Although children enjoy the best health care in history in developed countries, they are still not benefiting sufficiently from modern advances in pharmaceutical treatment. In some parts of the world, measures to address this situation are underway. Pediatric legislation is being addressed in the United States, and the issue is discussed within the European Union and in Japan. In fact, pediatric assessment of new drugs at an early development stage is now mandatory in the United States. This will result in the commitment of pharmaceutical companies to perform pediatric research once safety and efficacy data are available in adults. If the disease doesn't exist in children, then this requirement will be waived. In exceptional cases, where a new drug offers hope in a lethal or severe disease, an accelerated clinical development will be considered.  

Pediatric drug development is evolving into an area of shared responsibility of health authorities, clinicians, and pharmaceutical industry and parentpatient advocacy groups. Implementation will require ethical, therapeutic, and resource considerations. In addition, a fair compensation must be considered for those companies that are making additional investments in this area. 

					Child health care and progress of modern pharmaceutical treatment				

Pharmaceutical treatment of children has undergone fundamental changes over the last hundred years. Changes in this framework were provoked by catastrophes that mobilized enough public concern to address this issue.

 One such catastrophe occurred in the early 20th century. A number of children in the United States died of contaminated diphtheria vaccine. This led to the U.S. Biologics Control Act in 1902.

 In 1937, 105 patients, including 34 children, died after drinking an antibiotic preparation named Elixir Sulfanilamide. No one had performed human safety testing prior to prescribing of the drug. This tragedy led to the passing of the Federal Food, Drug and Cosmetic Act in 1938,

 and required pharmaceutical companies to submit a new drug application report to the FDA showing drug safety before the interstate shipping of any new pharmaceutical agent. The Act also banned dangerous drugs as well as false and misleading labeling.  			

In the 1960s, the use of thalidomide in pregnant women led to thousands of children born with phocomelia, a shortening or complete absence of one or several limbs.

 Legislation was introduced in the United States that required companies to prove both safety and efficacy of new drugs only after this catastrophe.  

					Drug discovery and clinical drug development 

Drug discovery and clinical drug development were processes hardly separated from each other a century ago. Chemists who synthesized new substances often tested the agents on themselves or members of their family. The Declaration of Helsinki

 was established by the World Medical Association following unacceptable trials by medical doctors in various countries. The evaluation of a new drug or treatment scheme is a fairly new concept, and is legitimate as systematically conducting experiments in patients. It took decades to establish the standard that patients should be fully informed when they participate in such an experiment. The framework that resulted, Good Clinical Practice (GCP), was first developed in the United States. It has expanded over the last decades and gained worldwide recognition.

 Although many have found it to be bureaucratic, GCP adherence ensures standardization and acceptability by most health authorities. The European Union's Clinical Trial Directive

 has been greatly influenced by this framework. 			

In 1963, Harry Shirkey described how the legislative changes introduced in response to drug toxicity in children proved advantageous to adults. However, this led to fewer drugs being recommended for use in children due to the insufficient clinical evidence of safety and efficacy. Shirkey used the term "therapeutic orphan" to describe this situation.

 This transfers the responsibility and the liability of treating a child to the treating physician/pediatrician and leaves the pediatrician with the alternative to not prescribe the drug as well as withhold potent medicine—or to prescribe the drug off-label.  

Pediatricians and physicians have learned to improvise their treatment. In most countries dosing regimens were developed for children—but with different frameworks. Most countries have one or several dosing schemes published by different institutions.

 Experiences with children's treatment have been published, and over time the pediatric community gained aconsiderable body of experience. Still, the pediatric/medical community remains several years to decades behind. As a result, children are disproportionally treated with older, less modern drugs.  			

					Globalization of modern drug development 				

A century ago, drug discovery was done by a multitude of national companies. Until a few decades ago, national states were eager to protect their own market and industry. Clinical trials performed abroad were often not accepted and had to be repeated in the respective country or region where registration was requested. Today, large international companies plan the drug development on a worldwide basis; it is not relevant where the clinical trial is performed. What

 important is that the data can be compared from the different countries where patients have been recruited. In Europe, some people believe that increased requirements for pediatric data will lead to more research conducted there. This will not happen automatically: European pediatric research institutions and networks are presently competing with investigation sites elsewhere. Some countries, such as Germany, are establishing national pediatric clinical research networks. At present, the research networks are not European-wide. In some disease-specific areas, e.g., oncology or pneumology, international cooperation has advanced further.  			

Several key factors have facilitated this internationalization. Most important are the two processes known as GCP and the International Council on Harmonisation, ICH. GCP applies to clinical trials

 while ICH sets the framework for the entire drug development and registration process. This must also be agreed upon by the health authorities and pharmaceutical industry of the United States, Europe, and Japan regions.

					Integration of pediatric assessments into the general drug development process

In the United States, there have been several attempts to inspire the pharmaceutical industry to generate more data in children. The first successful attempt was the creation of the voluntary Pediatric Exclusivity (PE) within the FDA Modernization Act (FDAMA) 1997, re-authorized as BPCA (Best Pharmaceuticals for Children Act) in 2002.

 In 1997, PE was accompanied by the Pediatric Rule, which gave the FDA authority to mandate pediatric clinical development in drugs where the authority saw a high clinical need. When the Pediatric Rule was struck down by a U.S. federal court in 2002, both houses of the government rapidly agreed with the new legislation: the Pediatric Research Equity Act (PREA).

 The rule re-established the FDA's authority to mandate pediatric drug development. PREA makes a pediatric assessment mandatory at the pre-IND meeting with the FDA. PREA and BPCA are linked by a common sunset of 30 September 2007, and it will be a political decision of both the U.S. Senate and Congress if this legislation will be continued. Through the link between PREA and BPCA, pharmaceutical companies and FDA are encouraged to negotiate a pediatric development plan that will at the end of the patent life result in a six-month prolonged exclusivity that protects drugs from generic erosion. 			

Following the U.S. example, a draft pediatric regulation was published by the EU Commission on 29 September 2004

 and will be debated in the EU parliament and by the EU Health Council in the coming months and years. A final EU legislation can be expected no earlier than 2006. The draft EU regulation provides mandatory pediatric drug development combined with a reward of six months patent exclusivity, but focuses more on mandatory requirements. A Pediatric Committee will supervise inclusion of a Pediatric Investigation Plan into all drug development plans.  

Due to the evolving framework in the U.S., the EU, and in Japan,

 pharmaceutical companies need to integrate pediatric assessments into the standard drug development process and to build up pediatric competence. ICH E 1115 describes three major scenarios of drug development in children:  

 1). severe or life-threatening diseases in children only, and no sufficient therapeutic alternatives are available 

2). severe or life-threatening diseases in children and adults and no sufficient therapeutic alternatives are available

Only in scenario 1) or 2) is an early development of a new drug in children ethically justified, taking into consideration the risk of exposure to a new substance. 

The discussions of the evolving pediatric legislative framework in the United States and Europe have helped to highlight the place of pediatric issues in drug development. Safety and efficacy data in adults will have to be generated before clinical trials in children are initiated where acceptable therapeutic alternatives are on the market and a "deferral" is issued for pediatric development. If the health authority confirms that the disease does not exist in children, no pediatric development will be required ("waiver"). Scenario 1) and 2), i.e., early pediatric development of a drug targeting a life threatening or serious disease for which no acceptable therapeutic alternatives exist, will therefore remain an exception. The major diseases of this type of scenario could be cancer or genetic diseases that cause early death in children.  

If a company decides to accelerate clinical drug development in children, test batteries in preclinical safety & toxicology and the development of pediatric formulations will have to be shifted into earlier development stages. Pediatric formulations can take up to two years for development. The decision to accelerate pediatric drug development requires a careful balance of therapeutic, financial, and logistic risks and benefits. No company has unlimited resources, and resources that are invested into failed projects will be missed in other projects with a high therapeutic potential.  

The 20th century witnessed significant changes in child health care. The general increase in the level of education, and the availability of information combined with technological advances, allows parents to communicate among each other and become partners in the complex process of child health care. Parents' knowledge of their children are now increasingly recognized by the medical community. Parents and advocacy groups should be treated as partners in child health care. This can be demanding, but the potential benefit of using the knowledge of parents and the influence of advocacy groups in campaigning for children's health issues far outweighs the challenges.  			

Pharmaceutical companies and health authorities are developing a shared responsibility in assuring that children benefit as early as possible from innovative therapies and new drugs. To achieve this goal, both sides need to strive towards a high level of trust between each other. For pharmaceutical companies this will mean keeping commitments made to health authorities and complying with the social responsibility of the respective company. For health authorities this will mean not to overload pharmaceutical companies with research requests that might result in unacceptable bureaucratic burden. It is further hoped that the health authorities of Japan, the United States, and EU, as well as other regions, harmonize their requests to pharmaceutical companies.  			

The more we push forward the boundaries of scientific knowledge, the more we see how children could benefit further. It would be desirable if the 21st century was described in the future as the time when children fully benefited from pharmaceutical progress.

Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation 

, "Paediatric Medicines: Global Development and Clinical Investigations," 

3. P. Wax, "Elixirs, Diluents, and the Passage of the 1938 Federal Food, drug and Cosmetic Act," 

4. H.B. Taussig, "A Study of the German Outbreak of Phocomelia," 

5. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. http://

6. ICH E 6 Guideline for Good Clinical Practice http://

www.ich.org/MediaServer.jser?@_ID=482&@_MODE=GLB

www.esf.org/sciencepolicy/141/Directive.pdf

8. American Academy of Pediatrics, Committee on Drugs, "Unapproved Uses of Approved Drugs: the Physician, the Package Insert, and the Food and Drug Administration: Subject Review," 

9. UK pediatric formulatry Medicines for Children, http://

www.rcpch.ac.uk/publications/formulary_medicines.html

, Wissenschaftliche Verlagsgesellschaft, Germany, June 2003. 

www.fda.gov/cder/pediatric/S-650-PREA.pdf

13. Proposal for a regulation on medicinal products for paediatric use and amending Council Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004 (presented by the Commission), http://

14. A. Uchiyama, "Pediatric Clinical Studies in Japan: Regulations and Current Status," 

15. ICH E 11: Clinical Investigation of Medicinal Products in the Pediatric Population. http://

www.ich.org/MediaServer.jser?@_ID=487&@_MODE=GLB

Articles

Feature Article

Pharmaceutical companies need to integrate pediatric assessments into the standard drug development process and build up pediatric competence.

Pediatric Drug Development

Weyers, Wolfgang (New York: Ardor Schribendi, Ltd., 2003) 755 pages.


This is a BIG book-broad in scope, lots of pages, and full of examples and pictures. It is intimidating and requires of its readers much reflective analysis. It alternatively shocks, rewards, and saddens because it provides so much irrefutable detail about researchers' inhumane treatment of subjects.

In the preface, the author states:
"Only by awareness of man's inhumanity to man medically, and the assessment of the factors that led to and enabled those abuses to be carried out, is there any possibility that physicians and researchers in the future will shrink from the idea of ever perpetrating them."

There are an overwhelming number of examples in the 19th and 20th centuries of deliberate infection of persons with pathogenic organisms (bacteria, viruses, fungi) for the expressed purpose of producing disease including syphilis, gonorrhea, warts, leprosy, and a variety of tropical diseases. Trials of therapeutic interventions were also poorly constructed and the morality of human experimentation was placed outside ethical codes characteristic of civilized living. The guilty parties, all named and pictured in this book, range from almost complete unknowns to several Nobel Prize winners. Even the application of informed consent in some of the most famous experiments in the history of medicine, such as Walter Reed's yellow fever tests in 1900, were flawed due to content and process issues. Not surprisingly, publications of these studies deliberately omitted procedural details that would have been ethically objectionable.

During the first half of the 20th century, German MDs suffering from lack of moral courage and strict obedience to authority committed some of the worst atrocities in the history of medical research. The author, however, is also unsparing in describing Japanese abuses involving anthrax glanders, cholera, and the plague. During and after World War II, Great Britain and the United States also performed plenty of unethical clinical research on prisoners, conscientious objectors, and active duty personnel. What set the Nazi's experiments apart from those of the allies was not the research itself or the quality of it (weak), but the "woeful lack of respect given to an individual test subject by the Germans."

The author goes on to discuss the infamous Tuskegee study and other stateside experiments at the Willowbrook School, the Fernald State School in Waltham, Massachusetts, and other institutions housing vulnerable populations. These studies, like the Nazi experiments, also focused on so-called "undesirables."

The last few chapters of the book focus on IRBs, recent University of Pennsylvania and Johns Hopkins deaths, the slamming of the door on prison research, the birth of bioethics and the Declaration of Helsinki. The book concludes with a fascinating discussion of ethical relativism:

"After his experiments on mentally disabled children had been uncovered, the dermatologist, John S. Strauss, stated that 'to judge something that took place in the 1950s by the standards of the late 1990s is inherently futile and, in many cases, unfair.'"  

The author points out that to accept this position, one would have to believe that the medieval practice of torturing criminals, 18th and 19th century slavery, and Nazi medical research were simply acceptable practices of that era that have since been abandoned. The author contends that past experimentation must be identified and cannot be evaded.

There are only mild criticisms of this work. It relies excessively on dermatology research to the exclusion of other therapeutic areas. It fails to mention the International Conference on Harmonization and FDA GCP rules. And it does not condemn administrators and nonphysicians for their contributions to abusive research.

This book should be read with Jonathan Moreno's 

Undue Risk: Secret State Experiments on Humans

 to obtain a more complete picture of contemporary unethical human experiments. It is recommended for readers who wish to more fully understand the reasons why GCP is so important.

Douglas R. Mackintosh, DRPH, MBA, MS HYG, is president of GCPA, Inc., 12208 Fairfax Station Road, Fairfax Station, VA 22039, (703) 988-9080, fax (703) 988-9082, e-mail: GCPadits@aol.com, http://members.aol.com.gcpaudits.

Media Review

The Abuse of Man: An Illustrated History of Dubious Medical Experimentation

Orphan drug development may take a back seat to profit and loss concerns. 


The most delicate aspect of European Union regulation of orphan drugs was pushed center-stage right at the end of 2004: how much money companies are entitled to for these products.

It came as no surprise. For all the pious talk of meeting unmet needs for neglected sufferers of minority illnesses, the tough reality is that money is the principal motivator for filling in the gaps in the therapeutic arsenal, just as it is for the development of more mainstream treatments. This is no negative reflection on the drug industry. Most new medicines come from private enterprise, and private enterprise has to be profitable, or it collapses-taking with it the chances of new medicines.

The awareness of this central challenge was at the heart of the European Union initiative earlier this year to commission a study into the commercial aspects of orphan drug development-and particularly whether prices are reasonable. The EU had already in 2000 put in place a procedure to stimulate orphan drug development, because it sensed a duty to assist European patients suffering illness without treatments. Reluctantly, it recognized that if the money isn't right, new orphan drugs won't appear. 

The reluctance sprang from a competing duty the EU sensed: to keep down the costs of health care, including the costs of orphan drugs (the orphans currently on the EU market cost from E6,000 to E300,000 per treatment per year). So it set up the study in the hope that it would help find the happy medium between reward for health care innovation and thrift for health care funding-by, for instance, checking on profitability levels after an orphan has been five years on the market, or limiting the market exclusivity conferred on it. As the study points out, member states have little negotiating leverage: these medicines have no therapeutic alternative and are often still investigational new drugs.

The European Union's official hopes, of course, conflict directly with the instincts of the pharmaceutical industry producing (or thinking of producing) orphan drugs. Drug firms in Europe gave a broad welcome to the 2000 mechanism for promoting orphan development. They are reluctant to admit, however, that so soon after the scheme was up and running, the EU should be seeking to find out how it can get more bang for fewer bucks, or more efficacy for fewer Euros. The drug industry's experience of pricing control mechanisms in Europe is long and bitter, and there is suspicion over the discussions now starting over how a new set of controls might be introduced.

 which appeared in late November from the health care consultants Alcimed, says the situation is confused: the conditions for marketing orphan drugs with European status in the EU 25 "are poorly understood and are a source of concern" for everyone in the market-member states, patient associations, and industry. "As yet," it says, "there is no consensus among the parties on an acceptable and feasible tool for measuring the profitability of an orphan drug."

It points to wide differences in prices paid by health care systems across the EU-Austria ranks highest in an assessment of annual cost per patient, followed by Germany and Denmark, with Finland, France, and Ireland representing the median, and Spain, Portugal, the United Kingdom, and Sweden at the bottom end of the scale.

In France (where conventional drug prices are notoriously low), a system allowing authorizations for temporary use permits companies marketing designated orphans to set their own price, with a guarantee of 100% reimbursement-leading, unsurprisingly, to high prices. By contrast, in the United Kingdom (where drug prices are normally comparatively high), the authorities exert strong pressure to keep orphan drug prices low. Meanwhile, Spain and Portugal retain their classical position of European countries with very low medicine prices.

The estimated potential annual turnover for the products covered by the study varies from E100 million to E1.5 billion. It demonstrates that some orphans may become small-time blockbusters, but are still well below the E7 billion turnover of the world's best-selling conventional medicine in 2002.

The industry may derive some comfort from the report. Europe's complex national pricing and reimbursement systems are largely to blame for wide price differences across countries, says the study. Typically, the ex-factory price of an orphan drug does not vary much from country to country-but once the various mark-ups and on-costs are taken into account, the price in the most expensive countries can be 70 percent more than in the cheapest countries.

And while it concludes that the average cost per patient of an orphan is higher than that of other medicines considered expensive in Europe, it points out that this cost is no higher than that of treatments with the same therapeutic target. The total cost of orphans currently accounts for only a small part of total medicinal product budgets.

Right from the outset, it dares to ask the key question: is this the right time to pose the question of profitability of orphan drugs? Given the relatively little experience with the scheme, an attempt to claw back some of its incentives may be premature, the study warns.

And it suggests that penalizing successful orphans by withdrawing or reducing the key incentive of market exclusivity "would risk substantially reducing the attractiveness of the regulation for the pharmaceutical industry." It could even have a spill-over effect on other orphan drug developers, discouraging the initiatives of new potential sponsors. 

Calculating "profitability" is fraught with difficulties too, the study concludes. How should it be conducted, it asks, for medicines such as Glivec that currently have two orphan indications? Or for products such as Onsenal, which has been granted an orphan indication but is already widely used for non-orphan indications? If the measure of profitability must involve only an orphan indication, for Glivec this means that profitability should initially be evaluated for chronic myeloid leukemia five years after the marketing authorization, granted on November 7, 2001, followed by another evaluation 6 months later for gastrointestinal stromal tumors, for which the marketing authorization was granted on May 24, 2002.

The study also casts doubt on the validity of the reasoning behind the proposed claw-backs for success. A member state might conceivably seek to withdraw marketing exclusivity in order to control health expenditures, it speculates. It goes on to argue that "the correlation between withdrawing market exclusivity and the price decrease of orphan drugs has not been established." If the aim is to seek price reductions by allowing direct competition, this is hardly likely to be successful in "a sector in which by definition it is not possible at the current time"-since the very nature of orphans is that they are for diseases for which treatments do not exist. 

Withdrawing exclusivity at five years would not help competition, the study goes on. Most orphans are protected by patents or the data protection system, so copies could not be marketed, and there is little incentive for development of a direct competitor with no prospect of market exclusivity as a reward.

Overall, the study goes a long way beyond its brief. Its key conclusion is that discussions of definitions of profitability of an orphan product are not only premature, but are also distracting attention from a more important challenge: providing patients with better access to orphan drugs via improvements to national reimbursement systems.

The EU scheme is still young, and all its aspects have not yet been implemented-in particular national incentives. "We have very little experience with the actual marketing of orphan drugs," it says, and those on the market have not yet had an opportunity to realize their potential. But, it says, it is accessibility to orphan drugs in the EU that "still requires considerable work and is undoubtedly the current priority."


1. "Study on Orphan Drugs," Aclimed, 2004, http://pharmacos.eudra.org/F2/orphanmp/doc/pricestudy/Final%20final%20report%20part%201%20web.pdf.			

View from Brussels

Orphan drug development may take a back seat to profit and loss concerns.

Paying the Price of Being an Orphan

Inadequate pre-approval testing and information disclosure may slow new drug development and change regulations.


The re-election of George W. Bush as president and continued Republican control of Congress reduce chances for any major expansion in health care coverage for the uninsured, or for Medicaid reform. Instead, the administration will champion social security and tax reform, which may include additional tax incentives for individuals and small businesses to obtain health coverage and establish health savings accounts.

Of particular importance to pharmaceutical companies is how the Bush administration finalizes the massive regulations and policies needed to establish the new Medicare pharmacy benefit. Direct government involvement in drug price negotiations is off the table, but rising health care costs and prices will draw intense scrutiny from both Republicans and Democrats anxious to restrain health care spending at a time of record budget deficits. To retain all the new benefits for seniors, including prescription drug coverage, policymakers will take a hard look at drug costs, utilization, and marketing and support efforts by Medicare drug plans to establish formularies, negotiate discounts, and support more treatment outcomes analysis. The key issue for pharma is whether the program boosts prescription drug use by seniors sufficiently to offset downward pressures on drug prices. 


The greatly expanded federal government involvement in paying for prescription drugs promises to heighten concerns in Washington about the Food and Drug Administration allowing unsafe drugs on the market. This is prompting a re-examination of new drug approval criteria and FDA oversight of marketed products. Initial revelations about antidepressants causing suicidality in children and patients using Merck's Vioxx suffering heart attacks have expanded to include a much broader range of therapies. The debate escalated markedly at a November Senate hearing when FDA safety officer David Graham cited serious safety issues with Astra-Zeneca's cholesterol agent Crestor, GlaxoSmithKline's asthma therapy Serevent, Pfizer's COX-2 inhibitor Bextra, Abbott's weight loss drug Meridia, and Roche's acne treatment Accutane. At the same time, FDA stiffened warnings about pregnant women taking Accutane and on proper use of the abortefacient Mifeprex (mifepristone or RU-486).

FDA officials insist that the Vioxx withdrawal and label changes demonstrate that the agency's drug safety system is working well. They maintain that approved drugs have benefits that outweigh risks and oppose proposals to establish an independent drug safety office. Nevertheless, some Congressional leaders and scientists have pointed to a too-cozy relationship between FDA and sponsors, and are investigating whether any parties tried to hide damaging information or mislead the public. Some experts are calling for re-reviews of approved drugs to ensure completion of Phase IV studies and to examine emerging safety signals. 

FDA has commissioned an Institute of Medicine study on the effectiveness of its postmarket review system, which will address the impact of establishing a separate drug safety office and the need for additional FDA authority to limit the use of unsafe products. FDA also has promised to publish final versions of three risk management guidances that were issued in May of 2004 and to hold more workshops and advisory committee meetings to discuss complex drug safety issues. But critics consider these steps inadequate to restore public confidence in the agency's ability to obtain full information on drug safety issues and to monitor appropriate drug use and prescribing after new therapies reach the market.


Concerns about drug safety promise to intensify efforts to expand public access to information about ongoing clinical trials and to full results of clinical studies. Sponsors have established a Web site to list study data voluntarily, but legislative proposals seek to mandate broader disclosure of both negative and positive research outcomes. In a related move, the National Institutes of Health (NIH) is finalizing an initiative to allow public access to the results of all NIH-funded research. Medical research societies with journals are questioning the cost of an NIH electronic publishing system and the timeframe for posting research results, as the debate accelerates on these issues.

On another front, FDA officials have promised to issue a major final rule revising labeling for drugs. This long-awaited policy adds a "highlights" section and reorganizes label information to help patients and physicians find key safety and prescribing information quickly. These changes support FDA electronic labeling initiatives and should facilitate government-wide efforts to provide medical information electronically as part of national e-prescribing and e-medical record systems. FDA also expects that these programs will encourage sponsors to submit clinical data and applications electronically to streamline review and approval processes. 


FDA efforts to lay out pathways to speed more new drugs to market would have been at the top of the 2005 priority list a few weeks ago; now all the turmoil about unsafe therapies is raising fears of tighter drug approval policies and curbs on R&D at companies embroiled in legal and regulatory battles. Despite this, FDA acting deputy commissioner Janet Woodcock will continue efforts to turn the March 2004 Critical Path report into new models for drug research and development. The agency has prepared an "opportunities list" of priority research activities that it believes will spur R&D and is seeking support from industry and academia in pursuing them. Key objectives are to develop new biomarkers and enriched study designs to streamline the costly clinical trial process. FDA also hopes to launch initiatives to develop research standards, test protocols, and more efficient data collection systems. 


In addition to drug safety and development, regulators and researchers will face a broad range of health care issues in coming months:

 The surprise shutdown of Chiron's Liverpool (UK) flu vaccine manufacturing facility in October and the resulting shortage of flu vaccine for this winter continues to focus public attention on vaccine research and regulation. Members of Congress are blaming FDA for failing to enforce manufacturing standards or recognize the severity of the problems at Chiron's plant. The situation is raising questions about the adequacy of FDA's foreign inspection program for manufacturers and of its enforcement approach. 

If Chiron is unable to correct its manufacturing problems and regain its license by January 2005, policymakers are likely to call for measures that will encourage manufacturers to enter the U.S. flu vaccine market. The list includes more support for research on new manufacturing methods; tax incentives for new plant construction; universal flu vaccination policy to broaden the market; government guarantees to buy back unused doses; and legislation to reduce the threat of liability charges against vaccine and drug manufacturers. 

 Even though Democrats failed to parlay support for increased purchase of drugs from Canada and other western nations into victory, the drug import campaign won't die down. For both political and fiscal reasons, the White House will be looking for ways to identify "safe" foreign sources of less costly medicines. Several new Republican senators championed broader drug importing as one way to expand access to affordable medicines and they will be seeking to fulfill their promises. 

 The Bush administration has supported generic drug development and marketing as a way to reduce drug costs for patients and payers without direct price controls. Now the debate is escalating over policies that could facilitate production of generic versions of biotech therapies. FDA held a public meeting on "follow-on proteins" in September and is co-sponsoring a workshop in February on the scientific issues surrounding this topic. Brand-name manufacturers maintain that full preclinical and clinical testing is needed to ensure that a follow-on protein is the same as an innovator biotech therapy. Generic firms counter that advanced analytical and manufacturing systems permit the development of similar biopharmaceuticals with an abbreviated testing process. FDA is examining whether its current regulatory approach can be extended to this area, but new legislation probably will be needed to clarify FDA's authority to approve generic versions of biotech drugs. 

 The flu vaccine shortage and the continuing debate over drug importing testify to the increasingly international nature of pharmaceutical research and product development. The Bush administration is under pressure to boost support for international efforts to combat the AIDS epidemic in third world nations, and cloning and stem cell research are drawing international scrutiny. A host of ethical and regulatory issues are emerging from the shift of more clinical trials to newly industrialized and developing nations where costs are lower and participants more available. These developments are challenging intellectual property protections for drugs and raising questions about third world access to needed therapies. 

FDA will continue efforts to harmonize new drug development and regulatory oversight by different nations. This year's focus will be setting global quality manufacturing standards. All these activities are slated to further focus attention on global price differentials for drugs, and on whether the U.S. market should underwrite biomedical research for the rest of the world.

 FDA faces new leadership, as well as a new home when it relocates most drug reviewers and chemists to its new White Oak campus. The move will provide an opportunity to reorganize the Center for Drug Evaluation and Research's Office of New Drugs and Office of Pharmaceutical Science, which is expected to alter how CDER reviews applications and collects information.

An early task for the new HHS secretary (see story on page 21) will be to name a permanent head of FDA, which has been led by an acting commissioner for much of the Bush administration. Leadership shifts at key House and Senate committees also will affect their approaches to dealing with issues affecting pharmaceutical companies and the nation's health care system.

Sidebar: Tommy Thompson Out and Michael Leavitt in at HHS


HHS secretary Tommy Thompson is leaving Washington to return to the private sector. President George W. Bush named former Utah Governor Michael Leavitt as the next head of the Department of Health and Human Services. In announcing his resignation, Thompson said that he is most proud of his role in overhauling Medicare, in making Americans more aware of health issues, in rebuilding the federal and state public health infrastructure, and in expanding involvement in the fight against AIDS. 

In an open exchange with reporters, Thompson stated that he is particularly worried about the nation's ability to protect against tampering of the food supply and to counter a pandemic flu outbreak. The secretary defended the administration's embryo stem cell research policy, insisting that stem cell research is limited more by a lack of trained researchers than by limits on federal funding. And he said that Congress should have provided HHS with authority to negotiate prices for the Medicare drug benefit.

Bush previously appointed Leavitt a year ago to head the Environmental Protection Agency, where Leavitt was embroiled in clean air issues that required his talent as an administrator and consensus-builder.

Leavitt faces some very difficult situations at HHS. A key challenge will be to manage HHS's vast range of public health and welfare programs during a period of shrinking resources. Bush wants to halve the federal deficit over five years, which puts spending for Medicare, Medicaid, and other health problems squarely on the chopping block. The big increases previously available to expand the National Institutes of Health already have disappeared. FDA is scrambling for resources to perform its mandated functions and will be hard-pressed to find any new money in its current budget.--Jill Wechsler

View from Washington

Drug Safety, Access Top Policy Issues for 2005

The data obtained by The Bellagio Child Survival Study Group

 has made the identification of priority research subjects more precise and relevant to developing countries. About 10.8 million children under 5 years of age die each year, mostly from preventable diseases (about 6 million), and almost all in poor countries. Sub-Saharan Africa accounts for 41% of these deaths; of the 42 countries worldwide with the highest mortality rates, 36 are African. The causes of these deaths are the familiar diseases of childhood: 25% of these sub-Saharan deaths are due to neonatal causes, 22% to malaria, 21% to pneumonia, 20% to diarrhea, and 8% to AIDS. Measles accounts for 1% of global death for those under 5 years of age.  

Roughly 6.8 million of these deaths could be prevented or treated by well-established and simple interventions against the main causes. However, global coverage of these interventions is under 50%. The key interventions are listed by Gareth Jones 

 and include breastfeeding, insecticide-treated materials, oral rehydration therapy, antibiotics for pneumonia, antimalarials, complementary feeding, water, sanitation, and hygiene. Several interventions need to be supported by better levels of evidence, which include rotavirus, pneumococcal vaccines, reduction of indoor air pollution, zinc for pneumonia, and intermittent antimalarial preventive treatment in infants.

Infant and child deaths in developing countries are often due to several risk factors and diseases, often acting synergistically (e.g., infectious diseases and malnutrition). The combined effects of these co-morbidities and multiple risk factors should be estimated collectively and independently. Accordingly, a major focus for research is to determine the most effective and cost-efficient approaches to providing these interventions at population level. Studies are required to determine the quickest route from knowledge to effective action, and must recognize that leadership, strong health systems, efficient use of resources, and poverty alleviation measures are critical elements.

At a recent workshop on Global Paediatric Research,

 Demisse Habte from the World Bank made a strong case for important infrastructural requirements. Habte stressed partnerships, fostering communication among researchers, tackling the "brain drain," building research capacity, training, advocacy, and ethical studies. Noting that only 3% of Cochrane Collaboration research were "effectiveness" studies, the issue of "the science of scaling up" of existing knowledge in the context of program implementation was repeatedly emphasized at this meeting. The gaps in knowledge of problems such as iron-deficiency, anemias, neonatal disorders, newer vaccines, and effect of birth spacing and obstetric care on infant and child survival also need attention through careful research. 

There remain many gaps in the evidence for effective action to improve child survival. These have been recently summarized

and are therefore not repeated here. Scrupulous examination of health delivery systems is an essential field for study.

 Sound data are required on epidemiology, services and community preferences, selection of appropriate interventions, scale of coverage with either selected or multiple interventions, matching supply with demand, and strengthening of health services. 

The Bellagio Group makes a strong case for directing resources and interventions for child survival to poor populations in all countries. In particular, it would address the inequities within countries as well as between countries. Victora 

 suggest the following as potential approaches for reducing inequities: improving knowledge and changing behavior; increasing access to water and sanitation; empowering women; rendering health care affordable, accessible, and user-friendly; enhancing human and other resources in facilities serving the poor, and providing adequate budget allocations. It is necessary to gather better evidence for the impact of all these approaches. 

Improving child health: Review of research

In a recent literature review of research for improving child health in developing countries, a set of key findings similar to those noted above were documented. These included research gaps in prevention of respiratory diseases and neonatal mortality (there are 4 million neonatal deaths worldwide every year), accessibility to vaccines, insufficient financial investments, inadequate selection of research priorities, and building of research capacity. 

HIV/AIDS is a catastrophe of vast magnitude, and Africa suffers disproportionately to the rest of the world. Studies to better understand, confront, and drive back this epidemic, and to prevent new infections and treat and care for those already infected, must unquestionably take precedence. However, we have just said that there is a huge agenda of unfinished responsibilities we owe to the majority of the world's children who do not receive the benefits of known or proven preventive and therapeutic measures. It follows that in the countries affected by the HIV epidemic, a balance must be established between research into the pressing demands of the majority—children sick and dying from easily treatable diseases—and the desperate needs of children at risk of or infected by HIV. Research funds in many countries in Africa are being diverted away from the former, given the prominence of HIV/AIDS, the fears and myths enfolding the disease, community awareness, and the escalating global response to it. Indeed, Gareth Jones and colleagues bemoan the "levels of attention and effort directed at preventing the small proportion of child deaths due to AIDS with a new, complex, and expensive intervention (that seem) to be outstripping the efforts to save millions of children every year with a few cents worth of (interventions). This must change."

 While this cautionary note could be questioned in the heavily HIV-affected region of southern Africa, in global terms we believe it is probably relevant. 			

By 2002 there were 3.2 million children (<15 years of age) living with HIV in the world; 800,000 children had become newly infected in that year and about 610,000 had died. This amounts to 1,671 child deaths per day, 70 deaths per hour and 1.2 deaths per minute! By the end of 2003, the figures for adults and children living with HIV/AIDS in sub-Saharan Africa were between 25.0 and 28.2 million, out of a global total of 34 to 46 million. In sub-Saharan Africa 3.0 to 3.4 million became newly infected with HIV (global total was between 4.2 and 5.8 million). There were 2.2 to 2.4 million deaths due to AIDS (global total was between 2.5 and 3.5 million).  							

Infants are mostly infected from their mothers, so antenatal prevalence figures are an important source of the extent of risk. These prevalences vary according to country and within countries. In southern Africa antenatal prevalences can be as high as 40% and over, in East Africa they are between 20% and 30%, and are lower in some West African countries. These figures are said to be higher than population-wide estimates. Accurate national figures of HIV incidence and prevalence are essential for developing policies and providing services. Such databases have to be strengthened or established in developing countries as they are a prerequisite for epidemiological and population-based studies. Although vertical transmission is generally accepted to account for about 95% of infant and child HIV infections, there have been dissenting voices. More research is required into the minority of infections (about 5%) from alternative sources of transmission such as sexual abuse, contaminated needles, blood products and tissue transplants, and injuries in health care settings. 

 found that 6.7% of children 2-9 years of age were HIV infected, while 4.7% of 10-to-14-year-olds were HIV infected. There is considerable scope for work determining the natural history and extent of HIV infection among children in different age groups in Africa. 

The intrauterine, intrapartum, and postnatal periods are when mother-to-child-transmission (MTCT) of HIV occurs. In developing countries MTCT at 24 months of infant age has been reduced from about 30%-45% to 16%-23% with the use of ARVs (antiretrovirals); the main effect has been on intrapartum transmission. It is widely recognized that in Africa, the percentage of HIV-positive women attending antenatal clinic (ANC) services who actually receive ARVs remains low. Attrition from the total numbers who attend ANCs occur in a cascade from those refusing HIV counseling, accepting HIV testing, returning for the HIV results, receiving the ARVs, and adhering to the regimen. Measures to improve this situation vary according to site and have to be addressed locally. 

There is a new cadre of healthcare workers who have to be trained: counselors. The number required per site, the training necessary, salaries, and regular support are all important and should form part of operational research. It is unclear whether a generalist counselor (who deals with counseling for HIV testing, infant feeding, ARV advice, and support) is preferable to a "specialist" single-issue counselor (one each for the three types of counseling). WHO has an excellent scheme for a comprehensive approach to pMTCT, preventing the transmission. This framework includes four levels of interventions: 

				2) Prevention of unintended pregnancies in HIV-infected women 

				4) Care and support for HIV-infected women, their infants, partners, and families. 

It will be very important to subject this broad-based approach to critical evaluation. For example, the social dimensions of the medium and long-term effects on family integrity, child growth and development, and the delay in orphanhood are putative benefits of extending care, especially ARVs, to the family. They can have major positive consequences. 

While some risk factors and the rates of transmission for the first two routes are documented, we have only an approximate understanding of the rates and determinants of breastfeeding transmission. Definitions of timing of transmission vary. Breastfeeding accounted for at least 24% and as much as 42% of overall transmission (intrauterine, intrapartum, and postnatal). The risk of transmission is constant throughout breastfeeding, and the risk is related to lower maternal CD4 count and male sex. The authors conclude that interventions to decrease breastfeeding transmission of HIV are urgently needed, and the mechanisms underlying the association between male sex and breastfeeding transmission should be further investigated.  

The role of the type of breastfeeding (exclusive versus mixed) on MTCT risks are being investigated in a number of African settings. The short, medium, and long-term impact of formula feeding and the avoidance of breastfeeding in HIV-infected populations on infant growth, development, and overall child mortality has to be monitored and evaluated. It is estimated that breastfeeding prevents about 13%-15% of all under-5 deaths in high and low HIV-prevalence  regions, respectively.

 It will therefore be of considerable interest to observe the impact of the policy choices governments make on breast or formula-feeding for HIV-infected women. 

There are at least four trials to assess the role of ARVs in reducing breastfeeding transmission: the results of two of these (SIMBA and MITRA) have been presented and show promising reductions of breastfeeding transmission associated with administration of ARVs to breastfeeding babies. However, the trial designs in both studies prevent firm conclusions on efficacy of the use of postnatal ARVs to reduce breastfeeding transmission. The use of HIV vaccines and passive immunization with specific antibodies to HIV in children are innovative approaches to preventing breastfeeding transmission. 

Much more work needs to be done to determine the ARVs employed and the implementation of trials to reduce mother-to-child-transmission of HIV-1. 

The all-embracing and comprehensive care of HIV-infected children, their mothers, siblings, and fathers is a challenge which now confronts developing countries. For the infant, the optimal management of the common and uncommon manifestations of progressive HIV infection, the concomitant opportunistic infections, and co-infections is still an open field for properly designed trials. For example, the most effective management of community-acquired pneumonias in HIV-affected populations has not been determined.  

Researchers will be constrained only by the limits of their imagination and creativity. At a minimum, these programs should be rooted in a milieu which ensures: 					

preparation and acceptance by the target communities 

strong information and data infrastructure 

dedicated budgets, procurement, supply and regular distribution of drugs, etc. 

Treatment programs should go hand in hand with prevention programs.  

There is a remaining lacuna in data on mortality of HIV-infected and HIV-exposed but uninfected children. Although natural history studies will probably be unethical, much can be gained by careful observation of treated children. The causes of differing child mortality rates according to geographical location in Africa, and the contribution of HIV/AIDS to under-5 mortality in HIV affected countries, are critical subjects for study. From some estimates, HIV/AIDS is responsible for up to 44% of child mortality in the high-prevalence regions.

AIDS orphans, all orphans, and vulnerable children, are often neglected by state health and welfare services, and frequently ignored by scientists. There are about 15.6 million AIDS orphans globally, 12.1 million of whom are in Africa, and possibly 391,000 in South Africa. In a recent national South African study,

 10% of children surveyed had lost a parent by the time they were 9 years old, and 25% had lost a parent by 15-18 years of age. There is much to be done in exploring and implementing the most effective support and rehabilitation measures for such children. 

1. Editorial, "The World`s Forgotten Children," 

2. R.E. Black, S.S Morris, J. Bryce, "Where and Why Are 10 Million Children Dying Every Year?" 

, "How Many Child Deaths Can We Prevent This Year?" 

 "Reducing Child Mortality: Can Public Health Deliver?" 

5. C.G. Victora, A. Wagstaff, J.A. Schellenberg, 

 "Applying an Equity Lens to Child Health and Mortality: More of the Same Is Not Enough," 

6. The Bellagio Study Group on Child Survival, "Knowledge into Action for Child Survival," 

7. A. Zipursky, "The Programme for Global Paediatric Research," workshop minutes (5 May, 2004) San Francisco, CA, USA. 

, "Improving Child Health in Developing Countries: The Critical Role of Research," 

9. N. Mandela, Human Sciences Research Council Study of HIV/AIDS, National Household HIV Prevalence and Risk Survey of South African Children, Human Sciences Research Council (2002). 

10. The Breastfeeding and HIV International Transmission Study Group, "Late postnatal Transmission of HIV-1 in Breast-fed Children: An Individual Patient Data Meta-analysis," 

11. N. Walker, B. Schwartlander, J. Bryce, "Meeting International Goals in Child Survival and HIV/AIDS," 

The data obtained by The Bellagio Child Survival Study Group has made the identification of priority research subjects more precise and relevant to developing countries.

Pediatric Research: Filling the Gaps

It is not intuitive that scientists, clinicians, and parents would allow the most complex, constantly evolving human beings—the pediatric population—to be treated with unstudied medicines and therapies, while demanding a high level of evidence for therapies for the adult population. Unfortunately, this happened during the recent decades of rapid scientific and therapeutic discoveries. Why would it be acceptable that a population that is growing, developing, and inherently highly variable would not be studied while the more stable, not growing, and less variable adult population would be? No one would argue that the 500- to 1000-gram infant is the same metabolically, physiologically or behaviorally as a preschooler or adolescent, much less a 70-kg adult. And yet we have prescribed, dosed and treated the pediatric population without pediatric studies of a drug's absorption, distribution, metabolism, elimination, or dosing, or without clinical trials to determine pharmacokinetics, pharmacodynamics, safety, and efficacy of the prescribed therapy.  

 Pediatric Trials: The Impact of U.S. Legislative and Regulatory Efforts			

In 1963, Dr. Harry Shirkey coined the phrase "therapeutic orphans" to denote the evolving situation with therapies used in the pediatric population.

 In 1977, the American Academy of Pediatrics called for adequate and well-controlled trials of the same quality and standards applied to therapies marketed for use in adults.

 In 1979, the Food and Drug Administration added a "pediatric" subsection to its label to permit more pediatric-specific information to be in the label.

 Despite the public call for more and better information on the therapies being used in children, we entered the 1980s with the majority of therapies being used in children having not been studied in that population.

 The era of development of therapies for HIV infections forced all concerned to recognize the serious consequences of such a failure. The first therapy approved for treatment of HIV (AZT-Zidovudine) was not available for children for many years after it had been studied and approved in adults. If a therapy is not being developed for the pediatric population, then there are no clinical trials in that population and limited access to a potentially new, life-saving therapy. Adults with HIV fought hard to have access to new therapies through such mechanisms as large, open treatment, investigational new drug (IND) programs and accelerated approval of new therapies for HIV. Therefore, new therapies were available not only through the usual approved and marketed drug process, but also available through the large expanded access programs and clinical trials programs for HIV therapies. This effort only highlighted both the lack of approved therapies and lack of access to clinical trials for new and promising therapies for the growing pediatric HIV population. 			

The crises of having children die because of lack of access or approved therapies propelled both NIH and FDA to develop approaches which would facilitate the development of pediatric trials of therapies for HIV. This approach would also illuminate the need for determination of new pediatric endpoints as well as pediatric trial design approaches. Pediatric trials became an important component of the drug development program for didanosine (ddi-Videx) and many subsequent therapies for HIV.  

In an effort to recognize that some data generated from adult trials could be used to avoid exposing children unnecessarily to duplicative information gathering, the FDA proposed a process called "extrapolation" in the early 1990s. Extrapolation was appropriate if the "course of the disease and the effects of the drug are sufficiently similar in adults and pediatrics...one may conclude that pediatric effectiveness can be extrapolated from adequate and well controlled studies in adults, usually supplemented with other information obtained in pediatric patients..." This mechanism was officially adopted by FDA in 1994.

  Though extrapolation is an important scientific and regulatory approach, it is not appropriate for many diseases or conditions. 			

In 1997, the FDA proposed, and in 1998 finalized, what was called the "Pediatric Rule."

 This regulation required all sponsors to develop studies for the pediatric population if they were to submit an application when there would be, or already was, substantial use of the product in the pediatric population or if the development of the product would result in a "meaningful therapeutic benefit" for pediatric patients. The limitations of this regulation were that it functionally applied only to applications submitted or to be submitted to the agency and to the adult indication under development. It was, however, very important in making everyone (sponsors, FDA, and researchers) begin to assess, think, and plan for pediatric needs early on in the drug development process. The Pediatric Rule did not go into effect until April of 1999, and FDA could not require studies to be submitted until December 2000, 20 months after the effective date. By October 2002, subsequent to a Court ruling, FDA was enjoined from enforcing the Pediatric Rule. The Pediatric Rule was effectively in force for less than two years before being enjoined. In December 2003, the Pediatric Research Equity Act (PREA) was enacted. This Act put into legislation most components of the Pediatric Rule and made the Act apply to all applications submitted since April 1999.

There was an important pediatric legislative initiative involving incentives to develop appropriate use information for drugs being used in the pediatric population at the same time as the activities surrounding FDA's Pediatric Rule efforts. Encompassed in the 1997 Food and Drug Administration Modernization Act was Section 111,

 an important step that provided an incentive for manufacturers to study products for which there would be a health benefit in the pediatric population to have studies conducted. This legislation enacted a voluntary process where FDA would define the products which needed pediatric studies, outline the necessary studies, and issue sponsors a Written Request (WR). The WR would contain the critical components (e.g., types of trials, number of patients) required to be performed if the sponsor were to be granted pediatric exclusivity. If the sponsor submitted studies which "fairly responded" to the WR, as determined by FDA's Pediatric Exclusivity Board, the sponsor received six additional months of marketing exclusivity. This process has been the "engine" that has moved pediatric drug development and, coupled with the Pediatric Rule and legislation, has been a highly effective pediatric drug development program. By September 2004, FDA had identified 294 products needing pediatric information, had defined the studies needed for these products, and had issued the WR. By this same date, studies have been submitted on 110 products and new labels with new pediatric information have been completed for 79 of these products. 

By the time of FDA's 2001 Report to Congress on the effectiveness and gaps in this incentive program, it was clear that the exclusivity incentive legislation was working for certain products.

 The gaps identified by the FDA were partially addressed by the Best Pharmaceuticals for Children Act of 2002.

 This Act, among other things, renewed the exclusivity incentives, created an off-patent process involving government contracts for pediatric studies, and mandated public disclosure of trial results from trials conducted under this authority.  

Efforts to define the impact of the Pediatric Rule have produced evidence that pediatric drug development was occurring as part of processes established by the rule, and had contributed to almost as many pediatric applications to the agency as the exclusivity provision. Because we cannot ascribe the reasons why a sponsor conducts pediatric studies, it is more difficult to directly link the effect of the Pediatric Rule. If the studies for a product were not in response to an FDA-issued Written Request, it was assumed the studies were not conducted because of Exclusivity. Confounding this issue is the agency's approach to its use of the carrot and stick (exclusivity and the Pediatric Rule). If a product was subject to the Pediatric Rule (embodied now in The Pediatric Research Equity Act [PREA]),

 the agency would also assess the appropriateness of applying its options to utilizing exclusivity pathways. If the product had patents or marketing exclusivity and studies were needed, both processes of the Pediatric Rule and Pediatric Exclusivity, where appropriate, would be employed. In other words, the studies asked for in the WR would parallel those requested under PREA. In some instances, the WR would be broader as there may exist a number of indications applicable to the pediatric population in addition to the adult indication for which an application was submitted. 

The impact of these regulatory and legislative activities can be seen in many areas beyond the resultant production of new labeling information. In addition to ethical issues that arose early in the course of implementation of pediatric trials, two issues which became immediately apparent were the lack of scientific information needed to permit development of appropriate trials and the emergence of deficits in pediatric trial infrastructure and trained personnel. Subsequent to conduct and review of many of these studies, the results submitted revealed that we knew even less than we had previously thought.

 Studies defined a new dosing regimen, new safety issues, or a lack of efficacy for 1/4 to 1/3 of the products studied. Some labels would have two or three types of changes incorporated (e.g., dosing and safety information; see Table 1).  

Table 1. Exclusivity: Summary of important findings from 79 labels 			

Of particular importance was the ability to define products where efficacy could not be demonstrated. In one clinical trial involving solid tumors, the trial was halted because of a high rate of disease progression and early deaths. This information was included in the label to better inform the practitioner concerning the results of this study (see Table 2). 

Table 2. Not sufficient evidence of effectiveness: N = 9  

Effects on growth were seen in studies involving antidepressants, treatments for Hepatitis C, inhaled steroids (dose dependent effect) and attention deficit/hyperactivity disorder. Topicals containing betamethasone and mometasone demonstrated adrenal-axis suppression in the populations studied. A high percentage (28% to 75%) of children in all age ranges demonstrated hypothalamic-pituitary-adrenal (HPA) axis suppression with topical application to even a limited body surface area. Topical calcineurin inhibitors [e.g., Elidel (pinecrolimus)] studied in patients two years and older were associated with an increased incidence of pyrexia, respiratory illness, and diarrhea. Bone demineralization was described in patients after a single course of therapy with Accutane, and other therapies were associated with newly described aggressive behavior or suicidal ideation. Table 3 provides examples of new adverse events that were defined during the conduct of pediatric studies.

The Pediatric Rule made everyone begin to assess, think, and plan for pediatric needs.

Applied Clinical Trials-01-01-2005