The clinical research and resources about medicinal herbs are the source to track new emerging trends regarding the use of natural plants. We should be ready, liberal and scientific regarding the use of traditional known herbs.
The statement of Charaka, the father of Indian Medicine, is noteworthy in this regard, though it was stated about three thousand year ago.
The great seer Charaka advised the coming generation of herbalists after classifying the ayurvedic herbs in fifty major pharmacological groups…
“These are the results and effects and use of medicinal plants as we have studied, experienced and researched and realized. Later if this description or the results or effects change, either change the description or remove that herb from the classification of that group. Use what is realized and effective on use.”
This statement is fully valid even now both for traditional users and scientific community.
The Preclinical Trials In Animals
These studies in animals are conducted before they are done on human being. The following article will deal about this topic in reference to modern drugs. The intention of this topic to give the visitors a definite view about the topic.
Many of the herbs – both known and unknown are tested on these parameters. Almost all the new herbs should be tested on this basis to affirm their safety.
Until the end of 19th century, the discovery of drugs was a matter of chance and serendipity. Paul Ehrlich (1854 – 1915) put an end to this by developing the idea and scientific basis of selective toxicity. Now the whole business of new drug development rests on biological selectivity and prediction of this on man.
There are two kinds of laboratories – industrial and academic. Industrial laboratories follow the ‘organized opportunism’ and the academic libraries follow the knowledge for its own sake. Both the approaches are complementary. Both kinds of labs are lacking with regard to herbal research in Clinical Research trials.
Clinical Research Trials & Four Approaches Toward New Medicine Discovery:
- Synthesis of analogues (similar), agonists (that bind on the same site in the cell) and antagonists (that bind on the same site in the cell but blocks the action) of natural physiological hormones other substances that modify already understood biochemical process.
- Modification of the structure of the known drugs will likely to produce more agents with similar properties or with minor differences.
- Random Screening.
- Discovery of new uses of drugs already in general use.
The herbal medicine clinical research trials can use all the four methods but the last two methods are worthwhile to explore respectively new and known herbs. Modern Herbal research is incorporating both kind of approaches.
Clinical Research Trials In Animals:
These clinical research trials serve the following purposes.
- Knowing the Pharmacodynamics – The action relevant to the proposed beneficial use and other effects at that dose. In case of most herbs, we can thus find other adjuvant benefits that I usually call ‘Side Benefit’.
- Knowing the Pharmacokinetics – How the drug is distributed and disposed of by the body. This knowledge is usually not available with most of the herbs.
- Toxicology – It refers to whether the herb or drug causes the injury. It is of three types. (A) Single dose toxicity or Acute toxicity is tested for 14 days. (B) Repeated dose studies or Subacute, Intermediate and chronic or long term toxicity. It ranges from 30 to 180 days. (C) The duration of repeated dose studies.
- Special Toxicology – It is of three types. (A) Mutagenicity tests – The ability to effect genetic changes in the cell is tested on the bacteria. (B) Definitive Carcinogenicity tests – This is not required prior to early studies in man until the drug is suspected for this kind of effect. (C) Reproduction Studies – The effects right from the male and female gametes to intrauterine life to formation and development of embryo to toxicity on fetus to its growth, parturition, behavior and ultimately the effects on the second generation. All these studies are extremely time consuming and requires great funds and latest equipments and labs. These are not done even on modern drugs.
The Ethics Of Using Animals In Clinical Research Trials:
This is very sensitive, controversial and sometimes disgusting issue. In many aspects animals are similar to us but for psychiatric effects animals are not useful to that extent.
We have to continue these tests until the knowledge of basic mechanisms advances, in vitro biochemical preparations and tissue cultures allow us to predict the effect in man. This all seems to be a far away issue today in Clinical research trials.
Predictions – Both Beneficial & Harmful – Pharmacology & Toxicology in Clinical Research Trials:
After all these experimentation comes the day of declaring results. By predicting the benefits and harms, the benefit and risk ratio is understood. When the benefits seem to overdo the harm, the further research and Clinical Research trials in man are conducted.
If researchers are successful to this extent, they are able to tell the therapeutic index – the ratio between maximum tolerated dose and minimum curative dose. The smaller is this ratio, the better for the safety of that drug for us.
When the drug in under suspicion, then case control studies are practicable.
Drug Quality For Clinical Research Trials:
The product should be pure, standardized and stable so that it can remain pure after years of shelf storage.
Concluding The Preclinical Research Trials In Herbal Research:
There is emerging trend especially in the developing countries that drug should have specific effect and without any minor physical or mental discomfort. This is just an imaginative medicine still. Even if the resources be infinite and the understanding of biochemical processes be at its top, there would never be any such ‘perfect remedy’.
The Perfect remedy lies in living holistically in accordance with nature. If a small portion of the money spent on developing drugs (one new drug takes several years and hundreds of million dollars in US) be use on studying the preventive and curative effects of herbal medicine, we as a whole of humanity would be better on the way to health and freedom from diseases. Most of the herbs that are being used traditionally need very little expense and time in validating their benefits and in standardizing them. We can hope and pray that this be heard and done.
The Therapeutic Trials In Man
When a new or old herb is predicted useful in man, then the time has come to test it in man. However it can take already a lot of time to test the herb in animals. So the herbs that are reported to have some adverse effects should be used in animals first and those ones in common use already should be studied in man.
Four Phases Of Clinical Research Trials
There is a planned way of introducing a new herb or drug for use in man. These are conventionally divided into four phases.
Phase One – Clinical Pharmacology:
- 20 to 50 persons are included in the herbal research.
- Healthy volunteers or patients are taken into the clinical trial.
- The biological effects, tolerance, safety and efficacy is studied.
- The absorption, distribution, metabolism and excretion is also studied where practicable.
Phase Two – Clinical Investigation:
- 50 to 300 persons are included in this advance study.
- Patients are accepted.
- Besides the above parameters, dose ranging, controlled studies are performed for efficacy and safety.
Phase Three – Formal Therapeutic Trials:
- In these randomized controlled trials 250 to 1000 people are taken in clinical trails.
- This provides the efficacy, safety and comparison on a substantial scale.
Phase Four – Post Licensing Or Marketing Studies:
- 2000 to 10,000 people are incorporated in these large scale studies.
- This surveillance is done for safety and efficacy, and further formal therapeutic trials and comparison with other medicines.
The above four phased studies are conducted for all the new drugs in Modern Medicine. Only first two phased studies of are conducted with reference to herbal clinical research trials. It is very rarely when the clinical research trials exceed the above level for herbal research.
Official Regulatory Guidelines For Clinical Research Trials In Man:
These guidelines belong to modern drugs except some points.
- The drug or herb is evaluated for its pharmacokinetics and bioequivalence i.e. how much is this medicine is available for beneficial effects after it absorption into the blood.
- Various Therapeutic trials are adopted for the efficacy and safety.
- Special groups of subjects – If the medicine is for some special group like the aged persons, females or pregnant ladies, then the agent should be studied in that group also.
- Fixed Dosage Combination products should require full justification.
- Interaction studies with other herbs or drugs or food articles should be considered.
- The Countries where a license is required for herbs use (Product License, like in India, all new herbal formulations should be patented after clinical trials) should include a draft or Data Information Sheet for prescribers and for patients.
Only in some countries where herbal formulations are patented like in India after herbal clinical research trials, there are provisions for following the above mentioned criteria for herbal research. However some of the guidelines, that need a lot of funds and practically not useful for herbal research esp. for herbs that are used traditionally for a long time, are not and perhaps should not be followed. In these cases only validation of efficacy and safety is fine.
Experimental Therapeutics Of Clinical Research Trials:
As more and more medicines are tested, the problem of who to test them grows. There are two main groups – healthy volunteers and volunteer patients. Some of the actions are demonstrable on healthy persons as anticoagulant and anesthetic action whereas some of the actions can’t be shown on healthy persons as antiparkinsonian, antimicrobial effects. Besides using man as experimental subject offers some ethical problem.
Doctors or Experimental bodies should follow the principles of therapeutic evaluation. It is essential to know a good therapeutic study from a bad one. Both the good and bad studies are sometimes thrown on doctors by vested interests. Some times bad studies are replete with jargons of formal therapeutic trials what on close observation would prove to be a fraud. These principles are for the benefit of the doctor as well as all the patients and persons.
Therapeutic Investigations Of Clinical Research Trials:
These investigations employ two kinds of outcome. First one is the therapeutic effects itself e.g. sleep, freedom from infection etc. Second one is a factor related to the therapeutic effect or Surrogate effect e.g. blood glucose or lipid, blood pressure.
Studies involving surrogate effects are measured by studying large numbers of patients over years. They are not essential prior to release of new drug or herbal formula for prescription. For these conditions, surveillance studies are used to complement the formal therapeutic trials.
Therapeutic Evaluation Of Clinical Research Trials:
There are two ways to conduct – First Formal Therapeutic Trials or Experimental Cohort Studies and Second Surveillance Programs e.g. Case control studies, observational cohort studies.
The Formal Therapeutic clinical research trials are devised to find out the best of a drug can do under conditions ideal for showing efficacy – uncomplicated disease from mild to moderate severity. Sometimes these studies are also called Explanatory Studies.
The second Surveillance programs are desirable after the success of first one and are conducted to find out whether it can be successful and safe in the routine medical practice, in all patients, patients with complications, with other medicines etc.
Formal therapeutic trials are expensive and hard to conduct. Surveillance studies are less precise but compensate for this by convenience, large size and its closeness to ordinary clinical practice.
Formal Therapeutic clinical research trials are not able to reveal – uncommon adverse effects or those that occur after prolonged use, effects in special patients groups like elderly, pregnancy; unexpected therapeutic effects like new uses, and interactions with other drugs.
Clinical Research Conclusion:
Doctors should follow the scientific techniques to uncover the most effective treatments and should avoid the unethical course of notoriously depending on the clinical impression in both conventional and herbal research. It has been pointed out that where the worth of a treatment , new or old, is in doubt, there may be a greater obligation to test it critically than to go on prescribing it supported only by habit or wishful thinking. All the methods discussed above are powerful tools in advancing therapy if used judiciously and by knowing the conditions where they are fruitful and where to avoid them in Clinical Research Trials.
Designing The Therapeutic Trials
The Need of Statistics: After getting the overview of therapeutic trial, there arises the need for correct statistical information. When clinical impressions or convinced opinions are used instead of convincing facts, the progress is delayed and the condition becomes pitiable.
Statistics can be defined as ‘a body of methods for making wise decisions in the face of uncertainty’. When used properly, it is a good tool for promoting efficient therapy.
Designing The Therapeutic Trial:
The general aspects of randomized controlled trials are given below. However, all of them can’t be attempted on any one occasion.
- Ascertaining whether a treatment is of value.
- Compared with other treatments, how great its value is.
- In what types of patients it is of value.
- The best method of applying the treatment, the dosage and the frequency of the dosage.
- The disadvantage and the dangers of the treatment.
Brandoff Hill in his book ‘Principles of Medical Statistics‘ defines the therapeutic clinical research trials as – a carefully ad ethically, designed experiment with the aim of answering some precisely framed questions. In its most rigorous form, it demands equivalent groups of patients concurrently treated in different ways. These groups are constructed by the random allocation of patients to one or other treatment.
Equivalent Group Of Patients In Clinical Research Trials:
When the treatment groups differ significantly in age, sex, race, duration of disease, severity of disease or another relevant factor, it won’t be possible to attribute differences in outcome to the treatment under investigation. The best way of getting equivalent groups is by allocating patients to them by random allocation.
The function of the randomization is to eliminate systematic biases, both known and unknown that could affect assignment to treatment.
Time And Space Of The Treatment In Clinical Research Trials:
Treatments should be carried out at the same place and at the same time. The historical controls i.e. controls from the past are nearly unacceptable.
Precisely Framed Questions:
Formulating the exact questions that are to be answered is essential before the begining of the trial.
Ethics Of Clinical Research Trials In Man:
The research involving human subjects can be of two types – Therapeutic that which actually have a therapeutic effect and can help the participant.; Non-therapeutic that which provides information that can’t be of direct use to participant like healthy volunteers and sometimes patients.
Our Right To Choose To Participate In Clinical Research Trials:
Potential participants have the right to autonomy i.e. they can choose for themselves whether or not to participate in the research. The issue of consent is prominent in discussions of the ethics of human experimentation and it is a principal concern of the Research Ethics Committees that are now the norm in medical research.
European Journal of Clinical Pharmacology (1980; 18: 129) summarizes it in a report: “As physician investigators seed knowledge about the safety and efficacy of medicines, which is a social good, the dignity of individuals must not be overridden. The therapeutic trial is both ethically required for the social good of more effective medical care and is capable of being designed in ways that respect the wellbeing and rights of individual participants.”
The overall objective of Clinical research trials must be that no patients should be worse off than he might have been in the hands of a reasonable and competent physician.
Interpretative Factors Of Clinical Research:
Some concepts need to be defined for interpreting the information received by therapeutic trial.
Hypothesis Of No Control:
It is used to tell whether a treatment is equally effective or better or less effective than the other treatment in comparison.
A statistical significance test will reveal how often a difference of observed size would occur due to chance or random influences, if there is no difference between the efficacy of treatments.
These reveal the precision of an estimate. A wide ranging confidence interval point to lack of information, whether the difference is statistically significant or not. It is a warning for placing much weight over such studies. Confidence Intervals are expressed as a range of values within which we may be 90% (or other chosen %) sure that the true value lies. Confidence intervals are extremely important in interpretation, particularly of small studies as they show the degree of uncertainty related to a result.
Types Of Error:
It is up to the clinician to decide the target difference and the acceptable probability level for both types of error.
- Type One – Finding a difference between treatments when in reality they don’t differ.
- Type Two – Finding no differences between treatments when in reality they differ.
The Size Of A Therapeutic Clinical Research:
The number of patients required for a therapeutic trial depends on the difference that the investigator regards as clinically significant and the number of the patients available. The estimate is provided to the clinician by the statistician after the clinician tell him about the magnitude of interest and the acceptance of the errors. The size is adjusted in two different ways.
- Fixed Sample Trials: It is decided beforehand – the difference to be sought; the precision with regard to time, energy and numbers of patients available; the number of patients to be treated and the testing of the results. In this fixed sample trials, there is less likelihood of arriving at falsely significant difference. But at the end there may be disappointment when the desired results are not met.
- Variable Number Trials: In this design the number of patients is not decided in advance. This clinical research trial is developed in response to the need of continuous or intermittent assessment as the trial proceeds. This trial stops either as soon as the statistically significant result is reached or when such a result becomes unlikely.
Double Blind Placebo Control Study
There are some other techniques for medical research that can be employed besides the therapeutic trials. These include double blind and single blind techniques, placebo control, parallel groups. We can further evaluate pharmacoepidemiological aspects as The Observational Cohort Study and Case Control Study along with Record linkage by computers.
The Measurable Difference By Clinical Research Trials:
Definitive Therapeutic trials are expensive, tedious and time consuming. Sometimes when the result comes, that can even be useless or vague in nature. Again the single trial will seldom give a conclusive answer to a therapeutic question. Confirmatory trials by other persons in other centers are needed to reach reasonable certainty.
Meta Analysis Of Clinical Research Trials:
When numerous trials have been done and results vary, it is necessary to do meta- or overall analysis. Simply an addition of results won’t solve the dilemma. However it should be remembered that the selected trials should be of high value.
Double Blind & Single Blind Techniques In Clinical Research Trials:
W. Modell in JAMA (1958; 167: 2190) describes the double blind technique, “This is a control device to prevent bias from influencing results. On the one hand it rules out the effects of hopes and anxieties of the patient by giving both the drug under investigation and a placebo or dummy of identical appearance in such a way that the subject (the first blind man) does not know which he is receiving. On the other hand, it also rules out the influence of preconceived hopes of, and unconscious communication by, the investigator or observer by keeping him (the second blind) ignorant of whether he is prescribing a placebo or an active drug. At the same time the technique provides another control, a means of comparison with the magnitude of placebo effects. This device is both philosophically and practically sound.”
A non-blind clinical research trial is called an ‘open trial‘.
The double blind technique should be used when evaluation depends on other than strictly objective measurements. Like the pain in Rheumatoid arthritis may look as objective but closer look may prove it to be subjective.
Sometimes the double blind technique is not possible like the side effects of an active drug reveal which patient is taking the active drug.
Placebo Medication As A Control In Clinical Research Trials:
Dummy or Placebo treatment is used with double blind technique. Its use is not invariably necessary nor indeed ethical. It is not permissible to deprive patients of effective therapy. But it is often preferable to discontinue the use of unproven efficacy or safety. Frequently, consent may be obtained to the use of placebo without impairing the scientific validity of the procedure.
The Use Of Placebo In Clinical Research Trials:
- Placebo helps in identifying the beneficial effects of a drug from the psychological effects of taking the medicine and the surrounding circumstances like increase interest by the doctor, more frequent visits etc.
- It establishes the drug effects from fluctuations in disease that occur with time and other external factors when the active treatment is witheld.
- It helps to avoid false negative conclusions.
Within Patient Group Parallel Study:
In Chronic stable diseases with no cure but with alleviation of symptoms alone, each of the treatment including placebo is given to each patient. In this way we use them as their own controls. It is important to ensure in a small series that each drug both precedes and follows each other drug the same number of times to avoid the risk of carry over effect. This study has some drawbacks like presence of a drug or metabolite and enzyme induction.
So Between Patient Group parallel studies are preferred. And they require large number of patients.
Further in acute self-limiting diseases, it is impossible to give more than one treatment to one patient. So the controls should be other patients.
The Historic Controls In Clinical Research Trials:
When the treatment is given to all patients of present group and it is compared with the past studies is called the historical controls. It is unacceptable for standards of treatment and diagnosis change, severity of diseases fluctuates.
The following table is taken from ‘Measurements in Rheumatoid Arthritis’ by Hart F. D. et al 1972.
|Common Troubles of Clinical Assessment|
|Enthusiasm and Scepticism – excellent, marvelous, useless||Pride|
|Change of Assessor – Do the measurements for me||Impurity – short of cases|
|Change of Time||Imbalance – sex, severity or treatment order doesn’t matter|
|Squeezing – You are much better now. How are you?||Error – Not significant|
Pharmacoepidemiology in Clinical Research Trials:
Three epidemiological approaches are used to determine the results of controlled therapeutic trials for performance of the treatment in community medicine. These are observational in nature in place of experimental.
The Observational Cohort Study:
In this forward looking or prospective study, all the patients taking the drug are collected and followed up to determine the outcomes – both therapeutic and adverse. Prescription event monitoring is an example where patients are observed after writing the prescription. The major trouble with this study is selection of an appropriate control group, the need for large number of patients, and prolonged surveillance.
The Case Control Study:
In this backward looking or retrospective investigation, the investigator assembles a group of patients who have the desired condition. Then a control group of patients who have not had an episode of the particular condition is assembled like from similar age, parity, smoking habits from hospital admissions, primary case records. Both groups are followed retrospectively.
The Observational method is cumbersome, expensive and can’t satisfy the urgent need for an answer after a doubt is raised. A case control study is done quickly with smaller number of patients. The disadvantages of case control study are the possibility of suspicion of intrusion of unknown and unavoidable biases in selection of patients and controls. Further it requires a definite suspicion of causality. So these don’t prove causality. They reveal only associations.
Clinical Research Trials & Record Linkage By Computers:
This allows correlation of Clinical Research trials in a population of life and health events with history of drug use. It is being developed as far as resources permit.
Reliability Of Published Clinical Research Trials:
In one published study it was reported that about 66% of published papers are acceptable and 33% unacceptable according to what are now generally agreed criteria.