Witness Testimony

Executive Summary

The American Academy of Pediatrics (AAP) is pleased to testify today before the Subcommittee on Oversight and Investigations of the House Energy and Commerce Committee. The focus of this hearing, "Publication and Disclosure Issues in Anti-Depressant Pediatric Clinical Trials," is both timely and complex. Over the last several years, the AAP has been a champion for disseminating information gained through pediatric clinical drug trials and has strongly supported these efforts as they relate to all medications, not only anti-depressants.

This subcommittee should be commended for their efforts to explore the publication and disclosure of pediatric clinical trial findings. However, the AAP and pediatric societies respectfully caution that this important issue is neither simple nor easy to navigate. Acknowledging the degree of difficulty must not be interpreted as a desire to avoid or delay addressing this issue. Rather, it is a plea that efforts begin NOW to engage the medical community, pharmaceutical manufacturers, researchers, scientific journals, policymakers and other stakeholders in an open, thoughtful, thorough discussion with the goal of developing constructive solutions to this vexing problem.

Today's testimony by the American Academy of Pediatrics and pediatric academic societies will address several issues:

• The need to disseminate pediatric findings of information is one of great importance to the pediatric community. Some progress has begun through the dissemination of information provision within the Best Pharmaceuticals for Children Act, but more is needed;
• The need to publish and disclose findings from clinical trials is not limited to a particular class of drugs or to just infants, children and adolescents. In fact, it is not limited to drugs, as the same concerns apply to clinical trials focused on other non-pharmacological therapies - but for practical reasons the AAP suggests that the initial efforts to create a clinical trial registry center on medication trials;
• The issues surrounding the need to publish and disclose all sentinel clinical trial findings are compelling and complex. Solutions require thoughtful and thorough review of the needs and barriers. It is critical that we give careful thought to the development of the means to summarize and review with accuracy the extensive trial data and results, and develop a system for dissemination of this information in a format that can be readily understood by the average U.S. citizen as well as the medical community.

It is not an issue of IF there is a need to provide health care professionals and patients appropriate information about clinical trials findings. Rather it is a matter of HOW the information is provided. It is no simple task to develop an appropriate mechanism but there are existing models such as the pediatric clinical trials summaries within the Best Pharmaceuticals for Children Act that may help shape the process. The AAP and pediatric societies stand ready to provide our expertise and participate in such a process.

Mr. Chairman, members of the Committee, I am Richard Gorman, MD, FAAP, a practicing pediatrician who has taken care of infants, children and adolescents for over 26 years. I am pleased to be here on behalf of the American Academy of Pediatrics (AAP), which represents 60,000 pediatricians nationwide.

Though I am a Clinical Associate Professor of Pediatrics at the University of Maryland School of Medicine, and chair of the AAP Committee on Drugs, it is in my practice, Pediatric Partners in Ellicott City, Maryland, that I see first-hand the need for appropriately studied and approved medicines for children. I can also say with a sense of pride that through the efforts of the Congress, the Administration, and the Academy and pediatric societies, I am able to provide better care to my young patients because of the passage of important pediatric-focused legislation such as the Best Pharmaceuticals for Children Act (BPCA - Pub Law105-155) and most recently the Pediatric Research Equity Act (PREA - Pub. Law 108-155). With over 80,000 pediatric visits annually in the five clinical sites in four counties in Maryland, my partners and I can attest to the importance of having information available regarding safe and effective pediatric drug dosing.

This testimony is also endorsed by the pediatric academic research community that includes the Ambulatory Pediatric Association, American Pediatric Society, Association of Medical School Pediatric Department Chairs and the Society for Pediatric Research also supports and endorses the Academy's testimony. These societies comprise academic general pediatricians, pediatric researchers, and full time academic and clinical faculty responsible for the delivery of health care services to children, the education and training of pediatricians, and the leadership of medical school pediatric departments.

Before I begin my formal testimony, I want to thank the Energy and Commerce Committee on behalf of the American Academy of Pediatrics and the pediatric academic societies for its leadership and support of legislation that advances children's health - particularly pediatric therapeutic issues. This hearing is yet another example of the Committee's strong desire to ensure that infants, children and adolescents are not an afterthought when it comes to clinical studies that may affect the health and wellbeing of our citizens. I would be remiss if I didn't also thank Representatives Jim Greenwood, Henry Waxman, Mike Bilirakis and the other members of the Subcommittee for their efforts on behalf of children.

The issue of today's hearing "Publication and Disclosure Issues in Anti-Depressant Pediatric Clinical Trials," is both timely and complex. Over the last several years, the AAP has been a champion for disseminating information gained through pediatric clinical drug trials and has strongly supported these efforts as they relate to all medications, not only anti-depressants.

The recent media attention regarding allegedly suppressed negative study results related to antidepressant use in children is just the latest volley on the issue of pediatric use of psychotropic medications. While the New York Attorney General's lawsuit against GlaxoSmithKline, the makers of Paxil, may be an appropriate trigger to action, the AAP and pediatric societies urge that the response by policymakers, whether in the public or private sectors, not be simply reactive but rather thoughtful and comprehensive.

This committee should be commended for their efforts to explore the publication and disclosure of pediatric clinical trial findings. However, the AAP and pediatric societies respectfully caution that this important issue is neither simple nor easy to navigate. Acknowledging the degree of difficulty must not be interpreted as a desire to avoid or delay addressing this issue. Rather, it is a plea that efforts begin NOW to engage the medical community, pharmaceutical manufacturers, researchers, scientific journals, policymakers and other stakeholders in an open, thoughtful, thorough discussion with the goal of developing constructive solutions to this vexing problem.

Let me propose an analogy: publication and disclosure of anti-depressant pediatric clinical trails is a small tip of an iceberg visible above the water line, giving warning to great danger lurking nearby - if we responded by simply addressing drug trials of antidepressants it would be comparable to removing only the tip of the iceberg - thereby obscuring the rest of the iceberg and increasing the overall danger.

I would like to address several issues during my testimony.

Disseminating Pediatric Clinical Trial Information:

There currently exists a mechanism to provide a public summary of clinical and medical information gathered through pediatric clinical trials of medications -- the "Dissemination of Information" provision within the Best Pharmaceuticals for Children law (Pub Law 105-115). The AAP was a catalyst for inclusion of this provision in BPCA.

Congress acknowledged that timely dissemination of information to pediatricians, health care practitioners, and the public about findings in the pediatric studies is critical to ensuring that infants, children, adolescents and their caregivers have appropriate information about the medications available for their use. Dissemination of information is intended to not only complement the label information by providing pediatricians and other health professionals with significant clinical findings that are necessary for pediatricians and physicians to review but which may not be included in the label.

The intention of the law is to make important information available to pediatricians and other health professionals within 6 months of submission of a report on a pediatric study, while ensuring that confidential and commercial trade secrets are not revealed through the summary process. These clinical and medical summaries are available on the pediatric page of the Food and Drug Administration web site. As an attachment to my testimony, I have included a copy of the pediatric Clinical Review of Effexor (venlafaxine) used for major depressive disorders (MDD) to illustrate the concise and useful information included in the summaries.

These pediatric clinical summaries are an important starting point. They currently focus on a narrow but important segment of pediatric clinical studies and may be used as a model for the development of a dissemination tool for all clinical trial data that is determined to have important clinical findings.

Determining the Scope of Clinical Trial Reporting:

Science must drive the process to define clinical trial reporting. Media attention, legal filings or isolated incidents should not dictate the availability or dissemination of the results of clinical trials. While there are compelling reasons to focus on medications related to the treatment of mental illness at this particular moment, given recent events, there is limited scientific rationale as to why medications for this class of conditions

should be highlighted over other medications in developing a national response to prevent subsequent miscommunication about clinical drug trial results. Unfortunately, limited access to clinical drug trial data has long had an impact on the choice and use of all classes of drugs - antidepressant use in children is only one recent example. We therefore strongly encourage the inclusion of ALL classes of medications within any registry or monitoring system that is developed as a result of this effort.

In addition, there is a need to define the kind of clinical trials that will be considered. Thus far, the discussions have focused on drug/medication trials; however, clinical trials include a great deal more than just drug/medication trials. Including all clinical trials (e.g., research related to human subjects; surgical, pharmacological, and non-pharmacological interventions; devices, etc.) may prove to be unwieldy to track in one database.

We anticipate that the effort required to develop a safe and effective clinical drug trial registry will be extensive and therefore recommend that the focus, at least initially, be on clinical drug trials. Clinical drug approvals are already overseen by one federal agency - the Food and Drug Administration (FDA) - and this may help facilitate the development of a single, centralized drug trial registry. The success (and challenges) of this registry can inform the later development of comparable efforts to promote broader access to clinical trials of non-pharmacological interventions.

Publication and Disclosure of Clinical Trial Data: Understanding the Challenges/Identifying Possible Solutions:

There is a need to define the scope of the challenges related to publishing and disclosing clinical trial data in order to best address them. A series of questions helps illustrate the information necessary in order to determine the best course of action: How are clinical trials being defined (e.g., just for medications or for non-pharmacological interventions as well)? Will the information released be peer reviewed (if not, who will review the data and at what time during the clinical trial)? How will the information be distilled and updated (e.g., summaries, full release of unfiltered trial results, etc.)? How are "negative studies" being defined? Who is the audience for these trial results (e.g., physicians, patients, researchers, etc.)? What is the intended outcome for releasing the clinical trials data (e.g., improved patient care, legal pursuits, etc)? What might be the unintended consequences of well-intentioned policies?

A number of proposals have been raised. Each comes with potential benefits but must be carefully examined within the context of potential issues. Proposals include:

• Medications have the FDA for oversight, but there is little to prevent a company or individual from posting "results" of their independent research that demonstrates the benefit of a completely non-efficacious or potentially harmful intervention (with claims based on seriously flawed research).
• Through the media and advertising industry there are many claims of product or intervention efficacy that are likely based on research that would not be judged as supported if subjected to the peer review process of professional journals (e.g., dietary supplements, some non-evidence-based mental health interventions, non-pharmacological diet or pain "treatments" to name just a few).
• Inclusion of a disclaimer that a study did not undergo "peer-review" will not likely have sufficient impact, especially if the study is posted on a government website along with the best of scientific studies. The general population may likely view the study as having more credibility, irrespective of any disclaimers.

Clinical Trial Registries and Databases: A central clinical trial registry or database for clinical trial information would go a long way towards addressing concerns about a lack of awareness outside the scientific community of the full nature, scope, and results of clinical trials.

One of the most frequently-cited rationales for registries is that such a database would lead to a decrease in reporting bias - the tendency of scientists to publish only those studies yielding positive results. However, this may not necessarily be the case. If all results, including negative ones, are available in a registry, then it is quite possible that the prevalence of positive studies reported in peer-reviewed journals might actually increase, since the negative studies will have already been disclosed elsewhere (and possibly in a relatively cursory manner).

There are many other concerns that must be addressed on this issue of a registry, including what entity will administer it and how compliance will be enforced, how the raw data will be filtered and presented in a way to allow those outside the scientific community to interpret it, concerns of industry over the disclosure of proprietary information, etc.

Clearly it is imperative that any effort to establish or expand clinical trial registries be well considered and thoughtful, as well as taken at a reasonable pace.

Conclusion and Recommendations

It is not an issue of IF there is a need to provide health care professionals and patients appropriate information about clinical trials findings. Rather it is a matter of HOW the information is provided. It is no simple task to develop an appropriate mechanism but there are existing models such as the pediatric clinical trials summaries within the Best Pharmaceuticals for Children Act that may help shape the process.

The AAP and pediatric academic societies propose the following initial recommendations:

• We urge Congress to broaden their investigation to include all medications, rather than simply anti-depressants. In addition, it is necessary to include all populations and ages in order to best improve patient care.
• While concerns related to publication and disclosure of clinical trial findings are not limited to medications, it may be necessary to begin with that therapy as an incremental step.
• Thoughtful and deliberative assessment of how data collection and registries are developed is essential. The role of peer-review of studies must be thoroughly explored. The AAP urges the medical community, pharmaceutical manufacturers, scientific journals, policy makers, researchers and other stakeholders to work together to identify the scope of the problems and develop appropriate solutions. We must work with deliberate speed but must also ensure that the solutions adequately address the problem and do not, in fact, cause even more problems.

On behalf of the American Academy of Pediatrics and the pediatric academic societies, thank you for the opportunity to testify on this important issue. We offer our assistance and expertise to the Congress and other stakeholders as this important discussion continues.

Attachments: FDA Summaries of Pediatric Clinical Review (Effexor/venlafaxine)