Cross-functional teams have been fashionable across many U.S. industries for at least 20 years. The idea seems greatcorporations are divided into departmental fiefdoms by definition. Such silos create poor communication and competing interests that do not serve the greater good; the answer is to develop products through teams of individuals from each silo. The results are supposed to be cooperation instead of warfare, goal-oriented employees instead of politically motivated employees, and innovation instead of stagnation. The concept has been famously applied to everything from automobiles to computers, and yes, pharmaceuticals. Cross-functional teams are great, except when they arent. Too often we see cross-dysfunctional teams.

Concern arises whenever a process or organizational fad is adopted in sweeping fashion by those who are not prepared properly for applying the wisdom hidden inside the fashion. Almost every biopharmaceutical company develops its products, particularly in clinical development, using cross-functional teams. But the creation of such a team does not by wish or magic create synergy, cooperation, and efficiency.


Do you recognize these signs of dysfunctional teams?

	Meetings that routinely start late or are repeatedly canceled or postponed. 

	Team members with hidden agendasobjectives that do not match the goals of the team they are on. 

	Meetings where some people consistently do not show up.

	Teams where one or two members dominate the dialogue by their seniority, volume, political connections, or lack of self-consciousness. 

	Teams with members who take the opposite, passive-aggressive tack, and dont say anything; they even accept assignments from the team, and then ignore them. 

	Teams that are doggedly formed with representation from each department as required by the companys policies, regardless of whether there is a staff member of value available from that department. 

	Teams that simply lack the skill to be a team, whose members have never been trained in team dynamics and effectiveness. 


An ironic and very common indicator that your company is guilty of dysfunctional teams is when a handful of outstanding team players are assigned to as many teams as possible. So many, in fact, that they have no time for their real job, or even sufficient time to make all their teams successful.

And most damaging are teams which perform poorly in a crisis (and every project has crises). Its easy for your team to shine when the trials are rolling along, youre meeting your targets (more or less), and proving your endpoints in sprightly fashion. When things are smooth, you may not ever be aware a dysfunctional team is lurking beneath the surface. Its when the problems start to hitlike the inevitable shortfall in subject recruitment, the equivocal trial result, the CRO cost overrun, or a shift in executive prioritiesthat you learn how functional your team really is, or isnt.

Whats the problem with a less than perfect project team? Isnt the organizational model so superior it can tolerate wide variances in quality? I would say no. A poorly performing team really is worse than effective and professional individual departments whose members just happen to communicate poorly. The sheer waste of time that a poorly functional team creates is like a black hole, sucking in scarce resources and even scarcer hours. 

Indeed, a single effective leader, empowered to command resources across departments when (and only when) needed, and equipped with the right process, is more likely to get the best of both modelsprofessional competency reinforced through departmental verticality, and good planning and smooth handoffs from all involved. This is a solution to dysfunctionality that is highly unfashionable, but worth exploring.


Lets assume that ultimately, a well-run, well-trained, well-staffed cross-functional team is a highly desirable model for clinical development. What should you be looking for to ensure your team is indeed functional? The first element is commitment: team members must be sincerely and honestly committed to the achievement of the teams objective and willing to be an honest and involved participant. The second element is skillall team members must know or be taught the dynamics of an effective team, the responsibilities they are taking on, and have the ability (either innate or learned) to work in the unique collaborative manner that teams demand.

The third key element of effective cross-functional teams is a strong, empowered, and properly trained leader. Each of these characteristicsstrong, empowered, and trainedare important and distinct. A team does not lead itself, nor is a leader simply a facilitator. Indeed, it is often recommended that a team designate separate roles among its members for leader, facilitator, and rapporteur (documenter). The leader must welcome the role and be willing to take command. He or she must be empowered by both the clinical development leadership and his or her own vertical department so that the teams decisions will be endorsed, funded, and supported. And the leader must be trained in the special skills the leader needs, as distinct from a participant.

The fourth key element is clarity and focusthe team must have clear objectives and be able to focus on them without distractions or unnecessary changes in direction. So, too, team members must be allowed by their departments to focus on team participation and not be pulled away constantly to other duties. Ideally, participants should feel that their personal interests match the interest of the team. This will ensure that the teams performance will serve the corporations self-interest.

The fifth key element of effective cross-functional teams is a mechanism for measuring performance. The team should know how to develop relevant and feasible metrics so that it can determine, or even anticipate, performance problems and increase the predictability of those inevitable crises, leading to a more rapid and effective response.

But the most important element of an effective cross-functional team is that which lies at the heart of effective clinical developmenta well-understood, proven, and documented process for clinical trial conduct.  If your organization has not figured out how to do clinical trials well under the conditions of your companys special circumstances, even the best trained and most well-intentioned team will founder. This is perhaps the most overlooked piece of the cross-functional fad; these teams will be only as good as the process they are asked to implement.

Cross-functional teams have proven themselves in our industry and others as a way to focus the energies of talented multidisciplinary staff on a common goal. But sitting down with an organizational chart and picking one person from each department will not be sufficient to realize the value in this approach. With commitment, skill building, a strong leader, clarity of objectives, performance metrics, and a good clinical trial process to implement, your cross-functional teams will live up to their expectations. o            

Articles

Process Improvement

Commitment, skill, leadership, a clear focus, performance metrics, and a proven process will keep your cross-functional team from dysfunction.

Cross-(Dys)Functional Teams

The European Unions initiative to provide incentives for the development of medicines specifically for children has received a rapid response. By the end of May, the EU had received more than 60 sets of comments on its consultation paper, Better Medicines for Children (see ACT July 2002). The majority have come from associations of health care professionals and academia, but also from patient associations, industry associations, nongovernmental organizations, and EU member states, ranging from the Sultan Qaboos University Hospital in the Sultanate of Oman to the Finnish Paediatric Society, and from the European non-prescription medicines association, the Association of the European Self-Medication Industry (AESGP), to the UK National Council of Women. Professional associations in the UK figure prominently among the respondents, including the British Epilepsy Association, Diabetes UK, National Eczema Society UK, the Coalition of People Living with HIV & AIDS, the Royal Society for the Promotion of Health, the Royal College of Physicians, the Royal College of Pathologists, the Royal College of Nursing, and the Royal College of Paediatrics and Child Health. This possibly reflects the fact that the UK Medicines Control Agency distributed its request for comments widely.

Separate comments were also received from three of the official bodies of the European Medicines Evaluation Agency, and even the EMEA executive director has responded in person. Other observations have come from a health insurance organization, and from several individuals and companies. The European Commissions own departments responsible for research, competition, and the EU internal market have also commented.


All of the comments welcome the Commissions consultation paper and indicate support for most of the ideas expressed in it. Several of the comments provide ideas on how to expand on the suggestions in a practical manner. All responders recognize the need to take specific regulatory measures to improve the availability of suitable adapted medicines for children. The urgency of promoting clinical trials for medicines for children, and the need to ensure that any framework put in place was underpinned by adequate resources and funding to meet its objectives, were frequently mentioned.

The comments show considerable support for the idea of incentives to encourage the development of new products. Respondents who expressed views on the duration of the market exclusivity provision, which was suggested in the EU consultation paper, recommended that it should last for 12 months. The idea of a kid marketing authorization as a mechanism for offering exclusivity was supported in principlebut questions were raised as to whether this would be sufficient to generate the necessary studies.

Patient or health professional associations, with particular interests in specific therapeutic areas, tended to stress the specific needs of children suffering from these diseasessuch as eczema or diabetes. Several respondents indicated childhood cancers as priority areas. The need for multidisciplinary involvement in any expert group or pediatric network to include patient support groups, pharmacists, nurses, and parents was emphasized by several respondents. But some respondents expressed concerns that incentives might result in medicines being developed for financial gain, rather than for the benefit of children.

Many of the comments focused on technical aspects of the EUs outline proposals. Putting mechanisms in place to avoid two companies embarking on the same set of studies was seen as essential. Most respondents underlined the need to improve and disseminate information on medicines authorized in some countries but not in others, and to ensure feedback on empirical success or failures from treatment with unauthorized medicinal products and/or medicinal products used off-label. The development of a central database received significant support. Also highlighted was the need for negative as well as positive results of trials to be made available, as a way to avoid unnecessary trials.

Most respondents stressed the need for specific and adapted pharmacovigilance systems, although most noted the high cost and risk of creating disincentives for industry. Industry respondents tended to recommend targeting these studies carefully. With some exceptions respondents supported establishing a pediatric expert group or committee within the European Medicines Evaluation Agency. However the importance of clearly defining the role and mandate of this group and of allocating sufficient resources for its operation was highlighted. Creating a network of excellence for the performance of pediatric studies, ranging from non-clinical to dose ranging, and from observational to pharmacovigilance, received wide support. Several organizations indicated examples of existing networks which could be integrated or used as models. It was also suggested that such a network could be used to develop specific methodologies.

There were also calls for training needs to be metand creating a steering committee to manage this was proposedand for setting up a register of pediatric studies. Several respondents also mentioned the challenge of generating information for pediatric sub-populations, in particular, neonates.

The likely outcome will be the drafting of a formal EU proposal for legislationbut this is unlikely to emerge until sometime in 2003, and could take another two years to be agreed upon and come into effect.


Meanwhile, the EU is pushing ahead with filling in some of the gaps in its new clinical trials rulesthe set of rules formally adopted in 2001 (Directive 2001/20/EC), which still needs a series of technical details to be put in place before it can become effective. During June it started consultations on one of the many missing pieces of the jigsaw puzzle by finalizing its proposals for detailed guidelines on the trial master file and archiving.

Not always the most exciting aspect of clinical trials, the question of archiving and retention of documents received a new topicality by the controversy over Enron and the shredding of documents by its auditor, Andersen. This new EU guidance on clinical trials eschews all flamboyance, and makes no reference to the wider worldexcept for a reminder that storage of personal data is also subject to the relevant parts of the EU rules on data protection (Directive 95/46/EC).

But its deadpan treatment of the question of document destruction nonetheless carries inevitableif unwittingresonances of the recent high-profile discussions of when to shred.

The reasons for destruction of essential documents should be documented and signed by a person with appropriate authority. This record should be retained for a further five years from the date that the essential documents were destroyed. The sponsor should notify investigators in writing when their trial records can be destroyed,  it intones quietly.

Overall, the new draft EU document provides guidance for sponsors and investigators on requirements on trial master files. Basing itself on the existing EU and ICH definitions of essential documents (as the documents which individually and collectively permit evaluation of the conduct of a clinical trial and the quality of the data produced), the new guidance says these documents, which serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with applicable regulatory requirements, should be filed in an organized way that will facilitate management of the clinical trial, audit and inspection to constitute the trial master file. 

In line with the existing rules, it spells out that essential documents must be retained (or archived) for sufficient periods to allow for audit and inspection by regulatory authorities and should be readily available upon request. The guideline gives details on the minimum set of documents to be retained; the quality of documents to be archived; the minimum standards for storage conditions; media transfer and certified copies, and retention times.

As the guidance notes, existing rules (notably the EU/ICH guidance CPMP/ICH/135/95 on Good Clinical Practice) already define the minimum set of documents to be archived. But it makes particular reference to the investigator site delegation list/log, quality control records, and statements that independent ethics committees are organized and operate in accordance with GCP.

As to quality of essential documents, they should be complete, legible, accurate, unambiguous, authentic and, as appropriate, certified after verification. Existing rules also, the new document recalls, state the responsibilities of the sponsor for implementing quality assurance and quality control to assure the quality of essential documents.

The media used to store essential documents should ensure that these documents will be promptly available, complete, and legible throughout the required period of retention. Any alteration to records should be traceable, and particular attention needs to be paid to records stored on electronic, magnetic, optical, or other non-indelible media, in which case suitable controls should be implemented to ensure that these records cannot be altered without appropriate authorization and the creation of an audit trail.

When original records are copied or transferred to other media for archiving, the system of copying or transfer should be validated to ensure that information will not be lost or altered. Copies or transfers should be certified for accuracy and completeness by someone with appropriate authority, as part of the quality control procedure. For media that require processing in order to turn records into a readable format, appropriate equipment must be available so that this processing can be done.

Storage facilities and their maintenance should reflect relevant EU and national standards, says the new draft guidance. They should ensure that essential records are maintained in a legible condition and can be retrieved promptly. Any change in the ownership and location of the documentation should be documented in order to allow tracking of the stored records. Adequate and suitable space should be provided for the secure storage of all essential records from completed studies. The facilities should be secure, with appropriate environmental controls and adequate protection from fire, flood, and unauthorized access. The storage of the sponsors documentation may be transferred to a subcontractor (such as a commercial archive), but the ultimate responsibility for the quality, integrity, confidentiality, and retrievability of the documents resides with the sponsor. 

The function of storage and archiving should be specified and the role assigned to identified archivists. Access to archives should be restricted to authorized personnel. An archive index or log should be maintained by the archivists to record all essential documents that have been entered into the archive, and to track and retrieve documents on loan from the archive. 

The investigator should make the sponsor aware of the storage arrangements for the documents. If the investigator becomes unable to store the essential documents, the sponsor should be notified in writing so that alternative storage arrangements can be agreed. Similarly, if the investigator is no longer able to maintain custody of their essential documents, the sponsor should also be notified in writing, and the investigator/institution should see to it that appropriate arrangements can be made.

The documents to be retained by the investigator may be stored in commercial archives. This may also be an option in some member states for source data, when the hospital or institution is unable to retain subjects trial records relating to clinical trials for a sufficient length of time. 

The sponsor should retain all sponsor-specific essential documents so as to meet all applicable regulatory requirements of the countries where the product is approved, and where the sponsor intends to apply for approvals. If the sponsor discontinues the clinical development of an investigational medicinal product for any or all indications, routes of administration, or dosage forms, the sponsor should maintain all sponsor-specific essential documents for at least two years after formal discontinuation or in line with applicable regulatory requirements. Sponsor-specific essential documents should be retained until at least two years after the last approval of a marketing application in the EU and until no pending or contemplated marketing applications in the EU remain, or at least two years have elapsed since the formal discontinuation of clinical development of the investigational product.

These documents should be retained for a longer period if applicable regulatory requirements say so, or if the sponsor needs them. Record retention times for sponsors also apply to the records retained by contract research organizations or other agents of the sponsor, unless arrangements have been made to transfer the documents to the sponsor. Any transfer of ownership should be documented. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained.

For trials that will not be used in regulatory submissions, it is the responsibility of the sponsor to consider whether the results will or may be included in a marketing authorization application, and to take the necessary steps to ensure appropriate retention of the essential documents. Essential documents of the sponsor and investigator from trials that are not to be used in regulatory submissions should be retained for at least five years after completion of the trial, and for a longer period if laid down in local regulatory requirements, or by agreement with the sponsor.

Finally, independent ethics committees should retain all relevant records for a period of at least three years after completion of the trial and make them available on request from the regulatory authorities. The documents should be retained for a longer period if local regulatory requirements so demand.

The draft document is open for consultation until the end of Septemberso interested parties who wish to use their summer vacation for making their own comments have time to do so.            

View from Brussels

Many stakeholders have already commented on the EU?s incentives for pediatric drug development.

Checking In on Children, Checking Up on Files

This month, at the request of the editors, I will deviate from my usual format to address a recent Guest Commentary by my colleagues, Stephen Raymond and Gerald Meyer. My purpose is several-fold. First, this commentary published in the June 

 May 2001) addressing the concept of eSource. The issue is a very important one, and is not yet the subject of any specific guidance by the FDA or other regulatory authorities. As such, it is essential to air the full spectrum of thinking on this topic. Dr. Raymonds views map to one end of the spectrum, while I have often propounded the other end. Second, there appears to be a shift in the FDA approach to eSource involving trusted third parties that is very important to discuss and fully understand, as it may affect all clinical trials with a centralized data source, not just eSource trials.  The introduction of the trusted third party concept doesnt appear in regulation or guidance, but has been discussed openly in public conferences and informal FDA meetings, and is being implemented by many sponsors of Web-based clinical trials.

I will start with a prcis of the position of Dr. Raymond and Mr. Meyer. They argue that technology providers often amplify or limit aspects of regulation that extend beyond the actual regulation. In doing so, the technology providers can inhibit sponsors from having the courage to use technology to its fullest advantage. The specific example cited is that of eSource. They argue that, in my column, I have added words like investigator control or local control that go beyond the regulations which require the investigator to prepare, maintain, and retain case histories. They are concerned that I put a burden of local ownership on the investigator that goes beyond the literal and intended meaning of 21 CFR 11 and related guidance. There is much more depth and subtlety to their argument, and I refer the reader to both my original column and this commentary (

This is a good opportunity for me to share my regulatory philosophy and perspective with you. In my other life (other than a columnist, that is) I am the founder of a company that sells a Web-based clinical trial data management system. It is one that technically works equally well as an eCRF or as an eSource system. My approach to regulatory issues is not biased by the architecture of the EDC system my company developed. In fact, the system was built around my philosophy. In any case, I base my approach on several fundamental principles. The first of these principles is regulatory conservatismI dont believe in pushing the envelope to its greatest point. Rather, I would prefer to take a more conservative stance and let others be on the bleeding edge when regulatory issues are involved.

Secondly, I fundamentally disagree with the strict constructionism expressed in the guest commentary. Dr. Raymond and Mr. Meyer state: So one looks primarily to the regulations and the guidance. These do constitute what FDA in the full force of its deliberations wants. Here is where I deviate in my thinking. Much of the principle and practice of the U.S. pharmaceutical industry derives from the collective results of individual interactions with the FDA. Regulations hold the force of law and must be adhered to; guidance helps interpret regulations but doesnt hold the force of law. However, much of the practice of GCP, for example, was established over decades through modifications developed through discussions with FDA officials, the results of field audits, and discussions at both public and private (company) meetings. The concept of a three-part NCR form, double data entry, and other similar concepts used in the collection of clinical data in paper-based clinical trials did not arise in regulation or specific guidance. They were developed through collective interpretation of years of interactions with the FDA.

Similarly, key officials of the FDA (always confirming that they are expressing their own opinions and not that of the agency) have discussed eSource in public and private meetings, Food and Drug Law Institute (FDLI) public teleconferences, and elsewhere. Unfortunately, we do not yet have field inspection reports and other FOI documents to add to this interpretation. But these will follow over time.

As someone who follows this area very closely, I will try to summarize the consensus of these comments, as I see it. I have heard these in many open meetings, a number of closed meetings, and several explicit discussions with FDA officials. Even if I am exactly right about this today, I may be wrong tomorrow, as the area is still in flux. The disclaimer is that these are my opinions only, and dont hold the force of law.

The investigator must maintain case histories. This is directly from GCP 21 CFR 312 62.b. These are the investigators records, and he or she must prevent them from being modified without their knowledge. Though you wont find this phrase in 21 CFR 312, it is a fundamental principle of clinical research. It is the reason that three-part NCR CRFs existso that the investigator maintains an original copy of the CRF data.

Electronic data makes this much more complicated. Electronic medical records are often collected and stored by a hospital offsiteperhaps hundreds or thousands of miles from an investigator. Such reports shouldnt be a problem as an eSource if the investigator has access to these records and the hospital or data center are agents of the investigator in some way. This is the typical arrangement, required by law in many states. There should be no concern here if the systems are of sufficient quality to qualify as medical records. The problems with eSource arise when considering eSource into an electronic CRF. In this scenario there is no patient data other than that collected on an electronic CRF. There are three versions of this scenario, all with different implications for GCP. In each scenario the FDA has made it clear that the systems, validation, and adherence to operating procedures around the eSource trial would be subject to very close scrutiny, as the integrity and attributability of the data rested entirely in an electronic system. The three scenarios are:

 The eCRF collects the data locally on the investigators computer, or within the investigators network (centrally at a hospital, for example). This scenario doesnt represent an issue as long as proper security, validation, and data integrity precautions are followed concerning the local computer. The FDA has accepted primary electronic data for years and would not object to this methodology because it represents local investigator maintenance of the record.

 The eCRF collects the source data centrally into a server at a sponsors site. This is the most problematic of scenarios. It is the equivalent of an investigator sending all three copies of a paper CRF in for data entry. Even if one copy came back to the site for permanent storage, the attributability (a key component of the ALCOA provisionsattributable, legible, contemporaneous, original, accurate highlighted in the Guidance on Computerized Systems Used in Clinical Trials) of the data would be lost. Because the sponsor administers the clinical trials system and database, they could theoretically modify the data without the investigators knowledge. If a copy were later given to the investigator for archival purposes, there would be no way for the investigator to prove that it had not been modified.

One could argue that strict SOPs could obviate a problem, but the stakes and ease of manipulation are too compelling to permit this at this time. Perhaps over time, and with the use of a foolproof encryption schema (which is probably impossible to achieve) such a scenario could be allowed. However, it is my understanding currently that eSource directly into a sponsors server would not meet the FDA standards of GCP.

 The eCRF collects the source data centrally into a server at a trusted third party (TTP). This concept has only recently been articulated by the FDA (the earliest public mention of this that I am aware of was November 2001 at the FDLI phone conference). Essentially, the TTP hosts the trial and maintains the database and trial software.

Because the sponsor pays for the TTP, it may reasonably be assumed that the TTP is the sponsors agent. Therefore, SOPs or other procedures must clearly establish that the TTP acts, in reference to the data, as the investigators agent. If the SOPs are properly written to ensure that a record may not be changed without the investigators permission and knowledge, and appropriate safeguards are in place (perhaps a contract between the TTP and the site, or rigorous SOPs concerning data access and modification), then it should be possible to perform an eSource trial using a TTP.

When contemplating a TTP, one needs to keep the principles of GCP in mind. If the TTP hosts the trial, but all administration of the system and database are performed by sponsor personnel, this might not be viewed as substantially different from Scenario B. The TTP must give assurances (either contractually, or otherwise) to the investigator that their data will not be modified without their express knowledge.

The relationship between sponsor and TTP is one that is not yet clearly defined in practice or in guidance. As above, a simple hosting facility might not suffice. On the other end of the spectrum, a CRO that accepts Transfer of Obligations from a sponsor under GCP might also be seen as a sponsors representative rather than an investigators. Only time and experience will help to define these various possibilities.

In summary, it is certainly possible under current interpretations of GCP to perform clinical trials for submission using an eSource strategy for data collection. While the landscape is ever shifting, it is currently difficult, if not impossible, for companies to adopt eSource with confidence. The time has come for the FDA to directly address this issue through specific guidance. Only then will this argument be settled in a way that gives the industry sufficient comfort to proceed.            

Technology Viewpoint

Paul Bleicher shares his regulatory philosophy and perspective and defends his position regarding eSource, in response to June?s Guest Commentary.

eSource Redux

The revised user fee program (PDUFA III) signed into law in June by President Bush emphasizes the need to spur clinical testing and development of new drugs and biotech therapies. Sponsors will pay higher fees for filing New Drug Applications but may obtain more assistance from Food and Drug Administration staffers on designing study protocols and drug development programs, particularly for innovative and high-risk therapies. The program also provides the agency with more flexibility in how it can use fee revenues and backs several new initiatives to streamline drug development and approval. 


Congress approved the Prescription Drug User Fee Act (PDUFA) reauthorization in May as part of a broader antibioterrorism bill that enhances the ability of public health agencies to respond to bioterrorist threats. The user fee measure benefited from strong industry and FDA support for this 10-year-old program that has accelerated the drug approval process. Total approval time for new drug applications (NDAs) has decreased from about 23 months pre-PDUFA to less than 12 months. And priority applications now are processed in six months. FDA officials also believe that their efforts to communicate to industry what data to submit has increased overall approval rates from 60% of submissions to about 80% today. 

FDA has achieved these gains by collecting substantial fees from manufacturers. Total user fees generated about $135 million in fiscal year 2001 and are expected to total $162 million this year. Combined with government appropriations, the program will provide FDA with about $325 million in total resources for drug review activities this year compared to about $120 million in 1992. These added resources have allowed FDA to increase its review staff for drugs and biologics by more than 900 staff-years through the end of this year. 

However, FDA officials found in recent years that the added revenues failed to support the large workload increase generated by the program for FDAs Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER). The situation was aggravated by a decline in anticipated user fee revenues caused by a decrease in submissions along with an increase in waivers and exemptions. Because FDA must spend enough appropriated funds to match user fee revenues, years of flat annual budgets forced CDER and CBER to siphon off funds from other programs to cover application review activities. Consequently, FDAs real resources for many programs not covered by PDUFA, such as postmarket drug surveillance, had contracted since 1992. FDA staffers struggled to meet deadlines for reviewing investigational new drug applications (INDs) and supplements and for scheduling and participating in an increasing number of meetings with sponsors to discuss study protocols. 


To remedy these problems, FDA officials began lobbying for PDUFA revisions more than a year ago. The aim was to increase fees and to gain more flexibility as to how the agency used the fees. Patient advocates and health professionals backed the agencys plan to expand postapproval safety activities, including the review of drug advertising. FDA and manufacturers subsequently negotiated a proposal that Congress found acceptable and approved as part of the bioterrorism bill. 

PDUFA III not only increases user fees paid by industry, but also makes revisions to put the program on a sound financial footing. The updated program sets specific revenue targets which FDA can adjust upward based on inflation and changes in total application review workload. User fees are slated to total $223 million in fiscal year 2003, compared to $162 million this year, and should rise to $260 million in 2007. These totals will come from application fees, product fees, and establishment fees ($74 million for each group next year), which are calculated annually. The fee for filing a full NDA is $313,000 this year and is expected to hit $500,000 in the near future. Small companies filing their first NDA or biologics license application (BLA) can obtain a waiver, but sponsors now pay fees for filing pediatric supplements, which previously had an exemption. 

In return, PDUFA III tackles several thorny issues related to how FDA reviews applications, although it makes very few changes in basic performance goals in this area. The agency will continue to review and act on 90% of standard NDAs and BLAs in 10 months, and priority applications in 6 months. Efficacy supplements have similar time frames, although there are new goals to reduce review times for some resubmitted supplements.

One concern addressed by PDUFA III is FDAs tendency to issue more approvable letters to sponsors to meet user fee action deadlines, but to then take months and go through multiple review cycles before final approval. The legislation aims to resolve this problem by calling for:

	Fast notification to the sponsor of any substantive deficiencies identified in the initial filing. 

	Additional guidance on CDER and CBER filing review processes, including communication with the sponsor about easily correctable deficiencies, needed planning for advisory committee meetings, and procedures for negotiating final product labeling.

	Replacing the approvable action letter with a complete response letter, which informs the sponsor in detail about what deficiencies remain and what actions are necessary for FDA to approve the application. 

	Clarifying procedures for a sponsor to file a major amendment to resolve deficiencies or to resubmit an original application. 

	Further evaluation of FDA first-cycle reviews to see if these changes improve the process. The agency will use a portion of a $7 million new initiatives fund to identify best practices that facilitate the review process. FDA also will conduct a broader analysis of CDER and CBER review processes to identify the need for system redesign or process reengineering. The fund also could be used to support access to external experts and to advance information management tools.


In addition to reducing delays in application approvals, the user fee reauthorization contains several initiatives to facilitate drug testing and development. The bill continues to encourage meetings between FDA and sponsors to discuss protocols and study plans. It spells out how companies should request formal meetings and procedures for documenting meeting discussions and agreements. 

Several new provisions aim to avoid disputes over protocol designs and application reviews and to assist sponsors in developing study plans that meet regulatory requirements:

	Formal program to resolve major disputes over procedures or scientific matters that may arise during product development or FDA review. This sets time frames for FDA to address appeals and for sponsors to provide additional data when requested. 

	Procedures for sponsors to request FDA evaluation of whether a protocol for a critical therapy will meet FDA scientific and regulatory requirements. This allows sponsors to submit questions about specific study issues (such as dose range or clinical endpoints) and gain assurance that FDA will adhere to the resulting agreement on design, execution, and analysis of an important clinical study.

	Additional assistance for sponsors developing biotech therapies. A manufacturer may request that FDA hire an independent consultant to review a clinical trial protocol for pivotal studies involving important new treatments. 

	Pilot tests to see whether even more interaction between the agency and sponsor will spur development of fast-track drugs and biologics. A second pilot will test a rolling review process. FDA will accept certain reviewable units of an application prior to submission of a complete NDA or BLA. FDA will develop guidances for implementing these tests and will hire an outside expert to evaluate their impact on drug development and review. 


The most notable innovation in PDUFA III is its authorization for FDA to use fee revenues to expand postmarketing surveillance of new products during the peri-approval period following approval of a new drug. This period will be two years for most products and up to three years for products considered to be higher riskthose that require a black box or bolded warning, a medication guide, or restricted distribution. The agency also will expand its ability to use outside health information databases to independently evaluate the use of new drugs with important safety concerns.

This initiative will encourage sponsors to develop risk management plans as part of drug development and to discuss with FDA relevant safety information and the need for additional postapproval safety studies before filing an NDA. A risk management proposal will assess limitations on safety information gained from clinical trials and present risk management tools to address known and potential risks. This includes identifying those risks that should be targeted in postapproval surveillance and examined in Phase 3 studies. FDA also gains the authority to publicize the failure of any company to complete agreed-on postmarketing studies. 

A final provision in PDUFA III calls for FDA to centralize information systems that track and fund the PDUFA program. This is part of an IT infrastructure consolidation initiative for all of HHS. It will establish a centralized process for all electronic submissions involving drugs and biologics, including the Common Technical Document developed by the International Conference on Harmonisation. 


Although Congress basically accepted and codified the PDUFA III agreement crafted by FDA and industry, legislators included several of their own provisions. One addition requires the agency to consult consumer and patient advocacy groups, health care professionals, and academics in the next round of user fee negotiations, which will begin in about four years. FDA has to publish the resulting PDUFA revision to address complaints that this years agreement was developed behind closed doors. 

The legislation also authorizes specific additional funding for CDERs Office of Drug Safety and its Office of Generic Drugs to expand their activities. And it boosts support for the Division of Drug Marketing, Advertising and Communications (DDMAC) to enhance its review of drug marketing materials.

However, some controversial measures were dropped from the final bill. A provision to provide an antitrust waiver for manufacturers that collaborate on bioterrorism counter measures was omitted, as was an effort to codify FDAs mandatory pediatric rule, which had become controversial in recent months. There also was a move to establish user fees for medical device makers, but that effort collapsed at the last moment.            

View from Washington

PDUFA III boosts manufacturer fees to expand postapproval surveillance and support new FDA review initiatives.

New User Fee Program Aims to Spur Drug Development

Feature Article

Everybody wants faster cycles and and quicker turnarounds with NDAs. In the U.S., will it soon be possible to go from testing to approval in 1000 days?

Developing New Drugs in 1000 Days

Studies show that electronic diaries get better results than paper diaries. These authors explain why.

Applied Clinical Trials-08-01-2002

Cross-(Dys)Functional Teams

Checking In on Children, Checking Up on Files

eSource Redux

New User Fee Program Aims to Spur Drug Development

Developing New Drugs in 1000 Days

Paper vs. Electronic Diaries