Questions in our

mind

By: Pundalik
Pai
 Questions are very
important

A person asking a question is at that moment a self-motivated learner i.e. a researcher. This is the behavior we should try to nurture.
E.g. Evolution
 My Question
Is there a difference between CRO,
SMO and RMO?
CRO - Contract Research Organization
 A Contract Research Organization (CRO) is a company
contracted by a pharmaceutical or biotechnological
manufacturer to manage clinical trials. CROs perform
services such as, data management, statistical analysis,
protocol design, and final report development. e.g. Quintiles,
paraxel etc.
 A CRO is an independent contractor with the sponsor. 
 One or more of the obligations of a sponsor, e.g. design of a
protocol, selection or monitoring of investigations, evaluation
of reports, and preparation of materials to be submitted to the
FDA etc. are handled by CRO.
SMO - Site Management Organization
 A Site Management Organization (SMO) performs and manages
research for individual Investigative Sites. SMOs'
responsibilities include patient recruitment and protocol
management. e.g. many hospitals, Klintelligen, Comargo etc.
 A SMO is an independent contractor with the CRO /
clinical investigator and their one or more of the regulatory
obligations e.g., preparation and maintenance of case histories,
ensuring compliance with IRB review and informed consent
requirements, AE reporting etc. are handled by SMO.
RMO - Research Management Organization
 A Research Management Organization (RMO) functions as a
combination of a CRO and SMO to manage research from the
conception and development of a project to the implementation
and completion at Investigative Sites. e.g. Advinus
 My Question
Hatch-Waxman Act
History-
 Drug approval process in 1962
 Challenges for generic mfg’s and innovators
 Need for an amendment in federal Food, Drugs and Cosmetics act.
 In1984 Hatch-Waxman act as an amendment
 Also called “Drug Price Competition and Patent Term Restoration
act1984”
OBJECTIVES OF HATCH-WAXMAN ACT
1. Reducing the cost associated with the approval of a generic drug.
2. Allowing Early-Experimental-Use.
3. Compensating the branded drugs manufacturers for the time lost from
the patent term because of the regulatory approval formality.
4. Motivating the generic drug manufacturers: Exclusivity.
 My Question
Submission options (NDA)
 Which act covers the submission of NDA?
Three types of submission are available under Section
505 of chapter V of the Federal Food, Drug and Cosmetic
Act:
1. 505(b)(1)
2. 505(b)(2)
3. 505(j)
 Section 505(b)

Provides for the submission of a New Drug Application to

support the approval of a drug
 Section 505(b)(1) – the full NDA
 Used for new chemical entities.
 Requires complete reporting of Chemistry, manufacturing and
controls, Non-clinical pharmacology/toxicology, Clinical
pharmacology.
 Clinical investigations proving safety and efficacy.
 Clinical trials Phase I, II, III. Filing of NDA
 Phase IV (post marketing)
 Right of reference
 Exclusivity
 Patent extension- Length of time required for regulatory
process + 50% of time required for clinical trials (Time cant
exceed 5yrs)
 Section 505(b)(2)- NDA
 Intended to encourage innovation without creating duplicate work and reflects
the same principle as the 505(j) application:
“it is wasteful and unnecessary to carry out studies to demonstrate what is
already known about a drug”
Hence a 505(b)(2) application contains full reports of investigations of safety and
effectiveness but at least some of the information required for approval comes
from studies not conducted by or for the applicant and for which the applicant has
not obtained a right of reference.
 It is Considered a full NDA.
 Exclusivity
 Reporting requirements
 Same active ingredient
 Previously reported safety and efficacy Information from studies not conducted
by applicant
 Relying on FDA’s prior conclusions on safety and/or efficacy from other NDAs
 Non-clinical or Clinical Information where applicant lacks the right of reference
Section 505(b)(2)- Contd.
 What can be filed as 505(b)(2) application:
 Change in dosage form/strength/route of
administration/content of excipients.
 Substitution of an active ingredient in a combination
product.
 Change in dosage regimen/indication
 Rx to OTC switch
 New combination
 Modification of active ingredient
 Naturally derived or recombinant active ingredient
 Bio-inequivalence
 Section 505(j)- ANDA
Generics
 These are the drugs which are produced and distributed
without patent protection. It may still have a patent on
formulation but not on active ingredient.
 Are cheaper to produce and market.
 Decrease the health care costs.-Can use the data for which
they don’t have right of reference.
 Difference between prescribablity & switchablity
 Bioequivalence
 Abbreviated New Drug Application (ANDA): A type of
new drug application (NDA) in which approval of a generic
drug is based on demonstrating that it is comparable to an
innovator drug product (the RLD)
 Applications are "abbreviated" because they generally do

not include preclinical and clinical data to establish safety

and effectiveness
 Instead, generic applicants must demonstrate that their

product is bioequivalent (i.e., performs in the same manner

and is comparable to the innovator product in active
ingredient, dosage form, strength, route of administration,
labeling, quality, performance characteristics and intended
use)
Definition:
The absence of a significant difference in the rate and extent to which the active
ingredient or active moiety in pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug action when administered at the
same molar dose under similar conditions in an appropriately designed study.
 My Question
Para Filings?
 Under the provisions of the HWA a generic drugs firm must certify its
intentions with respect to each patent associated with the generic drug
it seeks to market.
For a generic drug manufacturer to submit ANDA, four possibilities
exist under HWA:
1. That patent information on the drug has not been filed i.e. no patent
information appears in the orange book.
2. That the patent has already expired.
3. The date on which the patent will expire.
4. That the patent is invalid or will not be infringed by the
manufacture, use or sale of the drug for which the ANDA is
submitted”.
 These certifications are termed as paragraph I, II, III, and IV
certifications respectively.
 My Question
Referencing
Orange Book
 Whats in the name?
 “List of Approved drug products and their therapeutic
equivalence evaluations”.
 Abbreviations in the book AA, AB, AP AN?

Office of generic drugs (OGD)

OGD recommendations?
Home page (FDA.gov)

Drugs Guidance compliance & regulatory information

Bioequivalence recommendations for specific products

 My Question

How to consent pediatric patients in clinical trials?

 According to the Good Clinical Practice guideline

(ICH-GCP E6), “Informed consent is a process by which
a subject voluntarily confirms his or her willingness to
participate in a particular trial (voluntariness), after having
been duly informed of all aspects of the trial, its nature,
significance, implications and risks that are relevant to the
decision-making process (information/disclosure) in a
way that the patient can comprehend and understand the
relevant information (understanding)”.
 Four elements are required for a fully valid consent:
1. competency,
2. information/disclosure,
3. understanding and
4. voluntariness.
 Competency is a legal term used to indicate that a
person has the ability and is mentally capable to make
and be held accountable for his/her decisions
(competency).
 According to the Declaration of Human Rights, “a child
is to be considered as a person with all basic human
rights from the day of birth”.
 According to the note for guidance ICH Topic E11 (Clinical
investigation of medicinal products in pediatric population),
paediatric age groups are separated into the following categories mainly
based on physiological and developmental similarities and
pharmacological parameters:
1. Preterm newborn infants (<36th gestational week)
2. Term newborn infants (0 to 27 days)
3. Infants and toddlers (28 days to 23 months)
4. Children (2 to 11 years)
5. Adolescents [12 to 16-18 years (dependent on the geographical region].
 This categorization of age groups provides a basis for developing the
study design in paediatric patients.
 Assent- means having the child express agreement to undergo a medical
procedure in a clinical trial.
 Asking the child for assent recognises the dignity, integrity and
autonomy of self determination and respects the expression of the child’s
willingness to participate.
Differences in assent process among
different age groups
Parent information sheet  Detailed information on the study
 The structure and content of the drug
parent information sheet and the  Condition under study.
parent informed consent form
follows the same international rules
as for an adult patient information 2. Thorough risk and benefit
sheet and informed consent form. assessment
 Both parents need to give consent 3. Measures taken to preserve
and sign the informed consent form child’s safety
4. Rights of parents and child
5. Consider child’s presumed will /
 Important elements to be
Voluntariness of participation
considered when obtaining
parental consent 6. Enough time for parents to
consider the options available
and discuss with family
1. Complete, balanced and 7. Investigator and site staff
Understandable information available to answer questions
 The need and purpose for clinical 8. Keep parents informed
studies throughout the study
 Rationale for experimental
Questions
 References
 Federal Food Drug and Cosmetic Act—Chapter V, Section 505(b)
(2)
 21 USC 355(b)(2)
 21 CFR 314.50 – NDAs
 21 CFR 314.54 – 505(b)(2) applications
 21 CFR 314.108 – Exclusivity DRAFT Guidance for Industry:
Applications covered by section 505(b)(2).
 Challenges and practicalities of obtaining parental consent and child
assent in paediatric trials, Regulatory Rapporteur – Vol 7, No 6,
June 2010
 ICH Topic E11, Clinical investigation of medicinal products in
pediatric population.