Download Evaluating Regulatory Risk for Comparator Drug Products

PERSPECTIVE
Evaluating Regulatory Risk for Comparator
Drug Products
By Cesar Medina, MBA, RAC, and Fernando
Alvarez-Nunez, PhD
Evaluating risks and developing mitigation
strategies have become common industry practices in drug development. Regulatory agencies
have adopted risk-based approaches in quality
management, pharmaceutical development and
postmarket surveillance of medicinal products.1-4
In this article, we introduce methodology
to evaluate regulatory risks when sourcing and
preparing comparators for use in clinical studies.
This methodology is needed since there is currently little regulatory guidance that specifically
addresses sourcing and preparation of comparator drug products. We define regulatory risk as
the likelihood or potential that your comparator
will not meet the requirements of regulatory
authorities.
For example, a low-risk comparator drug
product will not require substantial supporting
information to gain regulatory acceptance for
its use in a clinical study. However, a high-risk
comparator drug product will likely require
substantial supporting information and has
the potential to result in a clinical hold. Highrisk comparators also have a high probability
of invalidating clinical data if they cannot be
proven to be equivalent to the commercially
available marketed product.
Comparators Are Important
Comparators are marketed products used as a
reference in clinical studies. They are regularly
used as a positive control against an investigational drug.
These types of studies, often called “headto-head” studies, compare how well your
investigational drug does against the comparator drug. The data from such studies may be
critical for qualifying your clinical studies and
demonstrating your drug’s safety and efficacy.
The knowledge gained in these trials can also
be essential in forming your drug’s risk/benefit
profile. The data from these head-to-head trials
are required if you want to make any marketing
claims for your product of superiority over the
comparator, such as improved safety or better
efficacy.5
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As you consider the importance comparators play in clinical development, it is imperative
to evaluate the regulatory risks when sourcing
and preparing comparator drug products.
Rating Comparator Risk
Rating risk is a very subjective process and
often is specific to the product and region. One
method to assess comparator risk is to measure
against anticipated regulatory requirements for
supporting data.
For this article, we rate risks on a scale of
1–5 as shown in Table 1. This rating scale is used
in this article to communicate the risks posed by
comparator sourcing and blinding strategies.
Low-risk comparators (rating 1) require little
to no supporting information to a gain acceptance by regulatory authorities. Then, as the
amount of information required by regulators
increases, the associated regulatory risk correspondingly rises.
High-risk comparators (rating 5) will likely
require substantial supporting information and
also have a potential to result in a clinical hold or
invalidation of clinical data.
Sourcing Comparators
The first risk evaluation should be done even
before the comparator is procured. Where the
comparator is sourced in relation to where it will
be used (clinical site) is not trivial. It is generally
recommended that your comparator be sourced
from the same region where it will be used to
provide assurance to regional authorities that
the product is safe and effective for a particular
indication.6-8
This does imply that the selected comparator is approved and/or registered for use in
that region. This strategy is known as regional
sourcing. Although regional sourcing presents
the lowest regulatory risk, it is not always practical when the clinical study is global and you
must consider many regulatory authorities.
Additionally, regional sourcing for global studies presents logistical planning challenges and
increased expenses.
Alternatively, a global sourcing plan identifies a single source that can be used in all regions
selected for the clinical trial. The ideal situation
would be to identify a single-sourced product
that is approved in all the respective regions, but
this is usually not possible. If you propose to use
a comparator that is not approved in a specific
region, regulators will most likely ask for additional information or an entire investigational
drug application for that particular comparator.9
Regulatory professionals must be able to
guide their teams in selecting the most appropriate sourcing plan and communicate the risks.
A good reference in determining the regulatory
risks when sourcing comparators is the graded
approach taken by the EU.
The EU outlines the required documentation and necessary data based on sourcing from
a specific Member State, Member States with
mutual recognition agreements, ICH countries
and non-ICH countries.10,11
As you move away from regional sourcing toward sourcing from a non-ICH country,
the burden of proof in substantiating regulatory
acceptance of the comparator increases. This
graded approach can be viewed as increasing
regulatory risk as depicted in Figure 1. This type
of analysis can be used to measure and communicate the regulatory risk introduced by any
selected sourcing strategy.
Modifying Comparators
Most often, comparator studies are doubleblinded, meaning that neither the doctor nor the
patient can identify the drug. This means that
the comparator cannot be provided to the clinic
without first blinding it in some manner.
Blinding comparators often requires modifications to the product, such as placing it in a
capsule (over-encapsulation) or removing its
commercial markings such as printed logos or
names (de-inking). The regulatory expectation is
that the selected blinding modification must not
change the product’s safety or efficacy.
The ICH Guideline for Good Clinical Practice
requires that if, significant formulation changes
are made in the investigational product or
comparator(s) products during the course of
clinical development, the results of additional
studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to
assess whether these changes would significantly
alter the pharmacokinetic profile of the product
should be available prior to use of the new formulation in clinical trials.12
In the EU, GMP Annex 13 requires similar
data, such that, if a product is modified, data
should be available (e.g., stability, comparative
dissolution, bioavailability) to demonstrate that
these changes do not significantly alter the original quality characteristics of the product.13
Common blinding techniques have been
previously reported and will not be discussed in
detail.14,15 But, it must be noted that each blinding
technique has its advantages and disadvantages
in demonstrating that the modification does not
alter the product’s safety or efficacy.
The greater the degree of modification that
is conducted on the comparator, the more difficult it will be to demonstrate that the product’s
safety and efficacy have not been altered. The
degree of modification can be used to evaluate
the regulatory risk imposed by certain blinding
techniques.
In the EU, a distinction is made between
minor and significant modifications for a comparator.16 For example, repackaging is considered
a minor modification while milling of tablets is a
significant modification.
The degree or significance of a modification must be evaluated on a case-by-case basis
to determine its regulatory risk. More significant
modifications will increase the requirements for
product release testing and stability analysis.17,18
Demonstrating bioequivalence of the modified
comparator to the original (unmodified) comparator also increases in difficulty with greater
Table 1. Comparator Risk Rankings Based on Regulatory Expectations
Risk
Rating
Low
1
Requires reference to market authorization in the respective region. Little to no
supporting CMC information required.
2
Requires supporting documentation of approval status in country of origin. Requires
some data to verify drug product stability. Bioequivalence likely demonstrated in vitro.
3
Requires supporting documentation of approval status and GMP compliance in country
of origin. Requires data to establish purity and shelf life. Bioequivalence may potentially
be demonstrated in vitro.
4
Requires supporting documentation of approval status and GMP compliance in country
of origin. Requires data to demonstrate purity and shelf life. Demonstrated process
understanding and controls required. Bioequivalence may potentially be demonstrated in vitro.
5
Requires substantial supporting information to demonstrate safety and efficacy. Likely
requires in vivo studies, extensive process characterization and possibly a separate
regulatory submission.
Medium
High
Regulatory Expectations
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Figure 1. Graded Approach to Regulatory Acceptance of Comparators Based on Sourcing and
Approval Status
modification, especially for low solubility or
modified release products.19
The product’s biopharmaceutical properties,
including solubility, permeability and bioavailability, must also be taken into consideration.
Bioequivalence of BCS Class 1 drugs (high solubility, high permeability) in immediate release
dosage forms can be justified solely based on
dissolution similarity.20 However, if the drug’s
biopharmaceutical properties (low solubility, low
permeability) pose bioavailability concerns or
the dosage form entails a unique drug delivery
mechanism, in vivo bioequivalence studies will
likely be the only acceptable method to demonstrate bioequivalence.
Using these characteristics, regulatory
risk can be assessed based on the specific drug
product attributes and the degree of modification. Table 2 provides a rank order of regulatory
risks and considerations for typical blinding
techniques based on their inherent degree of
modification.
Comparator Submissions (CMC)
Identification and modification details of
comparator drug products must be submitted as part of the clinical trial application (e.g.,
Investigational New Drug Application (INDA),
Investigational Medicinal Product Dossier
(IMPD), etc.) to health authorities prior to initiation of comparator clinical studies. In Common
TechnicalDocument (CTD) format, this information will be covered in Module 3 (Quality). Using
a risk-based approach, regulatory professionals
should evaluate whether the submitted information is commensurate with the degree of risk
posed by sourcing and modifications of the comparator drug product.
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For example, if the comparator is sourced
regionally, reference to its market authorization
would suffice. But if it is not sourced regionally,
you will most likely need to submit additional
information such as the manufacturer’s site registration, product registration or Certificate of
Analysis (CoA).
For modified comparators, the CMC submission should demonstrate that the modifications
have not significantly altered the original quality characteristics of the product such as shelf
life, dissolution, purity and bioavailability.
Supporting information may include dissolution
similarity data, compatibility studies, stressed
stability studies and drug product stability
studies.
As a regulatory professional, you can utilize the risk-based approach to help determine
whether the submitted information is sufficient to gain regulatory acceptance of your
comparator.
Conclusions
There is no question that comparator drug products are an important part of drug development.
Currently, there is little regulatory guidance that
specifically addresses sourcing and preparation
of comparator drug products for use in clinical
studies.
However, regulatory professionals are
tasked with providing regulatory guidance to
their organizations. The methodology described
in this article can be used by regulatory professionals and drug development scientists to
evaluate and communicate regulatory risks for
comparators. The intention is that risk assessments be conducted up front to help select the
Table 2. Regulatory Risk and Considerations for Typical Comparator Blinding Techniques
Blinding Technique
Regulatory Risk
1 = Low, 5 = High
Regulatory Considerations
Repackaging
(primary container
non-sterile)
1
May require some stability data to demonstrate that new packaging
does not alter the quality of the product. Bioequivalence is not
affected.
Over-encapsulation
(no new excipients)
2
Dissolution similarity must be demonstrated. Stability data required.
Bioequivalence likely justified by in vitro assessment (dissolution).
De-Inking
2
Must demonstrate the solvent used for de-printing is removed to an
acceptable level. Stability data likely required to verify that the solvent
does not impact the quality of the product. Bioequivalence is not affected.
Over-encapsulation
(new excipients)
3
Dissolution similarity must be demonstrated. Compatibility with new
excipient must be verified. Stability data required. Bioequivalence
potentially justified by in vitro assessment (dissolution).
Over-coating
3
Dissolution similarity must be demonstrated. Compatibility with
coating and coating process must be verified. Stability data
required. Bioequivalence potentially justified by in vitro assessment
(dissolution).
Milling and tablet/
encapsulation
5
Requires detailed characterization of the process and process
controls. The final drug product must be demonstrated to be
equivalent to original comparator. Impurity profiles and stability must
be well characterized. Likely requires in vivo bioequivalence study.
Repackaging
(primary containersterile )
5
Sterility of the product must be established within the new packaging.
The repackaging process must be demonstrated to be well controlled
and maintain sterility of the product. Stability data (chemical and
microbiological) are required.
most appropriate approach with the lowest
inherent regulatory risk.
As with any risk-based approach, to ensure
success, this risk analysis should be an iterative
process throughout product development.
References
1. US FDA Guidance for Industry: ICH Q8(R2) Pharmaceutical
Development, November 2009, CDER/CBER.
2. US FDA Guidance for Industry: ICH Q9 Quality Risk
Management, June 2006, CDER/CBER.
3. US FDA Guidance for Industry: ICH 10 Pharmaceutical
Quality Systems, April 2009, CDER/CBER.
4. US FDA Draft Guidance for Industry: Format and Content of
Proposed Risk Evaluation and Mitigation Strategies (REMS),
REMS Assessments, and Proposed REMS Modifications,
September 2009, CDER/CBER.
5. US Code of Federal Regulations, 21 CFR 202.1, Prescription
Drug Advertising. 1 April 2010.
6. Vudathala G, Simmons J. “Pharmaceutical Data Required
to Support Blinded Clinical Trials.” Pharmaceutical
Outsourcing. May/June 2006; 47-50.
7. Conzentino P, Bouvier A, Vudathala G, Owens G.
“Regulatory Chemistry, Manufacturing and Controls
(CMC) Requirements for Using Comparator Drug Products
in Clinical Trials.” Pharmaceutical Outsourcing. January/
February 2009;8-15.
8. Conzentino P. “Your Choice of Comparator or Positive
Control During Clinical Investigations.” Pharmaceutical
Outsourcing. October 2009; 40-44.
9. Op cit 6.
10.EMEA Guideline on the Requirements to the Chemical
and Pharmaceutical Quality Documentation Concerning
Investigational Medicinal Products in Clinical Trials, Section
3,4, March 2006, CHMP.
11. European Commission Draft Guidance, June 2010,
Harmonised Requirements for Non Investigational Medicinal
Products in CTA Submissions, Ad-Hoc Working Group.
12. ICH E6(R1) Guideline for Good Clinical Practice, Section
5.13.5, June 1996, ICH Expert Working Group.
13. European Commission Guidance, Annex 13 Manufacture of
Investigation Medicinal Products, Section 19, Volume 4 Good
Manufacturing Practices, July 2003.
14. Op cit 6.
15. Op cit 7.
16. Op cit 10.
17. Huynh-Ba K, Aubry A. “Analytical Development Strategies
for Comparator Products.” American Pharmaceutical Review.
2003: 6( 2);92-97.
18. Hager D, Kelly J, Tolliver A, Healy, D. “Conducting
Release and Stability Studies for Blinded Comparators.”
Pharmaceutical Outsourcing. October 2010;10-18.
19. U.S FDA Guidance for Industry: Bioavailability and
Bioequivalence Studies for Orally Administered Drug
Products—General Considerations, March 2003, CDER.
20. US FDA Guidance for Industry: Waiver of In Vivo
Bioavailability and Bioequivalence Studies for Immediate Release
Solid Dosage Forms Based on a Bi pharmaceutics Classification
System, August 2000, CDER.
Authors
Cesar Medina, MBA, RAC, is a manager in regulatory affairs,
CMC at Amgen Inc. He has 14 years of experience in drug development including regulatory responsibilities. He has several
publications in pharmaceutics research and is currently pursuing a master’s degree in regulatory affairs at Center of Bio/
Pharmaceutical and Bio/Device Development at San Diego State
University. He can be reached at [email protected]. Fernando
Alvarez-Nunez, PhD, is a principal scientist in the small molecule pharmaceutics at Amgen Inc. He has more than 20 years of
industrial and academic experience and is currently responsible
for leading scientists in developing clinical and commercial dosage forms. He is also a regular lecturer in pharmaceutical sciences
graduate courses at various universities. He has published several
papers on topics including solubilization approaches for poorly
soluble drug molecules. He can be reached at [email protected].
The views expressed herein represent those of the authors and do not
necessarily represent the views or practices of the authors’ employer or
any other party.
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