module 9 - clinical trials and babe studies

1

The given information is compiled from various offline / online sources, towards the sole

purpose of knowledge sharing.

Module 9

Clinical Trials, and BA/BE Studies

Clinical Trials

Clinical trials are generally considered to be biomedical or health-related research studies in human beings that follow a pre-defined protocol. Once can participate in a clinical trials to play a more active role in their own health care by gaining access to new research treatments before they are widely available, and contribute to medical research. Participants are chosen based on strict guidelines and inclusion/exclusion criteria. The inclusion and exclusion criteria are also used not only to identify the participants but also keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study.

The clinical trial team includes doctors and nurses as well as social workers and other health care professionals. They check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial, monitor the participant carefully during the trial, and stay in touch after the trial is completed. Informed consent

The research team provides an informed consent document that includes details about the study, such as its purpose, duration, required procedures, and key contacts. Risks and potential benefits are explained in the informed consent document. The participant then decides whether or not to sign the document. Informed consent is not a contract, and the participant may withdraw from the trial at any time. Benefits and risks of participating in a clinical trial

Benefits Play an active role in their own health care.

Gain access to new research treatments before they are widely available.

Obtain expert medical care at leading health care facilities during the trial.

Help others by contributing to medical research.

2



Risks The clinical trials may be unpleasant, serious or even life-threatening side effects.

The experimental treatment may not be effective for the participant.

The protocols may be inconvenient to the participants.

Side effects are any undesired actions or effects of the experimental drug or treatment. Negative or adverse effects may include headache, nausea, hair loss, skin irritation, or other physical problems.

Most of the clinical trials follow carefully controlled protocol. Confidentiality of the participant is maintained all the time.

People should know as much as possible about the clinical trial and feel comfortable asking the members of the health care team questions about it, the care expected while in a trial, and the cost of the trial.

A participant can leave a clinical trial, at any time.

Ideas for clinical trials usually come from researchers.

Clinical trials are sponsored or funded by a variety of organizations or individuals such as physicians, medical institutions, foundations, voluntary groups, and pharmaceutical companies, in addition to federal agencies such as the National Institutes of Health (NIH), the Department of Defense (DOD), and the Department of Veteran’s Affairs (VA). Trials can take place in a variety of locations, such as hospitals, universities, doctors’ offices, or community clinics.

A protocol is a study plan on which all clinical trials are based. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study.

A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the experimental treatment’s effectiveness.

A control is the standard by which experimental observations are evaluated. The control group is given either a standard treatment for the illness or a placebo.

Different types of clinical trials

Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.

Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning.

Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.

Screening trials test the best way to detect certain diseases or health conditions.

Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.

3



The phases of clinical trials Clinical trials are conducted in phases depending on the purpose.

In Phase I trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.

In Phase IV trials, post marketing studies delineate additional information including the drug’s risks, benefits, and optimal use.

(http://clinicaltrials.gov/ct2/info/understand)

Bio Availability (BA) / Bio-Equivalence (BE) Studies

Bioequivalence: Background Using bioequivalence as the basis for approving generic copies of drug products was

established by the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Waxman-Hatch Act.

This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials.

At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA’s approval process. Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.

http://clinicaltrials.gov/ct2/info/glossary#phaselll

http://clinicaltrials.gov/ct2/info/glossary#phaselv

http://clinicaltrials.gov/ct2/info/understand

4



NDA vs. ANDA Review Process

APPLICANT

ANDA

ACCEPTABLE &

COMPLETE ?

REFUSE TO FILE

LETTER ISSUES

Y

N

REQUEST FOR PLANT

INSPECTION

CHEMISTRY

MICRO REVIEW

LABELING

REVIEW

BIOEQUIVALEN

CE REVIEW

PRE-APPROVAL

INSPECTION RESULTS

OK?

LABELING OK?CHEMISTRY /

MICROBIO OK?BIO OK?

APPROVAL WITHHELD

UNTIL RESULTS

SATISFACTORY

NOT APPROVABLE

LETTER

BIO DEFICIENCY

LETTER

APPROVED ANDA

Y Y Y Y

NN N

N

GENERIC DRUG REVIEW PROCESS

Original Drug

NDA Requirements

• Chemistry

• Manufacturing

• Controls

• Labeling

• Testing

• Animal Studies

• Clinical Studies

• (Bioavailability/Bioequivalence)

Generic Drug

ANDA Requirements

• Chemistry

• Manufacturing

• Controls

• Labeling

• Testing

• Bioequivalence Study (In

Vivo, In vitro)

Note: Generic drug applications are termed "abbreviated" because they are generally

not required to include preclinical (animal) and clinical (human) data to establish safety

and effectiveness. Instead, generic applicants must scientifically demonstrate that their

product is bioequivalent (i.e., performs in the same manner as the original drug).

5



BIOAVAILABILITY

Bioavailability is a measure of the rate and extent of absorption of the active form or forms of a drug from its formulation as reflected by the concentration - time curve of the administered drug in systemic circulation.

BIOEQUIVALENCE

Two formulations of a drug are said to be bioequivalent if the rate and extent to which the drug reaches the systemic action after administration of their respective formulations are statistically comparable. In general, two products may be said to be bioequivalent if 90%Westlake’s confidence interval for Cmax, Tmax, mean AUC(0-t) is within ± 20% of that of the reference product. The margin may be reduced to± 10% for drugs with a very low therapeutic index, such as antiarrhythmic, antiepileptic and anticoagulant drugs.

PHARMACEUTICAL EQUIVALENTS

“Pharmaceutical equivalents” mean drug products that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same drug, in identical dosage forms, but do not necessarily contain the same ingredients, and that meet the identical compendialor other applicable standard of identity, strength, quality and purity, including potency and where applicable, content uniformity, disintegration time and/or dissolution rates.

PHARMACEUTICAL ALTERNATIVES

Pharmaceutical alternatives mean drug products that contain identical therapeutic moiety, its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respectivecompendial or other applicable standard of identity, strength, quality and purity, including potency and where applicable, content uniformity, disintegration times and/or dissolution rates.

THERAPEUTIC EQUIVALENTS

A medicinal product is therapeutically equivalent with another product if it contains the same active substance or therapeutic moiety and, when administered to the same individual, shows the same efficacy and toxicity as that product, whose efficacy and safety has been established.

6



CONVENTIONAL/IMMEDIATE RELEASE DOSAGE FORMS

A conventional dosage form is a formulation or a dosage form from which the active drug is released immediately following administration.

MODIFIED RELEASE DOSAGE FORMS

A modified release dosage form is defined as one for which the drug release characteristic of a time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage form such as solutions, ointments and promptly dissolving forms.

Should the following be defined from USP

Modified release dosage forms may be recognized as :

(i) Extended Release Dosage Forms and (ii) Delayed Release Dosage Forms

EXTENDED RELEASE DOSAGE FORMS

An extended release dosage form is defined as one that allows at least a two-fold reduction in dosing frequency as compared to that drug presented as a conventional dosage form.

The terms controlled release, prolonged action, sustained release and programmed release etc., are used synonymously with extended release.

DELAYED RELEASE DOSAGE FORMS

A delayed release dosage form is defined as one that releases a drug (or drugs) at a time other than promptly after administration, e.g., enteric coated products.

Cmax

This is the maximum drug concentration achieved in systemic circulation following drug administration.

Tmax

It is the time required to achieve maximum drug concentration in systemic circulation.

7



AREA UNDER THE CURVE (AUC)

Area under the curve is the total area under the biological fluid (serum, blood, etc.) concentration-time curve as determined by the Trapezoidal rule.

PHARMACODYNAMIC EVALUATION

It is a measurement of effect on a (patho) physiological process as a function of time, after administration of two different products to serve as a basis for bioequivalence assessment.

DISSOLUTION

Dissolution is defined as the process by which a drug substance from a dosage form dissolves in a dissolution medium to yield a solution.

DRUG DELIVERY SYSTEM

Drug delivery system is defined as a therapeutic system which releases drug at pre-determined rate for a fixed time either systematically or to a specified target organ.

ELIMINATION HALF LIFE

The half life (t½) is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.

PHARMACOKINETICS

Study of the kinetics of absorption, distribution, biotransformation and excretion of drugs.

Pharmacokinetics o “what the body does to the drug”

Absorption Distribution Metabolism Elimination

Pharmacodynamics o “what the drug does to the body”

wanted effects - efficacy unwanted effects - toxicity

8



Waivers of In Vivo Study Requirements

Criteria (21 CFR 320.22)

In vivo bioequivalence is self evident

Parenteral Solutions

Inhalation anesthetics

Topical skin solutions

Oral solutions

Different proportional strength of product with demonstrated BE

The Biopharmaceutics Classification System (BCS) Guidance

Purpose of the BCS Guidance: Expands the regulatory application of the BCS and recommends methods for classifying

drugs.

Explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of BCS.

BCS Classifications Class I - High Permeability, High Solubility

Class II - High Permeability, Low Solubility

Class III - Low Permeability, High Solubility

Class IV - Low Permeability, Low Solubility

CLASS BOUNDARIES

A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.

A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose.

A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.

Concept of “Half Life” ½ life = how much time it takes for blood levels of drug to decrease to half of what it was at

equilibrium

There are really two kinds of ½ life…

9



o “distribution” ½ life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs

o “elimination” ½ life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated

It is usually the elimination ½ life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug

“Rule of Five”

5x the elimination ½ life = time at which the drug is “completely” (97%) eliminated from the body

1x ½ life - 50% of the original drug removed 2x ½ life - 75% 3x ½ life - 87.5% 4x ½ life - 93.75% 5x ½ life - 96.875%

Bioequivalence

0

10

2030

40

50

6070

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trati

on

(n

g/m

L)

Test/Generic

Reference/Brand

module 9 - clinical trials and babe studies

Documents