interact with the genome or genetic make-up of an individual is another tool which is being used to selectively tailor a drug/dose to an individual. It helps in the selection of trial patients in whom the drug is predicted to have optimum efficacy and safety. Approximately one third of candidates fail during phase 1 testing due to poor toleration/absorption.
Phase 2 clinical trials are designed to provide additional safety data but the primary purpose is to determine the drug’s dosage range and clinical effectiveness in its targeted population. Here, patients with the disease under investigation are studied. Typically these trials are placebo-controlled, i.e., one group is administered a placebo (inert compound which is pharmacologically inactive and is formulated to simulate the test drug in physical appearance) while the other group of patients is given the test drug.
The investigators who conduct phase 2 trials are usually experts in the disease being studied and /or in the evaluation of the drug’s effects on the disease process.
Phase 2 trials generally involve between 100 and 500 subjects who have the disease/condition for which the drug is being developed. Phase 2 studies also may determine the minimum dose of the drug that is effective, and / or the upper dose that is sufficiently effective without undue toxicity.
Sometimes reference is made to phase 2a & phase 2b studies. Phase 2a studies are pilot clinical trials designed primarily to evaluate safety in selected populations of patients. Objectives may focus on dose response, type of patient, frequency of dosing, or other characteristics related to the drug’s safety. Phase 2b studies are well-controlled clinical trials designed to evaluate both efficacy and safety in patients with a primary objective of determining a dose range to be studied in phase 3.
Additionally, phase 2 studies may include pilot testing of QOL instruments to assess validity, variability and sensitivity to change. Validation is the action of proving that any process, procedure, equipment, material, activity, or system actually leads to the expected results.
Phase 3 clinical trials are well-controlled comparative studies designed to assess the safety and effectiveness of the drug in conditions approximating those in which the drug would be used if approved for marketing. They generally involve thousands of patients with a targeted disease and are frequently multi-centric. Data from these trials are pivotal for registration. A randomized, placebo and/or active controlled, double blind clinical trial is considered the gold standard to evaluate the drug’s safety and efficacy. However, it is possible that some adverse events may be missed even at this juncture, only to surface after the drug has been marketed, e.g., temafloxacin was withdrawn by the U.S. F.D.A. 6 months after it was launched. It is often said that the efficacy of a drug is measured in the controlled environment (strict inclusion and exclusion criteria, close monitoring of patients) of a clinical trial while its effectiveness is known only post-registration when it is used in a much larger patient population (often not strictly monitored or selected) in the unregulated atmosphere of general clinical practice. Efficiency is yet another term in pharmaco-economics which measures the cost-effectiveness of the product and its effect on disease outcome vis-à-vis other competitor products.
The data obtained in phase 1,2, and 3 trials are used to prepare documentation for regulatory approvals. Only about 8% of drugs approved for development are eventually approved for marketing.
Sometimes reference is made to phase 3a and 3b trials. Phase 3a trials are conducted after the drug’s efficacy is demonstrated but before regulatory submission of the New Drug Application (NDA). These trials are conducted in special patient populations, e.g., studies in children and in patients of renal dysfunction. Phase 3a data may also include assessments of patient function, health-related QOL, and/or health care utilization which may assist with formulary and drug reimbursement decisions. In India the concept of managed health care and disease management organizations has yet to arrive but with increasing patient awareness of health insurance, that day is not too far.
Phase 3b trials are conducted after regulatory submission of the NDA but prior to the drug’s approval and launch. They may supplement or complete earlier trials. They may also collect outcomes research data, including “real world” conditions in which the drug’s clinical, QOL, and economic impacts are assessed.
Phase 4 post-marketing surveillance studies are conducted after the drug has been approved.
Conclusion: Thus, out of thousands of compounds synthesized and screened, only 10-20 per year undergo pre-clinical testing, and only 5-10 enter phase 1 trials. Only about 1 out of every 15 drug candidates entering development actually receive regulatory approval. Understanding of the resources, in terms of staff, time and cost required to develop safe and effective products should enable one to have a fairer view of the premium price at which these products are marketed. After all a substantial proportion of the profits is ploughed back into research and in fact provides the sustenance for innovating and bringing better products to further enhance the quality of human health.

Indian Society for Clinical Research

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