ASHTON TWEED
How to Prevent
Further Delays in
the FDA Approval
Process
Are you wondering if the pharmaceutical industry will experience
any fallout from the recent issues confronting the Food and Drug
Administration (FDA)? It is reasonable to expect that with all the
product safety issues, hearings, and unfavorable opinions from
both the public and legislators the Agency will undoubtedly guide
our products down a more cautious drug development path.
Your company may be viewing FDA’s reaction with a sense
of trepidation and concern. However, consider that the FDA is
responding in much the same manner most companies would
under similar circumstances. For example, what do companies
do when they have had a less than stellar FDA inspection?
Or if they have had to recall a product due to safety concerns
and, adding further complications, an employee has suggested
the company knew of this potential safety concern but did not
react in a timely manner? The company’s Regulatory, Quality,
Manufacturing and Clinical Safety departments audit, investigate,
devise and implement solutions and, at the same time, the
company carefully orchestrates the critical increased interactions
with the FDA, public and investors. Quality now reigns and
more control is definitely better!
2
How to Prevent Further Delays in the FDA Approval Process
In response to this atmosphere of
heightened scrutiny, most companies are
now covering themselves in a blanket of
cautious conservatism which is expanding the time it takes to conduct business. To help companies address these
evolving timing issues, this paper lays
out prescriptive steps you can take to
minimize delays in your products’ FDA
approval process.
If your company hasn’t already
noticed, be assured it will take more
time for FDA activities than you have
allotted for in your drug development
project planning. Is there anything
your company can do to minimize
the amount of additional time? The
answer is yes, and the first step is to be
proactive and take the necessary actions
to prevent any additional back-and-forth
activities of any kind with the FDA
(FDA questions, requests for additional
information, etc.) Taking a proactive
approach should already be standard
practice at your company, and it won’t
cost you much time to make sure it is.
To determine which proactive
activities your company can undertake,
have your project team(s) evaluate your
respective drug development project
plans to assess where back-and-forth
FDA interactions could and most likely
will occur. Typically, Regulatory Affairs is involved with creating drug development plans just prior to the transfer
of the project from Research over to
Drug Development, and it is their responsibility to identify and handle these
interactions. Where your product is in
the development process will denote the
focus of the assessment.
Before we get into more in-depth
suggestions, bear in mind a few key
reminders about the current FDA
environment:
• It will take FDA longer than you
think or have been told it will (for
example by an overly optimistic
marketing executive, the Head of
Clinical Research, etc.).
• The FDA can change its mind at any
time on just about anything.
• Just because FDA has not asked
for something before doesn’t mean
they will not ask for it now or in the
near future.
Keys to Avoiding
Delays in the FDA
Approval Process
The following are suggested considerations for your project team. By addressing these considerations you should be
able to pre-empt time consuming back and
forth activity with the FDA. The considerations are arranged to follow the standard
drug development process with subsections for critical regulatory milestones.
Drugs in the
Investigational Phase
Pre-Investigational New Drug
Application (IND)
If you have yet to request your Pre-IND
meeting, take some extra time to consider
what questions you want FDA to answer
to include with your meeting request.
Remember, once this meeting is over you
are pretty much on your own until you file
the IND. There are several issues which
could delay the approval of your IND:
concerns that the starting dose is too high,
insufficient monitoring for safety and/or
the Phase 1 protocol has so many issues
and is so poorly designed that you are
placed on Clinical Hold. Pay very close
attention to what FDA tells you at the
meeting and not just what is captured in
the official meeting minutes.
www.ashtontweed.com
Products Entering or in
Phase II Studies
For products which are about to start
or are already in Phase II studies,
review the clinical development plans
to be sure these studies will produce
sufficient safety data to address populations of potential concern or make
sure the justifications for not generating the data will hold true now and in
the future. Additionally, if you have
received Fast Track Designation for
your drug, it would be wise to verify
that the clinical development plan is
still acceptable with the FDA.
End-Of-Phase II Meeting
Another milestone to revisit is the
End-of-Phase II meeting. Review
your materials to ensure that the
safety and efficacy data you’ve
planned to include in your meeting
package is sufficient or evaluate
if you should include more. Write
your description of the Phase III
study(s) to be detailed enough that
FDA will be able to provide critical
input. Check to see that the timing
from when the Phase II studies
are completed, the time allotted to
compile the specific amount of data
you have planned to present in the
meeting package to FDA, and the
date the meeting package must be
sent to FDA still works.
www.ashtontweed.com
Phase III Studies
Special Protocol Assessment for
Phase III Protocols
Special Protocol Assessment for Phase III
protocols has been in many cases a very
useful tool for industry. Even though some
may argue that this process takes longer
than we would all like, there is some confidence in knowing that once the study(s) is
completed with positive results there is high
probability FDA will approve it. Now, with
the increased safety concerns, it is reasonable to expect that FDA will still continue
to make every attempt to stick to the 45 day
process but will likely want more complete
and detailed information in the review
package. Pharmaceutical companies all do
this as general practice but taking time to
see if the package will pass the extra scrutiny before submitting to FDA is priceless.
If your company is preparing a Phase
III clinical protocol(s) for special assessment make certain that you have addressed
all FDA’s concerns which should have been
provided at the End-of-Phase II meeting.
• Has your statistical group provided
sufficient information in the package
which defines the planned Statistical
Analytical Plan (SAP)?
• Does the information describing the
Safety Monitoring Committee for the
study provide sufficient details to allow
FDA to feel comfortable?
How to Prevent Further Delays in the FDA Approval Process
It is critical that you address FDA’s
inputs and concerns in this filing
and not plan on taking care of them
later. If FDA comes back noting
you didn’t address something or
they have questions this will add a
great amount of clinical development time to the overall plan.
New Drug Application
will or has been Filed
3
505(B)(2) Applications
If your company is considering or has
already filed a 505(b)(2) application
you should not experience any delays
except the usual ones caused by patent
and exclusivity rights, unless the FDA
is expressing safety concerns regarding
the approved drug. Close monitoring of
the approved drug, including monitoring
FDA’s MedWatch site, must be an ongoing activity.
Recently Filed NDAs
Post Approval Phase
New Drug Applications currently
under review will continue to
move through the review process
as prescribed; however, it is
very likely they will be subject
to increased scrutiny, especially
those that are under expedited
review. This in turn may result
in an increase in the number of
FDA questions and requests for
additional information which
increases the review time.
Project teams should be
asking some rather specific
and tough questions of their
existing development plans to
be certain they are still accurate.
Company management must
insist on concrete justification for
revised assumptions.
Phase IV Commitment Study as
a Condition For Drug Approval
Companies that have an ongoing
Phase IV Study Commitment as part
of their product approval have already
experienced the increase in FDA
oversight, and they will feel increasing
pressure unless a study is on schedule.
FDA is just sharing with us the pressure
they are feeling from lawmakers who are
not happy with the progress of the study
commitments, and it is hard for FDA to
argue this point based upon the small
number of studies completed to date.
Take a look at the FDA Postmarketing
(Phase IV) Study Commitment website
and you will get a clear sense of why
FDA is so concerned.
4
How to Prevent Further Delays in the FDA Approval Process
If your company’s study is behind
schedule, upper management should
be very concerned and must get
involved. FDA wants to know how
you will solve enrollment problems,
why you think the changes to increase
enrollment will solve the problem(s)
and why the changes will enable the
study to be completed without additional delays. It is critical that FDA
knows upper management is aware
and involved in taking the necessary
steps towards completing the study.
It cannot be understated how critical
ongoing communications with FDA
are if you are in this situation.
If your company is in the process
of preparing or finalizing a Postmarketing Study Commitment protocol
with FDA, anticipate that it may take
a little longer to obtain the OK from
FDA. The real focus of this process
will be negotiating the date for study
completion.
Marketing Studies with
Approved Products
It would not be an unusual situation
for a company to have ongoing studies on their approved products that
are designed and sponsored by the
Marketing department. Updates on
these are to be included in your NDA
Annual Reports as well as the final
results. Has you company considered
reviewing both ongoing and planned
Marketing Department studies to see
where they may lead?
Ongoing Marketing studies may
be a quick way to address a safety
concern you may have for one of your
products. If this is the case, have the
protocol(s) reviewed and evaluated by
your clinical and statistical groups to
determine how it could be amended
so it can capture the data you need to
resolve the concern.
Once a product has moved
through the regulatory approval
process, there are still important communication milestones with the FDA.
These and other milestones are the
focus of our final section.
www.ashtontweed.com
www.ashtontweed.com
Maintenance Activities
Annual Reports
Standard regulatory product license
maintenance activities should move
along as they have with only two
possible exceptions. FDA has typically been very accommodating in the
past in allowing companies additional
time to file IND and/or NDA annual
reports. However, if your company
is going to be a little late to file your
next annual report it is in your best
interest to communicate this to FDA
as soon as possible to keep them informed and comfortable. A phone call
a day or two before your due date or
after the fact is unlikely to be received
well.
The other area to give some
extra attention to is the clinical and
safety information required for annual
reports. It may be useful to review the
How to Prevent Further Delays in the FDA Approval Process
regulatory requirements and compare them to your previous reports
and internal procedure(s). Also, pay
more attention to the published and
unpublished clinical trial data to be
provided. Though you may not have
had any questions and/or requests for
additional information from FDA on
previous annual reports, not providing
sufficient clinical and safety information now will probably result in an
FDA request for more. Though these
are not in and of themselves major
issues they simply result in taking
your valuable resources off of the top
priority projects.
Safety Reporting
To ensure your continuing streamlined
relationship with FDA, take a few
minutes and have those responsible
for investigational and marketed
5
product safety reporting review your procedures. Pay close attention to how your
company evaluates and makes reportable/
not reportable determinations. Be aware
that you may see an increase in requests for
additional information on safety reports.
Conclusion
It may seem an overwhelming task to keep
up with FDA’s changing regulations and
requests, but there are some very specific
steps you can take to plan for the amount of
time you’ll need to complete the FDA approval process. The best way to keep your
approval process on track is to ensure you
provide complete information at all your
FDA meetings to cut down on the back and
forth interaction with the FDA. With careful
planning and due diligence, your company’s
approval process can avoid stretching on.
6
How to Prevent Further Delays in the FDA Approval Process
Next Steps
We hope that this paper has given you
some points to consider as you plan
for your products’ FDA approval. We
would love to chat with you as you
develop your regulatory strategy. The
paper’s author, Louise Peltier, is available for telephone consultation. Please
call us at 610-725-0290 x 446 or
e-mail [email protected]
with any questions or to schedule time
to speak with Louise.
About the Ashton Tweed
Life Sciences White
Paper Series
How to Prevent Further Delays in the
FDA Approval Process is the second
in a series of white papers on current life sciences topics authored by
members of Ashton Tweed’s Executive Talent Bank. Professionals in the
Tips for Minimizing FDA
Approval Delays
• Objectively review and adjust your
existing drug development project plans
to identify possible FDA slowdowns.
• FDA meeting packages must be carefully prepared, critically reviewed and
submitted on time.
• Clinical protocols submitted for Special
Protocol Assessment (SPA) must address FDA’s concerns in the SPA filing.
• Phase IV Study Commitments must
become a priority.
• Annual Reports must provide all required safety information and be filed
on time.
www.ashtontweed.com
Ashton Tweed Executive Talent Bank
are highly experienced, entrepreneurial senior and executive level talent
(Director level through C suite) with
the skills required to fill roles from
discovery through commercialization.
Executive Talent Bank members serve
as interim executives who are immediately available to address clients’
urgent business needs within a clearly
defined time frame. By working with
interim executives, companies get the
best sensibly over-qualified candidates
in their area of need and someone with
a fresh perspective on the organization with precisely the skills needed
for a project or corporate transition.
To learn more about how our interim
executives could assist your company,
please visit www.ashtontweed.com or
call 610-725-0290 x 446.
The first paper in our series,
Roadmap to Reimbursement: A Howto-Guide on Securing Reimbursement,
is also available on our website at
www.ashtontweed.com.
www.ashtontweed.com
How to Prevent Further Delays in the FDA Approval Process
About the Author
Louise Peltier
Louise Peltier is a regulatory
affairs consultant with over 30
years of hands-on/multi-discipline
experience with pharmaceuticals,
biologics and in-vitro diagnostics.
She has held management positions in the areas of regulatory
affairs, quality assurance, and
manufacturing. Louise has extensive experience with developing
and implementing US and EU
regulatory registration strategies
from lead compound/assay selection to post-approval for products
in the areas of oncology, anesthetics, central nervous system,
reproductive, diagnostic imaging
agents and infectious disease.
CONTACT US
620 Lee Road Suite 130
Wayne, PA 19087
phone 610 725 0290
fax 610 725 0291
email [email protected]
website www.ashtontweed.com
The Executive Talent Bank Company
7