# Presentation: 232227

## Catalysts for enactment of PDUFA

- 1962 - Amendments to FD&C Act
- Origin of modern drug development process
- Requirement that drugs be shown to be safe and _effective_ prior to approval
- 1970’s - Emergence of “Drug Lag”
- Drugs approved in Europe years ahead of U.S.
- 1980’s - Emphasis on Patient Access
- AIDS, cancer, etc.
- 1992 - Prescription Drug User Fee Act
- Attempt to address chronic under funding of FDA new drug review program

**Peltzman, Sam. 1973. "The Benefits and Costs of New Drug Regulation," pp. 114-211 in Regulating New Drugs, ed. Richard L. Landau. Chicago: University of Chicago Press.**

**Notes:**
The modern history of drug regulation in the United States has been marked by the simultaneous pursuit of two goals—safety and efficacy. Since passage of the 1962 amendments to the Food and Drug Act, most members of the medical and regulatory establishment have regarded those two goals as complementary. 

By the early seventies, however, critics had begun to charge that the Food and Drug Administration (FDA), in its pursuit of these goals, was delaying or preventing the timely introduction of promising new drugs for seriously ill patients. 

A 1974 study by University of Chicago economist Sam Peltzman concluded that since 1962 the new rules had reduced the rate of introduction of effective new drugs significantly—from an average of forty-three annually in the decade before the amendments to just sixteen annually in the ten years afterward. Peltzman also found that the regulations also made it difficult for companies to introduce drugs that competed with existing drugs, thus reducing competition in the industry. 

The drug lag controversy intensified with the rise of the AIDS epidemic. 

The Center for Drug Development at Tufts University studied forty-six new drugs approved by the United States in the 80s and found that 72 percent were available on average 5.5 years earlier in foreign markets. Other studies, comparing drug approvals back to 1972, have suggested a similar time lag in the United States. 

Peltzman, Sam. 1973. "The Benefits and Costs of New Drug Regulation," pp. 114-211 in Regulating New Drugs, ed. Richard L. Landau. Chicago: University of Chicago Press. 

## History of PDUFA  

- PDUFA 1:  FY93-FY97
- Primary focus - decreased review times
- PDUFA 2:  FY98-FY02
- Re-authorized in 1997 as part of FDAMA
- Primary focus - decreased review times _and_ shortened development times
- PDUFA 3: FY03-FY07
- Re-authorized in 6/2002 as part of Bioterrorism Preparedness and Response Act
- Sound Financial Footing
- Expand interaction & communication in IND phase and during 1st cycle review
- Include post-market safety for 2-3 yrs post-approval

**Notes:**
In 1992, Congress enacted the Prescription Drug User Fee Act (PDUFA I).  This law provided additional resources to hire more medical and scientific reviewers to conduct premarket reviews, to hire support personnel and field investigators to speed up the application review process for human drug and biological products, and to acquire and support critical information technology infrastructure. 

The concept of a user fee program to augment FDA resources was first proposed by the Agency.  The lengthy time of drug reviews was attributed to the lack of adequate resources, a view put forth by the FDA and agreed to by the pharmaceutical industry.  A distinct need for resources on top of those appropriated by Congress was established with one principal goal:  there must be no real or perceived “paying for a drug approval.”  Over the past nine years this goal has been met.  Although performance goals were established in both PDUFA-1 and PDUFA-2, these were kept out of the statute and dealt with in a goals letter from the Secretary of HHS to Congress.  Thus, the PDUFA law itself is rather simple, covering the fee structure, how fees can be collected, and what they can be used for.

It is critical to note that the user fees are designed to be additive to the FDA appropriated base funds.  Congress, in its wisdom, added two “triggers” to assure that FDA could not collect user fees unless there was a baseline appropriation for all of FDA and the necessary funds within the full appropriation were spent on drug review activities.  Collectively the two “triggers” emphasize the ongoing public responsibility to provide FDA with adequate resources to carry out its mission to advance the public health. 

PDUFA-1 focused solely on the drug review process, reducing the time to FDA action to six months for priority drugs and twelve months for standard drugs.  FDA also agreed to process the backlog of pending applications within the first two years of the program.  Both goals were accomplished.  

While PDUFA-1 focused on FDA review time. With reauthorization of PDUFA in 1997, proposals were incorporated aimed at improving interactions during the clinical development phase of drug development with the hope that improvements in this lengthy process (6-8 years) could be realized with the same degree of success that occurred with the FDA review phase. Agreement was reached on a set of metrics that has made such interactions more predictable.  In addition, PDUFA-2 incorporated processes for resolving disputes, assessing special protocols, providing prompt feedback when sponsors submit information in response to a clinical hold, and simplifying the action letter that the sponsor receives following the review of an application.  Collectively, these enhancements are beginning to improve the drug development process. 

PDUFA has largely eliminated the drug lag that existed between the U.S. and the rest of the world. Today, roughly half of all new drugs are approved first in the United States, and less than 30 percent are marketed in Europe for over a year prior to U.S. approval.

The President’s budget request for Fiscal Year (FY) 2003 recommends that PDUFA be reauthorized through FY2007, and we have been engaged in discussions with consumers, health providers, and industry over the past year to develop proposals for PDUFA III.  These discussions have been very useful, and we hope to complete the consultation process in the very near future and forward our PDUFA III recommendations to the Department of Health and Human Services.  

## Similar user fees exist within the EMEA 

**PDUFA**

**Sources:  Ines M. Vilas-Boas, C. Patrick Tharp, “The Drug Approval Process in the U.S., Europe, and Japan:  Some Marketing and Cost Implications”, J. Managed Care Pharm 3, 1997, 459-465.**
**http://www.mhra.gov.uk/aboutmhra/aboutmhra.html**

- Current application free for single strength and one pharmaceutical form is €232,000 with an additional €23,200 for each additional strength and/or form
- Annual fee of €75,600 is assessed with a five year renewal fee of €11,600.
- EMEA goal of 75% funding from industry fees and 25% from European Commission
- In comparison ...
- UK’s Medicines and Healthcare products Regulatory Agency is funded entirely through user fees

**Notes:**
No fees in Japan

## PDUFA workload & commitments

**Notes:**
Summary of commitments

Some top line observations

PDUFA 1 – review times

PDUFA 2 – introduced process improvements to improve development process through greater scientific communication

PDUFA 3 – additional goals aimed at reducing multiple cycles for applications, mostly through greater scientific exchange

## Slide 5

**Notes:**
as PDUFA evolved it also was able to help drug regulation evolve a more modern approach and IT is a big part of that, basically make a nod to idea PDUFA 4 should be similarly forward looking to anticipate how development is continuing to evolve a more modern approach. 

## PDUFA III electronic applications and submissions - goals

- The Agency will centralize the accountability and funding for all PDUFA Information Technology initiatives/activities for CBER, CDER, ORA and OC under the leadership of the FDA CIO.  The July 2001 HHS IT 5-year plan states that infrastructure consolidation across the department should be achieved, including standardization.  The Agency CIO will be responsible for ensuring that all PDUFA III IT infrastructure and IT investments support the Agency’s common IT goals, fit into a common computing environment, and follow good IT management practices.
- The Agency CIO will chair quarterly briefings on PDUFA IT issues to periodically review and evaluate the progress of IT initiatives against project milestones, discuss alternatives when projects are not progressing, and review proposals for new initiatives.  On an annual basis, an assessment will be conducted of progress against PDUFA III IT goals and, established program milestones, including appropriate changes to plans.  A documented summary of the assessment will be drafted and forwarded to the Commissioner.  A version of the study report redacted to remove confidential commercial or security information, or other information exempt from disclosure, will be made available to the public.  The project milestones, assessment and changes will be part of the annual PDUFA III report.
- FDA will implement a common solution in CBER, CDER, ORA and OC for the secure exchange of content including secure e-mail, electronic signatures, and secure submission of, and access to application components.
- FDA will deliver a single point of entry for the receipt and processing of all electronic submissions in a highly secure environment.  This will support CBER, CDER, OC and ORA.  The system should automate the current electronic submission processes such as checking the content of electronic submissions for completeness and electronically acknowledging submissions.
- FDA will provide a specification format for the electronic submission of the Common Technical Document (e-CTD), and provide an electronic review system for this new format that will be used by CBER, CDER and ORA reviewers.  Implementation should include training to ensure successful deployment.  This project will serve as the foundation for automation of other types of electronic submissions.  The review software will be made available to the public.
- Within the first 12 months, FDA will conduct an objective analysis and develop a plan for consolidation of PDUFA III IT infrastructure and desktop management services activities that will access and prioritize the consolidation possibilities among CBER, CDER, ORA and OC to achieve technical efficiencies, target potential savings and realize cost efficiencies.  Based upon the results of this analysis, to the extent appropriate, establish common IT infrastructure and architecture components according to specific milestones and dates.  A documented summary of analysis will be forwarded to the Commissioner.  A version of the study report redacted to remove confidential commercial or security information, or other information exempt from disclosure, will be made available to the public.
- FDA will implement Capability Maturity Model (CMM) in CBER, CDER, ORA and OC for PDUFA IT infrastructure and investments, and include other industry best practices to ensure that PDUFA III IT products and projects are of high quality and produced with optimal efficiency and cost effectiveness.  This includes the development of project plans and schedules, goals, estimates of required resources, issues and risks/mitigation plans for each PDUFA III IT initiative.
- Where common business needs exist, CBER, CDER, ORA and OC will use the same software applications, such as eCTD software, and COTS solutions.
- Within six months of authorization, a PDUFA III IT 5-year plan will be developed.  Progress will be measured against the milestones described in the plan.

**Notes:**
PDUFA 3 had a lot of language aimed at improving IT resources and processes, enabling e-submissions as an important goal.

Within six months of authorization, a PDUFA III IT 5-year plan will be developed.  Progress will be measured against the milestones described in the plan.

FDA will provide a specification format for the electronic submission of the Common Technical Document (e-CTD), and provide an electronic review system for this new format that will be used by CBER, CDER and ORA reviewers.  Implementation should include training to ensure successful deployment.  This project will serve as the foundation for automation of other types of electronic submissions.  The review software will be made available to the public.

## PDUFA 3 fees put program on a more sound financial footing

- Increased fee revenues with total revenue targets for each year in statute
- $  222.9 M	   FY  03
- $  231.0 M	   FY  04
- $  252.0 M	   FY  05
- $  259.3 M	   FY  06 & FY 07
- Revenue targets increased for inflation from 2003
- Revenue targets may also be increased by _workload adjuster_ based on weighted volume of all review work
- NDAs and BLAs)
- Commercial INDs
- Efficacy Supplements
- Manufacturing Supplements

**Notes:**
End result, revenue – used efficiently – has transformed the agency (Janet will get into)

## Why PDUFA continues to be  important to the public health

- Before 1992, timeliness of FDA drug review was a big concern
- _PDUFA _
- User fees added resources for more review staff to eliminate the backlog of overdue applications and improve review timeliness
- FDA agreed to meet specific performance goals
- _Result_
- “Revolution in regulation of pharmaceutical products”
- More predictable, streamlined process
- Reduced review and approval times

**Notes:**
Process Improvements

Management Reforms – matrix organization