Not having been involved with regulatory filing aspects of
pharmaceuticals, reviewing Generic Drug User Fee Act Reauthorization (GDUFA II)
(1) was educational. After review my process simplification
instincts kicked in. If the current approval time line can be reduced from TEN months to THREE months, impact of the process will be lower drug costs.
Reading joint testimony of Drs. Woodcock, Marks and Shuren (2)
and having had time to review the application process, reinforced my thinking
that a time reduction is possible but to get there industry along with USFDA
would have to practice what chemical engineers and chemists are taught and
asked to practice for every manufacturing process they develop, design and
commercialize i.e. produce quality first time and all the time. In terms of
FDA’s vocabulary the filling and review processes would have to follow QbD
(Quality by Design) practices. FDA will have to follow what it has been asking
the industry to practice. Industry will also have to follow suit. I believe industry
will also get hands on practice about QbD and it will trickle through the whole
organization, a win-win.
Many associated and proficient with regulatory filings would
categorically say that filings are not a manufacturing process and such a time
reduction is impossible and cannot be done. Currently filing an application is
a task that is repeated by many to create quality application. It will generate
higher profits for the filer if they can reduce its approval time. It can be
continuously improved and deserves our attention. We improve every repetitive
task to facilitate our daily lives. So why not improve the FDA ANDA (abbreviated new drug application) application
filing and approval process? Improvements here could have far reaching impact
for other filings also.
I firmly believe that such a time reduction is possible but
many things will have to change to get there. Our thinking and work philosophy
has to change. In the current application process following challenges (1)
have been identified. Each challenge is reviewed.
- Submission completeness: It takes about four review cycles to
approve ANDA.
- Volume of applications
- Other factors. Several factors delay timely consumer access.
a) Risk Evaluation and Mitigation Strategies are used by Brand companies to
delay generic entry
b) Delaying or denying generic companies’ access to reference listed drug
products, thereby preventing companies from conducting studies
required for approval
c) Misuse of FDA’s citizen petition process as a means to block generic
approvals.
d) FDA generally cannot approve generics until patent and exclusivity on the
innovator product expire. Patent litigation and other legal challenges
can frustrate timely approval.
Submission Completeness:
In March 2, 2017 testimony Pre-ANDA program is suggested. I
believe that is the most brilliant idea for filing application and reducing
time. It is a step QbD implementation of the application filing process.
“About four reviews” needed for FDA application is equal to
FDA using four iterations to have a quality application. Current method to get
to an acceptable product (application) is a QbA (Quality by Analysis) practice.
I equate QbA to “Quality by Aggravation”.
FDA also has to practice what it is suggesting companies to
follow. Quoting FDA “This guidance (3) describes the concept that
quality cannot be tested into products; (ANDA application, to me is a product
of FDA’s work), in other words, it should be built-in or should be present by
design.”
Yes like manufacturing processes, applications for every
product are going to be different when it comes to content but the information filing
requirements are essentially going to be same. I believe a template application
that covers better than 90% of the filing requirements can be designed. A
standard application format could pare down four reviews to a single review and
completeness. This would be a monumental accomplishment. If accomplished, we
will automatically see the approval time reduction.
Currently it can take up to 45 days for the FDA reviewing
team to determine completeness of the application. FDA would have to figure out
how this time can be reduced to 15 days. Current review practices would have to
be modified. Long delays suggest that the filing team does not understand FDA’s
QbD expectations or FDA has not relayed them to applicants.
FDA has to create applications that clearly state what it
expects from the companies. A standard template has to be created. It's
possible that the current templates do not relay FDA expectations. A redesign
may be necessary. Once these applications are designed, companies and FDA staff
can be trained to follow the process. Workshops could be held on a regular basis
to train industry to what is needed.
I know such processes work. We had similar processes at
Illinois EPA in 1972 for various industry segments. We had timelines from
submission to approval of equipment design and operating permits. Based on our
questions, every industry submitted relevant information that facilitated
review and approval. FDA may have to benchmark to see which government agency
has the best application review and approval process. Elements can be
incorporated.
Another important aspect of the filing process would be to
involve the engineers and chemists who have created and commercialized the
process so the filled application is complete and represents a quality (QbD)
filing. It means that the companies have to do their homework. They know their
processes the best.
Every effort has to be made to pare ten months to 90 days.
It is a doable challenge.
Volume of Applications:
FDA can go with best basis planning scenario and deal with
ups and downs of the numbers. Ability to deal with such changes will be its operational
finesse strategy. Many businesses deal with such scenarios. Most likely I have oversimplified
the situation.
Other Factors:
* Risk Evaluation and Mitigation Strategies are used by Brand
companies to delay generic entry.
FDA has to develop a program or strategy to prevent such harassment. Roadblock
could be set but there has to be a resolution that is acceptable to each side. Generics
have to be on top of their game to counter such delay tactics. Legislatorial changes
might have to be incorporated. In our political system that could be a
challenge.
*
Delaying or denying generic companies’ access to reference listed
drug products, thereby preventing the companies from conducting studies
required for approval.
Congressional intervention might be needed. USP or others who have information
should be able to share the information. Congress can create a scenario to
assure necessary samples are available for the generics. This would be good for
their constituents. I believe FDA can intervene also.
*
Misuse of FDA’s citizen petition process as a means to block
generic approvals.
If the brand companies are abusing citizen’s petition process, there has to be
a counter strategy from the generics. I have not looked at this in detail but I
am sure that there are ways and means to counter this challenge.
* FDA generally cannot approve generics until patent and exclusivity
on the innovator product expire. Patent litigation and other legal
challenges can frustrate timely approval.
Generic filers have to develop their strategies. I believe if the approval time
is lowered from ten months to 90 days, companies could develop workable measures.
Filing company has to have a complete grasp of the situation and strategies.
If the approval process is lowered from ten months to 90
days, need for priority review most likely could disappear.
Breakdown of 90 Day Time:
I would break the 90 days in three segments. Initial review
has to be completed by FDA in 15 days from acceptance of the initial application.
FDA has to provide the company deficiencies of the application. Incomplete application
could be rejected. Companies will have 30 days to respond FDA’s requirements.
FDA would have 45 days after corrections, more than sufficient time, to review
and interact with the company and act on the application.
If for some reasons the company is not able to fulfill its
obligation after the initial 15 day FDA review and complete its deficiencies 30
days, they could stand to loose its application and would have to start over
again. With such a possibility, it would be in the best interest of all parties
to have quality application from the get go. It will be a QbD win for all.
It is very possible that facility inspections could be an
encumbrance in the approval process. However, having command of the designed
process would be reflected in the application. If it were not that would mean
that the designed and operating process is different from the filled
information. It would be tantamount to falsification of information and it
should be used to ban the company from shipping products to the US market.
What I am suggesting might be a challenge but until we take
on challenges progress is never made. By posting this blog I am not questioning
authority of FDA or any other government body but just presenting an alternate
perspective that would bring generics to the market quicker and lower
healthcare costs. I might also be incorrect in my conjectures and expectations
but it would be worth if we can make an improvement and lower drug costs.
Girish Malhotra, PE
President
EPCOT International
- Generic Drug User Fee Act Reauthorization (GDUFA
II)
Accessed March 16, 2017
- Testimony of Drs. Woodcock, Marks and Shuren
Accessed March 23, 2017
- Advancement
of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing
Base Guidance for Industry Accessed March 24, 2017
