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  5. Panel V - Presentations by Industry Groups, Prescription Drug User Fee Act Public Meeting November 14, 2005
  1. Prescription Drug User Fee Amendments

Panel V - Presentations by Industry Groups, Prescription Drug User Fee Act Public Meeting November 14, 2005

Panel IV - Presentations by Consumer Groups

MS. HENDERSON: We'll move on to our next panel, which are the industry groups, and I will ask them to come forward: Alison Lawton, Bruce Burlington, and Mary Gustafson. And here they come.

And as they get settled, in the interest of time, I'll start with Alison Lawton'sintroduction.

Alison is senior vice president of Global Regulatory Affairs and Corporate Quality Systems, and a corporate officer, for Genzyme Corporation, where she is responsible for all Genzyme products. Genzyme's diverse product portfolio means that she is currently responsible, globally, for biotechnology products including recombinant proteins, monoclonal antibodies, gene therapy, cell therapies, as well as pharmaceuticals, IVDs, combination products, and a range of device products.

Please join me in welcoming Alison Lawton.

MS. LAWTON: Thank you. Can I just make sure everybody can here me at the back. Yes?

So, on behalf of the biotechnology industry organization I want to say thank you for this opportunity to comment on the effectiveness of PDUFA program, and to support its continuation.

BIO membership includes many small start-up companies in early stages of product development which have not yet applied for FDA approval; biotechnology companies whose exclusive focus is on the development of biological products; and large well-established pharmaceutical companies that simultaneously pursue the research and development of small-molecule conventional drug products and complex biological products.

BIO member companies are committed to developing innovative therapies focused on unmet medical need. And member companies, regardless of their size or situation, all recognize the crucial importance of three general PDUFA goals: expediting the review and approval of new therapies; reducing the length of time it takes to bring an innovative concept through the development process to completion as an approved, safe and effective therapy; and making FDA processes and outcomes transparent and predictable to industry and to the public.

BIO believes that the overarching aim of the PDUFA program should continue to be measurable improvement in access for patients to new life-saving and life-altering medicines.

In large measure, the goals of PDUFA are being achieved. The statistics are clear: post-PDUFA, U.S. patients are the first in the world to have access to new products, as a percentage of total drug launches by country. And you saw some of that data this morning.

Prescription drug user fees, added to a sound base of appropriations for FDA, have provided the additional resources needed by the agency to reduce the backlog of applications that led to the so-called drug lag in existence before the enactment of PDUFA. PDUFA fees are intended to provide FDA with the ability to increase its review capacity, including medical and scientific expertise so the agency can become more efficient without reducing its commitment to the highest standards of review.

The intention of Congress in enacting PDUFA initially, and in renewing it twice, was, and we believe remains, that this program significantly contributes to and supports the safety and efficacy of prescription drug and biological products. PDUFA does this by providing FDA the resources it needs to continue to make sound, scientific, medical and regulatory decisions.

The PDUFA program both supports new medical innovation and is, itself, an innovation. Since its inception, PDUFA has helped to speed more than 220 new cutting-edge drugs and biologics sponsored by BIO member companies. And these products have made a difference to patient lives. Indeed, the PDUFA program is considered highly innovative in itself, and in 1997 received the prestigious "Innovations in American Government Award" sponsored by the Ford Foundation and Harvard University's John F. Kennedy School of Government.

PDUFA has earned this high praised as a mechanism for consistent, multi-year FDA funding needed to conduct more predictable, empirically-based product reviews.

We strongly support the renewal of PDUFA in 2007 when the current program expires, and believe that maintaining level funding will allow the successful continuation of the program.

As we examine the data being collecting during the course of the present program, we hope to achieve a better understanding of causes and possible solutions that will show that modest programmatic changes may contribute to even greater success.

We have some specific comments in three areas: safety, information technology, and performance goals.

So let me start with safety. BIO believes it's important to recognize that safety is an integral and paramount part of companies' considerations during research and development, and of FDA's deliberations during its application review. Indeed, FDA has stated that it spends half of its effort and resources during the course of a review in considering the product safety profile, and determining whether limitations on use or specific content in the labeling are needed to ensure consumer safety.

Because PDUFA funds were specifically designed to be allocated to activities related to application review, they clearly should be used by FDA for pre-market safety-related activities. During the most Congressional renewal of PDUFA, Congress, FDA and companies agreed that user fee resources should also be allocated to safety-related activities that occur in the early post-market period, when a great deal of safety information may be obtained as products transition from use in a relatively small number of patients enrolled in clinical studies, to use by many more people. This new PDUFA allocation, $63 million, provides for additional personnel, data base enhancements, funding of outside reviews, etcetera, focused particularly on the so-called "peri-approval period," that is, the first several years the product is on the market.

BIO does not agree with suggestions that PDUFA has contributed to a lowering of FDA safety review standards, or reduction in product safety, or that safety has taken a back seat to speed.PDUFA fees are, in fact, applied directly to safety evaluation, both in the pre- and post-market stages. And you heard this morning that there was a study from the Tufts Center, a study of drug development, which demonstrated that there's no evidence of correlation between the length of the application review and product withdrawals.

As PDUFA moves towards renewal, we want to focus on safety-related areas to determine if and how improvements can be made. And we look forward to discussing these in more detail as the process evolves.

BIO would like to see some emphasis placed on the greater efficiency, consistency, and predictability in the process of evaluating trade names. Trade name evaluation is an important aspect of safety, in that it helps minimize medication errors. Currently, we believe trade name review is not conducted in a timely manner, and consistent procedures do not seem to be in place for this aspect of application review. This is a significant issue for BIO member companies, and we believe that statutory changes are not necessary to make these improvements, so BIO looks forward to working with FDA to expeditiously improve the evaluation of trade names.

I'd now like to move on to information technology. Implementation of data and document standards is generally embraced by the biotechnology industry. During the course of PDUFA III there have been promising steps toward establishing the base architecture for paperless submissions. This goad is critically important, and we look forward to its achievement.

However, FDA appears to struggle with the existence of multiple external standard groups, and numerous IT groups within the FDA. We encouragethe agency to better consolidate and coordinate IT activities related to electronic submissions. We also encourage, and will continue to work with FDA to achieve this: better communication of IT initiatives and implementation.

In addition, it's crucial for companies to have sufficient advance notice of changes and of implementation of new requirements to be able to comply with the Agency IT changes. That is not currently happening uniformly.

So, finally, let me talk about performance goals. In general, we believe appropriate goals for review performance are in place and should be retained, but we want to highlight several matters.

Statistics currently available, including FDA's annual performance reports indicate that median approval times are not changing, notwithstanding the fact that, overall, PDUFA spending on application review has continued to increase annually. Moreover, the current median time to approval is longer than the comparable in 1999. It would be helpful for FDA to provide additional details regarding this issue and develop a clearer understanding of whether and how use of PDUFA funds are contributing to this apparent slippage.

One of Bio's key priorities in the most recent PDUFA renewal was to achieve an understanding of differences in product approval times between biological products and drug products, among review divisions, and between the Center for Drug Evaluation Research and the Center for Biologics Evaluation and Research. In particular, FDA used PDUFA resources to fund several studies to shed light on this, including studies of first-cycle review, the results of which will be helpful in understanding the time to approval. And we look forward to getting more data on these ongoing studies.

A critical issue identified in PDUFA renewal discussion was that of inconsistencies between and among reviewers and divisions. One goal of PDUFA III was the development and implementation of good review management principles. FDA has developed and disseminated this GRMP guidance, and has begun training the reviewers in both CDER and CBER regarding these best practices. This was an important achievement. However, sustained and continued commitment to observing the principles articulated in the guidance is critical to success. This includes continued dedication to performance and communication goals, training, and implementation of GRMPs.

While progress is being made, two areas represent opportunities for further examination and possible enhancement: labeling, and post-market commitment negotiations. Again, we feel that changes in the law are not necessary to achieve these efficiencies. And again we look forward to continuing our productive dialogue on these issues.

Another PDUFA III activity predicted to be a potential route to enhanced communication and reduced review time was the establishment of two continuous market application pilot programs. These programs have been implemented and are currently being evaluated by FDA. We look forward to learning from FDA how the CMA programs were implemented and used, and the FDA's views on these programs. We will also do our own assessment of the programs, although preliminary assessments appear to indicate that these programs were not used as often as we might have anticipated. And, in addition, it appears that while these programs were worth evaluating on a pilot basis, without compelling data regarding their success, they may not be worth continuing, especially if they have significant impact on FDA resources.

Overall, BIO believes that good progress is being made in meeting PDUFA III performance goals. As FDA itself has acknowledged, however, there has been little success with respect to meeting goals for management of meetings and other communications with applicants. Because this is an area of great importance to BIO member companies, who view good communication with FDA as their lifeline to predictability and success, we hope to continue to work with FDA to realize the meetings management goals established in PDUFA II.

We're aware that over the last several years FDA appropriations for drug and biologics review have remained flat when adjusted for inflation. Consequently the Agency has struggled to keep up with its review activities with the multiple other tasks with which it's charged. We will continue to urge Congress to ensure adequate FDA appropriations.

So, in conclusion, BIO believes that reductions in overall product development time and in FDA review time both are critical factors in improving access to medicines. PDUFA is key to this goal.

The program should be reauthorized in a timely manner and not redesigned with reforms unrelated to PDUFA's goals. User fees at current levels should continue to provide reliable additive resources for human drug and biologic review, while FDA works towards realizing the goals established in PDUFA III, with minor programmatic improvements.

I want to emphasize again Bio's view on the program is that it has been highly successful, and is a direct contributor to increased patient access to life-saving, breakthrough therapies, and we look forward to working with you in the coming months.

Thank you again for the opportunity to speak on behalf of Bio.

MS. HENDERSON: Thank you very much, Ms. Lawton.

Next on this panel is Dr. Bruce Burlington. Dr. Burlington is executive vice president for Quality, Regulatory, Safety, Compliance and Audit at Wyeth Pharmaceuticals, located in Collegeville, Pennsylvania. In this position, he has responsibility for the regulatory affairs, safety surveillance, quality operations, compliance operations and audit departments, all on a worldwide basis.

Please join me in welcoming Dr. Burlington.

DR. BURLINGTON: Thank you very much. I'm pleased to present a statement on behalf of the Pharmaceutical Research and Manufacturers Association.

When Congress in 1992 passed the Prescription Drug User Fee Act, it was a reasonable means for improving the review of new drugs. The average review time at that point had increased to nearly 34 months. And, as Dr. David Kessler stated, this was attributed largely to a lack of trained reviewers to undertake the work for the Agency. When the law was enacted it was established on two critical concepts. One of them is that the fees paid by the industry were to support additional reviews in the Food and Drug Administration; that only the timing of new drug reviews would be part of the metrics and goals. There was no assumption about the approvability of applications, individually or in general. There was a commitment by Dr. Kessler that the Agency would use these resources to produce faster reviews.

When the law was enacted and signed by George Herbert Walker Bush, the user fees were clearly to augment, and not replace, FDA's base appropriations. They are not a new tax. They are specified fees for improving drug-review services, and cannot be used to fund other obligations and functions.

There were, at the time of enactment, bedrock safeguards to assure user fees were additive to FDA's base budget, and that the fees were dedicated to the review of new drugs and related activities.

It is critical that Congress provide adequate base funding for non-PDUFA FDA activities in order to make the system work. These are reasonable and sound principles, and they must be maintained.

In addition, the framers of PDUFA established accountability to Congress for FDA performance as a basis for continuing the program. The goals and results under the PDUFA and its re-enactment have been transparent to all stakeholders; and FDA's performance has been excellent. They have consistently met PDUFA goals.

Further, as we have heard today, innovative medicines are routinely approved and launched and available to U.S. patients and consumers before they are available elsewhere in the world.

I won't dwell on the various elements of the re-enactment, the FDAMA or subsequent re-enactment of the legislation, but I would note--and this has already been addressed by my colleague from Bio--that funding for information technology initiatives had been part of the last two re-enactments, as well as the introduction of funding for post-market surveillance related to application review, and in the peri-application period.

As user fees near the end of the third five-year term, it's important that we consider the value that the program has brought; value to both society and the Food and Drug Administration, as well as the industry. We have realized the benefits envisioned when Congress enacted PDUFA in 1992. The FDA has increased the number of review staff. They have augmented post-market safety surveillance activities, and they have improved internal information technology capacity.

The pharmaceutical companies have been able to bring drugs more rapidly, and with more consistency, through the regulatory process to consumers. And patients have received faster access to innovative medicines, improving their health and quality of life.

This has been accomplished while the extent of safety data to support an approval has continued to grow, and while maintaining FDA's high quality standards as the gold-standard regulatory agency throughout the world.

As we consider PDUFA IV, it is important we bear in bind that accountability for goals and measurement of performance against these goals continues to be an important aspect of the program. Goal setting enhances performance. Every good manager knows: you get what you measure.

Today, in industry, we must with increasing stringency account for the way we use resources. There is a general constraint on the availability of new money in R&D across industry, as industry looks at the change in the payment model for pharmaceutical products. Many companies have taken steps to reduce their costs and overhead. It is not a time when there is a luxury of money which can be transferred from the research on pharmaceutical products to new applications.

Therefore, one of our considerations should be to minimize the work necessary to document achievements, and not reduce goal setting. FDA can maintain a performance-based environment and collect data on their performance much more efficiently than they have in the past. Electronic submission requirement makes it easier for electronic record-keeping, and offers the prospect of gained efficiency. Implicit in these efficiencies would be savings in manpower and funds so FDA can reallocate them to other activities.

In terms of data analysis for the information collected under the PDUFA program to date, FDA has developed an extensive data base. Analysis of this should assist the FDA in implementing their quality systems program, yielding greater consistency of reviews for the industry. Further the analysis of first-cycle reviews and multi-cycle reviews should provide important lessons, both to the Agency and to the companies, about how to better conduct their research and development of products, and bring more mature applications to the agency.

Under risk management, it is important that we continue the work begun in PDUFA III on risk management, with Agency working with the companies to bring the best benefit to risk ratio to consumers; the cornerstone of the new approach to drug safety issues used by both FDA and the industry, so that the approval of critical new medicines is not unduly delayed.

The Pharmaceutical Research and Manufacturers Association supports the re-enactment of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, both due for renewal in 2007, as well. They have worked as intended.

The number of new pediatric studies has increased markedly: 251 have been initiated by company proposals; and 93--and we've heard this morning, around 100--drug labels have been updated with significant new pediatric information.

The PDUFA legislation has worked and should be reauthorized. Positive results of PDUFA cannot continue without stakeholder commitment to a user fee program, full Congressional support of base appropriations. And I would note that Dr. Woodcock earlier this morning showed us that the appropriated base has eroded steadily over the last 12 years. This needs to be fixed.

Further improvements of the review process by FDA scientists are also an important element of PDUFA renewal. Patients, the public, as well as industry, need an unambiguous, consistent and predictable set of standards in the development of drugs for the future. FDA needs the assurance of adequate staffing and resources so that drugs now in development, and NDAs currently before the agency can be reviewed in a timely way.

Without continuation of PDUFA, opportunities for continued improvements in drug safety programs will be limited. Without a continuous assurance of PDUFA goals there is an uncertain future for the scientific breakthroughs that occur each day, and industry's work to turn them into pharmaceutical products for patients in need.

Thank you.

MS. HENDERSON: Thank you, Dr. Burlington.

Last on the industry panel is Mary Gustafson, senior director for Global Regulatory Policy at the Plasma Protein Therapeutics Association. Prior to joining PPTA, Ms. Gustafson served as senior director of Regulatory Affairs at Nabi Biopharmaceuticals in Boca Raton, Florida, and in regulatory positions at the FDA. While at FDA, she directed the Division of Blood Applications in the Office of Blood Research and Review in the Center for Biologics, as well as holding earlier positions in biologics compliance and productcertification.

Ms. Gustafson?

MS. GUSTAFSON: Thank you, Debbie. I do have slides.

PPTA is pleased to be part of today's program, and thanks FDA for initiating a public process for the important work of reauthorizing the Prescription Drug User Fee Act.


PPTA is the international trade association and standards-setting organization for the world's major producers of plasma-derived and recombinant analog therapies. These therapies are subject to prescription drug user fees, and include blood-clotting therapies, immunoglobulins, therapies for alpha-1 antitrypsin deficiency, and albumin. Our members also provide source plasma, which is the primary source material for the manufacture of plasma for plasma-derived protein therapies. Source plasma is not subject to user fees, and must be regulated using allocated funds.


The companies pictured on this slide represent the PPTA member companies that are subject to user fees for the therapies they produce. As others have mentioned, our companies viewed the Prescription Drug User Fee Act of 1992, and its two previous reauthorizations, as benefitting the industry and patients who receive our therapies. Thanks to the user fee program, life-saving therapies have been introduced to the market. The benefits of reducing time-to-market for these therapies cannot be overstated.


PPTA member companies, including those not subject to user fees, are regulated by the Center for Biologics Evaluation and Research. The products produced by our companies are reviewed in the Office of Blood Research and Review.

PPTA is concerned that CBER, and particularly the Office of Blood, is resourced adequately to perform all regulatory functions. CBER is unique in that it operates under both PDUFA and the Medical Device User Fee Program, MDUFMA, in addition to having significant programs that are not supplemented by user fees. And note: I said "programs," not functions or activities within a funded program.

It is very important to our companies that user fees in both programs are used appropriately, including tracing and accountability; but that the non-user fee programs are also adequately resourced with allocated funds to cover the full extent of the Office of Blood and CBER's needs.

Believe it or not, these programs are interactive for part of our industry. Manufacturers subject to PDUFA are dependent on reviews and policies affecting non-PDUFA products, and are dependent on test kits and other devices subject to MDUFMA.

While the user fee programs were always intended to be supplemental, we have concerns that the base allocations have eroded. It is important to maintain strong programs within the Office of Blood and CBER, whether under a user fee program or not. Therefore, we encourage Congress to provide adequate funding to CBER, and all of FDA, with user fees truly being supplemental.

PPTA was not part of the negotiations for PDUFA III. However PPTA members voiced a need for faster and more predictable lot release. CBER listened and developed internal lot-release standards independent of user fees. It is that responsiveness that we hope CBER will continue to be able to support, whether it's a funded activity or not. In order to allow this responsiveness, CBER, and FDA in general, needs to be adequately funded.


While review of the performance of the Office of Blood and CBER is favorable, we do feel that the program could be improved by increasing the transparency in reviews. While we know that as a commitment to PDUFA III CBER and CDER published a guidance document entitled "Guidance for Review Staff and Industry: Good Review Management Principles for PDUFA Products," this document provides timetables for various steps in the review process. We also acknowledge that the mid-cycle review and subsequent communication has improved the predictability of the review.

However, we still feel the process can be improved by adding a real-time tracking feature, ideally electronic, that would provide tracking information in real time that could be accessed by the manufacturer. We consider that such a system would increase the predictability of approval more than has been available now.

Being able to predict when a product will be approved is of great importance. It allows manufacturers to plan for launch of a product that may have substantial improvements over existing products. It allows the manufacturer to control inventories, schedule production runs, and plan for release of newly approved product without delay.

There is much focus today on safety in the first months and years after a new or changed product enters the market. We share these concerns. If enhanced surveillance is to be considered under the user fee program beyond what was funded under PDUFA III, we would advocate that any post-market surveillance program, or program to standardize post-market studies undertaken as Phase IV studies, be determined on an interactive basis between FDA, industry and stakeholders. Patients of our therapies are generally lifelong users, with valuable knowledge based on history and experience.


As part of getting ready for PDUFA IV negotiations, PPTA borrowed a survey tool developed by BIO. We were able to get responses before this meeting, perhaps because all of our member's logos fit on one slide.

Please consider these comments to be a snapshot in time, not a statistical sample of the entire PDUFA-funded industry, nor even consensus among our members at this time. But presenting them today may provide a hint of where a subset of the industry is on these issues.

The survey was divided into two questionnaires: the first questionnaire focused on the pilot programs initiated under PDUFA III. The pilots were associated with the continuous marketing application. The pilots were to test whether early review of selected applications and additional feedback and advice to sponsors during drug development will shorten drug development and review times. The first pilot addressed the rolling review of selected applications; the second, with increased accessibility to Agency reviewers during the development and review process.

As you can see, none of our members participated in these pilots for various reasons. Both of these pilots were designed for products with fast-track designation, and products at certain stages in the development. There were no products available for the first pilot.

As to the second, our members viewed the reviewer access adequate as is.

As to whether these programs should be continued, there was a mixed response.


Also included in the second questionnaire was a question about the special protocol assessment. No one had used it to date; again, a mixed review on its worth.


Participants in the survey were asked whether they reviewed the performance on changes to an approved application designed as CBE-30s to be adequate: specifically, were CBE-30s classified as pre-market approval applications after the 30-day time frame?

For the most part, CBER got good marks on this, however, some viewed it time to re-evaluate the classification criteria used within each category based on the experience gleaned in the near decade since the tiered changes-to-be-reported categories were codified.


In summary, PPTA member companies consider the Prescription Drug User Fee Program to be successful, and should be reauthorized. In the initial survey of member companies in preparation for renegotiating PDUFA, companies view the current goals to be adequate, with a few enhancements. Companies reported mixed reactions to some of the PDUFA III goals.

PPTA member companies are concerned that CBER, who regulates our products, is adequately funded to perform its functions in administering PDUFA and MDUFMA, and support its many non-user fee programs.

In terms of priorities, PPTA member companies desire a more transparent review process, and input and interaction in the design of any enhanced funded pre-marketing program.

Thank you.

MS. HENDERSON: Thank you very much, Mary. And thanks to our entire industry panel.

We will now take a 15-minute break, after which will have a panel of presentations by health professional groups, followed by an open public comment period.

So please return to your seats at 2:45.

[Off the record.]

Panel VI - Presentations by Health Professional Groups

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