|
|
|
European Biopharmaceutical Review
|
Christopher Stewart at MPI Research
explains how biologics development has helped enhance small molecule
development in light of variations in the regulatory environment
In my role, I am routinely asked questions about how to develop a
preclinical safety plan and the specific studies that should be
considered. This article aims to focus on a few investigational new
drug (IND) enabling studies. These questions result from the changes
and uncertainties of the regulatory climate. In the past, most
preclinical study types and designs were ‘checkbox’ for the regulatory
agencies. However, the impact of the guidance for biologically derived
drug development on changing the preclinical central dogma has been
quite substantial (ICH S6). The concept of the checkbox approach had
limited relevance with these biologically derived drug products because
of their unique attributes, and the thought processes emanating from
these discussions have now spilled over into the guidance for small
molecule development [ICH M3(R2)].
I am referring to the whole concept of the ‘case-by-case’ approach to
preclinical drug development plans. In my opinion, this is a positive
change for the regulatory environment and scientific community. It not
only promotes additional scientific thought across the whole of
preclinical drug development, but it also lends added credibility to
the concept of successfully satisfying the ‘three R’s’ (reduce, refine,
replace). Now, more than ever, it is critical to understand the
pharmacology of the drug in development, so that a preclinical study
programme can be designed with the potential to enhance the probability
of generating data that will increase the quality of the safety
assessment efforts.
It is obvious that rational preclinical safety assessment has always
been the philosophy that powered the regulatory tenets surrounding
preclinical research. However, inflexible regulatory criteria had a
tendency to temper the science, justifying the provision of information
that would minimally satisfy the needs of the regulatory agencies. This
limited (or boundary) approach to safety assessment was sufficient for
the most part, but it promoted a greater propensity to leave potential
safety hazards unexplored prior to entering clinical trials. By no
means am I implying negligence by those involved in drug development. I
am simply pointing out that data generation designed for the exclusive
purpose of meeting minimum regulatory requirements may not be
sufficient. Fortunately, new innovations in drug development and new
challenges posed by adverse drug reactions work to cause the regulatory
environment to continually renew itself. So how do I think growth in
the development of biologically derived drug products has benefited,
and is benefiting, small molecule drug development? I have highlighted
three points below, but there are others.
DEFINITIVE SCIENTIFIC JUSTIFICATION
As a scientist, I have always considered scientific justification to be
the driving force that propels the development of any treatment for a
disease. Thus, the case-by-case approach will benefit the preclinical
plans for small molecules by generating reliance upon a more tiered
approach to safety assessment (for example, expanded biomarker assays
will be quite useful for exploring this niche). The primary drawback to
this approach could be that more time is required to meet milestones,
so this must be factored into the preclinical safety assessment plan.
THE INTEGRATION OF APPROPRIATE AND SUPPLEMENTAL SAFETY PHARMACOLOGY ASSESSMENTS BACK INTO PIVOTAL REPEATED DOSE STUDIES
There are obvious reasons to explain why safety pharmacology requires
specialised regulatory consideration, but the industry’s approach to
implement ICH S7A/B posed a whole new set of challenges, which will not
be covered here. While direct pharmacological activity can be described
well under the auspices of ICH S7A/B, the acute dosing regimen
typically employed by this approach may miss delayed toxicities that
can be associated with secondary mechanisms of action or other factors.
Therefore, the willingness of regulatory reviewers to accept and often
encourage the judicious integration of safety pharmacology endpoints
with pivotal repeated dose safety studies has the added benefit of
enhancing the data available for safety assessment, while at the same
time potentially reducing animal usage.
A RENEWED ENVIRONMENT OF UNCERTAINTY
You might wonder how this could possibly be beneficial, but it is quite
clear when you look at a caveat of basic human nature. When we are
given boundaries (such as specific regulatory written criteria), it is
very easy to stay within them and not attempt to improve upon them.
However, removal of the boundaries (as in case-by-case) has caused
widespread stress on industry personnel as we struggle to regain our
clear direction in the changing regulatory environment. It is during
these times of rapid change that innovative thoughts are freed to shape
the future. I see this happening today, and I hope this renewed
environment will push the industry forward as a direct result of
scientific renewal. Then the new written regulatory boundaries can once
again provide specific criteria for preclinical drug development.
However, it is important to understand that these new criteria will
inevitably have modifiers (for example, drug class, therapeutic area,
routes of exposure and so on) for what should be included in a given
preclinical study plan. Thus, a combination of pragmatic and insightful
programme designs will provide necessary definition that will assist
with the effective implementation of the case-by-case approach for
small molecule drug development.
Based on these three points, and with so many potential considerations
for safety, prudent judgement will be the greatest asset for industry
as preclinical plans are prepared for presentation to regulatory
reviewers, which is why a good understanding of drug pharmacology and
potential side effects is critical.
Now that I have pointed out three areas where I see change in the
regulatory climate, I want to take a brief look at a single clarifying
thought about each point. HOW MUCH MORE SAFETY INFORMATION CAN REALLY
BE GAINED WITH THE
CASE-BY-CASE APPROACH?
The development of small molecules still requires the use of a rodent
and non-rodent species. In addition, the same safety parameters are
evaluated in the present as have been evaluated in the past. Therefore,
‘case-by-case’ really could be interpreted as ‘additional
considerations may be required after data are available.’ With this in
mind, be prepared to evaluate recovery in your first pivotal repeated
dose studies. Because it is not possible to predict all side effects,
the industry should consider this recovery evaluation to be a necessary
and rational inclusion as early as possible. It is not sufficient to
simply evaluate and determine an adverse effect level in setting
clinical doses. Thus, side effects that may not be considered adverse
at certain dose levels must have a reversibility characterisation as
early as possible or risk clinical delays.
WHEN IS IT ACCEPTABLE TO INTEGRATE SAFETY PHARMACOLOGY IN PIVOTAL REPEATED DOSE STUDIES?
This depends on whom you ask. The ICH M3 (R2) guidance specifically
states that this integration procedure should be considered. However,
this is controversial in the industry, because there is the risk that
practices implied under S7A/B may be diluted when integrated with a
repeated dose study. This concern has merit, but I agree with the
integration as a first-tier approach to evaluation of the core safety
pharmacology battery. The real challenge is to understand the logistics
for proper integration of safety pharmacology parameters without
compromising data integrity. Advances in monitoring technologies and
scientific rationale have helped to make this possible. With this
first-tier approach, a potential safety concern that is detected with
an integrated safety pharmacology parameter can be specifically
targeted in a follow-up independent safety pharmacology study. This
first-tier and follow-up approach has significant credibility because
many small molecules that have been in development present no
meaningful adverse safety characterisation information in an
independent safety pharmacology study. Therefore, this case-by-case
scenario should be utilised, as appropriate, to satisfy the three R’s.
While I see hesitancy from the industry to make this change, I also
observe the regulatory agencies routinely accepting the integration of
safety pharmacology with the pivotal repeated dose studies for small
molecules. So I reiterate that it depends on whom you ask.
WHEN WILL THE REGULATORY UNCERTAINTY GO AWAY?
I hope there will always remain an element of uncertainty in the
regulatory environment. Adverse drug reactions can sometimes be
predicted, but they continually present new challenges. The most
difficult challenges occur when the adverse drug reaction cannot be
predicted because the effect did not appear to be related to the
pharmacology of a drug. Therefore, we must continue to be diligent in
the preclinical regulatory environment. I believe the case-by-case
approach is the way the regulatory agencies have chosen to promote
continuous scientific renewal and technological advancement. Thus, the
industry must adopt the case-by-case mindset. |
Read full article from PDF >>
|
|
 |
|
| Rate this article |
You must be a member of the site to make a vote. |
|
Average rating: |
0 |
| | | | | |
|
|
 |
Industry Events |
 |
BIO-Europe Spring® 2012 — 6th International Partnering Conference
19-21 March 2012, Amsterdam RAI Convention Center, Amsterdam, The Netherlands
BIO-Europe Spring is the springtime counterpart to EBD Group’s flagship conference, BIO-Europe, and continues the tradition of providing life science companies with high caliber partnering opportunities. Featuring EBD Group’s sophisticated, web-based partnering system, partneringONE®, the event enables delegates to efficiently identify, meet and get partnerships started with companies across the life science value chain, from large biotech and pharma companies to financiers and innovative start-ups.
More info >> |
|
 |
News and Press Releases |
 |
DASGIP Product Catalog 2012 now available for download
The new DASGIP Product Catalogue is now available online. The catalogue offers a user-friendly update on our technology. You will find a comprehensive overview on our portfolio including information on recently launched products such as our Bioprocess Software Suite DASware and the Minibioreactor System DASbox.
More info >> |
|
|
