10 BioPharm International eBook March 2018 www.biopharminternational.com
Outsourcing Resources Complete Response Letters
The CRO is really only account-
able to the terms and conditions
spelled out in your contract with
them. So if you don't understand
the ins and outs of all that, you're
just setting yourself up for further
disappointment and risk, if and
when things go wrong.
The real challenge is, once you're
in this predicament, what can you
do? Assuming you cannot start
over, what can be done to limit
your risk and liability from today
forward? That is all about doing
increased oversight, increased test-
ing on your end, etc.
So, as a simple example, instead
of simply reviewing the clinical
research associate's trip reports, start
doing more cooperative monitor-
ing visits. Instead of waiting for
the CMO to tell you about prob-
lems—or discovering them after the
fact—put a temporary point person,
a 'person-in-the-plant' to get you
through the remaining batches to
limit problems and issues.
H i r e a t h i rd pa r t y to do a
detailed assessment of the CMO—
and give you a list of 'here's what
you as the contract owner/sponsor
should do' recommendations. You
already know that you have prob-
lems with the supplier.
You want a third party to give
you insight and advice into what
you should do—not what the sup-
plier needs to fix, because the sup-
plier may simply ignore it, and
leave you holding the bag.
IMPACT ON PROJECT
COSTS AND TIMELINES
B i o Ph a r m : W hat i mpac t i s t he
increase in CRLs having on drug
development costs and timeframes,
and on the industry in general?
Ave llanet (Cerullean Associates):
I'm not sure that anyone has a
firm grasp on this, because it really
depends on the variables involved
in the specific case.
What I see and hear around the
United States and in Europe is that
people are getting soured on using
just one CRO to run their trials. My
larger clients, for example, are shift-
ing to a model in which they use
multiple CROs on short-term con-
tracts—almost a probationary type
of contract for a small trial or arm
of a trial—to limit their exposure
and to be able to better evaluate
which CRO works well with them.
Obviously, this is not really an
option for smaller firms. In those
cases, I'm pushing them to write
short-term contracts with financial
penalties for compliance failures.
It takes some thinking through
and back-and-forth, so there are
no cookie-cutter templates avail-
able, but everyone ends up hap-
pier because money is now tied
directly to compliance and good
quality data. In the short-term, the
increase in CRLs is going to drive
up the cost of drug development as
people adjust to the requirements.
That said, the first firms out of the
gates who 'get it'—which can look
at the example CRLs that FDA is
going to release and incorporate
lessons learned—is going to see its
approval rates skyrocket.
It 's goi ng to b e i nte r e st i ng
to watch over the next three to
five years, and I'm pretty sure the
financial analysts for the large
investors are pay ing ver y close
attention to which f ir ms seem
to 'get it' and which spend their
money and time spinning wheels,
r e p e at i n g p a s t m i s t a ke s , a nd
struggling. Startup firms seeking
financing must be able to clearly
answer how they will avoid the
mistakes that caused CRLs in simi-
lar startup firms.
Smith (The FDA Group): I've cer-
tainly seen an increase in the
industry's attention to FDA inspec-
tional findings and how they may
apply the results to their own oper-
ations. But it's a bit easier to stay
abreast of 483 issues than it is to
track deficiencies in CRLs, which
are much less in the public domain.
No doubt that as firms learn
what FDA expects, they're doing a
better job of meeting those expec-
tations up-front. The significant
increase in FDA g uidance that
we've seen in recent months is
very helpful. And I see more firms
finally understanding the fact that
FDA reviewers want more informa-
tion in applications—not to cause
pain, but to better understand how
the process, the API, the formula-
tion, [and] the finished product
came together.
It's not just about the finished
product; it's about months and
years of research, culminating in
the final application. This change
had required investing more time
and money up front, but I believe
that this approach is bringing bet-
ter quality products to market and
assisting FDA in the application
review process as well.
REFERENCES
1. A. Feuerstein, "An Open Letter to Dr. Scott
Gottlieb o FDA Transparency," STATnews.
com, January 27, 2018, https://www.
statnews.com/2018/01/17/open-letter-
gottlieb-fda/
2. M. Nisen, "The FDA Should Shine More
Light on Drug Rejections," Bloomberg.
com, January 18, 2018, www.bloomberg.
com/news/articles/2018-01-18/fda-crl-
letters-more-transparency-is-better
3. P. Lurie et al., "Comparison of Content
of FDA Letters for Not Approving
Applications for New Drugs and
Associated Public Announcements From
Sponsors' Cross-Sectional Study," BMJ
2015:350 h 2750 (2015), www.bmj.
com/content/350/bmj.h2758?utm_
source=STAT+Newsletters&utm_
campaign=39de12a8bb-
Readout&utm_medium=email&utm_
term=0_8cab1d7961-
39de12a8bb-149677969
4. A. Shanley, "Moving Toward Direct-
to-Patient Models," pharmtech.com,
November 1, 2017, www.pharmtech.
com/moving-toward-direct-patient-
models
BP
