CLINICAL PHARMACOLOGY AND PHARMACODYNAMICS

Clinical pharmacology:

Definition:

Clinical pharmacology is the science of drugs and their clinical use. It has a broad scope, in the discovery of new target molecules, to the effects of drug usage in whole populations.

The main objective is to promote the safety of prescription, maximize the drug effects and minimize the side effects.

It is important that there be association with pharmacists skilled in areas of drug information, medication safety and other aspects of pharmacy practice related to clinical pharmacology.

Clinical pharmacology has a wide variety of branches which includes

a. Pharmacodynamics.

b. Pharmacokinetics.

c. Drug development.

d. Drug interactions.

e. Adverse drug reactions.

f. Toxicology.

A. Pharmacodynamics:

Definition:

The study of how a drug acts on a living organism, including the pharmacologic response and the duration and magnitude of response observed relative to the concentration of the drug at an active site in the organism.

These branches include the clinical studies. These clinical studies can be studied under various regulatory guidelines which include,

CLINICAL STUDY DESIGN DOCUMENTATION, PRESENTATION AND INTERPRETATION AS PER REGULATORY GUIDELINES OF EUROPEAN COMMUNITY :

Pharmaceutical companies spend billions of dollars every year on carrying out clinical study by conducting clinical studies for their potential products. These studies are funded by charities, government research councils and other bodies. A set of official guidelines has been issued in Europe that cover many aspects of clinical trials. Any incorrect procedures lead to refusal to grant the relevant marketing approval.

a. The most important of these guidelines is following of Guidance on Good Clinical Practice (GCP).

b. It also sets out the basic requirements on

1. The protection of trial subjects.

2. The design of procedures to be used in the trial.

3. The recording and reporting of results.

4. The documentation that is required, and the monitoring and audit of the trial to ensure that these requirements are being met.

Since 1990, there has also been an international process, known as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), which involves representatives of the regulatory authorities and industry associations of Europe, Japan and the US.

The objective of the ICH is to harmonize pharmaceutical regulatory requirements on an

International basis to minimize the possibility that tests and trials on new medicinal products have to be repeated for the purposes of obtaining regulatory approval in different Countries.

In broad terms, the European law states that, where an applicant wishes to obtain marketing approval for a new medicinal product the pharmaceutical companies must follow the follow the key points they include,

All clinical trials should be carried out in accordance with the Declaration of Helsinki (world medical association) the freely given informed consent of each trial subject should be obtained and documented.

The clinical trials should not begin before the authorization of ethical committee.

All aspects of conduct of the trial should be documented in pre-established, written procedures (e.g. written protocols) and documentation and records of the trial should be archived for specified minimum periods of time.

The clinical study design, should include the following points:

A description of the type/design of trial to be conducted(e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages.

A description of the measures taken to minimize/avoid bias, including: Randomization.

A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labeling of the investigational product(s).

The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.

A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial and entire trial.

All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.

The act by a regulatory authority (ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial should be deemed appropriate by the regulatory authority(ies).

CLINICAL STUDY DESIGN DOCUMENTATION, PRESENTATION AND INTERPRETATION AS PER REGULATORY GUIDELINES OF UNITED STATES AUTHORITIES:

The U.S. Food and Drug Administration is a scientific, regulatory, and public health agency that oversees items accounting for 25 cents of every dollar spent by consumers.

Clinical Trial Design: Authorities conduct CLINICAL STUDY DESIGN based on scientifically designed protocols, which balance potential risk to the research participant with the possible benefit to the participant and to society.

1. The study design usually performed in normal health subjects.

2. For the study of the drug analytical methods should be validated for accuracy, precision, and sensitivity.

3. Different methods yield different results so a standard method should be employed in the total course of study.

4. The design should be authorized by the FDA authorities for further release in to the market.

Clinical interpretation is important in evaluation of the results of the clinical study.

A small difference between drug product and standard, significantly produce a very big difference in therapeutic response during the clinical interpretation of the data.

Presentation of data:

1. According to US FDA data should be presented in graphical form and talker forms. ANOVA is needed to determine statistical significance between the standard and the drug designed in the pharmacological parameters.

2. Enough care should be taken for the storage of data until it is presented

3. The guidelines taken for the study and the approvals given by the FDA agencies should also be included with the presentation of the final data.

4. Further the drug is finally released in to the market for the usage if the FDA satisfies with the presented data.

CLINICAL STUDY DESIGN DOCUMENTATION, PRESENTATION AND INTERPRETATION OF REGULATORY GUIDELINES IN INDIA:

India has become hub for clinical trials among South Asian countries due to abundant availability of large and diverse patient's pool, faster enrollment of patients, availability of trained investigators, plenty of super specialty hospitals with excellent infrastructure and increasingly accommodating regulatory environment.

It is estimated that nearly 20% of all global clinical trials will be conducted in India by 2010.

In volume terms, it is the worlds fourth largest market in unit sales, but ranks 13th in value terms with an annual revenue of approximately US$ 5 billion.

The world has identified India as an emerging hub for collaborative and outsourced research and development (R&D) and went on to observe that Indian pharma companies had topped drug filings with the US FDA for 2003, with a total of 126 DMFs(DRUG FILINGS), accounting for 20% of all drugs coming into the US market, higher than Spain, Italy, Israel, and China.

For a drug to do the clinical studies, it should be registered in Clinical Trials Registry-India (CTRI).

In order to make clinical data available on online clinical registry has been initiated by Indian Council of Medical Research. (ICMR).

The 2 goals of this ICMR is the transparency and accountability of clinical research.

In India study design was approved by Indian council of medical research (ICMR); and ethical guidelines was provided by the institutional ethics committee (IECs).

This study design should be according to the regulatory guidelines framed by the ICMR and drug controller of India.

The study design should be presented to the drug controller of India for the approval of the investigational new drug.

Interpretation of the clinical studies should be done and it should be according to the guidelines mentioned by ICMR committee.

The interpretation should provide the adverse effects, and any toxic reactions that are seen with the drugs that are developed.

Drug registration is done only after the submission of the interpretation data ,and the drug was finally released in to the market.

ICH-GCP compliance for the study design:

Drugs Controller General of India (DCI) has the prominent role in overseeing clinical trial in India along with Ethics committee.

The DCGIs office depends on external experts and other government agencies for advice.

Additional permissions are required for the export of blood samples to foreign central laboratories.

The Indian Council of Medical Research (ICMR) guidelines for clinical trials insist on the setting up of ethics committees at the institutional levels.

The IEC (Indian Ethical Committee) responsibility is to scrutinize and approve the clinical trial before the study begins and also to conduct periodic reviews of the progress of the trial.

The implementation of the GATT(General Agreement on Tariff and Trade) has opened a new opportunities for India to concentrate on the clinical trial market.

In January 2005, India adopted a new rule that will allow pharmaceutical companies to begin phase II and Phase III trials concurrently with trials of the same phase conducted abroad, thereby reducing clinical development time.

With the latest amendment (20th January 2005) to the Schedule Y of Drugs and Cosmetic Act 1945, the reporting of adverse events from clinical trials has become clearer and unambiguous.

Good clinical practice represents the requirements for protection of participantsin clinical trials.

It also provides the detailed requirements for investigators and sponsors with regard to planning execution, documentation, analysis, and reporting of studies.

The above steps are taken in order to ensure the quality and logical consistency of data findings and conclusions.

Purpose of ICH (international conference on harmonization) : to ensure the safety and efficacy, and most efficient, and cost effective drugs to be produced in India.

Principles of ICH:

According to ICH clinical trials should be conducted ethically with declaration of ICMR regulatory guidelines.

The main principles include:

1. Rights, safety, & well being of subjects are important.

2. Study must be scientifically designed.

3. Investigators must be qualified.

4. Records must be maintained for accurate reporting, interpretation, and verification.

5. Clinical trials must meet the Good Manufacturing Practices

CLINICAL TRIALS

Clinical Research Industry has billions of dollars every year on carrying out clinical trials for their potential products, The main survival point of the pharmaceutical industry is innovation and for introducing grown around the world at an unbelievable rate in the past few years. Now a days Pharmaceutical companies spend new drugs in the market, the companies have to conduct clinical trials as per ICH GCP guidelines as well as guidelines of the country where trial is planned.

Definition: As per Drugs and Cosmetics Rules, 1945,"Clinical trial" means a systematic study of new drug(s) in human subject(s) to generate data for discovering and / or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and /or adverse effects with the objective of determining safety and / or efficacy of the new drug."

Clinical trials are designed to help us find out how to give a new treatment safely and effectively to people.

A clinical trial is a tool for testing a drug, device, or technique.

Clinical trials are necessary to evaluate the medicines before they enter in to market.

These clinical trial studies were extensively done in animals and in humans to find out the efficacy and safety of the drug product which is to be marketed.

The following phases are involved in the clinical trials which includes:

1. Phase -I.

2. Phase -II.

3. Phase -III.

4. Phase -IV.

Phase -I: clinical trials test a new biomedical intervention in a small group of people (e.g., 20-100) for the first time to evaluate safety (e.g., to determine a safe dosage range and to identify side effects).

These clinical trials are developed after the investigational new drug application is submitted.

Main purpose: The main purpose of this phase is to determine drug toxicity profile and to assess tolerability.

In most of the cases children and pregnant women and serious primary diseases(eg: cardiac, hepatic, renal, hematological disorders) are excluded in this phase.

In general patients receiving contaminant drug therapy should be excluded (eg: malignancy therapy).

Individuals with mild but stable illness may also be included in this phase.

In general out patients are not be utilized as initial recipients of investigational new drug in this phase.

Hospital employees and volunteers may be in some cases may be utilized as intial recipients in this phase, since they can be under the supervision of clinical investigator.

Generally healthy human volunteers are selected for this phase studies.

The initial dose of drug is usually low i,e one tenth of the highest no-effect dose observed during the animal studies.

The phase-I clinical trials are designed to determine the:

1. Human pharmacology of the drug.

2. Structural activity relationship.

3. Side effects associated with increasing doses.

Qualification & investigators:

Phase -1 clinical studies are performed by investigators skilled in initial evaluation of a variety of compounds for safety and pharmacological effect.

Where the patients with a specific disease are being studied the investigator should be expert in treating that disease.

Procedure for carrying out of phase-I clinical trials:

The procedure involved in this phase is physical examination followed by laboratory screening tests should be performed to screen out individual with medical abnormalities. These tests include

1. Urine analysis.

2. Platelet estimation.

3. Bun (serum creatinine).

4. Liver functional studies.

5. Post prandial blood sugar

6. E.C.G and other drug related tests.

Prior to administration of new drugs the subjects or patients shall not been allowed to take the OTC drugs.

Single dose studies of phase-I:

a. The phase -I studies are desirable to begin with small group eg: 5 on a drug or 5 on a placebo for a period of 5-7 days to observe the adverse effects and will move to the larger groups.

b. The subjects should be seen at least once daily.

c. Practical examination will be performed during and post therapy and all laboratory examinations should be repeated at least once in week.

d. The duration of drug study will be dependent up on the nature of the drug.

e. Blood levels should be tested with single and multiple doses.

f. The subjects ability to tolerate the drug & any un pleasant effects of drug are observed and recorded.

g. Capsules without any excipients will be used for Investigational drug studies for the case of orally administration of drugs.

h. Phase -1 study are useful in selecting different analogues of the lead compound.

If the studies demonstrate sufficient merit and if the order of drug toxicity is low, phase-2, a study begins.

Phase -II studies:

Subjects patients selected for early phase 2 studies should ordinarily be free from hematologic hepatic, renal, and cardiac and other serious diseases.

Carried out relatively in small group of targeted patients.

Phase -2 studies involve controlled clinical studies to evaluate the effectiveness of drug ,this phase involves the study of side effects and toxicity symptoms that were not shown during animal clinical trials.

Qualifications of investigators:

Only clinical experts in the disease being treated are used as investigators in phase -2.

Procedure:

Dose response studies are performed to determine the optimum dosage regimen for treating the disease.

During the phase, additional data are collected on the drugs pharmacokinetic studies were undertaken to determine dose response and dosage ranging called phase -2a studies.

Each patient is monitored for the appearance for the drug effect while the dose is carefully increased to determine the minimum effective dose.

Then the dose is extended beyond the minimally effective dose to the level at which a patient reveals extremely undesirable toxic or adverse effect.

The greater the range between the dose of drug determine minimally effective and that which causes severe side effects the greater is the drugs safe margin, called as phase-2b studies.

If the clinical results of phase -2 indicate the safe margin for the new drugs, these studies can be ended with the approval of FDA.

Patients should ordinarily be seen by the investigators at least for 2-4 weeks.

Specialized safety and pharmacological lab tests are performed.

When the investigational drug is altered significantly in months, to accommodate blood analysis studies should be performed.

Routine safety tests to be done at frequent intervals, if these tests are satisfactory then phase -3 studies were carried out.

Phase -III studies:

These are better known trials of safety and efficacy.

Include several 100-1000 patients in controlled and uncontrolled trials.

Objective:

The objective is to determine the usefulness of drug in an expanded patient base.

This phase includes further toxicological studies that occurring the patients during the course of study.

Procedure:

Large scale, multi center clinical studies are performed with the final dosage from developed in phase-2.

Many additional clinicians having patients with the condition for drugs intended use or recruited to participate in this trial.

Several dosage strength of proposed drug may be evaluated during this stage using formulations intended to be proposed in new drug application and in marketing.

Sufficient information on drugs safety & effectiveness is expected to be gathered during phase -3 to evaluate the overall benefit risk relationship of the drug and file a complete information of the drug.

These studies are done to determine safety and efficacy of the drug product in large population with disease or condition for which the drug was developed.

Finally these studies concentrate on the new toxic effects that occurred in large group of population which were not evident in previous phases of clinical studies.

After the phase -3 studies the New Drug Application was submitted.

Submission of New Drug Application (NDA):

An NDA is submitted to FDA for review and approval after completion of clinical trials that show to the satisfaction of medical community that the drug product is effective in all parameters is reasonably safe as demonstrated by animal and human studies.

For example : of 20 drugs entering clinical testing 13-14 will successfully complete phase-1 trials and go on phase -2, about 9 will complete phase -2, and go to phase -3,and only one or two will clear phase -3 and on average per year only about 20 drugs will ultimately be approved for marketing

S.NO

NUMBER OF PATIENTS

LENGTH

PURPOSE

% OF DRUG SUCESSFULLY COMPLEETING

Phase -1

20-100

Several months

Mainly safety

67

Phase -2

Up to 100

Several months to 2 years

Some term safety & mainly efficacy

45

Phase -3

100-1000

1-4 years

Safety effectiveness and dosage

5-10

Phase IV:

After the NDA is submitted and before approval to market the product is obtained approval from FDA, manufacturing scale up activities occur.

Scale up is the increase in the batch size from the clinical batch, the submission batch or both, up to the full scale production batch size using finished market production.

The drug formulation may be modified slightly as a result of data obtained during the manufacture scale up and validation process.

US-FDA approved drugs during recent years;

YEAR

TOTAL DRUS APPROVED

2001

24

2002

17

2003

21

2004

31

2005

03

2006

10

2007

19

2008

12

E.g. Some of the US-FDA drugs approved drugs for HIV and its complications;

APPROVED DRUG

TREATMENT FOR CONDITION

Alitertinoin

Cutaneous lesions in aids patients related to kaposis sarcoma

Atazanavir

HIV-1

Dronabinol

For stimulation of apetite and to prevent loss of weight in AIDS patients

Immunoglobulins

Infection prophylaxis in pediatric patients effected with HIV.

Interferon ALFA-2a

AIDS related kaposis sarcoma.

Interferon ALFA-2a

AIDS related kaposis sarcoma.

Paclitaxel

AIDS related kaposis sarcoma.

After the FDA grants market approval of the drug, the product development may continue.

The drug product may be improved as a result of market demands, supply, and regulatory factors.

Some time the approved drugs are banned due to the unwanted side effects.

e.g. Analgin (for blood disorder), Rofecoxib (cardio vascular disease).

In such banned cases these use should be discouraged.

DRUG

INDICATION

CAUSE FOR BAN

Analgin

Analgesic

Bone marrow depression

Cisapride

Acidity, constipation ,GERD

Irregular heart beats

Furazolidine

Anti-diarrhoeal

Carcinogenic

Nimesulide

Pain killer, fever

Hepatotoxic

Piperazine

Anthelmenthic

Causes nerve damage

Nitro furantoin

Anti-bacterial cream

carcinogenic

DESIGN DOCUMENTATION OF CLINICAL DATA:

Factors such as age, sex disease state, food habits, Time of sample to be administered are to be considered in study design documentation.

The design includes:

1. Experimental design.

2. Study population.

3. Sample size and dropouts.

1. EXPERIMENTAL DESIGN:

This design includes the following sub divisions;

a. Replicated cross over design.

b. Non-replicated design.

A. Replicated cross over design.

This design is recommended when an individual bioequivalence is used to allow the estimation of in various measurements following the four period, two-sequence and two-formulation method.

For this design lots of T & R (test and reference), formulations should be used for repeated administrations which should be separated by proper wash out period.

The Three period design can be tabulated as follows

PERIOD

1

2

3

SEQUENCE

1

T

R

T

2

R

T

R

A greater number of subjects are tested in this type of design to obtain the efficacy of the new drug.

B. Non-replicated design:

A conventional study design such as the standard two formulation , two-period, two-sequence cross over design used for bio-equivalence comparision.

Here an average number of populations are used.

2. STUDY POPULATION: Unless otherwise indicated by a specific guidance recruited for in-vivo bio equivalence studies should be 18 years, or elder and capable of giving informed consent.

An attempt should be made to enter an heterogeneous a study population as possible, with a reasonable balance of males and females, young and elderly and subjects of different racial groups.

Restrictions to entry in to studies should be based solely on safety considerations.

In some studies, it may be useful to recruit patients for whom the drug product is intended.

In this situation sponsors/applicants should attempt to enter the patients whose disease process is stable for the duration of the study.

IND (investigational new drug) may be required for some studies to ensure safety of patients.

3. SAMPLE SIZE AND DROP-OUTS:

A minimum number of 12 subjects should be included in any study.

Number of subjects for this studies are based on either the population or individual bio-equivalence approach should be estimated by stimulation, because analytical methods/approaches for estimation are not available

Sponsors should provide a sufficient number of subjects in the study, to allow for drop-outs, because replacement of subjects during the study could help in the statistical model and analysis.

Sponsors who wish to replace the drop-outs during the study should be done according to the protocol.

Additional subjects will not be allowed to enter in to the study, as it will affect the analysis of the total study design.

PRESENTATION OF CLINICAL DATA:

The obtained data from the clinical study can be presented in the following manner;

The drug concentration in biological fluid determined at each sampling time should be furnished on the original scales for participating in the study.

The derived pharmacokinetic measures should also be furnished on the original scale.

The mean, standard deviation, and co-efficient of variance for each variable should be calculated and tabulated in the final report

In addition to the arithmetic mean and standard deviation (or co-efficient of variance) for TEST AND REFERENCE products; and geometric means should also be included.

The measures taken for the test subjects should be displayed in parallel with the data obtained in their study.

The ratio of individual geometric mean of the test product to the individual geometric mean of reference product should be tabulated side by side for each subject.

The presentation of the clinical data should be done according to the regulatory agencies concerned

INTERPREATION OF CLINICAL DATA:

OBJECTIVES:

To explain differences in approaches to safety data and efficacy data.

To demonstrate that adequate attention needs to be given to the assessment, analysis, and reporting of adverse events to permit valid assessment of potential risks of intervention.

To highlight the distinctions between rare, serious adverse events and common, non-serious adverse events

To define terms commonly used in the description of adverse events.

To explain methods by which causality for adverse events can be assessed.

The interpreted data should be stored in online services, and it should be available during audits that were conducted by the regulatory agencies.

The interpretation of clinical data must also includes the total study details that was conducted, which includes the adverse reaction of drugs, and toxicological studies e.tc.

STATISTICAL ANALYSIS OF CLINICAL DATA

The experimental results of clinical studies can be analyzed in many ways; one of the simplest method of analysis of clinical data is by statistical analysis method.

STATISTICAL ANALYSIS:

Statistical Analyses to be used must be clearly identified and should form basis of the statistical model for the clinical Study.

Before 1970s clinical data was determined based only on the values of cmax values for the generic product; which should be within + or 20% of those reference products.

During recent years FDA requires the confidence limits to the mean data , using an analysis known as the two/one sided test procedure.

The test formulation was considered to be bio equivalent to the reference only if

AUCtest Cmax of test

By this procedure if the test and the reference products are not bio-equivalent they will differ by 20-25% in both AUC and in Cmax results.

The generic manufacturer should carry out the tests at least to 90% confidence for providing the values regarding the mean responses of the products that should be within limits of 0.8-1.5.

Since these tests are carried out at 0.05 level of significance these can be reliable.

In some cases the value or range (20-25%) can be given up to 30%. E.g. Anti-psychotics.

Any subsequent deviation(s) should be described and justified in the Final Report.

Results of the statistical analyses should be presented in a manner that is likely to facilitate the interpretation of their clinical data.

FACTORIAL DESIGNS:

Factorial designs are used in experiments where the effects of different factors or conditions on experimental results are to be elucidated.

Some practical examples where factorial designs are used are; experiments to determine the effect of pressure and lubricant on the hardness of table formulation, to determine the effect of disintegrant and lubricant concentration on tablet dissolution.

Factorial designs are the choice for the simultaneous determination of several factors and their interactions.

Definitions:

1.FACTOR:

A factor is an assigned variable such as concentration, temperature, lubricating agent, drug treatment or diet.

The choice of factors to be included in experiment depends up on experimental objectives.

A factor may be qualitative or quantitative.

Quantitative factor has numerical value assigned to it, e.g the factor concentration may be given the values 1%,2%,3% and examples of qualitative factors are treatment, diet, batches of materials, tablet diluents.

Qualitative factors are assigned names rather than numbers.

LEVELS:

The levels of a factor are the values or designations assigned to the factor.

Examples of levels 300 and 500 for the factor temperature, 0.1 molar and 0.3 molar for the factor concentration, drug and placebo for the factor drug treatment.

The trials that comprise factorial experiments consists of all combinations of all levels of all factors. As an example two factor experiment would be appropriate for the investigation of effects of drug concentration on the tablet. If both factors were at two levels four runs would be required as follows:

SYMBOL

FORMULATION

1

Low drug and low lubricant concentration

a

Low drug and high lubricant concentration

b

high drug and low lubricant concentration

ab

high drug and high lubricant concentration

Here low and high refers to the factor concentration

Advantages of factorial designs:

In the absence of interaction, factorial designs have maximum efficacy in estimating the drug effects.

If interaction exists factorial designs are necessary to reveal and identify the interactions.

Since factor effects are measured over varying levels of other factors, conclusions apply to a wide range of conditions.

Maximum use is made of the data since all main effects and interactions are calculated from all of the data.

Factorial designs are orthogonal, all estimated effects and interactions are independent of effects of others.

For example the result obtained is only due to main effect of interest and is not influenced by any other factors.

A simple factorial design helps in revealing the difference in action of drugs which are tested in different locations. For e.g. if the tests performed on the patients of Newyork and the patients of los angels give different results, factorial design will reveal the causes for the differences such as climatic conditions, body nature e.t.c.

Thus the factorial designs are useful in the estimation of different factors or conditions on experiment result.

and

< 1.2

0.8