CLINICAL TRIALS

A clinical study is an organized research conducted on human beings to

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investigate new methods of preventing, detecting, diagnosing, or treating an

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illness or disease.

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Clinical trials on patients in different countries are approved and monitored by

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different regulatory agencies like:

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1. In India, Drug Controller General of India (DCGI) office under Central Drug

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Standard Control Organization (CDSCO).
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2. In UK, Medicines and Healthcare products Regulatory Agency (MHRA),

3. In USA, Food and Drug Administration (FDA).

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• The clinical trial process – money, time, resources and sound planning.

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• Clinical development plan contains a summary of the pre-clinical findings and

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of market research done for the drug.

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• Clinical development plans usually include target dates for the studies, the

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objective of each study, and the proposed study design for achieving the

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• A clinical development plan - studies required for registration and approval.

• Four phases I, II, III and IV.

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• Phase I trials determine the safety of a new treatment.

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• Phase II trials determine whether the drug shows one or more clinical

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indications.

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• Phase III trials study whether a new treatment is better than standard

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treatment.

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• Phase IV trials find more information about a new treatment that has been
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already approved for use in patients.

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• First in man (healthy volunteers).

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• To establish safe dosage range.

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• To determine the metabolic and pharmacological actions of the drugs in

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humans.

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• Conducted on 20 to 80 healthy human volunteers for 3 to 6 months.

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DIFFERENT KINDS OF PHASE I TRIALS

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• SAD - Single Ascending Dose studies

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• MAD - Multiple Ascending Dose studies

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• Food effect studies

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SAD - SINGLE ASCENDING DOSE STUDIES

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• Small groups of patients.

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• Single dose of the drug.

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• Monitor ADR, Pharmacokinetic data.

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• Increases the dose up to maximum tolerable dose.

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MAD - MULTIPLE ASCENDING DOSE STUDIES

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• Asses pharmacokinetics & pharmacodynamics.

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• Patients receives multiple low doses of the drug.

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• Samples (of blood, and other fluids) are collected at various time points and

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analyzed.

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• The dose is subsequently increased for up to a predetermined level.

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 FOOD EFFECT

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• Short trial designed.

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• Investigate any differences in absorption caused by food and its effect on the

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pharmacokinetic profile.

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 PHASE 1

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Phase I trials address:

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✓ How rapidly the drug is absorbed ?

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✓ Where is the drug distributed in the body?

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✓ Which organs or organ systems are involved in metabolism of the drug?

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✓ How quickly is the drug eliminated from the body?
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Only about 70% of experimental drugs passes Phase I clinical trials
MAXIMUM RECOMMENDED STARTING DOSE
(MRSD)

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• Derived from NOAELs, NOAELs to HED

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• HED = animal NOAEL x (Wanimal/Whuman)(1-b)

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• Where W is the weight in kg and b is a correction factor used to convert

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mg/kg to mg/m2.

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• MRSD for the first human clinical trial is derived from the no-observed
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adverse effect levels (NOAELs). conversion of NOAELs to human equivalent
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doses (HED) and application of a safety factor.

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Pre-clinical toxicology studies will generate basically three types of findings that

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can be used to determine the NOAEL:

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• overt toxicity, e.g., clinical signs, macro and microscopic lesions

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• surrogate markers of toxicity, e.g., serum liver enzyme levels

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• exaggerated pharmacodynamic effects.
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 PHASE 2

• Conducted on 100 to 300 patients.

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• The trial may last from six months to two years.

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To establish:

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• Clinical efficacy

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• Determine the incidence of adverse drug reactions

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• Define the optimum therapeutic usage and provide detailed pharmacokinetic
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and pharmacodynamic data to substantiate the adequate trial of the drug

• On average, pharmaceutical companies are spending anywhere between

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$100 and $800 million per each drug tested.

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• Spending on clinical trials in the U.S. is forecasted to rise to $32 billion by

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2011.

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• Why would anyone spend that much money on drug development?
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• Why does it cost so much to conduct a clinical trial?

• Why does it take so much time to conduct a clinical trial?

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• Drug Disease interaction

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• Drug Drug interaction

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• Dosage interval

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• Risk Benefit information

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• Efficacy and safety for subgroups
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 PHASE 2

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Phase II trial address:

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✓ What is the minimum effective dose?

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✓ What is the maximum tolerated effective dose?

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✓ Is the drug effective in mild, moderate and severe cases of the disease or

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condition?

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✓ Is the drug effective for all expected indications?
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Only about 35% of experimental drugs passes Phase II clinical trials.

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• Controlled and uncontrolled trials – performed after obtaining preliminary

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evidence from phase II about effectiveness and safety.

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• Involves several hundred to several thousand patients and lasts 1 to 5 years.

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• Drugs effectiveness and ADRs – large group of patients – long period of

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exposure - to establish safety and efficacy of drug.

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• Provides adequate basis for extrapolating the results to the general
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population.

• Different patient sub-groups, such as children, elderly and perhaps those with
liver or kidney impairment.
 PHASE 3

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• In phase II and III, regulatory bodies can impose a clinical hold if a study is

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unsafe or if the protocol is deficient in meeting its stated objectives.

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 PHASE 3

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• Phase 3a - conducted after the drugs efficacy is demonstrated but before

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regulatory submission of the new drug application (NDA)

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• Phase 3b : Trials that are conducted after regulatory submission of the NDA

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but prior to drugs approval and launch. It is also called as pre-approval studies

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and may supplement or complete earlier trials or they may seek different

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kinds of information – QOL, Economic impacts.
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PHASE 3

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 PHASE 3

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Phase III trials address:

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✓ Overall risk-benefit relationship

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✓ Adverse reactions in large group of patients over a longer period of exposure

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✓ The ideal dosage regimen

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✓ Is the drug allowed to be marketed?
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Only about 25% of experimental drugs passes Phase III clinical trials
POST MARKETING SURVEILLANCE / PHASE IV
CLINICAL TRIALS

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• ADRs come to light after the drug has been in the market for a while and used

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by very large numbers of patients. Eg., Thalidomide

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• Done after a drug has been shown to work and has been granted a license

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POST MARKETING SURVEILLANCE / PHASE IV
CLINICAL TRIALS

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Phase IV clinical trials address :

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✓ More about the side effects and safety of the drug?

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✓What the long term risks and benefits of the drug are?

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✓How well the drug works when it’s used more widely than in clinical trials?

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 SUMMARY
• Clinical development plan contains a summary of the pre-clinical findings and

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of market research done for the drug.

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• New drug application (NDA)- Following completion of I-III phases of clinical

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trials, company analyzes all of the data and files an NDA with FDA, if the data

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successfully demonstrate safety and effectiveness.

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• The phase IV trial address more about the side effects and safety of the drug,

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the long term risks and benefits of the drug.
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