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PGY-2 Legislative Advocacy Presentation February 28, 2012 Lacy-Ann Landell, MD Ryan Morgan, MD Improving Research, Development, Access, and Safety of Pediatric Drugs and Medical Devices

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Overview Background Barriers to the development and access of pediatric drugs and devices Regulatory/Legislative History Current Legislation Future Directions

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50-75% of drugs prescribed to children have not been tested in children Why is this a problem? Medication effects differ in children compared to adults Overall efficacy Metabolism / Clearance Side effect profiles differ Effects on growth, development, fertility, etc. Results are toxicity, drug resistance, longer illnesses, pain and suffering, morbidity and mortality, and increased cost to the health care system Different formulations (liquid solutions, chewable tablets) may be necessary for children Children are not just small adults!

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The Ideal Pediatric Drug An ideal pediatric drug should have several key features: Age specific Tailored to body weight, metabolism Pediatric safety profile Researched in children, addressing pediatric issues like growth and development Variable administration Easily dissolvable, tasteless, ability to sprinkle on foods, etc Variable formulations Fixed dose combination pills for chronic conditions, higher concentration drugs for smaller doses

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Historical Examples of Medications Not Appropriately Tested in Children Chloramphenicol In 1960s, used off-label in children and neonates, resulting in serious adverse effects. The immature UDP-glucoronyl transferase enzyme system in infants livers leads to inefficient conjugation of the drug The neonatal kidneys are unable to excrete the unconjugated product Over 2-9 days, infants can develop vomiting, gray discoloration of the skin, hypotonia, cyanosis, hypotension, and death

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Historical Examples of Medications Not Appropriately Tested in Children Sulfa drugs displacement of bilirubin from binding sites jaundice and kernicterus Tetracycline affects growing bone and teeth and can cause bony abnormalities and permanent teeth discoloration Aspirin Reyes Syndrome (when given for viral illness) Rash, vomiting, hypoglycemia, hepatotoxicity, brain injury

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Product Labeling The product label contains information about medication formulation, indications, dosing, and side effect profile (derived from clinical trials) Because most drugs prescribed for children have not been tested in pediatric populations, important information on their risks and appropriate use for these patients is not available on the product labels. Off-label use occurs when drugs are prescribed for purposes other than those included under the terms of the FDA product approval or in a patient population in whom it has not been studied. Off-label use of drugs is common in adults but far more prevalent in children. While such use can be beneficial to the patient, it can also result in adverse reactions due to a lack of understanding of the drugs overall profile in the patient population.

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Off-label drugs Most medications used on pediatric cardiac patients are used in an off-label manner Lidocaine, amiodarone, procainamide, dopamine, dobutamine, norepinephrine, isopril, milrinone, propanolol, esmolol, sotalol, metoprolol, carvediolol, labetalol, nitroglycerine, amlodipine, nifedipine Most psych meds Zoloft, Prozac, etc. ALBUTEROL!!! Not approved for kidsoops Dexamethasone not approved for pregnant women in premature labor Bactrim and clindamycin for MRSA infections

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The Pediatricians Dilemma: Do I chose to withhold a potentially effective treatment that is useful in adults or do I expose my patient to a drug that I dont know is safe?

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AAPs Response Off-label use should be based on expert clinical judgment, published literature and sound scientific evidence. Physicians who choose to prescribe a medication with limited pediatric data have a public and a professional responsibility to assist in the systematic development of the information about that drug for the benefit of other patients (AAP Policy Statement). FDAs MedWatch program for reporting serious adverse events.

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Barriers to Pediatric Drug Development Economic Ethical Logistical / Technical Legislative

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Economic Barriers to Pediatric Drug Development New drug approval process requires, on average, $350 million $12.6 billion investment by the pharmaceutical industry yearly (doubles every 5 years) Testing in children most often requires independent studies and can double the cost of clinical trials Children tend to be on medications for shorter durations of time (antibiotics vs. statins) and tend to have conditions that they outgrow (asthma, ADHD, frequent infections) Reimbursement from Medicaid and private insurance companies is lower for some drugs when prescribed for pediatric rather than adult patients

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Barriers to Pediatric Device Development Far fewer children require implantable devices compared to adults, but the amount of devices specifically designed for them are disproportionately lacking When developing a device (i.e. prosthetic heart valve) for children, multiple sizes must be developed and manufactured. All of these require independent manufacturing lines, etc., while a relatively small number of each are actually used. Mass marketing one-size-fits-all works for adults but not for childrendeveloping new devices for the treatment of children does not pay. Clinicians must resort to improvising with existing materials.

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The Ethics of Pediatric Drug Development and Research on Minors Principles Children should not be enrolled in research unless necessary to answer an important question about health and welfare of children Research involving children must be characterized by a balance of risks and potential benefits Research offering no direct benefit to children must be restricted to that posing minimal risk

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The Ethics of Pediatric Drug Development and Research on Minors Those at fault: CLINICIANS willing to prescribe off-label drugs, leading to delays in research PHARMACEUTICALS act in financial self-interest Pursue clinical trials on children late in a drugs life cycle, after establishing its market value and the worth of pursuing pediatric indications Cost considerations trump study design quality, so studies may not be powered for certain indications ACADEMIC INSTITUTIONS do not reward their researchers for participating in clinical trials Want them to be primary investigators on NIH R01 grants rather than being on a long list of co-investigators

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Logistical/Technical Barriers Lacking infrastructure in which to conduct pediatric research Few pediatric clinical research centers Declining number of pediatric pharmacologists Inadequate teaching of pharmacology / therapeutics in medical school Too few physician-scientists Lack of pediatric assessment tools

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Legislative Barriers to Drug Development: The FDA Drug Approval Process Average of 12 years and $350 million 1/1000 novel candidates that enter lab testing make it to human testing After an average of 3.5 years of lab testing, medications are submitted to the FDA for the beginnings of clinical trials

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Phase I Trial on healthy volunteers (~20-80) to establish a drugs safety and overall profile (~1 year) Phase II Trial on 100-300 patient volunteers to assess effectiveness (~2 years) Phase III Trial on ~1000-3000 patients in multiple institutions (likely randomized) to determine effectiveness and identify adverse reactions (~3 years) Pharm company submits application (~100,000 pages) to FDA potentially approved after 2-2.5 years, then available for providers to prescribe Phase IV Post-approval studies aimed at examining drug in fashion in which it is actually prescribed

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Regulatory and Legislative History In 1992, the BPCA - Best Pharmaceuticals for Children Act is introduced to Congress. In 1997, the BPCA is enacted as a part of the FDA Modernization and Accountability Act. In 1998, the Pediatric Rule is declared by the FDA. In 1999, the Pediatric Rule is enacted. In 2002, the BPCA is enacted as its own act. In 2003, the PREA - Pediatric Research Equity Act is introduced to Congress and later that year the president signs it into law. In 2007, numerous BPCA and PREA improvements are signed into law as a part of the FDA reforms (Food and Drug Administration Amendments Act (FDAA).

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Pediatric Formulations Platform In 2009, the NIH and the FDA entered into a Inter-Agency agreement to make an open-source, publicly available approach to manufacturing pediatric oral meds. Look for pediatric formulations of commercially available products Determine best formulations for specific drug categories (based on solubility, light sensitivity, bitterness)

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Current Legislation The two main laws that encourage and require drug manufacturers to study their products in children are BPCA and PREA. These laws have been in effect for over a decade with pediatricians constantly advocating for them. BPCA: Guarantees six additional months of market exclusivity to pharmaceutical companies following the completion of pediatric studies requested by the FDA. PREA: Mandates new pharmaceutical agents to be studied in children and requires pediatric studies in some drugs already on the market. The Pediatric Rule requires pharmaceutical companies to test specific drugs for use in children. Pediatric Medical Device Safety and Improvement Act of 2007

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Other Helpful Steps National Institute of Child Health and Human Development (NICHD) and the National Institute of General Medical Sciences (NIGMS) co-funded six pediatric positions under NIGMS T32 Post Doctoral Programs in Clinical Pharmacology The WHO launched 'Make medicines child size' initiative in December 2007 to increase awareness and move toward improving the availability of safe, effective, quality medicines for children. WHO Model Formulary for Children contains independent prescriber information on over 240 medicines based on the WHO Model List of Essential Medicines for Children. Creation of an online clinical trial registry for trials involving children and developing guidelines for conducting these trials in resource-limited settings.

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Future directions New problems arise Critical drug shortages cytarabine for AML; methotrexate for ALL Lower profit margins = less being made by pharmaceutical companies Drugs losing patents Medications that are actually approved for children are no longer profitablethus are not being made Financial crisisdecreasing numbers of new drugs in the pipeline Current legislation needs to be re-enacted (October 2012)

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Advocate!!! What we can do Call your senator or congressman! Sen. Kristin Gillibrand - (202) 224-4451 Sen. Charles Schumer - (202) 224-6542 Congressman Charles Rangel VOTE. Get involved with the AAP. Participate in clinical trials. Report adverse effects of off-label medications MedWatch

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References AAP Committee on Drugs. Uses of Drugs Not Described in the Package Insert (Off-Label Uses). Pediatrics. 2002;110(1):181-183 Improving Access to Safe Drugs and Medical Devices for Children. American Academy of Pediatrics. Retrieved February 27th, 2012 from http://www.aap.org/en-us/advocacy-and-policy/federal-advocacy/Pages/Improving-Access-to-Safe-Drugs-and-Medical-Devices- for-Children.aspx http://www.aap.org/en-us/advocacy-and-policy/federal-advocacy/Pages/Improving-Access-to-Safe-Drugs-and-Medical-Devices- for-Children.aspx Medicines: Medicines for Children. World Health Organization. Fact sheet #341. Retrieved February 27th, 2012 from http://www.who.int/mediacentre/factsheets/fs341/en/index.html http://www.who.int/mediacentre/factsheets/fs341/en/index.html Pediatric Formulations Platform. Best Pharmaceuticals for Children Act. National Institute of Health. Retrieved February 27th, 2012 from http://bpca.nichd.nih.gov/collaborativeefforts/initiatives/index.cfmhttp://bpca.nichd.nih.gov/collaborativeefforts/initiatives/index.cfm Pediatric Product Development. U.S. Food and Drug Administration. Retrieved February 23 rd, 2012 from http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm Addressing the Barriers to Pediatric Drug Development: Workshop Summary. Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation. Washington (DC): National Academies Press (US); 2008.National Academies Press (US) Pasquali, SK, et al. Off-Label Use of Cardiovascular Medications in Children Hospitalized With Congenital and Acquired Heart Disease. Circulation: Cardiovascular Quality and Outcomes. November 2008; vol. 1 no. 2 74-83.