Capstone for Master of Arts in Health and Human Services Administration (Doherty, 2012)

RARE PEDICATRIC DISEASE AND DISORDERS 1

Health Policy and System Improvements to Benefit Children with Rare Disease

Susan R. Doherty

St. Mary’s University Minnesota

Schools of Graduate and Professional Programs

Health and Human Services Administration

HS698 Capstone Project

Instructor: Jerry Lovrien, MHA

December 1, 2012


Table of Contents

Chapter One: Introduction ...............................................................................................................3

Purpose Statement ................................................................................................................3

Significance..........................................................................................................................3

Scope ....................................................................................................................................5

Terms ...................................................................................................................................5

Chapter Two: Literature Review .....................................................................................................9

Individual Context for Patients ............................................................................................9

Research and Operational Frameworks Impact Outcomes ................................................10

Economic Drivers in Pediatric Medicine ...........................................................................11

Academic and Scientific Contributions .............................................................................12

Health Policy and Public Awareness Contribute to Information Exchange ......................15

Chapter Three: Recommendations ................................................................................................17

Ethical Considerations and Gaps in Research, Care and Standards of Treatment .............17

Lessons Learned.................................................................................................................20

Recommendations for Policy Advancement and Further Research ..................................21

References ......................................................................................................................................25

Attachments ...................................................................................................................................31

Orphan Drug Act (Public Law 97-414, as amended) .......................................................31

AMA Code of Medical Ethics: Code 2.138 Genetic Testing in Children .........................36

AMA Principles of Medical Ethics: Opinion 2.215 – Treatment Decisions for Seriously

Ill Newborns.......................................................................................................................37


Chapter One: Introduction

Purpose

This research will seek to understand the resources and potential gaps related to the

follow up care, services and financing for children diagnosed with rare pediatric diseases and

disorders. These findings will contribute to public policy recommendations for children’s health,

thereby improving survivorship and quality of life for them and their families.

Significance

The number of individuals impacted by any one rare disease is very small (e.g. <105

children diagnosed with Hepatoblastoma in the United States each year). Often, the treatment

protocols are not well understood, standardized, or researched and the return on investment for

drug companies is too low to incentivize research. Consequently, this leaves attending

physicians, families and young patients in a state of limbo further jeopardizing the health of the

child. In the instances of the children surviving into adulthood, a significant proportion of them

will become categorically a part of the five percent of the population that accounts for nearly half

of all health care expenditures (Stanton, 2005). Given the complexities surrounding healthcare

and improvements of outcomes in medicine, it is of individual and collective importance to

understand the needs and survivorship for patients with rare diseases, particularly in children.

In 2008, healthcare was a $2.3 trillion industry (www.kaisered.org) and there is no sign

of anticipated slowing of growth over the next several decades. The healthcare industry

consumes nearly eighteen percent of the United States GDP (www.usgovernmentspending.com).

These dollars are spent largely on adults (e.g. Medicare population with chronic diseases and end

of life care needs). In contrast, the United States Department of Agriculture estimates the annual

http://www.kaisered.org/

http://www.usgovernmentspending.com/


cost for child-rearing expenses between$11,600 – $13,530, with healthcare making up anywhere

between 16 – 33 percent of this amount dependent upon the child’s age and other health

considerations (Lino, 2010).

More broadly, approximately five percent of all healthcare dollars in the US are aimed at

pediatric health. Reliable data is not readily available pertaining to the specific allocation of

healthcare dollars focused on a narrow population of children with rare diseases and disorders.

The investment in pediatric health in general appears nominal despite the opportunity for

potential longevity, long-term savings with preventative and supportive interventions and the

hope of significant research learnings that can be broadly applied to common, chronic diseases

well beyond the pediatric population.

As Conwell and Cohen (2005) have illustrated, few dollars are allocated to people under

the age of eighteen. As people age, their healthcare expenditures generally rise.

Source: Conwell LJ, Cohen JW. Characteristics of people with high medical expenses in the U.S.

civilian noninstitutionalized population, 2002. Statistical Brief #73. March 2005. Agency for

Healthcare Research and Quality, Rockville, MD. http://www.meps.ahrq.gov

http://www.meps.ahrq.gov/


Scope

This paper explores the current state of care, services, research and financing for children

with rare diseases and disorders. In doing so, the goal is to better understand how broad

complexities overshadow key health policy considerations related to narrow populations of

patients, (e.g. children with rare diseases) which may contribute to the analysis and shaping of

public policy agenda specifically related to improving long-term outcomes for these patients.

Terms

Disease Registry. The phrase refers to a system of registration for all cases of a particular

disease or disorder in a defined population (http://www.atsdr.cdc.gov/glossary.html).

Epidemiology. The term epidemiology as defined by the Centers for Disease and

Prevention is the study of the distribution and determinants of health-related states of events in

specified population, and the application of the this study to the control of health problems

(www.cdc.gov/osels/scientific_edu/ss1978/lesson1/Section1.html).

Estimate the Burden of Disease. The term refers to the incidence, prevalence, survival

and proportion of cured (Gatta et al., 2012).

Genetic Information Nondisclosure Act (GINA). This act focused on the economic

risks and necessary protections for those diagnosed or identified as having a rare disease or

carrying the gene for a rare condition.

Health Care Expenses. The term is defined the United States Department of Agriculture

as the expenses not covered by insurance, prescription drugs and medical supplies not covered

by insurance, and health insurance premiums not paid by an employer or other organization.

These services include physical and mental health (www.cnpp.usda.gov).

http://www.atsdr.cdc.gov/glossary.html

http://www.cdc.gov/osels/scientific_edu/ss1978/lesson1/Section1.html

http://www.cnpp.usda.gov/


Hospice Care. According to the Center for Medicaid and Medicare (CMS), the term is

used to describe the health services and supports including “education to the patient/family about

the patient’s disease process, the palliation and management of the patient’s symptoms, the safe and

effective use of medication and medical equipment used by the patient, and the physical,

psychosocial and spiritual aspects of the dying process” http://www.cms.gov/Medicare/Provider-

Enrollment-and-Certification/SurveyCertificationGenInfo/downloads/SCLetter09-19.pdf).

HIPAA. The acronym HIPAA stands for Health Insurance Portability and Accountability

Act of 1996 (P.L.104-191) and included the Privacy and Security Rule (45 CFR Part 160 and

Subparts A and E of Part 164). The U.S. Department of Health and Human Services states that, “A

major goal of the Privacy Rule is to assure that individuals’ health information is properly

protected while allowing the flow of health information needed to provide and promote high

quality health care and to protect the public's health and well being. The Rule strikes a balance

that permits important uses of information, while protecting the privacy of people who seek care

and healing” (http://www.hhs.gov/ocr/privacy/hipaa/understanding/consumers/index.html).

Incidence. The term refers to the number of new cases of disease in a defined population

over a specific period of time (http://www.atsdr.cdc.gov/glossary.html).

Mature Minor. The term mature minor has varied application in common and case law

and is sometimes characterized as the Mature Minor Doctrine, meaning the “legal principle

which allows a minor to make decisions about his or her health and welfare, if they can show

that they are mature enough to make a decision on their own. This prevents the usual necessity

for parental consent from becoming a barrier to treatment about which children may be reluctant

to inform parents. Not all states recognize the common-law mature-minor doctrine. In the states

http://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/downloads/SCLetter09-19.pdf

http://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/downloads/SCLetter09-19.pdf

http://www.hhs.gov/ocr/privacy/hipaa/understanding/consumers/index.html



where it exists, the mature minor doctrine takes into consideration the age and situation of the

minor to determine maturity, in addition to factors and conduct that can prove maturity. This

doctrine has been consistently applied in cases where the minor is sixteen years or older,

understands the medical procedure in question, and the procedure is not serious. Application of

the doctrine in other circumstances is more questionable”

(http://definitions.uslegal.com/m/mature-minor-doctrine/).

Minors and Emancipation. The term minor refers to a person under the age of 18 years

in the United States. Minnesota Statutes define who is a minor and who is an adult at MN Statute

§ 645.451. Generally, being "emancipated" means that a minor has the same legal

responsibilities as an adult. Minnesota Statutes do not specifically define a process by which a

minor can become emancipated (http://www.mncourts.gov/selfhelp/?page=2039).

Orphan Drugs. The term refers to those drugs “intended for the treatment of rare

disorders, because the number of patients affected is so small that it is not profitable to invest in

research and development or to market them” (Lavandeira, 2002). The United States

government drives funding and research in orphan drugs by way of the Orphan Drug Act of 1983

(Public Law 97-414).

Palliative Care. The term palliative care is defined by the Office of the Inspector

General within the U.S. Department of Health and Human Services care focused on pain control,

symptom management, and counseling for both the patient and family

https://oig.hhs.gov/fraud/docs/alertsandbulletins/hospice.pdf).

Pediatrics. The term refers to patients of 21 years of age or younger and in some

instances, under the age of 18 years (www.fda.gov).

http://definitions.uslegal.com/m/mature-minor-doctrine/

https://www.revisor.leg.state.mn.us/statutes/?id=645.451

https://www.revisor.leg.state.mn.us/statutes/?id=645.451

http://www.mncourts.gov/selfhelp/?page=2039

https://oig.hhs.gov/fraud/docs/alertsandbulletins/hospice.pdf

http://www.fda.gov/


Pediatric Subpopulation Approximate Age Range

newborn birth to 1 month of age

infant 1 month to 2 years of age

child 2 to 12 years of age

adolescent 12-21 years of age

Prevalence. The term refers to the existing disease cases in a defined population during a

specific time period (http://www.atsdr.cdc.gov/glossary.html).

Rare Disease Act of 2002 (Public Law 107-280). This Act was signed into law on

November 7, 2002, with the intent to establish the Office of Rare Diseases as a federal entity

able to recommend a national research agenda, coordinate research, and provide educational

activities for researchers.

Rare Diseases Orphan Product Development Act. This Act increased governmental

investment in the development of diagnostics and treatments for rare diseases and disorders by

establishing regional centers of excellence for clinical research and doubling the funding for the

Orphan Product Research Grant Program.

Rare Disease and Disorder (RDD). The term is defined by the World Health

Organization (WHO) as all pathological conditions affecting 0.65-1 out of every 1000

inhabitants (Lavandeira, 2002). Within the United States, the term "rare (or orphan) disease," as

defined in the Orphan Drug Act of 1983, is a condition affecting fewer than 200,000 in the

United States or a disease with a greater prevalence but for which no reasonable expectation

exists that the costs of developing or distributing a drug can be recovered from the sale of the

drug in the United States (http://www.nih.gov/news/pr/nov2003/ncrr-03.htm). Internationally,

the definition applies to small numbers of individuals (Aronson, 2006).


http://www.nih.gov/news/pr/nov2003/ncrr-03.htm


Chapter Two: Literature Review

Much of the literature related to children with rare disease has been focused on the

development and successes of pharmacological interventions, disease specific treatment

protocols and the resources necessary to fund care and research. Yet, little analysis has been

dedicated to the systemic organization of services, comprehensive tumor and disease registries

and tracking systems, and the epidemiological contributors to the onset of disease and disorder in

children. This may be due to the small number of new cases diagnosed and high mortality rate

with a significant number of the diseases. Some of the thousands of rare diseases have

diagnosable characteristics, while others have complex and sometimes unrelated symptoms

making diagnosis often impossible. Given the young age of onset for many children, it is also

difficult to fully assess symptoms (e.g. location and intensity of pain) unlike the interactive

physician/patient relationship in the adult population.

Individual Context for Patients

Dodge, et al (2011) concluded, “rare disease affects many children and its incidence and

prevalence are often unclear.” Even disease-specific burden (incidence, prevalence, survival and

proportion of cured) is challenging given the lack of comprehensive international disease

registries (Gatta, et al., 2012). Additionally, full understanding of disease or disorder related

impairment varies by disease and individual (Guillem, et al., 2008).

It has been shown that patients are often reliant on their own research and knowledge to

guide the symptom management and treatment of their unique disease process. As Helms and

Schultz (2012), concluded, “Due to the low prevalence and the lack of expertise, the patient is

forced to become knowledgeable about his own disease state.” This is especially true for

patients experiencing symptoms of an ultra-rare disease (<1:2,000,000) and likely drives


enhanced dependence on electronic exchange of information related to the disease process

(Hennekam, 2011).

Research and Operational Frameworks Impact Outcomes

In an abstract submitted for presentation at the Annual Conference on Clinical Research

for Rare Disease, Connolly and Beggs (2010) outline key weaknesses of rare disease research:

- Small population size.

- Difficulty in finding start up funding for research.

- Lack of interest for career focus for rare disease.

- Lack of collaboration.

- Lack of infrastructure for continued support and collaboration.

An additional consideration is disparity for those at risk of or surviving with rare disease.

Holtzclaw (2011) articulates the need to devise policy agendas that work to “prioritize research

and solutions for health disparity and its consequence for the rare disease community.” The

manifestation of the disparity is more evident as it relates to investment in pharmacological

research and development that contribute to best practice treatment in areas of medicine with few

patients (Lavandeira, 2002). Yet there have been improvements as demonstrated by the increase

in orphan drugs getting to market for the pediatric population:

From 2000 – 2009, 1138 orphan drugs were designated and 148 received

marketing approval, of which 38 (26 percent) were for pediatric diseases. The

proportion of approvals for pediatric products increased from 17.5 percent (10 of

57) in the first half of the decade, to 30.8 percent (28 of 91) in the second (Thorat

et al., 2012).


Variance is known to erode outcomes for patients and deteriorates return on investment

of resources. As noted by Stargardt and Schreyögg (2012) “small area variations in healthcare

infrastructure may result in differences in early detection and outcomes for patients with rare

diseases.” This also applies to the level of the individual researcher or clinician in that there is a

need for standardization and use of best practices, yet innovation and flexibility contribute to

new approaches to diagnosis and treatment. The variance even in small tasks of researchers can

alter the conclusions (Kessel, 2012). Ultimately, this can impact the treatment protocol carried

forward in the healthcare setting. Great caution needs to be exercised relative to the interest of

the children for whom the research is aimed given the risk of variance in research, treatment and

outcomes.

Economic Drivers in Pediatric Medicine

Health policy and economics are real considerations in making recommendations relative

to rare diseases particularly given the “frequent utilization by people with rare diseases of

multiple health professionals and their need for specialized services, investigations, equipment

and orphan drugs significantly impacts on health expenditure” (Zurynski et al., 2008).

Consequently, the impact extends far beyond those directly affected by rare disease.

The discussion about rare pediatric disease exists in the broader context of the healthcare

including the medical arms race in which Robinson and Luft (1985) laid out the progression of

healthcare organizations to focus on volume, driving efficiencies and total cost of care and

maximizing profits. This is being further developed in the accountable care organizational

(ACO) model of today and the progression toward specialization, consolidation, and public

accountability and transparency.


Within healthcare organizations, there are growing challenges, including and not limited

to forces such as:

- Competitive market pressures

- Erosion of government payment

- Increased consumer demands

- Need for enhanced capital pools to fund the physical plant and healthcare

technology

- Public and regulatory scrutiny including expectations of corporate transparency

(e.g. public reporting of quality data) and the patient privacy and confidentiality

being honored (e.g. HIPAA and GINA)

- Recruitment and retention of a highly sophisticated pool of health professionals

including specialty and sub-specialty physicians and researchers.

Given these complexities, even expansive integrated hospital and group practice

networks and academic health centers have few resources allocated to focus on the health needs

of narrow populations of patients including those with a diagnosis of a rare disease.

It is only recent history that such major pieces of legislation as the Orphan Drug Act of

1983, the Rare Disease Act of 2002 (Public Law 107-280), and the Rare Disease Orphan Product

Development Act were enacted in the United States. With these contemporary moves to advance

policy legislation, the federal government has created a focus on rare disease and the research

network needed to connect scientists and institutions in the private and public sectors. In 2003,

the National Institutes of Health established the Rare Diseases Clinical Research Centers

(RDCRCs) and initially allocated $51 million over a five-year period of time for the


development of the Data and Technology Coordinating Center (DTCC) and grants to eight

institutions. These efforts continue to be refined through efforts such as the NIH collaborating

with the Food and Drug Administration to establish a national policy for rare-disease studies

(Drakulich, 2011).

Academic and Scientific Contributions

An Australian healthcare financing plan looks to address a number of the major funding,

information exchange, and access to services challenges by making a recommendation for more

centralized control and direction for rare disease management. The plan would work to provide

“coordinated response to service development, career support, and health professional and

community education, and would promote research and advocacy for affected children and their

families (Jaffe, 2010). The same line of thinking has increasing support in the United States

given increased support for the “emergence of registries as a tool to evaluate outcomes of

diseases is vital in observing the course of the illness and collect data on incidence and treatment

patterns” (Gliklich, R., & Leavy, 2011).

New application of existing drugs has been shown to bring about cost-effective treatment

strategies and the nuances of the rare diseases often lends more insight into more common

disorders (Forman et al., 2012), yet little analysis has been done to determine the impact of the

broad application of orphan drugs on the overall healthcare delivery system and financing

constraints (Tambuyzer, 2010). Additionally, caution and a focus on patient safety are needed

since access to funding for orphan drug therapies has increased. As noted in one European

research study, “As opposed to market authorization, orphan drugs gain reimbursement more

easily than non-orphan innovative drugs.” Unfortunately, as a number of experts have pointed

out “(the) lower quality of evidence of clinical efficacy and safety, more uncertainty on cost-


effectiveness and higher product prices are accepted for orphan drugs” (Dupont and Van Wilder,

2011).

Estimates place fewer than five percent of rare diseases being a current focus of

substantial drug development and it is widely stated that allocation of resources for rare diseases

diverts resources necessary for “treating patients with more common diseases wherein cost-

effective treatments may more readily exist” (Fishman and Skrepnek, 2012). Researchers

Gliklich and Leavy (2011) point out an additional challenge given “designing in and conducting

studies that enroll children may be more complex than studies for adults.”

Access to Orphan Drugs Despite Poor Quality of Clinical Evidence

Source: British Journal of Clinical Pharmacology, Apr2011, Vol. 71 Issue 4, p

488-496, Chart p 492.


Health Policy and Public Awareness Contribute to Information Exchange

Public awareness can provide support and contribute to the advocacy of public

investments in research as well as philanthropic dollars being focused on rare diseases and

disorders. This has led to attempts to aggregate and organize rare disease efforts with private

dollars. Some of this work is underway through programs such as the R.A.R.E. Project (Dolgin,

2010) and includes national corporate campaigns and a day of global observation, including

Raise Your Hand to Fight Rare Diseases campaign in support of Rare Disease Day observed on

February 28 each year (Lundbeck, 2002).

In May 2012, Lara Logan of 60 Minutes covered the conflicted fiscal nature of rare

disease research and the few lead scientists focused on the rare diseases that afflict millions of

people. Her televised interview keys in on Dr. William Gahl, who heads up the Undiagnosed

Diseases Program at the NIH in Bethesda, Maryland (Safer, et al., 2012) and how the very

human aspects of unknown disease process prompts researchers to stay fixated on resolving

individual cases (e.g. a forty-five year old woman with nearly a life-time of “muscles torturing”

her) while seeking disease-wide research answers (e.g. genetic mapping of disease specific

characteristics). Often, families and foundations narrowly direct their funds, while the R.A.R.E.

Project and researchers such as Dr. Gahl work to bring interests together under a broader

umbrella.

Collaboration and innovation are essential for breakthroughs and continued momentum in

the area of rare disease. Social media serves as an immerging medium for information exchange

as well as a means to create momentum for funding. By way of crowd funding (Vance, 2012),

new and quick dollars can be focused on particular researcher’s endeavors that may have


otherwise been overlooked. As then-medical student Jimmy Lin told Bloomberg Business week,

“little funding from a lot of Web users could mean breakthroughs for some of the 350 million

people (world-wide) with rare diseases” (Vance, 2012). As a result of his efforts in collaboration

with other researchers and scientists interested in the approach, the Rare Genomics Institute

(RGI) was formed and a number of projects are undertaken each year including the identification

of specific genes related to fetal development and giving much-need diagnostic answers to

parents and physicians caring for young patients with similar characteristics and delayed

development.

The dissemination of information and exchange of ideas occurs to a great extent by way

of the Web and government-sponsored data bases, particularly the National Organization of Rare

Disease (NORD) where comprehensive reports can be generated at a nominal fee (Kostrzewski

and Baker, 2006). At the institutional level, projects to streamline the pathways for “facilities and

cooperating academic researchers to carry preclinical and clinical testing” are in the early phases

of planning making full implementation years from actualization (Hudson, 2009). In countries

within the European Union, such as Belgium, public consultation and awareness of rare diseases

are a priority and the governmental policies reflect this prioritization of the policy agenda

(Budde, 2009). Further, it has been demonstrated that the flow of electronic data and disease

specific information exchanges can level the playing field in terms of geographic distance to an

academic health center because researchers and front-line physicians can collaborate to ensure

there is not a delay in the diagnosis of a rare disease (Roll, 2012).


Chapter Three: Recommendations

Ethical Considerations and Gaps in Research, Care, and Standards of Treatment

The most basic human instinct of compassion for those afflicted with rare diseases,

particularly children, has significant social, economic, legal, and even religious complexity in the

United States and globally.

The biomedical research industry continues to apply standards for use of medications and

devices, and there is literature exploring the process for ethical review in an effort to minimize

risk for patients with rare disease. Yet, there are outstanding issues related to the use of

registries and networks (Hannson, 2012). These concerns are heightened when examined

through the lenses of children with rare diseases as they are categorically a vulnerable population

and are at a higher risk for taking extraordinary steps in order to “rescue” them from the disease

or disorder. Parents and physicians may feel compelled to seek treatments even if the drugs and

procedures are not as thoroughly vetted, especially if the review process is bureaucratic and lacks

clarity as it relates to the particular disease or disorder, use of drug or procedure in an innovative

fashion, and if there are not enough participants or funding for trials and peer review.

As a result of the concerns over the vulnerability of children as subjects of clinical

research trials, the frameworks put into place within the United States requires ethical

consideration to the design and implementation for human subjects and should be continually

evaluated for special populations, such as children with rare disease. This poses a conflict in that

there are intervention and control groups for research design to be legitimate. If the intervention

is anticipated to improve outcomes or in the midst of the trial, it comes to light that the


intervention improves outcomes, those managing the clinical trial face the dilemma of whether to

maintain the “control arm” of the study, which then prevents subjects from receiving treatments.

The researchers in one particular study explored the “direct gene transfer to the central

nervous system to treat late infantile neuronal ceroid lipofuscinosis to illustrate some of these

ethical issues and explore possible solutions to real and apparent conflicts between scientific and

ethical considerations” (Inmaculada de, et al., 2011). This study underscores the need to

examine case by case circumstances for specific diseases and, even more detailed is how each

individual child is responding to treatment making the process costly, tedious, and open to

scrutiny.

As we mature in the use and protection of personal health-related information, public

policies such as the HIPAA regulations address issues such as protection when one focused on

genetic testing:

The Genetic Information Nondiscrimination Act (GINA) was signed into law on

May 21, 2008. GINA protects individuals against discrimination based on their

genetic information in health coverage and in employment. GINA is divided into

two sections, or Titles. Title I of GINA prohibits discrimination based on genetic

information in health coverage. Title II of GINA prohibits discrimination based

on genetic information in employment (HHS.gov, 2012).

What is lacking is the recognition and full exploration of the consequences of children as

individuals who are not able to consent to the genetic testing and are thereby reliant upon others

to protect their personal health information.

http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ233.110.pdf


The social ramification of having a child with a rare disease and disorder are in many

ways coming of age with the internet and global media. Little research has been done on the

implications of the social exposure as the children reaches adulthood and much of their identity

is public and detailed. The heighten awareness, access and exchange of information are an asset

to caregivers, researchers and clinicians. With this comes the risk of exploitation and

glamorization of the children. In a quest to raise funds, not-for-profit organizations showcase

children challenged by disease, thereby removing their current and future medical and social

privacy. Given this is done in the spirit of philanthropy and commitment to alleviating suffering,

the oversight boards and medical advisors for such organizations must strive to balance the long-

term interests of children with the serious risk of death and disability if funds are not directed to

research, treatment and care.

Another area of ethical consideration as it relates to children, or minors, is at what age

and level of capability are they able to participate in decision-making about their care, treatment,

and even the right to cease treatment which may result in early death from the disease process or

complications. Each state defines the legal age of 18 as the point at which minors reach the age

of majority, but the age and legal standards for being emancipated in advance of 18 years varies

by state. Minnesota Statutes do not specifically define a process by which a minor can become

emancipated. The courts review “petitions for emancipation” to make case by case

determinations and there is not guidance in the form of petitions or instructions for obtaining

emancipation (http://www.mncourts.gov/selfhelp/?page=2039). When conflict arises to

approach, continuation or forgoing treatment between parents and what may be characterized as

a mature minor, the courts are often left to be the mediator and determiner of care and treatment.

http://www.mncourts.gov/selfhelp/?page=2039


The lack of common law consistency on these matters places children at risk as they mature and

become more aware and capable of making determinations for their own care.

Even where there is a recognition and application of a mature minor doctrine as it relates

to consenting to care, there remains a lack of standardization across the states and professional

practices (e.g. child/adolescent psychology, pediatric oncology, palliative medicine).

Given the tremendous immediate, and likely ongoing, physical, emotional, cognitive,

developmental and social consequences for children with rare disease, there is clearly a gap in

pediatric-oriented hospice and palliative services available. Often tertiary and quaternary care

centers, such as academic health centers and teaching hospitals, will have such services, but even

within these sophisticated organizations, there are gaps in patients and families being offered and

engaged in order that they might more fully benefit from pain and symptom management, end-

of-life decision-making, and grief and loss counseling. These gaps would only be magnified for

those experiencing cultural and economic disparities, rural health services, or denial in not being

able to recognize the severity of their child’s health.

All ethical considerations exist within the unique cultural, religious and family dynamics

of the individual child with rare disease. The unique dimensions of the human experience impact

the view of the child, parents, and health professionals, are ever changing with the progression of

a rare disease, and likely amplified by the pressures and stress of health of the child. When these

considerations are coupled with the financial weight for the individuals and the system of care,

each child should be entitled to a thorough ethical review with periodical reconsideration for all

aspects of involvement in biomedical research, treatment, care, and symptom management,

including access to palliative and hospice services as deemed appropriate.


Lessons Learned

Given the finite dollars allocated to healthcare and the competing interests and health

needs of a diverse and aging population, taking a more comprehensive view of rare disease

translational research (bench-to-bed) is paramount. As one expert summarizes the state of affairs

related to rare disease researcher, “common data elements can also provide framework for

patient registries to be developed and, looking ahead so scientists may be able to use that

information for natural-history studies and to develop biomarkers for clinical trials” (Drakulich,

2011).

A leader in dedicating resources and system organization to address the needs of those

identified as being at risk of or having a rare disease is Children’s Hospital Boston. In recent

years, the clinician and researcher-led team at the Manton Center: A Home for Orphan Diseases

(affiliate of Children’s Hospital Boston) has organized services, funding and infrastructure to

uniquely address the existing weaknesses in rare disease research.

Clearly, the strengthening and expansion of disease registries within the United States

and internationally would accelerate the collaboration and identification of patterns and

treatment breakthroughs. Researchers within the European Union are striving to further regulate

drug pricing and availability (Denis, et al., 2010) in an attempt to manage costs and improve

outcomes. The public will need to be informed, educated and engaged in this movement as there

is the ever-present desire to honor patient privacy while working to meet the public interest.

Sharing sensitive, and sometime identifiable, genetic information even when protected (e.g.

HIPAA regulations) is a frightening prospect to individuals and families.


Recommendations for Policy Advancement and Further Research

As with most areas of complexity and rarity in healthcare needs within populations,

children with rare disease experience significant gaps in the system available to them. Most

healthcare delivery systems lack a mechanism for readily recognizing, screening, and referring

children at risk of or symptomatic of rare disease. Further, even if they are appropriately

diagnosed there is a lack of well-defined, funded and accessible palliative (symptom support

management) and hospice services specifically designed for children, especially those with rare

disease and at significant risk for acute and chronic pain, debilitating consequences of treatment

(e.g. surgical loss of limbs), social isolation and family disruption.

Research has shown that access to these services improves quality of life, and in many

cases, actually extends life because of the management of pain, fatigue, depression, and family

crisis. The portals to accessing the healthcare system and the supports needed for high quality

palliative and hospice services could be characterized as the necessary bookends of care for

children with rare disease. This could then free the families, clinicians and researchers to invest

in the next iteration of prevention, diagnosis, treatment and survivorship for children into

adulthood.

The complex challenges of balancing the need for standards and guidelines with individual

determination (Rosato, 2002) results in individual nuances and a lack of mass research and peer

reviewed literature related to children with rare disease. To confront this issue, both policy

makers and researchers and clinicians should work to advance the outcomes for children with

rare disease by collaborating by considering the following:


Investing in domestic and international professional conferences and educational forums

specifically targeting the causes and consequences of rare disease in children in an effort

to spawn academic and research interest, investment in funding treatment and care, and

advancement of known best practices.

Develop and advance standards to protect the individual privacy and dignity of children

(and adults) including a review of United States HIPAA and GINA regulations in light of

unique needs of those with rare disease, the need to raise funds beyond traditional

government sources, and the open, interactive nature of the digital world (e.g. search

engines that can comb data and identify individuals with unique characteristics, including

those with rare disease).

Educate the public, especially those considering pregnancy and parents of newborns and

young children, on the benefits and complexity of genetic testing of children and the

benefits of discussing, in advance of a health crisis, treatment decisions for seriously ill

newborns (AMA Principles of Medical Ethics – Opinion 2.215). Included in this

education should be information from credible authorities on health and medicine (e.g.

AMA’s Code of Medical Ethics – Opinion 2.138 – Genetic Testing of Children).

Advocate and seek sustainable funding for an international registry for rare disease to

address gaps in access to information (e.g. genetic links, emerging patterns, and increase

incidence) for researchers, clinicians, and caregivers, and to interface, rather than

replicate, disease specific registries.

Draft and advance a compact for treatment standards for children with rare diseases (e.g.

when to rescind research trial to provide all children access to known treatments prior to

completion and publication of results if deemed to be life-saving) to be developed,


endorsed and followed by the biomedical industries, researchers, clinicians and

government agencies.

Advocate for the recognition of the individual autonomy and involvement of children in

their own care and health-related decision-making including a federal and state

exploration of standardization and expansion of the concept of mature minor doctrine to

include minor to consent for care and to refuse treatment when deemed appropriate;

consider abandonment of concept of assumed incompetence by minors to direct their care

particularly for children fourteen years and older given the research that supports their

decisions will be similar to those they make when they reach age of maturity and will

then be fully directive unless incapacitated (Rosato, 2002). This approach may improve

compliance and long-term survivorship.

Encourage the establishment of a common nomenclature for diagnosis, treatment, care,

and research related to rare disease in children (e.g. Children’s Hospital Boston model)

within the private and public American healthcare system.

Encourage a thorough governmental review of the cost and economic impact of current

financing mechanisms (or lack of mechanisms) in place to diagnosis, treat, and care for

children with rare disease, including the state Medicaid programs and the catastrophic

coverage pools that are the place of last resort coverage for people with significant health

needs. This will be particularly important as recent healthcare reform policies are

implemented (e.g. assurance of coverage regardless of diagnosis, adult children provided

coverage on parent’s health plan until age 26).

Engage researchers and policy makers in dialogue to advance analysis of benefits, even

beyond those of individuals, derived from investments in diagnosis, prevention, early


intervention, treatment, and care that will apply to broad populations at risk of or afflicted

with other disease and illness.

In the absence of a concerted effort by clinicians, researchers and policymakers to

collectively frame the issues that put children with serious disease at further risk of

complications, needless stress and suffering, and even premature death, the families and

caregivers will strive to provide access to a diagnosis and treatment as best they can, in most

cases, regardless of cost or challenges posed by the system. Fragmentation of the systems

(care, research, and educational) slow the progress of bringing forward new screenings,

interventions, services and supports for this population and will add significant costs to the

already taxed system of care in the United States and around the world. Policy changes and

collaborative engagement in an interdisciplinary fashion by specialized researchers,

clinicians and health policy experts moving beyond the silos of medicine and governmental

institutions to seek broader, collective solutions for rare disease in children would advance

health for all humankind.


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Attachments

Attachment 1

Orphan Drug Act

Orphan Drug Act -- Excerpts

(Public Law 97-414, as amended)

CONGRESSIONAL FINDINGS FOR THE ORPHAN DRUG ACT

The Congress finds that---

(1) there are many diseases and conditions, such as Huntington's disease, myoclonus, ALS (Lou

Gehrig's disease), Tourette syndrome, and muscular dystrophy which affect such small numbers

of individuals residing in the United States that the diseases and conditions are considered rare in

the United States;

(2) adequate drugs for many of such diseases and conditions have not been developed;

(3) drugs for these diseases and conditions are commonly referred to as "orphan drugs";

(4) because so few individuals are affected by any one rare disease or condition, a

pharmaceutical company which develops an orphan drug may reasonably expect the drug to

generate relatively small sales in comparison to the cost of developing the drug and consequently

to incur a financial loss;

(5) there is reason to believe that some promising orphan drugs will not be developed unless

changes are made in the applicable Federal laws to reduce the costs of developing such drugs and

to provide financial incentives to develop such drugs; and

(6) it is in the public interest to provide such changes and incentives for the development of

orphan drugs.

RECOMMENDATIONS FOR INVESTIGATIONS OF DRUGS FOR RARE DISEASES

OR CONDITIONS

SEC. 525 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT [21 USC 360aa].

(a) The sponsor of a drug for a disease or condition which is rare in the States may request the

Secretary to provide written recommendations for the nonclinical and clinical investigations

which must be conducted with the drug before---

(1) it may be approved for such disease or condition under section 505,

(2) if the drug is a biological product, it may be licensed for such disease or condition under

section 351 of the Public Health Service Act.

If the Secretary has reason to believe that a drug for which a request is made under this section is

a drug for a disease or condition which is rare in the States, the Secretary shall provide the

person making the request written recommendations for the nonclinical and clinical

investigations which the Secretary believes, on the basis of information available to the Secretary

at the time of the request under this section, would be necessary for approval of such drug for

such disease or condition under section 505 or licensing of such drug for such disease or

condition under section 351 of the Public Health Service Act.


(b) The Secretary shall by regulation promulgate procedures for the implementation of

subsection (a).

DESIGNATION OF DRUGS FOR RARE DISEASES OR CONDITIONS

SEC. 526 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT [21 USC 360bb]. (a)

(1) The manufacturer or the sponsor of a drug may request the Secretary to designate the drug as

a drug for a rare disease or condition. A request for designation of a drug shall be made before

the submission of an application under section 505(b) for the drug, or the submission of an

application for licensing of the drug under section 351 of the Public Health Service Act. If the

Secretary finds that a drug for which a request is submitted under this subsection is being or will

be investigated for a rare disease or condition and---

(A) if an application for such drug is approved under section 505, or

(B) if a license for such drug is issued under section 351 of the Public Health Service Act,

the approval, certification, or license would be for use for such disease or condition, the

Secretary shall designate the drug as a drug for such disease or condition. A request for a

designation of a drug under this subsection shall contain the consent of the applicant to notice

being given by the Secretary under subsection (b) respecting the designation of the drug.

(2) For purposes of paragraph (1), the term "rare disease or condition'' means any disease or

condition which

(A) affects less than 200,000 persons in the United States, or

(B) affects more than 200,000 in the United States and for which there is no reasonable

expectation that the cost of developing and making available in the United States a drug for such

disease or condition will recovered from sales in the United States of such drug. Determinations

under the preceding sentence with respect to any drug shall be made on the basis of the facts and

circumstances as of the date the request for designation of the drug under this subsection is

made.

(b) A designation of a drug under subsection (a) shall be subject to the condition that---

(1) if an application was approved for the drug under section 505(b) or a license was issued for

the drug under section 351 of the Public Health Service Act, the manufacturer of the drug will

notify the Secretary of any discontinuance of the production of the drug at least one year before

discontinuance, and

(2) if an application has not been approved for the drug under section 505(b) or a license has not

been issued for the drug under section 351 of the Public Health Service Act and if preclinical

investigations or investigations under section 505(i) are being conducted with the drug, the

manufacturer or sponsor of the drug will notify the Secretary of any decision to discontinue

active pursuit of approval of an application under section 505(b) or approval of a license under

section 351 of the Public Health Service Act.

(c) Notice respecting the designation of a drug under subsection (a) shall be made available to

the public.

(d) The Secretary shall by regulation promulgate procedures for the implementation of

subsection (a).

PROTECTION FOR UNPATENTED DRUGS FOR RARE DISEASES OR CONDITIONS

SEC. 527 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT [21 USC 360cc]. (a)

Except as provided in subsection (b), if the Secretary---


(1) approves an application filed pursuant to section 505(b), or

(2) issues a license under section 351 of the Public Health Service Act

for a drug designated under section 526 for a rare disease or condition, the Secretary may not

approve another application under section 505(b) or issue another license under section 351 of

the Public Health Service Act for such drug for such disease or condition for a person who is not

the holder of such approved application or of such license until the expiration seven years from

the date of the approval of the approved application or the issuance of the license. Section

505(c)(2) does not apply to the refusal to approve an application under the preceding sentence.

(b) If an application filed pursuant to section 505(b) is approved for a drug designated under

section 526 for a rare disease or condition, or if a license is issued under section 351 of the

Public Health Service Act for such a drug, the Secretary may, during the seven-year period

beginning on the date of the application approval, or of the issuance of the license, approve

another application under section 505(b) or issue a license under section 351 of the Public Health

Service Act, for such drug for such disease or condition for a person who is not the holder of

such approved application or of such license if---

(1) the Secretary finds, after providing the holder notice and opportunity for the submission of

views, that in such period the holder of the approved application, of the certification, or of the

license cannot assure the availability of sufficient quantities of the drug to meet the needs of

persons with the disease or condition for which the drug was designated; or

(2) such holder provides the Secretary in writing the consent of such holder for the approval of

other applications, or the issuance of other licenses before the expiration of such seven-year

period.

OPEN PROTOCOLS FOR INVESTIGATIONS OF DRUGS FOR RARE DISEASES OR

CONDITIONS

SEC. 528 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT [21 USC 360dd]. If a

drug is designated under section 526 as a drug for a rare disease or condition and if notice of a

claimed exemption under section 505(i) or regulations issued thereunder is filed for such drug,

the Secretary shall encourage the sponsor of such drug to design protocols for clinical

investigations of the drug which may be conducted under the exemption to permit the addition to

the investigations of persons with the disease or condition who need the drug to treat the disease

or condition and who cannot be satisfactorily treated by available alternative drugs.

GRANTS AND CONTRACTS FOR DEVELOPMENT OF DRUGS FOR RARE

DISEASES AND CONDITIONS

SEC. ___ OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT [21 USC 360ee] (a) The

Secretary may make grants to and enter into contracts with public and private entities and

individuals to assist in

(1) defraying the costs of qualified clinical testing expenses incurred in connection with the

development of drugs for rare diseases and conditions,

(2) defraying the costs of developing medical devices for rare diseases or conditions, and

(3) defraying the costs of developing medical foods for rare diseases or conditions.

(b) For purposes of subsection (a):

(1) The term "qualified testing" means---


(A) human clinical testing---

(i) which is carried out under an exemption for a drug for a rare disease or condition under

section 505(i) of the Federal Food, Drug, and Cosmetic Act (or regulations issued under such

section);

(ii) which occurs after the date such drug is designated under section 526 of such Act and before

the date on which an application with respect to such drug is submitted under section 505(b) or

under section 351 of the Public Health Service Act; and

(B) preclinical testing involving a drug is designated under section 526 of such Act and before

the date on which an application with respect to such drug is submitted under section 505(b) or

under section 351 of the Public Health Service Act.

(2) The term "rare disease or condition" means (1) in the case of a drug, any disease or

conditions which (A) affects less than 200,000 persons in the United States, or (B) affects more

than 200,000 in the United States and for which there is no reasonable expectation that the cost

of developing and making available in the United States a drug for such disease or condition will

be recovered from sales in the United States of such drug, (2) in the case of a medical device,

any disease or condition that occurs so infrequently in the United States that there is no

reasonable expectation that a medical device for such disease or condition will be developed

without assistance under subsection (a), and (3) in the case of a medical food, any disease or

condition that occurs so infrequently in the United States that there is no reasonable expectation

that a medical food for such disease or condition will be developed without assistance under

subsection (a). Determinations under the preceding sentence with respect to any drug shall be

made on the basis of the facts and circumstances as of the date the request for designation of the

drug under section 526 is made.

(3) The term "medical food" means a food which is formulated to be consumed or administered

enterally under the supervision of a physician and which is intended for the specific dietary

management of a disease or condition for which distinctive nutritional requirements, based on

recognized scientific principles, are established by medical evaluation.

(c) For grants and contracts under subsection (a), there is authorized to be appropriated

$30,000,000 for each of fiscal years 2008 through 2012.

ORPHAN PRODUCTS BOARD

SEC. 227 OF THE PUBLIC HEALTH SERVICE ACT [42 USC 236]. (a) There is established in

the Department of Health and Human Services a board for the development of drugs (including

biologics) and devices (including diagnostic products) for rare diseases or conditions to be

known as the Orphan Products Board. The Board shall be comprised of the Assistant Secretary

for Health of the Department of Health and Human Services and representatives, selected by the

Secretary, of the Food and Drug Administration, the National Institutes Health, the Centers for

Disease Control and, any other Federal department or agency which the Secretary determines has

activities relating to drugs and devices for rare diseases or conditions. The Assistant Secretary

for Health shall chair the Board.

(b) The function of the Board shall be to promote the development of drugs and devices for rare

diseases or conditions and the coordination among Federal, other public, and private agencies in

carrying out their respective functions relating to the development of such articles for such

diseases or conditions.

(c) In the case of drugs for rare diseases or conditions the Board shall---

(1) evaluate---


(A) the effect of subchapter B of the Federal Food, Drug, and Cosmetic Act on the development

of such drugs, and

(B) the implementation of such subchapter;

(2) evaluate the activities of the National Institutes of Health and the Alcohol, Drug Abuse, and

Mental Health Administration for the development of drugs for such diseases or conditions,

(3) assure appropriate coordination among the Food and Drug Administration, the National

Institutes of Health, the Alcohol, Drug Abuse, and Mental Health Administration, and the

Centers for Disease Control in the carrying out of their respective functions relating to the

development of drugs for such diseases or conditions to assure that the activities of each agency

are complementary,

(4) assure appropriate coordination among all interested Federal agencies, manufacturers, and

organizations representing patients, in their activities relating to such drugs,

(5) with the consent of the sponsor of a drug for a rare disease or condition exempt under section

505(i) of the Federal Food, Drug, and Cosmetic Act or regulations issued under such section,

inform physicians and the public respecting the availability of such drug for such disease or

condition and inform physicians and the public respecting the availability of drugs approved

under section 505(c) of such Act or licensed under section 351 of this Act for rare diseases or

conditions,

(6) seek business entities and others to undertake the sponsorship of drugs for rare diseases or

conditions, seek investigators to facilitate the development of such drugs, and seek business

entities to participate in the distribution of such drugs, and

(7) reorganize the efforts of public and private entities and individuals in seeking the

development of drugs for rare diseases or conditions and in developing such drugs.

(d) The Board shall consult with interested persons respecting the activities of the Board under

this section and as part of such consultation shall provide the opportunity for the submission of

oral views.

(e) The Board shall submit to the Committee on Labor and Human Resources of the Senate and

the Committee on Energy and Commerce of the House of Representatives an annual report---

(1) identifying the drugs which have been designated under section 526 of the Federal Food,

Drug, and Cosmetic Act for a rare disease or condition,

(2) describing the activities of the Board, and

(3) containing the results of the evaluations carried out by the Board.

The Director of the National Institutes of Health and the Administrator of the Alcohol, Drug

Abuse, and Mental Health Administration shall submit to the Board for inclusion in the annual

report a report on the rare disease and condition research activities of the Institutes of the

National Institutes of Health and the Alcohol, Drug Abuse, and Mental Health Administration;

the Secretary of the Treasury shall submit to the Board for inclusion in the annual report a report

on the use of the credit against tax provided by section 44H of the Internal Revenue Code of

1954; and the Secretary of Health and Human Services shall submit to the Board for inclusion in

the annual report a report on the program of assistance under section 5 of the Orphan Drug Act

for the development of drugs for rare diseases and conditions. Each annual report shall be

submitted by June 1 of each year for the preceding calendar year.


Attachment 2

AMA’s Code of Medical Ethics - Opinion 2.138 - Genetic Testing of Children

Genetic testing of children implicates important concerns about individual autonomy and the

interest of the patients. Before testing of children can be performed, there must be some potential

benefit from the testing that can reasonably be viewed as outweighing the disadvantages of

testing, particularly the harm from abrogating the children’s future choice in knowing their

genetic status. When there is such a potential benefit, parents should decide whether their

children will undergo testing. If parents unreasonably request or refuse testing of their child, the

physician should take steps to change or, if necessary, use legal means to override the parents’

choice. Applying these principles to specific circumstances yields the following conclusions:

(1) When a child is at risk for a genetic condition for which preventive or other therapeutic

measures are available, genetic testing should be offered or, in some cases, required.

(2) When a child is at risk for a genetic condition with pediatric onset for which preventive or

other therapeutic measures are not available, parents generally should have discretion to decide

about genetic testing.

(3) When a child is at risk for a genetic condition with adult onset for which preventive or other

therapeutic measures are not available, genetic testing of children generally should not be

undertaken. Families should still be informed of the existence of tests and given the opportunity

to discuss the reasons why the tests are generally not offered for children.

(4) Genetic testing for carrier status should be deferred until either the child reaches maturity, the

child needs to make reproductive decisions, or, in the case of children too immature to make

their own reproductive decisions, reproductive decisions need to be made for the child.

(5) Genetic testing of children for the benefit of a family member should not be performed unless

the testing is necessary to prevent substantial harm to the family member.

When a child’s genetic status is determined incidentally, the information should be retained by

the physician and entered into the patient record. Discussion of the existence of this finding

should then be taken up when the child reaches maturity or needs to make reproductive

decisions, so that the individual can decide whether to request disclosure of the information. It is

important that physicians be consistent in disclosing both positive and negative results in the

same way since if physicians raise the existence of the testing results only when the results are

positive, individuals will know what the results must be. This information should not be

disclosed to third parties. Genetic information should be maintained in a separate portion of the

medical record to prevent mistaken disclosure.

When a child is being considered for adoption, the guidelines for genetic testing should be the

same as for other children. (IV)


Issued June 1996 based on the report "Testing Children for Genetic Status," adopted June

1995.

Attachment 3

AMA Principles of Medical Ethics

Opinion 2.215 - Treatment Decisions for Seriously Ill Newborns

The primary consideration for decisions regarding life-sustaining treatment for seriously ill

newborns should be what is best for the newborn. Factors that should be weighed are (1) the

chance that therapy will succeed, (2) the risks involved with treatment and nontreatment, (3) the

degree to which the therapy, if successful, will extend life, (4) the pain and discomfort associated

with the therapy, and (5) the anticipated quality of life for the newborn with and without

treatment.

Care must be taken to evaluate the newborn’s expected quality of life from the child’s

perspective. Life-sustaining treatment may be withheld or withdrawn from a newborn when the

pain and suffering expected to be endured by the child will overwhelm any potential for joy

during his or her life. When an infant suffers extreme neurological damage, and is consequently

not capable of experiencing either suffering or joy, a decision may be made to withhold or

withdraw life-sustaining treatment. When life-sustaining treatment is withheld or withdrawn,

comfort care must not be discontinued.

When an infant’s prognosis is largely uncertain, as is often the case with extremely premature

newborns, all life-sustaining and life-enhancing treatment should be initiated. Decisions about

life-sustaining treatment should be made once the prognosis becomes more certain. It is not

necessary to attain absolute or near absolute prognostic certainty before life-sustaining treatment

is withdrawn, since this goal is often unattainable and risks unnecessarily prolonging the infant’s

suffering.

Physicians must provide full information to parents of seriously ill newborns regarding the

nature of treatments, therapeutic options, and expected prognosis with and without therapy, so

that parents can make informed decisions for their children about life-sustaining treatment.

Counseling services and an opportunity to talk with persons who have had to make similar

decisions should be available to parents. Ethics committees or infant review committees should

also be utilized to facilitate parental decision making. These committees should help mediate

resolutions of conflicts that may arise among parents, physicians, and others involved in the care

of the infant. These committees should also be responsible for referring cases to the appropriate

public agencies when it is concluded that the parents’ decision is not a decision that could

reasonably be judged to be in the best interests of the infant. (I, III, IV, V)

Issued June 1994 based on the report "Treatment Decisions for Seriously Ill Newborns ,"

adopted June 1992.

http://www.ama-assn.org/resources/doc/code-medical-ethics/2138a.pdf




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Capstone for Master of Arts in Health and Human Services Administration (Doherty, 2012)

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