Dr. Dhruva Kumar Sharma

Department of Pharmacology

SMU/SMIMS

Saturday, the 23rd Of Aug, 2014

Clinical Trials: Phases And Types

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Protocol:

• Definition

• Aims and Objectives

• History

• Drug development process and Phases

• CRO

• Phases of clinical Trials

• Types of clinical trials

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• Clinical trials are prospective biomedical orbehavioral research studies on humansubjects that are designed to answerspecific questions about biomedical orbehavioral interventions (novel vaccines,drugs, treatments, devices or new ways ofusing known interventions), generatingsafety and efficacy data

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AIMS AND OBJECTIVES OF PERFORMING CLINICAL TRIALS

● Discovering and confirming the role of new drugs for the future pharmacotherapy of mankind as a whole

● To evaluate safety and efficacy of experimental drug relative to its adverse drug reactions both in healthy volunteers and concerned patients

● Licensure process of a new drug

A short history of the clinical trial-562BC

• The evolution of clinical research traversesa long and fascinating journey

• The first documented experimentresembling a clinical trial - military leader“King Nebuchadnezzar”

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• The experiment looked at two groups who either partook of “the King’s meat” and wine at the royal table, or did not (vegetables and water only), over a trial period of ten days

• After ten days, the “vegetables and water group” looked healthier and much more physically fit

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• Not exactly a randomized, double-blinded, placebo-controlled clinical trial, but the modest experiment may have been one of the first times in human history that a medical test, however rudimentary, guided a decision about public health

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• In 1747: One of the most famous clinicaltrials was James Lind's demonstrationthat citrus fruits cure scurvy

• He compares the effects of various acidicsubstances, ranging from vinegar to cider,on groups of afflicted sailors

• His study concluded that within six days,the group who were given oranges andlemons had largely recovered from scurvy

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International clinical trials day: 20th May

• International clinical trials day is celebrated on 20th May

• In 1862/1906: FDA was founded

• In 1863: Concept of a Placebo was first introduced in the world of clinical trials

• In 1923: Concept of randomization

• In 1943: The UK Medical Research Council’s (MRC) trial to treat the common cold is the first double blind controlled study 10

• In 1947: The Nuremberg Code

• In 1964: The Declaration of Helsinki was developed to establish a code of ethics

• In 1990: The International Conference on Harmonization (ICH) was established

• Also In 1996: ICH/GCP guidelines

• In 2000: The Common Technical Document (CTD) standard is established, creating a single standard for the presentation of information to regulatory agencies in the EU, USA and Japan

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Drug development process: 3 phases

1. DRUG DISCOVERY PHASE: -During which the candidate molecules are chosen on the basis of their pharmacological properties

2. PRECLINICAL PHASE: -During which a wide range of animal studies are performed, e.g., pharmacokinetic, pharmacodynamicand toxicity studies

3. CLINICAL TRIAL PHASE:-During which the lead compound is evaluated for efficacy, safety, and adverse effects in human volunteers and patients

Pre-clinical evaluation phase (Animal studies)

• Wide range of animals studies are performed

• Involves screening, evaluation, pharmacokinetics and short-term toxicity in animals

• The aim during this phase of development is to satisfy all the requirements that are needed before a compound is considered fit to be tested for first time in humans

• Pre-clinical phase usually require – 2 to 4 yrs. for completion

Pre-clinical evaluation phase

The major areas are-

• Pharmacodynamic studies

• Toxicological studies

• Pharmacokinetic studies

• Assessment of safety index

TOXICOLOGICAL STUDIES-

• The aim is to determine safety of the compound in at least two animals species (rat & dog) by oral or parenteral routes

a) Acute toxicity-

- single doses /small groups of animals

observed for overt effects and mortality for 1-3 days.

- LD 50 is calculated

SUB-ACUTE TOXICITY-

• Identify target organs susceptible to drugs toxicity

• Three doses are used on two animal species

• Animals maintained at the max. tolerated doses for a minimum period of 4 weeks to a max. period of 3 months

• Finally ,the animals are killed and subjected to histopathological examination.

Chronic toxicity-

• Goals are same as for sub-acute toxicity.Usually two animal species (one rodent and one non-rodent)Duration- 1-2 years

May run simultaneously with clinical trials

Special toxicity-• Effects on reproductive performance • Teratogenicity• Carcinogenicity• Mutagenicity• Local toxicity

• When the new drug passes the pre-clinical pharmacological screening, the manufacturer may file a

‘Preclinical New Drug’ Or

‘Investigational New Drug’ (IND) application to an authorized drug control body of the respective country

• In UK- CSM (Committee on Safety of Medicine)• In USA- FDA (Food and Drug administration)• In INDIA- Drugs Controller General, Govt. of India,

New Delhi

• The IND application must contain the following information about the test drug in question-

1. The chemical structure, source, manufacturing data with details of its purity.

2. The preclinical data about pharmacodynamics, pharmacokinetics and toxicological studies with ED50 and LD50 data.

3. Specifications of the dosage forms in which it has to be administered to the human beings.

4. A detailed description of the investigational protocol to be undertaken (including the dose and route of administration )

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5. The names and qualifications of each investigator and the facilities available to them

6. An agreement from the sponsors to submit annual progress report regularly

7. A certification that “informed consent” will be obtained from human volunteers and that ‘Ethics of research of human beings’ will be strictly followed

• Clinical trials are conducted only aftersatisfactory information has been gatheredthat satisfies health authority/ethicscommittee

• Depending on product type and developmentstage, investigators initially enrol volunteersand/or patients into small pilot studies, andsubsequently conduct progressively largerscale comparative studies

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• As positive safety and efficacy data aregathered, the number of patients typicallyincreases

• Clinical trials can vary in size, and caninvolve a single research entity in onecountry or multiple entities in multiplecountries

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• Hence, a full series of trials may cost hundreds of million dollars

• The burden of paying is usually borne by the sponsor, which may be a

governmental organization

Pharmaceutical industry

Biotechnology

medical device company

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CRO

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• A contract research organization (CRO) is anorganization that provides support tothe pharmaceutical, biotechnology, and medicaldevice industries in the form of researchservices outsourced on a contract basis

• A CRO may provide such services asbiopharmaceutical development, biologic assaydevelopment, commercialization, preclinicalresearch, clinical research, clinical trialsmanagement, and pharmacovigilance

• Many CROs specifically provide clinical-study and clinical-trial support for drugsand/or medical devices

• CROs range from large, international full-service organizations to small, nichespecialty groups

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• CROs that specialize in clinical-trials services canoffer their clients the expertise of moving a newdrug or device from its conceptionto FDA marketing approval, without the drugsponsor having to maintain a staff for theseservices

• There are over 1,100 CROs in the world

• The largest CROs, according to Industry StandardResearch, are Quintiles, Parexel, Covance, Pharmaceutical Product Development (PPD), Icon, INCResearch, and inVentiv Health Clinical

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• With regulatory approval, human testingmay then go forward (usually in threephases)

• Drug is formulated into a suitable dosageform and clinical trials are conducted in a“LOGICAL PHASED MANNER”

• A fourth phase of data gathering andsafety monitoring is becoming increasinglyimportant and follows after approval formarketing

• Once approved, the great majority of drugsbecome available for use by any appropriately

licensed practitioner

• Highly toxic drugs that are nevertheless

considered valuable in lethal diseases may be

approved for restricted use by practitioners

who have undergone special training in their

use and who maintain detailed records

• Enormous costs: $150 million to severalbillion, are involved in the development ofa single new drug that reaches themarketplace

• Less than one third of the drugs tested inclinical trials reach the market place

• Only 2 of 10 marketed drugs return theirresearch and development (R&D)investments, thus providing considerablemotivation to develop “blockbuster drugs”

• Increasing regulatory challenges and litigation

resulting from real or suspected drug toxicityafter approval further increase the cost ofdeveloping new drugs

• Unfortunately, only 10–15% of the new drugsthat achieve marketing approval representsignificant advances in safety andeffectiveness

• The remainder are merely molecular variants(“me-too drugs”) on true breakthrough drugs

Clinical Trials: IND (for Phase I,II,III)Ethical Considerations

• In each of the three formal phases of clinicaltrials, volunteers or patients must beinformed of the investigational status of thedrug as well as the possible risks and must beallowed to decline or to consent to participateand receive the drug

PHASES OF CLINICAL TRIALS

Conventionally there are four phases of

clinical trials :

Phase I Clinical Trials

Phase II Clinical Trials

Phase III Clinical Trials

Phase IV Clinical Trials

Additions :

Phase 0 – Microdosing Stategy

Phase V Clinical Trials – mainly an extension of

Phase IV Clinical Trials.

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PHASE I : Clinical Pharmacology and Toxicity

● Carried out by qualified clinicalpharmacologists/trained physicians

● Non Blind or Open lable trials

● Total number of subjects : 25-100; TimeRequired : 6 months - 1 year

● The drug is tested in normal healthyvolunteers (extremes of ages; elderly and children are

excluded)

● Phase 1 trials for cancer and anti-HIV drugsare done in patients.

Objectives Of Phase I Clinical Trials :

1. To check for :

Safety

Tolerability

2. To determine whether human and animals show significant pharmacokinectic differences

3. To determine a safe clinical dosage range in humans

For safe clinical dosage range

Begin with 1/5th or 1/10th the maximum tolerated dose (mg/kg) in animals and calculate it for an average human body weight of 70 kg.

The drug is then given in small increments till therapeutically effective dose is obtained.

4. To determine pharmacokinetics of the drug in humans.

5. To detect any predictable toxicity

There are different kinds of Phase I trial

SAD - Single Ascending Dose studies

● Features :

● - small groups of subjects are given a single dose of the drug

● - they are observed and tested for a period of time

● No adverse effects observed, the dose isescalated, and a new group of subjects arethen given a higher dose than previousgroup

● This is continued until intolerable sideeffects or adverse effects start showing up[at which point the drug is said to havereached the Maximum tolerated dose(MTD)].

2) MAD - Multiple Ascending Dose studies

Features -

To understand better the pharmacokinetics & pharmacodynamics of multiple doses of the drug

A group of patients receives multiple low doses of the drug, while samples are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.

3) Food effect

A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given

● These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed

Phase II trials

OrSafety and efficacy (SE) trials

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Phase II : Therapeutic Exploration and Dose Ranging

● Conducted by Physicians who are trained as Clinical Investigators

● Last an average of 2 years.

● Number of subjects: 100-400; Volunteer patients, selected according to specific inclusion and exclusion criteria

● Multicentered Randomised controlled Trials of the new drug is undertaken

Obective:

To Estabilish -

- Final formulation

- Dose of the drug

-Statistical End Points that represent

the targeted favourable outcome of

the study

End points may be:

a) Definitive End Point – which measures the drug effect directly

b) Surrogate End Point – which is predictive of the definitive end point

Phase II Clinical Trials are divided into

EARLY and LATE PHASES

EARLY PHASE II[Establish Dose range]

● Usually a Randomised Single Blind Design

● A small number of patients upto 200

● Potential therapeutic benefits, side effects and adverse effects are observed

● Main obejective – to estabilish a dose range for more definitive trials to be undertaken in the next late phase here

Late Phase II [Efficacy]

● Randomized Double Blind Design

● Larger number of patients: 200-400

● Specifically designed to study efficacy (how well the drug wroks at prescribed doses)

Types Of Study Design

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ANALYTIC DESCRIPTIVE

EXPERIMENTAL NON EXPERIMENTAL

Randomised

Clinical Trial

Non

Randomised

Clinical Trial

Community

Survey

Case-

Control

Cross

sectional

Case-

CohortCohort

Randomized Controlled Trials

Avoidance of bias

• Use of a control group

• Blindness

• Randomization

Randomization: Meaning

• Not a random sampling

• Random allocation

– Cannot predict the treatment to be given whether Active treatment or Placebo

• Eliminates selection bias

Randomization

• We want to assign a group of subjects to one of two groups—Treatment A or Treatment B

– How can we do this in a random manner?

Randomization

Random assignment

• Flip a coin

– “Heads”—Tx A

– “Tails”—Tx B

Randomization

Random assignment

• Roll a six-sided dice

– Even number—Tx A

– Odd number—Tx B

Randomization

Random assignment

• Table of random numbers

• Computer generated list

Random assignments

Random assignment• Alphabetical

– Tx A = patients with last name A–M– Tx B = patients with last name N–Z

• Telephone number/social security number– Tx A = last digit odd– Tx B = last digit even

• Sequential– Tx A = morning patients– Tx B = afternoon patients

• Bed number– Tx A = odd bed number– Tx B = even bed number

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•UNBLINDED, OPEN TRIAL

•SINGLE BLIND

•DOUBLE BLIND

•TRIPLE BLIND

BLINDING

Double-Blinded Single-Blinded

• Open Trial:

- both the researcher and the subject knows the full detail of the treatment

Blind Trials:

• Method of “control experimentation”

• One / both parties are not informed of the treatment being given

• Reduces bias arising from the treatment knowledge

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Reduces bias like

• Recruitment and treatment allocation

• Patient care

• Attitudes of patients to treatments

• Assessment of endpoints

• Handling of discontinuations

• Exclusion of data from the analysis

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• Single-Blind Trial (Subject is blinded)

• Bouble Blind Trial (Investigator + Subject are Blinded)

• Triple-blind trial (Researcher + Investigator + subject are blinded)

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Phase III Trials

Or

Comparative Efficacy Trials

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Phase III : Therapeutic confirmation / comparison

● Large Scale Multicentred (heterogenous population) randomised double blind study, carried out by several physicians.

● Number of patients – 1000 – 5000 plus.

● Lasts an average of 5 – 6 years.

● Further estabilish safety and efficacy and possible drug and food interactions.

● Designed to verify the efficacy of the new drug with the current 'gold standard' treatment; and to minimise errors in the information gathered in Phase I and Phase II trials.

● Therefore these trials are made using DOUBLE BLIND CROSSOVER STUDIES

● Most expensive, time-consuming and difficult trials to design and run

● At the end of the trial – Statistical analysis of data is performed to determine the significance of the results

● P-value of < 0.5% is taken as significant

New Drug Application

● On satisfactory completion of Phase III trials a 'New Drug Application' is filed with the Drug Control Authorities of the country

● It contains :

- Complete detailed monograph of the product including information about dose, dosage forms, dosage schedule, routes of drug administration, side effects, adverse effects

- Results of the trials

- Proposed registered name of the product

- Package insert

● If documentation is acceptable and is in compliance with the regulations, the drug control authorities can allow the drug to enter the market with 'New Drug Status'

Phase IV : Post Marketing Surveillance/studies

● It is the post licensing phase

● No fixed duration

● Performance of the drug is monitored for several years

● After the drug has been marketed for general use, data is collected on a pre structured proforma about the efficacy, acceptibility and adverse effects

• Data obtained from general practioners and physicians of both hospital and private set up

• Data is collected to discover any rare/unique side effects or adverse effects; or previously unknown therapeutic benefits of the drug / its active metabolite

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● It is a global report

● During the 'New Drug Status' period the manufacturer is supposed to report any new information about the drug concerning its safety

● Periodic Safety update Report (PSUR) is to be submitted every 6 months for first 2 years and then annually for the next 2 years

● Further therapeutic trials involving special groups like children, elderly, pregnant /lactating women, patients with renal/hepatic disease, etc. (which are generally excluded during clinical trials) may be undertaken at this stage

● Modified release dosage forms, additional routes of administration, fixed dose drug combinations, etc. may be explored

Phase 0 : Micro Dosing Strategy in Clinical Trials

● New strategy to reduce the cost and time of the drug developement process

● These are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies

● Duration – 4-6 months

● Involves administration of single subtherapeutic doses(< 1/100th of the dose) of the study drug to a small number of healthy volunteers (10 to 15) and pharmacokinetics is worked out using highly sophisticated instrumentation, such as Accelerator

mass spectrometry with radiolabelled drug, LC tandem

mass spectrometry to measure ultra low dose levels

● Primary goal – to inform decision making regarding further development of relevant compounds

● Knowing the pharmacokinetics of the drug can also help in selection of the ideal candidates for the study

● Especially important for oncology , as anticancer drugs are therapeutically toxic, and microdosing studies are therefore more helpful here to decide the appropriate drug to be studied

● May reduce overall cost of clinical trials

Limitations of Phase 0 Clinical Trials

● Gives no data on safety or efficacy

● By definition a dose too low to cause any therapeutic effect

● But questions still have been raised by experts about whether Phase 0 trials are useful, ethically acceptable, feasible, speed up the drug development process or save money, and whether there is room for improvement

Phase V Clinical Trials

● Extension of Phase IV Clinical trials

● Phase V is a growing term used in the literature of translational research

● It refers to comparative effectiveness research and community-based research

● It is used to signify the integration of a new clinical treatment into widespread public health practice

Types Of Clinical Trials

• Cancer clinical trials differ according to their primary purpose

• They include the following types:

– Treatment. These trials test the effectiveness of new treatments or new ways of using current treatments in people who have cancer

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• The treatments tested may include newdrugs or new combinations of currentlyused drugs, new surgery or radiationtherapy techniques, and vaccines or othertreatments that stimulate aperson’s immune system to fight cancer

• Combinations of different treatment typesmay also be tested in these trials

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• Prevention: These trials test newinterventions that may lower the risk ofdeveloping certain types of cancer

• Most cancer prevention trials involvepeople who have a higher than averagerisk of developing a specific type of cancer

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• Some cancer prevention trials involvepeople who have had cancer in the past;these trials test interventions that mayhelp prevent the return (recurrence) of theoriginal cancer or reduce the chance ofdeveloping a new type of cancer

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• Screening: These trials test new ways offinding cancer early

• Cancer screening trials usually involvepeople who do not have any signs orsymptoms of cancer but have a higher thanaverage risk of developing a certain type ofcancer because they have a family historyor history of exposure to cancer-causingsubstances (e.g., cigarette smoke).

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• Diagnostic. These trials study new tests orprocedures that may help identify, ordiagnose, cancer more accurately

• Diagnostic trials usually involve peoplewho have some signs or symptoms ofcancer

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• Quality of life or supportive care: Thesetrials focus on the comfort and quality oflife of cancer patients and cancer survivors

• New ways to decrease the number orseverity of side effects of cancer or itstreatment

• How a specific type of cancer or itstreatment affects a person’s everyday lifemay also be studied

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Sibling Clinical Trial

• This study will examine families in which one sibling of a sibling pair, or twin pair, has developed a systemic rheumatic disease and one has not, to see if and how the two differ in the following:

• Blood cell metabolism

• Types of cells in the blood

• Environmental exposures or genetic factors that might explain why one developed disease and the other did not

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• Families in which one sibling has developed a systemic rheumatic disease, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, dermatomyositis, or myositis, and the other has not, are eligible for this study

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• The siblings may or may not be twins, but must be of the same gender and be within a 3-year age difference

• Biological parents, or, in some cases, children, will also be included in the study

• Normal, healthy volunteers will serve as control subjects

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References:

Katzung – Basic & Clinical Pharmacology,

12th Edition

Sharma – Priciples of Pharmacology,

2nd Edition

K.D Tripathi

www.fda.gov

www.clinicaltrial.gov

www.icmr.nic.in/guidelines/GCLP

www.cdsco.nic.in/

Fundamentals of clinical operations, Health care sciences,SMU, MR0001

Regulatory Affairs-I,Health care sciences,SMU, MR0002

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