BA and BE studies.
Seminar presented in All India Institute of Medical Sciences (AIIMS - New Delhi).
Focus in Pharmacokinetic parameters (Cmax, AUC)
Single dose PK study, Steady state PK study, Modified drug release PK study, In vivo mechanisms, invitro mechanisms, Pharmacodynamic Study, Comparatice Clinical Trials. Biowavers and Biosimilimars.
Reference: CDSCO guideline, USFDA guideline, ICH guidelines
This slide show reflects general considerations of Bio-availability & Bio-equivalence studies for orally administered drugs. The presentation also accommodates US - FDA's approach and specific recommendations for such studies.
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The International Council on Harmonisation (ICH) defines an institutional review board (IRB) as a group formally designated to protect the rights, safety and well-being of humans involved in a clinical trial by reviewing all aspects of the trial and approving its startup. IRBs can also be called independent ethics committees (IECs).
An IRB/IEC reviews the appropriateness of the clinical trial protocol as well as the risks and benefits to study participants. It ensures that clinical trial participants are exposed to minimal risk in relation to any benefits that might result from the research.
IRB/IEC members should be collectively qualified to review the scientific, medical and ethical aspects of the trial.
Per the FDA, an IRB/IEC should have:
At least five members.
Members with varying backgrounds.
At least one member who represents a non-scientific area (a lay member).
At least one member who is not affiliated with the institution or the trial site (an independent member).
Competent members who are able to review and evaluate the science, medical aspects and ethics of the proposed trial.
This slide show reflects general considerations of Bio-availability & Bio-equivalence studies for orally administered drugs. The presentation also accommodates US - FDA's approach and specific recommendations for such studies.
INSTITUTIONAL REVIEW BOARD (IRB/IEC).pptxRAHUL PAL
The International Council on Harmonisation (ICH) defines an institutional review board (IRB) as a group formally designated to protect the rights, safety and well-being of humans involved in a clinical trial by reviewing all aspects of the trial and approving its startup. IRBs can also be called independent ethics committees (IECs).
An IRB/IEC reviews the appropriateness of the clinical trial protocol as well as the risks and benefits to study participants. It ensures that clinical trial participants are exposed to minimal risk in relation to any benefits that might result from the research.
IRB/IEC members should be collectively qualified to review the scientific, medical and ethical aspects of the trial.
Per the FDA, an IRB/IEC should have:
At least five members.
Members with varying backgrounds.
At least one member who represents a non-scientific area (a lay member).
At least one member who is not affiliated with the institution or the trial site (an independent member).
Competent members who are able to review and evaluate the science, medical aspects and ethics of the proposed trial.
This presentation is a brief overview of ICH-GCP guidelines. Although ICH-GCP is a very vast topic, still this presentation will cover almost all the points. The reader will be able to discuss about the roles and responsibilities of various personnel in clinical trials.
The Investigator's Brochure (IB) is a comprehensive document summarizing the body of information about an investigational product (IB) obtained during a drug trial.
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An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's CDER, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product.
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An overview of ICH-GCP guidelines of clinical trials.
Good clinical practice (GCP): a standard for the design , conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.
ICH-GCP is an International Conference on Harmonization Good Clinical Practice.
The guideline was developed with consideration of the current good clinical practices of the European union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the world health organization
Bioavailability & Bioequivalence Studies
https://youtube.com/vishalshelke99
https://instagram.com/vishal_stagram
Sub :- Research Methodology
M.Phrmacy Semister 1
Savitribai Phule Pune University
Bioavailability:
Bioavailability is defined as a measure, of the rate and amount of drug, which reaches the systemic circulation unchanged following the administration of a dosage form.
Absolute bioavailability:
When systemic availability of a drug administered orally
is determined in comparison to its I.V. administration, denoted by F.
Relative bioavailability:
When systemic availability of a drug after oral administration is
Compared with that of oral standard of the same drug
( Solution or suspension ) and denoted by Fr.
- Whilst the realization of the CTD took many years, there is now a common format for the submission of Marketing Authorizations Applications across the three ICH regions - Europe, Japan and the USA.
- This should facilitate pharmaceutical companies to make simultaneous filings in the ICH regions as it will eliminate the extensive work previously required to convert, for example, a US dossier to an EU dossier and vice versa.
Regulations for drug approval in USA, E.U & India
Pharmaceutical industry is the most regulated of all the industries. Regulations are put in order to develop the most efficient and safe pharmaceutical products. It takes more than 8 to 15 years to develop a new drug product & costs more than $ 800 million.
This presentation is a brief overview of ICH-GCP guidelines. Although ICH-GCP is a very vast topic, still this presentation will cover almost all the points. The reader will be able to discuss about the roles and responsibilities of various personnel in clinical trials.
The Investigator's Brochure (IB) is a comprehensive document summarizing the body of information about an investigational product (IB) obtained during a drug trial.
Abbreviated New Drug Application [ANDA]Sagar Savale
An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's CDER, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product.
The NDA application is the vehicle through which drug sponsors, such as biotech and pharmaceutical companies, formally propose that the FDA approve a new pharmaceutical for sale and marketing
An overview of ICH-GCP guidelines of clinical trials.
Good clinical practice (GCP): a standard for the design , conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.
ICH-GCP is an International Conference on Harmonization Good Clinical Practice.
The guideline was developed with consideration of the current good clinical practices of the European union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the world health organization
Bioavailability & Bioequivalence Studies
https://youtube.com/vishalshelke99
https://instagram.com/vishal_stagram
Sub :- Research Methodology
M.Phrmacy Semister 1
Savitribai Phule Pune University
Bioavailability:
Bioavailability is defined as a measure, of the rate and amount of drug, which reaches the systemic circulation unchanged following the administration of a dosage form.
Absolute bioavailability:
When systemic availability of a drug administered orally
is determined in comparison to its I.V. administration, denoted by F.
Relative bioavailability:
When systemic availability of a drug after oral administration is
Compared with that of oral standard of the same drug
( Solution or suspension ) and denoted by Fr.
- Whilst the realization of the CTD took many years, there is now a common format for the submission of Marketing Authorizations Applications across the three ICH regions - Europe, Japan and the USA.
- This should facilitate pharmaceutical companies to make simultaneous filings in the ICH regions as it will eliminate the extensive work previously required to convert, for example, a US dossier to an EU dossier and vice versa.
Regulations for drug approval in USA, E.U & India
Pharmaceutical industry is the most regulated of all the industries. Regulations are put in order to develop the most efficient and safe pharmaceutical products. It takes more than 8 to 15 years to develop a new drug product & costs more than $ 800 million.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
Regulatory consideration for biosimilars by fdaGopal Agrawal
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Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (as per FDA)
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Vaccination Strategies: Oncolytic virus for melanoma, Dendritic Cell therapy for CA Prostate.
Immune Checkpoint inhibitors. PD1 and PD L1 inhibitors.
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2017 AHA/ACC criteria for Hypertension management in brief.
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||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
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MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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Bioavailability and Bioequivalence Studies
1. Bioavailability and Bioequivalence studies
Dr Pranav Sopory
Junior Resident (Academic)
Department of Pharmacology
AIIMS- New Delhi
Mob: +91-9999491690
Email: pranav.sopory@gmail.com
BA/BE
1
2. Contents
1 Introduction on BA/BE
2 Discussion of a “single dose” PK study
3 CDSCO guidelines
4 Cases requiring a “steady state” PK study
5 Special considerations for modified-release drug products
6 Methods apart from PK studies
7 Approval without BE study
8 Biowaivers
9 Biosimilars
10 Conclusion
BA: Bioavailability
BE: Bioequivalence
CDSCO: Central Drugs Standard Control Organization
PK: Pharmacokinetic 2
3. BA and BE
• BA of a drug is defined as the extent and rate to which the active
ingredient or active moiety from the drug product is absorbed and
becomes available at the site of drug action.
• BE is achieved when the extent and rate of absorption are not
statistically significantly different from those of the reference product
when administered at the same molar dose (under similar conditions in
an appropriately designed study).
3
4. CDSCO (2005) approved methods to establish BE:
1. In vivo study
A. PK study
• Highest order of preference among BA/BE study: USFDA
B. PD study
• Active drug/ its metabolite cannot be detected in biological matrix
• Can be detected but not with sufficient accuracy or sensitivity
• Can be detected but has no correlation to its action (topical)
C. Comparative clinical study
• Absence of PK parameters along with lack of meaningful PD parameters
• PK and PD studies are not feasible
2. In vitro study
4
5. BE: in brief
BA is measured via AUC and Cmax
1. Measure AUC and Cmax for the test drug
2. Measure AUC and Cmax for the reference drug
3. If the ratio (test/reference) falls between 80-125% range: BE established
5
6. PK study: For a single dose
Time after drug
administration
(hours)
Drug
concentration in
plasma (ng/ml)
0.017 (1 min) 0.49
0.08 (5 min) 0.99
0.17 (10 min) 10.12
0.5 (30 min) 50.01
1 90.10
2 87.10
4 65.71
8 41.11
12 20.22
24 6.00
36 1.31
PK parameters
1. Cmax
2. AUC(0-t)
3. AUC(0-∞)
4. Kel
5. t1/2
6
10. Calculating AUC (0-∞) from AUC(0-t) and Kel
• Involves extrapolation of 2%
• Upto 20% allowed
10
11. Why not just measure the exposure to the drug (AUC)?
11
12. Statistical analysis & criteria to establish BE
• To assume normality of data, logarithmic transformation of PK
parameters: Cmax and AUC
• The 90% confidence interval for the ratio of the population means (test/reference)
OR
• Two one sided t-tests with the H0 for non-BE at the 5% significance level
• To establish BE:
1. 90% C.I. for Cmax and AUC should fall within the BE range (80-125%)
2. This is equivalent to the REJECTION of two one sided-t tests with the H0 for non-
BE at the 5% significance level
3. Assess Tmax if clinically relevant
12
13. PK parameters are lognormally distributed
• A normal distribution reaches from (– ∞) to (+ ∞)
• A lognormal distribution reaches from 0 to (+ ∞)
There are physiologic limits to PK parameters. They cannot be
negative.
Also the data is highly skewed.
• To perform statistical tests: LOGARITHMIC TRANSFORMATION
• The values are normally distributed
• The values are less skewed
13
14. Why the 80-125% range to establish BE?
• USFDA: differences in systemic drug exposure up to 20% are not clinically significant.
• Shouldn’t the appropriate range be 80-120% (100% ± 20%)?
• PK parameters are log-normally distributed.
• Thus, the symmetrical ± 20% has to be in the log-transformed space so that the statistical
test of bioequivalence will be valid.
Maximum BE
14
15. Exceptions to the criteria
• USFDA: Distinct limits for permissible differences in BA required for drugs that
have:
1. A narrow therapeutic window (90% to 111.11%, ln ratio: -0.105 to + 0.105)
2. A wide therapeutic window (75% to 133%, ln ratio: -0.286 to +0.286)
3. A non-linear PK within the therapeutic dose range (tighter limits due to fluctuations in conc.)
• Suprabioavailability
a. Reformulation followed by a fresh BE study
b. Otherwise perform a clinical trial 15
16. Study design: CROSSOVER DESIGN
• Standard: 2 sequence 2 period (2X2) crossover design
• Test drug: T
• Reference drug: R
• Study design (TR, RT)
Randomisation
Washout
period
Test drug
Reference drugTest drug
Reference drug
Advantages:
• Each subject serves as his/her
control (decreased confounding
variation)
• Statistically efficient; require lesser
subjects (≥16 subjects: CDSCO)
Disadvantages:
• Order effect
• Carry-out effect
• Intra-subject variability 16
17. PK study: Study design: Other designs
1. REPLICATE CROSSOVER STUDY DESIGN
• For highly variable drugs
• Study design (TRTR, RTRT)
• Minimum no. of subjects: 24 (USFDA)
• Allows comparisons within subject variances
2. PARALLEL STUDY DESIGN
• For drugs with long half-lives
• Administer each treatment to a separate group of subjects with similar demographics
• USFDA: Measure truncated AUC [eg. AUC(0-24)]: PK simulations show it to be an
equally effective parameter.
Period 1 2 3 4
Group 1 T R T R
Group 2 R T R T
17
18. Requirement of BA/BE studies
Establish BE in case of:
1. NDA: Early and late clinical trial formulations
2. Post-marketing changes: Clinical trial formulations and to be
marketed formulations
3. ANDA: for generics
NDA: New Drug Application
ANDA: Abbreviated New Drug Application
18
19. Regulations for generic drugs
• 1984: USFDA authorized “Drug Price Competition and Patent Term
Restoration Act”.
• USFDA approved generic drugs under this act based on BA/BE studies.
• MCI: Indian Medical Council (Professional Conduct, Etiquette and Ethics)
(Amendment) Regulations, 2016 – Part – I.
• “Every physician should prescribe drugs with generic names legibly and preferably
in capital letters and he/she shall ensure that there is a rational prescription and use of
drugs.”
19
20. CDSCO guidelines: Introduction
1. Reasonable assurance that the test product when compared to the
reference product is therapeutically and clinically equivalent and
interchangeable.
2. Assessing this via clinical trial is cumbersome.
3. Systemic exposure profile during clinical trials in early drug
development serves as a benchmark for subsequent BE studies.
20
21. Definitions in the guideline
Reference product:
• Identified by licensing authority as “Designated Reference Product”/ “Global
Innovator Product”.
• Contains the same active ingredient(s) as the new drug.
• Applicants seeking approval to market a generic equivalent must refer to the DRP to
which all generic versions must be shown to be bioequivalent.
• For subsequent new drug application, the Licensing Authority, may however, approve
another Indian product as DRP.
Active Moiety Salt/ester Dosage form Excipient Equivalence
Pharmaceutical
equivalents
+ + + - BA/BE outcome
Pharmaceutical
alternatives
+ +/- +/- N/A BA/BE outcome
Therapeutic
equivalents
+ +/- +/- N/A +
(Clinical efficacy)
21
+ : Similar - : Not similar
22. In vivo BE studies are necessary
A. Oral immediate-release with systemic
action when one or more of the
following criteria applies:
1. Indicated for serious conditions requiring assured
therapeutic response;
2. Narrow therapeutic window
3. Complicated PK (Non-linear)
B. Non-oral and non-parenteral
formulations designed to act by
systemic absorption
(e.g. transdermal patches, suppositories)
C. Modified-release drug formulations
D. FDC products with systemic action
E. Non-solution pharmaceutical products
for non-systemic use (nasal, ocular,
dermal, rectal, etc.): Act without
systemic absorption.
In these cases, the PK parameter concept is not
suitable. Perform comparative clinical study or
pharmacodynamic study
22
23. Study conditions: Characteristics to be investigated
Measurement of active drug substance(s) in the biological matrix
Measurement of drug metabolites
• Limitations in the analytical method
• Drug concentration is too low to be recorded
• Prodrugs
• Drugs with a very short half-life
Racemates (90% of drugs in the market) should be measured using an achiral assay
method
Measure individual enantiomer in case of
• Different PD parameters (eg: S-enantiomer of citalopram more potent)
• Different PK parameters (eg: l-enantiomer of MTX: 40 times higher AUC than d-enantiomer)
23
24. CDSCO - Bioanalytical methodology: Pre-study phase
Sensitivity:
• Reliable lowest limit
quantification of
plasma concentration
• Limit of detection
should be lower than
limit of quantification
Precision and Accuracy
• Document on 3 concentrations (lowest measurable,
medium and Cmax)
24
Intra-assay COV ≤ 20%
Range of accuracy: ± 15%
Accuracy: (Accepted value – Observed value*) X 100
Accepted value
25. Cases requiring an additional “Steady state study”
1. Toxic drugs requiring multiple dose therapy e.g. many cytotoxics.
2. Drugs with long terminal half life and blood concentrations after a
single dose cannot be followed for a sufficient time.
3. For modified-release products where it is necessary to assess the
fluctuation in plasma conc. over a dosage interval at steady state.
25
26. PK parameters assessed in steady state study
• Statistical analysis of
1. AUC(0-𝛕)SS: AUC over one dosing interval.
2. Cmax
3. Cmin
4. Degree of fluctuation
• Criteria to establish BE
Same as single dose study
26
27. AUC(0-tau), C(max), C(min) and Degree of fluctuation
Dose No Cmax
(ug/mL)
Cmin
(ug/mL)
Cavg
(ug/mL)
1 3.2 1.6 2.4
2 4.8 2.4 3.6
3 5.6 2.8 4.2
4 6 3 4.5
5 6.2 3.1 4.65
6 6.3 3.15 4.725
Calc. Cmax SS Cmin SS CavgSS
CavgSS (ug/mL): Cmax SS + Cmin SS
2
Degree of Fluctuation: Cmax SS - Cmin SS
CavgSS
Why measure AUC(0-tau)
27
28. Special considerations for Modified-release drug products
Consideration 1:
RP: FOOD AFFECTS ABSORTION?
• ?/YES: Two 2X2 crossover
• NO: 3X3 crossover
Consideration 2:
ACCUMULATION?
AUC(0-tau) /AUC(0-∞) ?
• ≥0.8: Unlikely: SINGLE DOSE Study
• ≤0.8: Likely: Additional SS Study
3. If test product first market entry: RP: IR
4. Additional parameter: Cpd: pre-dose
conc. just before steady state is achieved
28
29. Requirements of a PD study
1. Response measured should be a pharmacological effect.
(substitute for plasma conc.)
2. Response should be measured in a double blinded fashion.
3. Pilot study can be conducted to check non-responders
4. If placebo effect can occur, include a third period/phase in
the study design
5. Crossover or parallel study design can be used
6. Conventional acceptance rate applicable for PK study is
not appropriate (too large). The range should be defined in
the protocol on a case-to-case basis
29
30. • PK evaluation of acarbose is difficult because <2% is absorbed
systemically.
• Glucobay® 100 mg tablet (Bayer Healthcare) Vs. Generic acarbose
100‐mg tablet
• PD parameter: Gmax (Serial blood samples over 24 hours)
30
31. Cases requiring Comparative clinical trials
1. Absence of PK parameters along lack of meaningful PD parameters
2. PK and PD studies are not feasible
3. Parameter: Clinical endpoint
31
32. PK: Analytical studies for dihydroartemesnin: Not feasible
45 patients followed up for 28 days
• Mean time to fever subsidence (clinical parameter)
• Cure rate by Day 28 (clinical parameter)
• Time to parasite clearance 32
33. Biowaiver: in vivo BA/BE studies are waived
Applicant has to provide data to substantiate in vitro studies
Different strengths of drug manufactured by the same manufacturer where all of the following
criteria are fulfilled:
1. The ratio of active ingredients and excipients between the strengths is essentially the same, or, in
the case of small strengths, the ratio between the excipients is the same;
2. The method of manufacture is essentially the same
3. An appropriate equivalence study has been performed on the highest strength, unless a lower
strength is chosen for reasons of safety
4. In case of systemic availability- pharmacokinetics have shown to be linear over the therapeutic
dose range
33
34. CDSCO Guideline: BE study not necessary for approval
New drug Active substance(s) Excipient
A. Parenteral (IV, IM, SC, IT) adm. as aqueous
solution
Same concentration Comparable
concentrations
B. Solution for oral use Same concentration Not suspected to affect
GI transit or absorption
of active substance
C. Gas - -
D. Powder for reconstitution as a solution Meets criterion A. or
B.
Meets criterion A. or
B.
E. Otic or ophthalmic or topical product
prepared as an aqueous solution
Same concentration Comparable
concentration
F. Inhalational product or a nasal spray: adm.
with/without the same device as the
reference product (in vitro testing to
document device performance between
reference and test product)
Same concentration Same concentration
For E. and F. the applicant is expected to demonstrate that the excipients in the new drug are
comparable concentrations as those in the reference product
34
35. What about Biopharmaceuticals
• Vaccines, , blood components, gene therapies, tissues, monoclonal antibodies
• TERM: Biosimilar
• Establishing biosimilarity
1. Animal study
2. A clinical study or studies [including the assessment of immunogenicity and
pharmacokinetics (PK) or pharmacodynamics (PD)] that are sufficient to demonstrate
safety, purity, and potency in 1 or more appropriate conditions of use for which the
reference product is licensed and for which licensure is sought for the biosimilar product.
CDSCO guidelines available:
http://www.cdsco.nic.in/writereaddata/Proposed%20Guidelines%20for%20Similar%20Biologic%202016.pdf 35
36. Retrospective analysis comparing BE parameters between innovator
drugs and USFDA approved generic drugs b/w 1996-2007 (12 y)
Result:
1. The average difference in Cmax: 4.35% and in AUC: 3.56%
between generic and innovator products
2. 98% of BE studies: the generic product AUC differed from that of
the innovator product by less than 10%.
36
38. Conclusion
• Concept of BE has been adopted by the pharmaceutical industry &
national regulatory authorities throughout the world.
• Generics help patients by making drugs available at affordable price
while retaining their quality.
• Translates into increased opportunities for Indian pharmaceutical
companies (Current value: US $ 55 billion)
Thank you38
39. PK terms
1. Cmax: maximum drug concentration achieved in systemic circulation following drug
administration
2. Cmin: minimum drug concentration achieved in systemic circulation following
multiple dosing at steady state
3. Cpd: the pre-dose concentrations determined immediately before a dose in given at a
steady state
4. AUC 0-t: from 0 h to the last quantifiable concentration, to be calculated using the
trapezoid rule
5. AUC 0-∞: from 0h to infinity to be calculated as the sum of AUC0-t plus the ratio of
last measureable concentration to the elimination rate constant
6. AUC 0-𝛕: AUC over one dosing interval following single dose or modified release
products
7. AUC 0-𝛕 (SS): AUC over one dosing interval in multiple dose study at steady state
8. Kel: Terminal elimination rate constant calculated from a semi-log plot of plasma
concentration versus time curve
9. t1/2: time necessary to reduce the drug concentration in the blood, plasma, serum to
one-half after equilibrium in reached
39
Editor's Notes
To prove BE, TESTS have to be performed. They can be PK, PD, Comparitive Clinical trials.
BABE can be PK, PD, comparative clinical trial
Gut to liver to systemic circulation
Same molar dose…
After administering a single dose: Take blood samples to measure Drug Concentration
CDSCO doesn’t mention AUC(0-infinity) in this definition.
Confidence interval: DATA DISTRIBUTION: 90% of your data contains the true mean.
One sided t-test only see superiority or inferiority
Unpaired: two groups,,, Paired: pre-post analysis.
Tmax will be relative in:
eg. Drugs for status epilepticus..
Vomiting occurs within time 2Tmax
High level statistics
If the upper limit was 120%
Non-linear PK: FLUCTATION IN PARAMETERS
1. Multiphasic absorption (alpha: central to peripheral, beta: from peripheral: cleared by metabolism and excretion)
2. Enzyme saturation: Because in a saturated process the elimination rate is no longer proportional to the drug concentration but decreasing at higher concentrations
Washout period: should be more than 5 half-lives of the moieties to be measured
ORDER of drugs affects outcome. Eg. drug with many adverse effects given first, making patients taking a second, less harmful medicine, more sensitive to any adverse effect.
CARRY OVER CONFOUNDS: which confounds the estimates of the treatment effects. A bolished with appropriate washout periods.
Intra-subject variability: Differences in the plasma levels of a given drug in the same subject when given on different occasions
Washout guidelines: EMA AND FDA GUIDELINES: ATLEAST 5 t1/2
IND: Before starting
DEF GENERIC DRUG: A drug product that is comparable to brand/reference listed product in dosage form, strength, route of administration quality and performance characteristics and intended use.
Modified relase: Different adhesive system to make the drug stick to mucosa.
Different dissolution systems.
Some may seem confusing. Remember, BABE is also used after trial for the same drug before approval.
NON SOLUTION: SOLUTE> SOLVENT……..Non-solution pharmaceutical products, which are for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc., application) and are intended to act without systemic absorption. In these cases, the equivalence is established through, e.g. comparative clinical or pharmacodynamic, dermatopharmacokinetic studies and/or in vitro studies
Chiral HPLC
PRESISION: Reproducibility of result
Test Precision and accuracy on the reference drug
(The terminal half-life: time taken for the plasma concentration to reduce by half after reaching pseudoequilibrium::: is especially relevant to multiple dosing regimens, because it controls the degree of drug accumulation, concentration fluctuations).
Assume: After every dose: you achieve a conc. of 3.2 ug/mL
DOF between Reference and test product should also be in reference range.
MR products are affected for food absorption unless otherwise proven…..
AUC 0-inf plays a role in MDR also.
Maybe Cpd is to compare between Immediate release and Modified release
Acarbose inhibits alpha glucosidase and prevents conversion of starch to glucose
PK: not possible, it is very fast acting
PD: Not possible
CCT: only thing which can be done
Clinical trial: FOR NDACompartive Clinical trial: ANDA
Biowaiver not mentioned in CDSCO guidelines.
WHO!
in vitro:
DISSOLUTION, DISINTERGRATION AND SOLUBILITY TESTS
Give reference of WHO Site!
Large molecules mainly proteins, Mabs,
Manufacturing process has to be very precise…
Some other company: difference is likely to arise..
Immunogenicity arises…
Efficacy may also change..!!!
DO FROM START: preclinical, clinical………