Unearthing Changes at the Office of Generic Drugs and

1 This presentation does not necessarily represent the opinion of the presenter nor “Teva Pharmaceuticals”.

Unearthing Changes at the Office of Generic Drugs and Understanding their Impact on the Future Growth and Evolution of the Generic Drug Industry

Gary Buehler, R.Ph. Vice President, Global Regulatory Intelligence & Policy

July 24, 2014

American Conference Institute

Legal & Regulatory Summit on Generic Drugs


Outline

OGD’s status as a Super Office

Impact and Significance of personnel reorganizations

Growing Pains

Communication

Budget


CDER Organizational Chart


OPS Organizational Chart


FDA Office of Generic Drugs – Pre GDUFA


FDA Office of Generic Drugs – Post GDUFA


Where are the Chemists?

The Chemists and their attendant PMs make up almost 50% of the personnel of the current OGD.

With the proposed creation of the Office of Pharmaceutical Quality (OPQ), however, the OGD Chemists will be located with the new drug chemists and no longer under the control of OGD.

This will facilitate FDA speaking with “One Quality Voice” and improve consistency of review across the groups.

It will also allow better knowledge sharing between the NDA and ANDA reviewers so there is a better understanding of the inherent risks of some products.

Carrying the risk-based theme forward, the new organization will also provide a framework for using a team-based approach for the more complex applications, utilizing the expertise of different reviewers.


Significance of Being a “Super Office”

Direct Access to Center Director (regular 1:1s)

OGD Director is a member of Center’s Senior Leadership Team (SLT)

One less budget layer

Equal standing with OND and other Super Offices

Allows for greater flexibility for expansion


Office of Research Standards, Rob Lionberger, Ph.D. Division of Therapeutic Performance

Conducts regulatory science research to make generic versions of complex products available to the American public.

Establishes equivalence standards for generic drugs that will ensure therapeutic equivalence.

Evaluates post-approval safety, product use or bioequivalence issues with approved generic drugs.

Translates the results of regulatory science research into guidance and standards for ANDA review.


Office of Research Standards, Rob Lionberger, Ph.D. Division of Quantitative Methods and Modeling (DQMM)

Provides expertise in advanced quantitative methods for the generic drug program and supports GDUFA regulatory science activities, guidance development, and ANDA review.

Coordinates modeling, simulation and data-mining for OGD activities and establishes the scientific computing infrastructure for OGD.

Provide modeling and simulation expertise to all of OGD.

Uses a range of tools to address therapeutic equivalence questions, post-market product concerns and bioequivalence method development.


Impact – Office of Research Standards

Faster and expanded availability of BE recommendations for complex products (recent posting for inhalers)

Meetings to discuss development of ANDAs for complex products

More innovative BE recommendations based on emerging science (cyclosporine ophthalmic)


Office of Bioequivalence, John Peters, M.D.

Division of Bioequivalence I, II, III Adding a third Division to address GDUFA workload.

Increased scrutiny up front on applications to ensure that applications are as complete as possible before they are filed.

Emphasis on information justifying deviation from guidances or modification of accepted parameters.

Continue to provide bioequivalence recommendations for posting on the Individual Product Bioequivalence Recommendations Guidance.



Division of Clinical Review Considerable expansion of the Division of Clinical Review (DCR).

Insistence on seeing CRFs for clinical endpoint studies because the lack of this information causes a significant review delay (not popular with industry but necessary to meet GDUFA guidelines).

DCR to become more independent with respect to safety decisions and toxicology decisions.

Toxicologist to be hired.

Many decisions that were consulted to OND are now made in OGD and sent to OND for concurrence.



Division of Clinical Review OGD Safety and Surveillance Team

o Coordinating point for REMS and Safety Labeling.

o Enhanced Postmarketing Surveillance of generic products.

o OGD Safety Team will work as a complement to the OSE efforts, similar to what OND does.

o Analyze all reports of potential safety issues from:

• Manufacturing

• Formulation

• Excipients

• Size/other physical characteristics

• Adverse events

• Lack of effect

• Perceived inequivalence

• Quality concerns



Division of Clinical Review OGD Safety and Surveillance Team (continued)

o Protection of human subjects – since most BE studies may be initiated without input from OGD (no IND needed), OGD tries to publish very detailed guidances to assure both appropriate study design and safety considerations.


Impact – Office of Bioequivalence

Greater scrutiny of BE sections of ANDAs at filing

Continued emphasis on posting additional products on the Individual Product BE Guidance

Less delay from clinical and toxicology consults

More efficient review of clinical endpoint studies

More direct involvement of OGD in safety surveillance


Office of Generic Drug Policy, Keith Flanagan, Esq.

Division of Legal and Regulatory Support Dedicated legal staff to work on H-W issues

Will work together with OCC and ORP

Staff will increase significantly

Division of Policy Development Will become a Guidance machine

Planned guidances on a variety of topics include:

o Amendment tiers

o PAS

o Controlled correspondence

o Quality submissions

o RTR decisions

o Priority decisions

o IID


Impact – Office of Generic Drug Policy

More Guidances

Development of more formalized procedures on how applications are prioritized in OGD

Hatch-Waxman policies to be formulated in OGD


Office of Regulatory Operations, Jason Woo, M.D.

Division of Project Management – Aaron Sigler, R.Ph. Staff will increase significantly following PDUFA model

Many new hires

Division of Labeling Review – Carol Holquist, R.Ph. Staff will increase to accommodate GDUFA metric demand

Division of Filing Review – Iain Margand, R.Ph. RTR Guidance to be finalized

Increased scrutiny on filing to limit the number of low-quality submissions

Division of Quality Management Systems - TBD


Impact – Office of Regulatory Operations

Move involvement of PMs (similar to their involvement in OND)

More scrutiny of applications at the filing stage

Increased filing requirements (new RTR Guidance)


OGD Growing Pains

As a result of the GDUFA infusion of resources, the OGD will double in size (from 300 to somewhere over 600).

This will require the formation of additional review teams with the attendant promotion of seasoned, productive reviewers to supervisory positions.

It will also require the hiring of over 300 new reviewers and other staff.

During this time, the rate of incoming applications will probably be increasing.


OGD Growing Pains

In addition, many new areas have been created in OGD, providing opportunities for current employees and new hires.

As the current employees transfer to these new opportunities, they leave a void in their current area.

The new hires will also have to be trained, and as more experienced reviewers and project managers move into higher positions, there are fewer mentors to train the new hires.


OGD Leadership Challenges

Directors

Backlog of Applications The backlog of original applications is probably around 3,000 now

with the backlog of prior approval supplements approaching that number.

For Fiscal Year 2013 (Oct 1, 2012 through Sep 30, 2013), OGD received 968 original applications and approved 440 ANDAs.

Gary Buehler 2000 – 2010

Keith Webber (Acting) 2010 – 2012

Greg Geba 2012 – 2013

Kathleen Uhl (Acting) 2013 – Present


OGD Leadership Challenges

Why can’t FDA hire a director?

Even with user fees, OGD will still be under-resourced

OGD is a beacon for confrontation Lawsuits

Internal disagreements with OND

External criticism from brand industry, patient advocate organizations, and the press

Day to day stresses of running a large organization in the government

Lastly, the pay ($124,995-$157,100 listed on the recent announcement)


Challenges - GDUFA

When PDUFA I was initiated in 1992, there were escalating metrics over the 5 year period for priority applications (6 months) and standard applications (12 months).

GDUFA I, on the other hand, has metrics for: Original ANDAs

Prior Approval Supplements

Amendments

Controlled correspondence

Backlogged applications

Inspections

In addition, the existing backlog of OGD was much greater than the existing backlog of OND when user fees were initiated.


Challenges - GDUFA

OGD is quickly formulating a plan to deal with the rapidly approaching metrics in October 2014.

They are “practicing” meeting metrics now to get used to working to a deadline.

They realize that they have metrics to meet on all “backlog” applications and all applications submitted after October 2014, but they also realize that the applications submitted in user fee years 1 and 2 also need to be reviewed.

They are trying very hard to have policies and procedures in place with accompanying guidance so that the industry understands what the expectations of the Office are.


Challenges - GDUFA

Remember – this is the government – change does not come easily.

Numerous layers of supervision have to be vetted and addressed to implement guidances, policy changes, and reorganizations. This is why you see so many individuals in “Acting” positions.

OGD’s doubling in size is needed and long overdue, but with it comes tremendous challenges with respect to office organizational structure.

I don’t believe that the industry understands what a high hill this is.


Challenges - GDUFA

OGD is meeting quarterly with GPhA to hear the concerns of the industry.

They want to be responsive to these concerns.

Overall, the industry needs to work with the Office and understand that many of their desires may have to wait.

OGD thinks a FedEx-type tracking system for pending applications is a great idea – they just do not have the IT systems in place to do it at this time.


Communication

Very important to the generic industry. We really need some idea of how our applications are progressing through the review process to be able to effectively prepare for product launch.

The OGD MAPP 5200.3, “Responding to Industry Inquiries with Respect to ANDAs in OGD”, was not well received by the industry.

It was characterized by Bob Pollock in his blog as “The MAPP to Nowhere”.

Why did this MAPP cause such a stir in the generic industry?


Communication

Past Years

The present OGD administration has characterized the communication that used to occur in OGD as somewhat chaotic and disruptive. To a point, I agree.

They stated that the generic industry would call various individuals in the office seeking information on their pending applications. They would often get varying responses.

Some of these responses implicated other areas within or outside OGD that were “holding up” the review.

This caused a certain level of friction when the industry would call these areas.

I believe this behavior was more the exception rather than the rule – but I certainly acknowledge that it did occur.


Communication

MAPP 5200.3

To address the communication issues, OGD issued MAPP 5200.3.

The MAPP stated there would be only one point of contact for industry and one point of contact for FDA (the RPM – although they could name an alternate if they were not in the office).

The MAPP lists eleven bullet points the RPMs need to follow in communicating with industry – the last two having to do with what is to be done when the industry person gets “disruptive or rude”.


Communication

MAPP 5200.3 (continued)

In essence, the responses received were not useful.

I have been told that consideration is being given to revising this MAPP.

Industry can certainly accept one point of contact – they would just like to get some useful information from that person.


Budget

The Federal budgeting systems is interesting to say the least.

FDA has two sources of funding – Budget Allocation (BA) and User Fees (UF).

BA, until 2012, was the sole funding for OGD.

The budget for Federal agencies has to be proposed by the President and passed by Congress each year.

The Federal fiscal year begins on October 1, but the budget for that year is almost never passed by that date.

In the interim, Federal agencies have to operate under a continuing resolution using the previous year’s spending patterns or less if a cut in the budget is anticipated (10, 20, 30% less).


Budget

When the budget is passed by Congress (usually the spring of the following year), the budget bumps down from HHS to the Commissioner to Center Director to Super Office Director, etc.

This takes more time at each step – we are probably in late April or mid-May by now.

When everyone has taken their cut, the review divisions at FDA get their budgets – around the end of May.

At the end of June/beginning of July, the review areas are told they must use their money by the end of July because the budget close-out is beginning.


Budget

All BA money must be used by the end of September or it goes back to the Treasury.

User Fee (UF) money, however, can be used from one year to the next (FDA does not have to give the unused portion back to industry).

The availability of UF money will make it possible for OGD to initiate and complete long-term regulatory research because the money can be used from one year to the next.


Conclusion

Multiple changes will occur in OGD over the next few years.

Initially, reviews and approvals may slow down until new employees are hired and trained and everyone becomes accustomed to the revised processes.

OGD is working with the generic industry through regular meetings with GPhA to identify problem areas.

They want to provide a review system that is fair and efficient.

The next few years could be trying for both the industry and FDA but, in the end, I believe everyone will be pleased with the final result.

Documents

Unearthing Changes at the Office of Generic Drugs and