|
|
|
|
|
|
|
Back
|
|
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.
Definition
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).
|
Parameters
|
|
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.
|
|
|
Phases of Clinical Drug Development in Humans
|
|
|
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).
|
|
|
Phase 1
|
|
|
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
|
|
|
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
|
|
|
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
|
|
|
|
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.
|
|
|
|
|
|
| |
|
|
|
|