Building quality measures into the regulatory review process

1 Assessing performance and setting targets -- 2 Current regulatory reforms and improvements in the review process -- 3 Current regulatory reforms: CBER -- 4 Improving the review process: The view of the Japanese MHW -- 5 Comparing the performance of the Canadian TPD with other regulatory authorities -- 6 Measuring performance: The view of the TGA -- 7 Why have targets for the review process? The view of the EMEA -- 8 Why have targets for the review process? An individual viewpoint -- 9 Key milestones in the regulatory review process -- 10 How do you measure the quality of the scientific assessment and the review process? The view of the MCA -- 11 Ensuring the quality of the scientific assessment and the review process: The FDA’s good review practice initiative -- 12 Outcome of syndicate discussions -- Meeting participants.

Effective immunization programs have markedly diminished the incidence of vaccine-preventable diseases. As a result, there now exists in society a lower awareness of the actual risks associated with the diseases themselves and a greater prominence of the potential risks of adverse effects associated with vaccines.Concern regarding public reactions to new vaccine safety issues may place pressure on policymakers and/or health care providers to act quickly in response to new information. However, this concern must be tempered by the necessary caution required to assess the intended and unintended risks and benefits of any action undertaken. The interplay of these potentially competing demands is well illustrated by the recent safety concern involving the use of thimerosal in vaccines.Thimerosal is a mercury-containing compound that has been widely used as an antimicrobial agent in vaccines for over 60 years. Human exposure to mercury may have potentially significant health consequences. By mid-1999, the Food and Drug Administration (FDA) had discovered that children could be exposed to an amount of mercury from vaccines that exceeded 1 of 3 existing federal safety thresholds. After this realization, the organized medical and public health communities in the United States became involved in a series of urgent and intense discussions to determine an appropriate response to the issue. This manuscript describes and analyzes the process that led to the July 7, 1999, joint American Academy of Pediatrics (AAP)/US Public Health Service (PHS) statement on thimerosal,1 with the goal of suggesting improvements for managing similar vaccine safety concerns in the future.We conducted structured interviews with over 15 individuals involved in the discussions and negotiations leading to the joint AAP/PHS statement on thimerosal. The individuals represented both the governmental agencies and nongovernmental organizations involved, including the FDA, the Environmental Protection Agency (EPA), the Centers for Disease Control and Prevention (CDC), the National Vaccine Program Office (NVPO), the AAP, and the American Academy of Family Physicians (AAFP). Interviews were conducted through face-to-face meetings or by telephone between January and April 2001. Table 1 lists the individuals interviewed who allowed their identities to be published.The development and implementation of immunization policy in the United States is a cooperative effort among many entities in the public and private sectors (Table 2).The concern over thimerosal in vaccines originated from a confluence of independent events, 1 informal and 1 formal, within the FDA. In the spring of 1998, some individuals within the FDA's Center for Biologics Evaluation and Research (CBER) began to informally consider the increased number of recommended vaccines and the amount of substances, such as mercury, contained in them to which vaccine recipients were exposed. Available literature to help quantify their concern was limited.The formal identification of thimerosal as a concern arose through the FDA's efforts to comply with the Food and Drug Administration 2Modernization Act.2 As mandated by Congress, Section 413(a) of the Act required the FDA to compile a list of drugs and foods that contain "intentionally introduced" mercury compounds and to provide a quantitative and qualitative analysis of these compounds within 2 years of the Act's enactment.The FDA's previous formal review of thimerosal in biological products had occurred in 1976. The convergence of concerns over mercury in vaccines that occurred within the CBER beginning in April 1998 prompted the agency to reassess the risks of thimerosal.3One of the steps of this risk assessment was to investigate the potential exposure of humans to thimerosal in vaccines. Based on the information submitted by industry and FDA internal data, the CBER determined that thimerosal was present in over 30 licensed vaccines in the United States.4,5 The amount of mercury by weight present in each of these vaccines was calculated. The CBER then referred to the recommended childhood immunization schedule to determine the amount of mercury to which young children may be exposed. Of the vaccines that a child could receive in the first 2 years of life, those that contained thimerosal were the 2 available formulations of the hepatitis B vaccine and some formulations of the diphtheria-tetanus-acellular pertussis and Haemophilus influenzae type b vaccines. Looking at cumulative exposure over the first 6 months of life, an infant 6 months old who received all recommended vaccine doses on schedule could be exposed to up to 187.5 μg of mercury.Another step in the risk assessment process was to determine whether thimerosal actually constituted a true health risk; that is, whether there were data demonstrating that this amount of mercury could be potentially harmful to children. To identify whether there were any known health risks from exposure to thimerosal, the CBER conducted a literature review and queried the Vaccine Adverse Event Reporting System, a national surveillance system for voluntarily reported adverse events associated with vaccines. The CBER found that at low doses, thimerosal has been associated with rare hypersensitivity reactions, such as persistent skin sensitization at the site of vaccination. At very high doses (ie, 1000 times higher than levels found in vaccines), thimerosal has been reported to cause neurologic and renal toxicity.An early assessment of the health risks of all forms of mercury by the World Health Organization (WHO) found that insufficient information was available to perform risk calculations for human exposure to ethyl mercury compounds, the type of mercury contained in thimerosal.6 However, the WHO did note that the limited data available suggested that ethyl mercury was probably less hazardous than methyl mercury, because it is metabolized faster in the body.The WHO and 3 US governmental agencies—the FDA, the EPA, and the Agency for Toxic Substances and Disease Registry (ATSDR)—had developed independent guidelines for safe exposure to methyl mercury (Table 3).7–10 Because no guidelines exist for ethyl mercury exposure, the FDA used the guidelines for safe exposure to methyl mercury as a guide for determining whether the mercury (ethyl) dose from thimerosal in vaccines approached a level of concern or health risk.The existence of 3 differing US federal guidelines for methyl mercury was a source of confusion and contention in determining the appropriate response to concern regarding thimerosal in vaccines. Each agency developed their guidelines for different purposes. The most conservative of these guidelines was the level established by the EPA to serve as a warning of mercury in the environment to trigger additional investigation. The ATSDR guideline is set below levels that might cause an adverse health impact in those most sensitive to a particular substance. The FDA guidelines were developed as safe limits for long-term consumption of food contaminated with mercury, particularly fish, which is the main exposure route of humans to methyl mercury. No guidelines were available to assess the risk of exposure in bolus doses by intramuscular injection.Nevertheless, the existing methyl mercury guidelines were the best information available at the time for assessing risk from ethyl mercury exposure. The CBER calculated exposure limits for each of these guidelines based on the average weight at various percentiles in female infants between birth and 26 weeks of age (Table 4). Based on these calculations, the CBER determined that potential exposure to mercury from the recommended childhood vaccines in the first 6 months of life could exceed the EPA methyl mercury guideline, but not the ATSDR, FDA, or WHO guidelines. However, the CBER was unable to determine with certainty whether exposure to thimerosal in vaccines was harmful.In April 1999, results from the preliminary risk assessment were discussed at an internal FDA meeting, and participants realized that there was a clear need for additional data. The CBER began to consult with toxicologists both within the FDA and at the National Center for Environmental Health, and several vaccine researchers, including Neal Halsey, MD, Director of the Institute for Vaccine Safety at Johns Hopkins University. The FDA also initiated discussions with vaccine manufacturers regarding the need to develop thimerosal-free vaccines.3Dr Halsey was invited by the FDA to an internal meeting in mid-June 1999 where he was asked to provide feedback on the results of their preliminary risk assessment regarding thimerosal. On learning of the FDA data, and personally verifying the calculations of the levels of mercury to which children could be exposed, he believed that the issue warranted serious concern and urgent action. At the time, Dr Halsey was soon to complete his term as Chair of the AAP Committee on Infectious Diseases (COID). Dr Halsey previously worked within the CDC's immunization program and had been a member of the Advisory Committee on Immunization Practices (ACIP). As such, he had extensive experience and professional relationships within the US immunization policymaking arena. Beginning around June 24, 1999, Dr Halsey informed many of these contacts of his concern regarding the potential health effects of thimerosal and the results of the FDA's preliminary risk assessment. After notifying the Director of the CDC's National Immunization Program, Dr Halsey met with CDC personnel at the National Immunization Conference on June 25. He also informed several other individuals, including the incoming Chair of the COID, the Chair of the ACIP, and a member of the AAP Board of Directors. In addition to his concern regarding the potential health effects of mercury exposure in infants, Dr Halsey expressed the need for urgent action on the issue because the FDA was planning to send a letter to vaccine manufacturers in the beginning of July 1999 regarding the need to remove thimerosal from vaccines, at which point the information about thimerosal would become public. He believed that publicity surrounding this issue, without action on the part of the PHS and/or the AAP, could result in long-term damage to public confidence in the national immunization system.After Dr Halsey informed these initial contacts of his concerns regarding thimerosal, conversations began to occur among the parties. The Interagency Vaccine Group (IAG) held a conference call on June 28 and reviewed the information from the FDA's preliminary risk assessment. After this call, the IAG formed a special workgroup to address the thimerosal issue. CDC immunization officials also conferred with the AAP, vaccine companies, and internal CDC toxicologists.Significant differences of opinion surfaced regarding the accuracy of the exposure and risk-assessment information concerning thimerosal, its importance, and the need for any immediate discussion or action.To quickly bring representatives of several organizations involved in immunization policymaking together to discuss the issue, a meeting was organized by Dr Halsey and Dr Cooper for June 30, 1999, at the AAP offices in Washington, DC. The selection of the venue for this meeting was deliberate. The initial course of action for the government normally would have been for the ACIP and the National Vaccine Advisory Committee (NVAC) to meet to discuss the issue. However, governmental advisory boards are required by the Federal Advisory Committee Act to provide adequate public notice of meetings and publish meeting agendas in the Federal Register. Given how quickly some individuals believed a meeting should occur, it was not possible to officially convene these advisory bodies in such a short time frame. By having an informal meeting at the offices of the AAP, a frank discussion of the scientific and biological veracity of all available information could take place without delay. As a result, however, this meeting precluded the formal involvement of the ACIP and the NVAC.Drs Cooper and Halsey developed a list of invitees, which included representatives of the CDC, FDA, EPA, AAP, vaccine manufacturers, and toxicologic consultants. An initial goal of the meeting was to achieve consensus on a course of action, as many believed that public presentation of differing views would likely confuse practitioners and parents, and potentially undermine confidence in the national immunization system.At the meeting, FDA representatives shared the results of their preliminary risk assessment, outlining what was known and unknown about the issue and describing the difficulties in determining whether the level of mercury in vaccines should be of concern. Because of the complexities in interpreting the data regarding the potential risk of harm from thimerosal, there was disagreement among the parties present as to its significance. Disagreements existed between organizations, within organizations, and among the toxicologists present at the meeting. Some participants believed strongly that the potential threat to health from thimerosal was significant; others believed that there was no clear evidence that thimerosal was harmful, particularly when compared with the clear health risks of delaying childhood vaccines. The 2 AAP committees represented at the meeting, the COID and the Committee on Environmental Health, were in sharp disagreement on this point. There was also a varied sense of exigency, with some participants believing that urgent action was required, whereas others thought the process should slow down to include other parties in the discussion and address perceived significant gaps in the scientific data. Actions proposed by participants at the meeting ranged from immediately stopping administration of all vaccines containing thimerosal to children under 6 months of age to encouraging vaccine manufacturers to expedite the elimination of thimerosal from vaccines.An overriding concern expressed by all parties at the meeting was the need to maintain the public's trust in the US immunization system by striking the appropriate balance between acknowledgment of the potential risk of harm from thimerosal and the actual risk of harm from not immunizing against vaccine-preventable diseases.It became clear during the June 30, 1999 meeting that no consensus would be reached that day regarding an appropriate course of action. Sharp disagreements regarding the clinical significance of thimerosal exposure were not resolved. Specific individuals who felt most strongly regarding the potential health risk of thimerosal exposure stated that they would independently make public statements if their respective organizations did not support their contentions. The meeting concluded with all participants agreeing that no statement would be released by any individual or organization until after the July 4th weekend, and that discussions between the PHS and the AAP would continue in an attempt to achieve a unified public statement. Leadership in both the AAP and the PHS believed that releasing a joint public statement was crucial for preserving the public's trust in the immunization system.PHS officials in the CDC and elsewhere believed that vaccine manufacturers should be encouraged to expedite the elimination of thimerosal from vaccines, but did not want to make any changes to the childhood immunization schedule. However, CDC officials also felt strongly that it would be in the best interests of the national immunization system and the public's trust for a statement to be developed jointly with the AAP. This prompted David Satcher, MD, PhD, the US Surgeon General and Assistant Secretary for Health, to be involved in the negotiations.After the June 30 meeting, there was significant debate within the AAP as to the appropriate course of action to be taken. Over the next several days, there was constant reconsideration and revision of positions taken among both individuals and committees.On review of available information and opinions, the AAP Board of Directors decided to put forth the position in their negotiations with the PHS that the birth dose of the hepatitis B vaccine be temporarily delayed. They considered the risk of disease to be low except for infants of HBsAg-positive mothers. The Board of Directors believed that hospitals should already have procedures in place to determine the hepatitis B status of mothers and treat the infants of HBsAg-positive status mothers appropriately.Other parties were informally involved in the discussions leading to the joint statement. The AAFP did not think the issue warranted such urgency and believed that the health effects data for methyl mercury on which the EPA guidelines were based were questionable.Many conference calls, meetings, and sharing of draft statements occurred within and between the AAP and the PHS over the course of the July 4, 1999 holiday weekend. The Surgeon General held several discussions with the AAP president to negotiate a compromise position. Although they were extremely concerned about both the short- and long-term consequences of delaying administration of the hepatitis B vaccine, PHS officials agreed to the recommendation to present a unified position to the public.The joint statement was officially released in the late afternoon of July 7, 1999,11 and was published in the MMWR Morbidity and Mortality Weekly Report on July 9, 1999.1First and foremost, it is clear that all parties involved in this process acted in the manner they believed was in the best interest of children in the United States. Even parties that differed most strongly never doubted the intent or purpose of those with whom they disagreed.Only 2 weeks transpired between the time that leaders of the major national organizations involved in US immunization policy learned about the issue of thimerosal in vaccines and the release of the joint AAP/PHS statement. During that time, these individuals and their organizations worked diligently to develop a response that they believed balanced the potential risk from exposure to thimerosal with the actual risk of vaccine-preventable disease and would ensure continued public confidence in the nations' immunization system. Considering the complexity of the information available and the gaps in information relevant to specific concerns, it is not surprising there was significant disagreement regarding the potential risk associated with thimerosal. To some, the process could be considered a success, in that compromise was reached and the "crisis" was addressed. However, others have publicly the that the recommendation to the birth dose of hepatitis B vaccine practitioners and put infants at risk for hepatitis B vaccine as to that the process was a of how not to public health of the IAG would have first learned of the thimerosal issue from FDA who would have informed the of its review of the thimerosal in vaccines. In this however, an individual of the government was the first to many of these soon the FDA should have is a of as is how information should have been other parties. The FDA was to an issue with the IAG when there were many surrounding the potential health risks In the FDA must be sensitive to issues to any under its IAG is to among federal agencies with vaccine issues through meetings and other To the IAG must achieve a balance between that are informed of and agencies to data to other parties the information is released to the public. such to be there must be confidence among the parties that their all from and shared efforts with each the must be as independent and to its of this issue is to ensure that the and of the are not under the or perceived or of any the through the that serious be by the Office of the Secretary for Health and Human to the of the of the including the of and the of meeting that occurred at the AAP offices in Washington, on June 30, 1999, was a in the discussions leading to the joint statement. the of this type of meeting and the in which it was organized was for the AAP, the of action was of the of the Board of are as to the of who or was concern expressed from many was the of vaccine industry representatives at the meeting. The meeting occurred the time of the vaccine safety in Congress, and in a environment in which of between industry and immunization policymakers had been Some participants at the meeting believed that having industry representatives at a meeting could have this may also have the of some meeting the of the vaccine industry to a immunization system be Vaccine manufacturers a of vaccine development and and their in different of immunization policy is concern is that some parties did not in this meeting such as the AAFP or representatives of hospitals that would be by the in the hepatitis B the of the 2 federal immunization advisory the ACIP and the did not in the initial thimerosal because of the perceived of the Federal Advisory Committee Act on meetings on very short The CDC and the have reviewed the and have found that exist for meetings on an to the birth dose of hepatitis B vaccine was not taken by any to the the risk of thimerosal exposure with the known risk of of hepatitis B disease was for However, in some leading to the joint AAP/PHS of the potential impact of delaying the birth dose of the hepatitis B vaccine did not receive some in of stopping the birth dose of hepatitis B vaccine, there was acknowledgment of the potentially significant of the of hospitals the the for this policy to these or the of procedures for determining the hepatitis B status of mothers. There to be effort to the existing literature on the impact of changes in immunization and the times for the of there was an confidence by some in the of hospitals to all mothers for hepatitis B status previous had of such of the impact of the joint statement on infant hepatitis B are now beginning to be have that some hospitals all with hepatitis B vaccine, including those to HBsAg-positive possible is the of information or of the recommendation by hospitals and Because of the of appropriate for and the hepatitis B status of this in policy has led to the of at 1 infant from hepatitis have also that many hospitals have not to doses of the hepatitis B vaccine the of thimerosal-free The of the first dose of hepatitis B vaccine at birth is illustrated by a recent that that children who received the first dose at birth were likely to complete the hepatitis B times of regarding immunization that all parties involved to the short- and long-term intended and unintended consequences of their proposed This type of analysis could take the of the and structured risk assessment process used by other government such as the of the major issues concern and urgency among all parties was the manner in which the would the issue. over the accuracy of in and for vaccine issues in is well However, an overriding issue is the of how should concern over the time of for public or individual health with policymaking must balance concern over the risk of public regarding safety issues with concern over the to ensure that information be to the public.The FDA the safety and of products they are for use and the process of a constant of products available to However, the of thimerosal an to FDA In the when thimerosal was for use in this there were limited available to assess for the of there is no for the FDA to vaccine with is in to some other federal such as the In was that be by the EPA years. Because no such process has been for the FDA, thimerosal not In for a containing mercury, the of most concern is on system At this time, the FDA has no for of the products it the FDA not have a to identify the cumulative amount of thimerosal, which children would receive over the course of the recommended immunization schedule. Each vaccine was for use as an independent agent and the amount of thimerosal contained in each individual vaccine no concern. was when the cumulative amount from all the vaccines contained in the recommended immunization schedule was calculated that concern that should consider to the FDA the to perform of vaccine In that the FDA its and the FDA develop a for of the cumulative amount of to which individuals may be exposed as a result of specific federal of the issues to all parties involved was the existence of differing federal for exposure to mercury from the EPA, the FDA, and the Although each agency had a different purpose in a specific safety the that there was no clear federal consensus on this issue was This allowed different parties to the discussion to over to support their federal agencies that have differing safety for exposure to specific to develop a federal consensus on safe exposure levels determine under which the different guidelines are to be than 1 federal is each agency should be with the for determining a different safety AAP is an organization for its to the of the health and of children. the internal debate that place within the AAP on this issue involved disagreement on the course of action that would be of to the children of the United AAP Board of Directors to its committees for and information regarding specific issues on which it must set However, the exists that the course of within the was in some than the Board of Directors on this issue from specific individuals were to the they may have represented the of the AAP is very that all be to maintain use of this in times of This help ensure that the consensus of than specific individuals, are to help guide the AAP Board of Directors regarding policy have on a of immunization The of these has been and At point efforts have been to information of those involved in immunization policy and in the or review of from the Institute of are now to in such committees for of and having their publicly and public if have the potential to cause significant and professional involvement of leading in the on childhood vaccines were to soon after the June 30, 1999, meeting at the AAP As such, concern over the manner in which any action or might be perceived in this type of environment a of concern and over many this was perceived as a course of action under by a process not in the best interests of the immunization system or children. This also to the development of a and the to act in interviewed but not of the parties involved in this As such, have an and assessment of the events that place in late June and early July However, there exists the that some information may not have been In these interviews were conducted 2 years after this process there may be some of the information process that in the in immunization as a result of concern to thimerosal was and Although there are significant differences of opinion regarding the of the the immunization system in the United States and was by the Program for and Health,

e17554 Background: The duration and complexity of regulatory review processes are increasingly associated with the slow pace and high cost of clinical trials. To evaluate and minimize the impact of these factors, City of Hope (COH), a NCI-designated Comprehensive Cancer Center, developed a strategic initiative to improve the efficiency and effectiveness of its clinical research review processes. The ongoing initiative is supported by Six Sigma-based techniques for problem identification and process optimization that have been successfully applied in other industries. Methods: The Six Sigma process improvement methodology known as DMAIC (Define, Measure, Analyze, Improve, and Control) was applied to five different clinical trial submission types (new study submissions, amendments, continuations, internal adverse events, external adverse events) reviewed by the COH Institutional Review Board (IRB), Cancer Protocol Review and Monitoring Committee (CPRMC), and Data and Safety Monitoring Board (DSMB). A consistent set of metrics and expectations were created for each review process to evaluate pre-review queue times, review process durations, submissions returned for corrections, and submissions returned with conditional approvals. Results: Over 7,900 submissions received during a 15 month period were evaluated quarterly to identify opportunities for improvement and the effects of previously implemented solutions. Multiple root causes for submission defects and delays were identified, including: (1) staffing and training deficiencies, (2) suboptimal workload distribution, (3) unclear policies and processes, (4) submission standardization opportunities, and (5) workflow automation and other information technology opportunities. Ongoing remediation efforts have yielded substantial improvements. Conclusions: Although Six Sigma process improvement techniques were originally developed for manufacturing applications, they can be applied in a clinical research setting to improve regulatory review processes. The methodology was most effectively introduced incrementally via application to specific problems rather than a traditional top-down implementation. Support provided by NCI P30 CA33572. No significant financial relationships to disclose.

THE AUGUST 24, 2006, DECISION BY THE US FOOD AND Drug Administration (FDA) to approve over-thecounter (OTC) sales of the emergency contraceptive Plan B—1.5 mg of levonorgestrel taken after unprotectedsexual intercourse—wasamajordevelopment ina long and contentious regulatory process. Since the drug is more effective the sooner it is used, the delay in obtaining it imposed by its prior prescription-only status limited its effectiveness. In the interest of making Plan B available more quickly when needed, the distributor (Women’s Capital Corp, Washington, DC) applied to the FDA in April 2003 for approval of OTC status. In December 2003, a joint FDA advisory committee voted 23-4 in favor of approval. It did so on the basis of evidence that the drug is both effective and safe and that it met all FDA criteria for OTC availability. The committee also took into account the likelihood that improved access could prevent at least some of the 3.1 million unintended pregnancies (including the 25 000 that result from rape)—and, hence, some of the more than 1 million elective abortions—that occur in the United States every year. Although the FDA almost always accepts its advisory committees’ recommendations, in the case of Plan B it twice refused to grant approval of OTC status; the current approval decision came nearly 3 years from the time of the committee vote. As 2 of the committee members who voted for approval, we like many others were surprised and troubled by the FDA’s extended inaction. The agency justified its position primarily on the grounds that the number of women aged 14 to 16 years in the manufacturer’s actual use study (5% of the 585 women actually enrolled in the study) was too small to allow meaningful inferences about the consequences of its use in younger women. Although that narrow statistical point may have some merit, it cannot explain the tortuous and highly irregular process of decision making, uncovered in a subsequent Government Accountability Office inquiry, that led the FDA to withhold initial approval. It is therefore difficult to avoid the conclusion that the Plan B regulatory process was “a story of the entanglement of politics, science and religious beliefs. At the heart of it is the question of whether emergency contraception is or could be a form of abortion.” Public assertions such as the recent claim that “the proven ‘anti-implantation’ action of the morning-after pill is really nothing other than a chemically induced abortion” certainly seem to support that interpretation. The authors of such claims have offered no supporting evidence regarding Plan B’s mechanism of action. On the contrary, what has been offered are assertions that “the exact mechanism of action of Plan B is unknown” and that “the dirty little secret is, nobody really knows.” Such sweepingstatements of uncertainty not only directly contradict the claim that Plan B’s anti-implantation action is “proven” but also promote general misunderstanding and misuse of doubt in science. Doubt is the very core of the scientific enterprise, an essential part of the process by which scientific hypotheses are tested; on the other hand, doubt is sometimes exploited as a powerful way of subverting sound science-based public policy. Driven by the belief by some that interference with implantation is a form of abortion, the politics of doubt about Plan B’s contraceptive mechanism appears to have contributed not only to the delay in its OTC availability but also to the continuing refusal by some emergency services to provide the drug to rape survivors as well as refusal by some pharmacists to make it available to individual patients. In fact, a great deal is known about how Plan B prevents pregnancy. Now that the drug will be more widely available, it is more important than ever that the scientific evidence on its contraceptive mechanisms be as widely known as possible, so that decisions about its use can be fully informed. A summary of that evidence follows.

The influence of patient advocates on FDA regulatory decision making has increased. Despite enhanced engagement with FDA, there remain challenges to achieving the regulatory goals of patients within FDA's regulatory framework. Gaps exist between patient advocates' knowledge of the agency's processes and FDA's need for rigorous, clinically meaningful patient experience data. This study examined the policy process in which patient experience data are collected by patient advocates and provided to FDA for regulatory decision making. Semistructured, narrative interviews were conducted with 14 professionals working in patient advocacy or at FDA. The purpose was to examine, in depth, participants' perceptions and experiences regarding this new regulatory process. Interviews were coded and examined for themes. The use of patient experience data by FDA is an evolving regulatory process. Participants identified a number of barriers and contributors to regulatory success. Well-organized and sophisticated patient advocacy groups with access to scientific and policy expertise are more likely to find success meeting FDA's patient experience data requirements. A conceptual model of this regulatory process was developed. Use of patient experience data by FDA has the potential to positively influence the regulation of medical products in the United States. Success within this new regulatory process will depend on clear guidance from FDA regarding the collection, analysis, and use of patient experience data. Patient advocacy groups must enhance internal capacity and expertise while engaging in substantive collaborations with FDA and other stakeholders in order to meaningfully contribute to the regulatory review of new therapeutics.

The determination of whether a drug or medical device is safe and effective requires statistical proof of valid clinical trial information. Quantitative biostatistical measures from anatomic and functional medical images are now providing objective and reproducible measures of drug and device effects. These highly precise biostatistical measures can be used to quantitatively analyze the efficacy and occasionally the safety of these drugs and devices. Since medical imaging information is digital, or is readily digitized, it can be visualized and measured in a variety of ways to evaluate the validity of the data. Moreover, with advanced image processing and data visualization tools, this information can be electronically organized and submitted directly to the U.S. Food and Drug Administration (FDA) reviewer. Biomedical imaging and computer-based data visualization technologies have the ability to substantially decrease the time required for clinical development and regulatory review while providing more valid data.

The Office of Information and Regulatory Affairs (OIRA) within the Office of Management and Budget (OMB) has played an important role in the federal regulatory process for many decades. The regulatory review process is multifaceted, and several Executive Orders and laws have been enacted over the years that added various requirements to improve the process. Existing requirements regarding drinking water regulation under the Safe Drinking Water Act (SDWA) are briefly reviewed in this article, including the following: administrative procedures; evaluation of significant regulatory actions; consideration of small entities; paperwork reduction; achieving regulatory flexibility; unfunded mandates reform; input from state and local governments; input from Indian tribal governments; protection of children; actions affecting energy supply, distribution, or use; use of voluntary consensus standards; environmental justice; SDWA consultation provisions; effect on technical, financial, and managerial capacity; congressional review; and, defining a new regulatory process.

To date, the turn toward market-based regulatory tools in the environmental, health, and safety context has tended to focus on taxes, tradable permits, and information disclosure rules, With comparatively little attention devoted to environmental assurance bonds. This paper argues that environmental assurance bonding offers particularly attractive regulatory approach for contexts--such as the present state of nanoscale science and engineering--in which both the risk and the benefit sides of the regulatory equation are characterized by great uncertainty. Historical examples and existing scholarly analyses of environmental assurance bonding are reviewed, and the resulting lessons are situated within the larger debate over economic cost-benefit balancing and precautionary approaches to environmental law and policy. In particular, the paper argues that environmental assurance bonding displays the virtue of symmetric humility, paying due heed to the dynamism and complexity both of sociolegal systems such as markets and of biophysical systems such as aquatic ecosystems. ********** I. INTRODUCTION II. UNCERTAINTY AND COMPLEXITY IN THE ENVIRONMENT A. Sociolegal Systems B. Biophysical Systems III. UNCERTAINTY AND COMPLEXITY IN THE MIND A. Rationality in Social Choice B. Rationality in Individual Choice IV. THE PROMISE OF ENVIRONMENTAL ASSURANCE BONDING A. Environmental Assurance Bonding B. Symmetric Humility V. CONCLUSION I. INTRODUCTION Human history becomes more and more race between education and catastrophe. H.G. Wells, Outline of History (1920) On January 30, 2009, U.S. President Barack Obama issued memorandum to the heads of executive departments and agencies expressing an intention to study and revise the manner in which the Office of Information and Regulatory Affairs (OIRA) within the Office of Management and Budget (OMB) conducts regulatory impact review, including economic cost-benefit analysis of proposed rules. He wrote: The fundamental principles and structures governing contemporary regulatory review were set out in Executive Order 12866 of September 30, 1993. A great deal has been since that time. Far more is now known about regulation--not only about when it is justified, but also about what works and what does not. Far more is also known about the uses of variety of regulatory tools such as warnings, disclosure requirements, public education, and economic incentives. Years of experience have also provided lessons about how to improve the process of regulatory review. In this time of fundamental transformation, that process--and the principles governing regulation in general--should be revisited. I therefore direct the Director of OMB, in consultation with representatives of regulatory agencies, as appropriate, to produce within 100 days set of recommendations for new Executive Order on Federal regulatory review. Among other things, the recommendations should offer suggestions for the relationship between OIRA and the agencies; provide guidance on disclosure and transparency; encourage public participation in agency regulatory processes; offer suggestions on the role of cost-benefit analysis; address the role of distributional considerations, fairness, and concern for the interests of future generations; identify methods of ensuring that regulatory review does not produce undue delay; clarify the role of the behavioral sciences in formulating regulatory policy; and identify the best tools for achieving public goals through the regulatory process. Under pressure from nongovernmental organizations such as the Center for Progressive Reform, (1) the Executive Order review process was opened up for broader public comment. The resulting input suggested that, despite the President's suggestion that a great deal has been learned about the design and impact of regulations, civil society remains deeply split regarding the desirability of regulatory cost-benefit analysis (CBA) as tool for evaluating proposed policies. …

The use of state of art digital instrumentation and control (I&C) in safety and safety related systems in nuclear power plants has become prevalent due to the performance in terms of accuracy, computational capabilities and data archiving capability for future diagnosis. Added advantages in computer based systems are fault tolerance, self-testing, signal validation capability and process system diagnostics. But, uncertainty exists about the quality, reliability and performance of such software based nuclear instrumentation which poses new challenges for the industry and regulators in using them for safety and safety related systems. To obtain adequate confidence in licensing them for use in NPPs, CBS were deployed gradually from monitoring system to control system (i.e, non-safety, safety related & lastly safety systems). Based upon the experience over a decade, AERB safety guide AERB/SGID-25 was prepared to prescribe the criteria and requirements to assess the qualitative reliability of such software based nuclear instrumentation. This paper describes the regulatory review and audit process as required by the above guide. Further, Software Configuration Management (SCM) is an important item during life cycle of CBS, whether it is design phase or operating phase. Configuration control becomes necessary due to operation feedback, introduction of additional features and due to obsolescence. Therefore configuration control during operating phase for CBS becomes all the more important. This paper elaborates on the regulatory approach adopted by AERB for regulatory review and control of design modifications in operating phase of NPPs. This paper also covers a case study of AERB audit on verification & validation activities for software based safety and safety related systems used in an Indian plant.

Continual learning in medical devices: FDA's action plan and beyond

Novel emerging technologies such as tissue engineering, which utilize the approaches of molecular and cell biology, biotechnology, as well as materials science and engineering, are being used in the development of a wide range of biomedical products developed by industries regulated by the U.S. Food and Drug Administration (FDA). The FDA's mission is to promote and protect the public health by ensuring the safety and effectiveness of pharmaceuticals and medical devices, including those manufactured by novel technology, as assessed by scientific principles and methods. Regulatory review is conducted on a product-by-product basis. To accomplish its mission over the wide range of products in its regulatory purview, the FDA has six centers, each staffed with the scientific and regulatory expertise to evaluate the products in the center's jurisdiction. Recent legislative and regulatory changes are designed to simplify and facilitate the administrative process for evaluating novel combination products emanating from such interdisciplinary technology as tissue engineering and to resolve questions of product regulatory jurisdiction. Under the new procedures, the FDA may designate a lead FDA center for product review based on the primary mode of action of the combination product, with additional center(s) designated to assist in the evaluation in a collaborative or consultative capacity. In addition, FDA centers have increased their cooperation and information sharing with regard to evolving interdisciplinary technology. The FDA InterCenter Tissue Engineering Initiative was established to develop information on intercenter efforts in the evaluation of tissue engineering applications and to identify areas for further consideration. The FDA InterCenter Tissue Engineering Working Group, comprised of staff from the Center for Biologies Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), Center for Drug Evaluation and Research (CDER), and Center for Veterinary Medicine (CVM) has developed a Draft Report considering recent developments in tissue engineering and scientific and regulatory issues in the product application areas. The Working Group has identified generic safety and effectiveness issues for consideration by the research and development community in its development of products. The FDA centers are using multiple approaches at their disposal in the evaluation of tissue engineered products including research, data and information monitoring, regulatory guidance, training and education, and cooperation with public and private groups.

Statistical methods that are commonly used in the review and approval process of regulatory submissions are usually referred to as statistics in regulatory science or regulatory statistics. In a broader sense, statistics in regulatory science can be defined as valid statistics that are employed in the review and approval process of regulatory submissions of pharmaceutical products. In addition, statistics in regulatory science are involved with the development of regulatory policy, guidance, and regulatory critical clinical initiatives related research. This book is devoted to the discussion of statistics in regulatory science for pharmaceutical development. It covers practical issues that are commonly encountered in regulatory science of pharmaceutical research and development including topics related to research activities, review of regulatory submissions, recent critical clinical initiatives, and policy/guidance development in regulatory science. Devoted entirely to discussing statistics in regulatory science for pharmaceutical development. Reviews critical issues (e.g., endpoint/margin selection and complex innovative design such as adaptive trial design) in the pharmaceutical development and regulatory approval process. Clarifies controversial statistical issues (e.g., hypothesis testing versus confidence interval approach, missing data/estimands, multiplicity, and Bayesian design and approach) in review/approval of regulatory submissions. Proposes innovative thinking regarding study designs and statistical methods (e.g., n-of-1 trial design, adaptive trial design, and probability monitoring procedure for sample size) for rare disease drug development. Provides insight regarding current regulatory clinical initiatives (e.g., precision/personalized medicine, biomarker-driven target clinical trials, model informed drug development, big data analytics, and real world data/evidence). This book provides key statistical concepts, innovative designs, and analysis methods that are useful in regulatory science. Also included are some practical, challenging, and controversial issues that are commonly seen in the review and approval process of regulatory submissions. About the author Shein-Chung Chow, Ph.D. is currently a Professor at Duke University School of Medicine, Durham, NC. He was previously the Associate Director at the Office of Biostatistics, Center for Drug Evaluation and Research, United States Food and Drug Administration (FDA). Dr. Chow has also held various positions in the pharmaceutical industry such as Vice President at Millennium, Cambridge, MA, Executive Director at Covance, Princeton, NJ, and Director and Department Head at Bristol-Myers Squibb, Plainsboro, NJ. He was elected Fellow of the American Statistical Association and an elected member of the ISI (International Statistical Institute). Dr. Chow is Editor-in-Chief of the Journal of Biopharmaceutical Statistics and Biostatistics Book Series, Chapman and Hall/CRC Press, Taylor & Francis, New York. Dr. Chow is the author or co-author of over 300 methodology papers and 30 books.

Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real World Experience

Modern-day licensing began in the 1940s with the formation and constitution of the World Health Organization (WHO) and its recommendation that global standards be established in relation to the safety, quality and efficacy of biological, pharmaceutical and similar products and extending this to their labelling and advertising (Crout 1998). However, there is little conformity between countries worldwide as to how the review is conducted including what stages comprise the process, who carries out each stage, what criteria are employed, how long it takes or, indeed, whether there is a review process at all. About 30 % of WHO member states either have only a very rudimentary drug regulatory authority or none at all, whilst only 20 % are thought to have a well-developed drug registration system (Ratanawijitrasin and Wondemagegnehu 2002).

The Result of a Phase 1 Study of Selinexor in Combination with High-Dose Melphalan and Autologous Hematopoietic Cell Transplantation for Multiple Myeloma