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Gregory Conko - PDUFA Re Authorization Comments

Gregory Conko - PDUFA Re Authorization Comments

Ratings: (0)|Views: 99|Likes:
The Competitive Enterprise Institute appreciates the opportunity to submit these comments regarding the FDA’s proposed recommendations for reauthorization of the Prescription Drug User Fee Act. PDUFA has helped patients by ensuring that the FDA has greater resources available to review New Drug Applications and Biologics License Applications, and in turn ensuring that the agency is capable of providing more timely access to new medicines.

Still, there remain numerous shortcomings in agency oversight of drug and biologics development and marketing. CEI is therefore pleased to see that the FDA’s proposed recommendations for PDUFA reauthorization include several items that could begin to address these concerns. Among these are the agency’s proposals to explore more formalized and transparent tools for weighing the risks and benefits of new medicines and a commitment to use patient reported outcome measures in assessing risks and benefits.

No medicines are perfectly “safe” in the sense that they have no potentially negative side effects. For many products, including drugs and biologics that treat serious life-threatening or disabling diseases, medicines may be considered safe enough, even in the presence of substantial known risks. Unfortunately, the FDA’s current process for assessing and balancing benefits and risks is largely ad hoc, informal, and qualitative, relying primarily on the intuitive judgment of the agency’s medical review staff and expert advisory committees. Implementing a more formalized and comprehensive benefit-risk framework would better advance the agency’s important goals.

More formalized, quantitative benefit-risk analysis is not a panacea. But implementing improved processes would help manufacturers better understand the kinds of data that must be generated during pre-clinical and clinical testing, help FDA product reviewers better systematize their decision-making, and help patients and medical clinicians better assess the utility of new products when prescribing treatment regimens. Although the quantitative assessment of benefits and risks will always suffer from inadequacies, making greater use of quantitative assessments will nevertheless lead to an evaluation process that is more transparent, predictable, and rational.

Denying approval for a drug or biologic that is known to be risky, but which nevertheless has a positive benefit-risk balance could harm more patients than it would help – particularly when the product is intended to treat serious life-threatening or disabling conditions that have few other available treatment options. Indeed, while benefit-risk analysis and benefit-cost analysis have been criticized for inappropriately justifying decisions to place potentially risky products on the market, a more appropriate name for the process would be “risk-risk assessment.” That framing best describes why the analysis is useful: Its ultimate goal is to identify which of many possible choices would lead to the best, or safest, overall outcome.

In the end, benefit-risk assessment is not a dispositive tool that can make choices for agencies. Rather, it merely provides a framework for agency decision makers to “organize available information” by forcing them “to state their assumptions clearly, exposing possible biases to criticism and correction.” Therein rests another important feature of benefit-risk assessment in the drug and biologics approval process. Ultimately, the purpose of benefit-risk assessment is not to replace the judgment of medical experts in the decision-making process, but to put the FDA’s expert judgments on record, explain the agency’s reasons for approving or denying approval for new products, and hold those decisions up to public scrutiny.
The Competitive Enterprise Institute appreciates the opportunity to submit these comments regarding the FDA’s proposed recommendations for reauthorization of the Prescription Drug User Fee Act. PDUFA has helped patients by ensuring that the FDA has greater resources available to review New Drug Applications and Biologics License Applications, and in turn ensuring that the agency is capable of providing more timely access to new medicines.

Still, there remain numerous shortcomings in agency oversight of drug and biologics development and marketing. CEI is therefore pleased to see that the FDA’s proposed recommendations for PDUFA reauthorization include several items that could begin to address these concerns. Among these are the agency’s proposals to explore more formalized and transparent tools for weighing the risks and benefits of new medicines and a commitment to use patient reported outcome measures in assessing risks and benefits.

No medicines are perfectly “safe” in the sense that they have no potentially negative side effects. For many products, including drugs and biologics that treat serious life-threatening or disabling diseases, medicines may be considered safe enough, even in the presence of substantial known risks. Unfortunately, the FDA’s current process for assessing and balancing benefits and risks is largely ad hoc, informal, and qualitative, relying primarily on the intuitive judgment of the agency’s medical review staff and expert advisory committees. Implementing a more formalized and comprehensive benefit-risk framework would better advance the agency’s important goals.

More formalized, quantitative benefit-risk analysis is not a panacea. But implementing improved processes would help manufacturers better understand the kinds of data that must be generated during pre-clinical and clinical testing, help FDA product reviewers better systematize their decision-making, and help patients and medical clinicians better assess the utility of new products when prescribing treatment regimens. Although the quantitative assessment of benefits and risks will always suffer from inadequacies, making greater use of quantitative assessments will nevertheless lead to an evaluation process that is more transparent, predictable, and rational.

Denying approval for a drug or biologic that is known to be risky, but which nevertheless has a positive benefit-risk balance could harm more patients than it would help – particularly when the product is intended to treat serious life-threatening or disabling conditions that have few other available treatment options. Indeed, while benefit-risk analysis and benefit-cost analysis have been criticized for inappropriately justifying decisions to place potentially risky products on the market, a more appropriate name for the process would be “risk-risk assessment.” That framing best describes why the analysis is useful: Its ultimate goal is to identify which of many possible choices would lead to the best, or safest, overall outcome.

In the end, benefit-risk assessment is not a dispositive tool that can make choices for agencies. Rather, it merely provides a framework for agency decision makers to “organize available information” by forcing them “to state their assumptions clearly, exposing possible biases to criticism and correction.” Therein rests another important feature of benefit-risk assessment in the drug and biologics approval process. Ultimately, the purpose of benefit-risk assessment is not to replace the judgment of medical experts in the decision-making process, but to put the FDA’s expert judgments on record, explain the agency’s reasons for approving or denying approval for new products, and hold those decisions up to public scrutiny.

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Published by: Competitive Enterprise Institute on Oct 26, 2011
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1
 C
OMMENTS OF THE
C
OMPETITIVE
E
NTERPRISE
I
NSTITUTE
R
EGARDING
FDA’
S
P
ROPOSED
R
ECOMMENDATIONS FOR
P
RESCRIPTION
D
RUG
U
SER
F
EE
A
CT
R
EAUTHORIZATION
 Docket No. FDA-2010-N-0128, 76 Fed. Reg. 56201 (September 12, 2011)
The Competitive Enterprise Institute (CEI) appreciates the opportunity to submitthese comments regarding the FDA’s proposed recommendations for reauthorization of the Prescription Drug User Fee Act. CEI is a non-profit research and advocacyorganization that studies the impact of regulation on the economy, public health andwelfare, and consumer choice. For the past 25 years, CEI has been extensively involvedin issues related to drug, biologics, and medical device regulation, medical productlabeling, and other public health and consumer protection issues.The Prescription Drug User Fee Act has helped patients by ensuring that the FDAhas greater resources available to review New Drug Applications and Biologics LicenseApplications, and in turn ensuring that the agency is capable of providing more timelyaccess to new medicines. Prior to enactment of PDUFA in 1992, median NDA reviewtimes for standard submissions often exceeded two years, giving rise to a scenario inwhich new medicines were frequently available to patients in other industrializedcountries a full year or more earlier than to patients in the United States. After 1992,median review times for standard submissions were halved, and priority submissions arenow typically reviewed in as little as six months.
1
 The health benefits of speedier approval decisions have been remarkable. Oneseminal study examined at all 662 drugs approved by the FDA from 1979 to 2002, aswell as all drugs withdrawn from the market during that period. It concluded that thefaster pace of approvals beginning in the 1990s benefited patients with an extra 180,000to 310,000 years of life.
2
Although some FDA critics have argued that the agency nowspends too little time reviewing NDAs and BLAs, there is no evidence that speedierreviews have decreased patient safety, or that longer reviews would improve the agency’scapacity to identify patient hazards prior to approval.
1
Food and Drug Administration, “Trends in NDA and BLA Submissions and Approval Times,”http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/PerformanceReports/PDUFA/ucm209349.htm.
2
E.R. Berndt, A.H.B. Gottschalk, T.J. Philipson, and M.W. Strobeck, “Industry Funding of the FDA:Effects of PDUFA on Approval Times and Withdrawal Rates,”
 Nature Reviews Drug Discovery
, Vol. 4,No. 7 (July 2005), pp. 545-554.
 
2The primary safety limitations associated with FDA reviews lay, not withreviewers being rushed to make approval or disapproval decisions, but rather with theinability of clinical trials to reveal a product’s benefit/risk profile fully. Some risks andbenefits can only be revealed after marketing approval is granted and the products areused by large patient populations. Dragging out the review of a new drug or biologic istherefore unlikely to improve patient health. Indeed, the rate of drug approvalwithdrawals remained essentially unchanged from the pre-PDUFA to post-PDUFA eras,despite rising and falling approval times during that period,
3
indicating that PDUFA hasnot resulted in greater risk to patients.But, while PDUFA has successfully enabled FDA to provide a speedier approvalprocess, there remain numerous shortcomings in agency oversight of drug and biologicsdevelopment and marketing. Among these are increasing burdens being heaped onmanufacturers during the clinical trial phases of drug development, a lack of communication and transparency between FDA and manufacturers both before andduring the NDA and BLA review process, and a potent political environment thatincentivizes FDA to resolve issues related to the heterogeneity of risks and benefitswithin patient pools by denying approval.CEI is therefore pleased to see that the FDA’s proposed recommendations forPDUFA reauthorization include several items that could begin to address these concerns.Among these are the agency’s proposals to explore more formalized and transparent toolsfor weighing the risks and benefits of new medicines and a commitment to use patient-reported outcome measures in assessing risks and benefits.
Enhancing Benefit-Risk Assessment
Under the Food, Drug and Cosmetic Act, the FDA is tasked with ensuring thatnew drugs and biologics are safe and effective. But no medicines are perfectly “safe,” inthe sense that they have no potentially negative side effects. For many products,including drugs and biologics that treat serious life-threatening or disabling diseases,medicines may be considered safe enough, even in the presence of substantial knownrisks. What matters is that the expected benefits outweigh the expected harms.The net effects of a medicine are not always well characterized, however. Drugsand biologics are generally tested in only a few thousand patients, leaving much unknownat the time an approval or disapproval decision must be made. The full benefit-risk profile of medicines is also not fully known even after they have been marketed for manyyears and used by hundreds of thousands or millions of patients. In practice then, theFDA must make a judgment about whether the potential benefits of new medicinesoutweigh their potential risks.
3
Michael A. Friedman, Janet Woodcock, Murray M. Lumpkin, et al., “The Safety of Newly ApprovedMedicines: Do Recent Market Removals Mean There Is a Problem?”
 Journal of the American Medical Association
, Vol. 281, No. 18 (May 12, 1999), pp. 1728-34.
 
3The FDA’s current process for assessing and balancing the benefits and risks of medicines is largely ad hoc, informal, and qualitative, however, relying primarily on theintuitive judgment of the agency’s medical review staff and expert advisory committees.
4
 As a 2007 Institute of Medicine (IOM) report indicated, more standardized and robustanalysis of risks and benefits could improve agency decision-making with attendantimprovements for public health.
5
The IOM report recommended that the agency “developand continually improve a systematic approach to risk-benefit analysis for use throughoutthe FDA in the pre-approval and post-approval settings.”
6
 In response to the IOM’s recommendation, the FDA announced in April 2010 thatit would introduce a five-item, mostly qualitative, risk-benefit grid that would considerthe seriousness of the condition to be treated, the availability of alternative treatments,clinical data on the risks and benefits associated with a new drug’s use, and relevant risk management practices associated with the product.
7
The purpose, according to Office of New Drugs Director John Jenkins, was to provide a template that would help the agency“visualize these risk-benefit decisions” that the agency already makes, while addressing“the critical issues that go into decision-making,” and “transparently represent[ing] howdecisions were made.”
8
 The FDA’s adoption of this risk-benefit grid was an important first step forwardin improving the transparency and predictability of agency decision-making. However,implementation of a more formalized and comprehensive benefit-risk framework woulddo even more to promote those important goals. More formalized benefit-risk analysis isnot a panacea. But implementing improved processes would help manufacturers betterunderstand the kinds of data that must be generated during pre-clinical and clinicaltesting, help FDA product reviewers better systematize their decision-making, and helppatients and medical clinicians better assess the utility of new products when prescribingtreatment regimens.Because clinical trials must, by necessity, be conducted with a limited number of patients and over a relatively short time period, assessing a drug’s benefits and risks ischallenging at best. And changes in many symptoms, such as pain and cognitive or motorskills impairment, necessarily rely on qualitative reports on the individualized experienceof patients, which makes quantification and cross-comparison difficult if not impossible.Similarly, because the value of particular symptomatic improvements and a tolerance forrisk vary among patients, the balancing of benefits and risks must necessarily entailsubjective judgments.Although the quantitative assessment of benefits and risks will always suffer frominadequacies, making greater use of quantitative assessments will nevertheless lead to an
4
 
See
, Institute of Medicine,
The Future of Drug Safety:
 
Promoting and Protecting the Health of the Public
 (Washington, D.C.: National Academies Press, 2007), p. 123.
5
Ibid.
6
Ibid.
7
Cole Werble, “FDA ‘Grids’ for More Transparent Risk-Benefit Decisions,”
The RPM Report 
, April 26,2010.
8
Ibid.

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