Ralph S. Tyler
Joseph H. Young
HOGAN & HARTSON, LLP
111 S. Calvert Street, Suite 1600
Baltimore, MD 21202
September 17, 2001 Attorneys for Amici Curiae
TABLE OF CONTENTS
INTEREST OF AMICI 1
INTRODUCTION 3
ARGUMENT 5
A. Nontherapeutic research is an essential
component of medical research 6
B. Risk is an inevitable consequence of medical research 11
CONCLUSION 14
TABLE OF CITATIONS
Page(s)
Regulations
45 C.F.R. § 46.102 11
45 C.F.R. § 46.405 11
45 C.F.R. § 46.406 7, 8, 9, 11
45 C.F.R. § 46.407 9, 11
Additional Protections for Children Involved as Subjects
In Research, 48 Fed. Reg. 9814 (March 8, 1983) 10
Proposed Regulations on Research Involving Children,
43 Fed. Reg. 31786 (July 21, 1978) 10
Research Involving Children: Report and Recommendations of the
National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research, 43 Fed. Reg. 2084
(January 13, 1978) 10
Other
Piantadosi, S., Clinical Trials, A Methodological Perspective
(John Wiley & Sons, Inc., 1997) 6
Pocock, S., Clinical Trials: A Practical Approach
(John Wiley & Sons, 1983) 6
Random House Dictionary of the English Language
(2nd ed. 1987) at 586 6
INTEREST OF AMICI
Amici are the Association of American Medical Colleges, the Association of American Universities, the Johns Hopkins University, and the University of Maryland Medical System Corporation. Individually and collectively, amici or their members are deeply involved in all aspects of medical, public health, and human developmental research. Amici strongly support the motion of appellee Kennedy Krieger Institute, Inc. ("KKI") for reconsideration of the Court's August 16 decision. Amici are exceedingly concerned about the immediate and long term consequences of the Court's broadly worded decision.
As detailed below, the Court's unprecedented holding (see Slip Op. at 93-94)
would prohibit a wide spectrum of critically important research involving persons
under a legal disability. This is precisely the type of research in which amici
or their members have been, are, and expect to be engaged. Amici submit this
brief because of their commitment to continue to do the type of research upon
which we all depend to advance knowledge to cure and prevent human diseases
and developmental disorders.
The Association of American Medical Colleges ("AAMC") was founded
in 1876 and represents the interests of its members, including all of this country's
125 accredited medical schools, over 400 teaching hospitals and thousands of
medical school faculty, medical students, and medical residents, on issues relating
to medical and health research, education, and other matters. Among the AAMC's
members are the Society for Pediatric Research, the American Pediatric Society,
the Association of Medical School Pediatric Department Chairs, and the Ambulatory
Pediatric Association.
The Association of American Universities ("AAU") was founded in 1900
and currently consists of 61 universities in the United States and two in Canada.
The AAU member institutions include the principal research universities in this
country. Both AAMC and AAU, as well as their respective member institutions,
are vitally concerned with the development of sound legal rules and public policies
that affect the conduct of research and that research in academic institutions
be conducted consistent with the highest ethical standards.
The Johns Hopkins University Schools of Medicine, Nursing, and Public Health
are preeminent centers of teaching and research. In addition to training doctors,
nurses, and public health officials, these Schools and their respective faculty
and staff members are engaged in cutting edge research of diseases and disorders
afflicting children and other persons under legal disability.
The University of Maryland Medical System Corporation owns and
operates the University of Maryland Medical Center. Section 13-305(a) of the
Education Article of the Maryland Code provides that: "The medical system
will serve as the primary clinical setting for University students in health
care fields to receive educational and research experiences." Consequently,
much, if not most, of the clinical research of the faculty of the University
of Maryland System's School of Medicine is conducted at the Medical Center.
The School of Medicine is among the public institutions that receive the largest
amounts of federal grants for human research.
INTRODUCTION
Amici do not ask the Court to reverse its decision in these cases.
As the Court held, these cases should return to the circuit court for proceedings
consistent with the Court's holding that KKI owed a duty to the plaintiffs.
In those further proceedings, the issues to be resolved include the precise
contours of KKI's duty, whether the duty was violated, and, if so, what injuries
plaintiffs suffered as a result of any breach. While those proceedings should
go forward, the Court should review, reconsider, and rescind that portion of
its decision which would have a devastating impact on health and human developmental
research.
Under the plain terms of the Court's holding, consent to participation
in health research in cases involving children and others under legal disability
is, as a matter of law, unavailable whenever there is a risk of any harm to
the participant. The overall cost of such a rule in terms of lost advances in
medical and health knowledge (and ultimately lost opportunities to cure diseases
and prevent suffering and the loss of life) will far outweigh the asserted advantage
of protecting individual rights. Moreover, research involving human subjects
occurs within an existing legal framework of federal regulations and Institutional
Review Board ("IRB") oversight. This framework, established after
years of considered deliberation by medical professionals, ethicists, advocates,
and government regulators, is designed to protect the rights of the individual
study participants. As the Court recognized, if a study participant's rights
are violated, the civil tort system should afford a remedy. The civil tort system
should not be used, however, to prohibit medical and human developmental research.
There is no denying the seriousness of the issues with which the
Court grappled in these cases. Rather than a broadly sweeping holding, the seriousness
of these issues counsels in favor of a far more cautious approach and a far
narrower decision than the one which the Court issued. If, contrary to the view
of amici, this State is to adopt a code for human research that is vastly more
restrictive than that of any other state or that of the federal government,
this critically important and truly radical public policy decision should be
the subject of careful study and extensive debate in the Legislature.
Amici ask the Court to recall and rescind the opinion issued herein
on August 16. In place of that Opinion, the Court should issue a new opinion,
with the result unaltered, but without the broad holding that would prohibit
a great deal of extraordinarily important medical and public health research.
ARGUMENT
The specific portion of the Court's holding that amici respectfully
submit should be reconsidered is as follows:
We hold that in Maryland a parent, appropriate relative, or other applicable
surrogate, cannot consent to the participation of a child or other person under
legal disability in nontherapeutic research or studies in which there is any
risk of injury or damage to the health of the subject.
Slip Op. at 93-94.
Amici disagree profoundly with this prohibition. A rule prohibiting "nontherapeutic
research or studies in which there is any risk of injury" (emphasis added)
would prohibit virtually all medical and public health research involving children
and other persons under a legal disability. By its plain terms, the Court's
broadly worded holding would prohibit even genetic studies requiring no more
than needle sticks, as a needle stick presents a risk of harm. It would also
prohibit the long accepted health research protocol in which children and other
persons under a legal disability may receive a placebo, as distinguished from
a potentially effective therapy or preventive strategy, in order to conduct
a scientifically sound study that will yield statistically significant results.
The governing federal regulations do permit research which is not risk free
even when the research does not hold out the prospect of direct benefit for
the individual subject.
A. Nontherapeutic research is an essential component of medical research.
Medical and health research is the search for a deeper understanding of human diseases and for new strategies of disease prevention and treatment. The highest standard of medical and health research methodology is the prospective, randomized, "double blind" study in which some participants receive a placebo to ensure that any improvement in the treated group is due to the therapy or prevention strategy being tested. / As one of the leading texts on the design of clinical trials notes,
In many diseases, there exists no effective standard treatment so that it is appropriate for the control group in a randomized trial of new therapy to remain untreated. Also, even if alternative therapies do exist, the early (phase II) trials of a new treatment may require short-term evaluation for the existence of some therapeutic effect by comparison with untreated controls.
Pocock, S., Clinical Trials: A Practical Approach at 92 (John Wiley & Sons,
1983). See also Piantadosi, S., Clinical Trials, A Methodological Perspective
at 71 (John Wiley & Sons, Inc. 1997) ("If the disease is mild and self-limited
or no treatment is the standard of practice, then a placebo might be appropriate.").
In "placebo control" studies, some participants receive a placebo,
and not the medication, treatment, or prevention strategy that is being tested.
For the placebo recipients, the research holds no "prospect of direct benefit
for the individual subject," see 45 C.F.R. § 46.406, or, in the language
of the Court, is "nontherapeutic." Under the Court's broad holding,
therefore, this standard research methodology would no longer be lawful in Maryland
in research involving persons under a legal disability if there is "any
risk."
Amici or their members have conducted and are currently conducting numerous
"placebo control" studies involving children or others under a legal
disability. For example, Johns Hopkins Medical School faculty are engaged in
important research to find a cure or treatment for sickle cell anemia, a chronic
hereditary blood disease occurring primarily among Africans and African-Americans.
As part of that research, some children with the disease receive a placebo (sugar)
while others receive an investigational drug. To date, sickle cell anemia research
programs are nontherapeutic for all participants because the drugs administered
to some have not been proven effective and the others have received a placebo.
The same is true for research involving any disease for which there is no known
curative treatment or effective prevention. The research is nontherapeutic (i.e.,
"does not hold out the prospect of direct benefit for the individual subject,"
45 C.F.R. § 46.406) and, as discussed below, not risk free for those research
participants who receive an experimental intervention that ultimately proves
ineffective. By definition, the research is always nontherapeutic for those
who receive a placebo and, again, not risk free.
A tragic and certainly unintended consequence of the Court's broad holding
is that children and others under a legal disability who are afflicted with
a serious illness for which there is no known prevention, treatment, or cure
will be denied the benefit of any experimental therapy or preventive strategy.
To evaluate experimental interventions that may benefit some, researchers must
be able to test those interventions by not providing them to other persons who
have, or are susceptible to, the same illness.
The process for developing vaccines is another compelling example of a type
of research in which amici or their members are involved but which the Court's
broad holding would prohibit. After vaccines have been tested in laboratory
animals, preliminary trials are conducted with healthy children to demonstrate
safety and ability to stimulate an immune response, and later trials are conducted
to demonstrate efficacy. The children involved in the preliminary trials receive
no therapeutic benefit and they face some potential risk of harm. Without these
trials, however, it is impossible to demonstrate that a new vaccine is safe
and efficacious.
In sharp contrast to the Court's broad holding, federal regulations recognize
that it is lawful to conduct medical and health research involving children
even though the research may not or does not benefit the individual research
participant. The Department of Health and Human Services ("HHS") is
authorized to "conduct or fund research in which the IRB finds that more
than minimal risk is presented to children by an intervention or procedure that
does not hold out the prospect of direct benefit for the individual subject
. . . ." See 45 C.F.R. § 46.406. In such cases, the IRB must find,
inter alia, that "[t]he intervention or procedure is likely to yield generalizable
knowledge about the subjects' disorder or condition which is of vital importance
for the understanding or amelioration of the subjects' disorder or condition
. . . ." Id. In addition, HHS will, in appropriate circumstances, conduct
or fund research that the IRB does not believe meets these requirements if the
Secretary has determined that "[t]he research presents a reasonable
opportunity to further the understanding, prevention, or alleviation of a serious
problem affecting the health or welfare of children . . . ." See 45
C.F.R. § 46.407(b)(2)(i) (emphasis added).
In its opinion, the Court refers to these HHS regulations in the context of
analyzing whether there is a special relationship/duty between KKI and the plaintiffs.
See Slip Op. at 72-75. Plainly, however, the HHS regulations are not limited
to the issue of special relationship/duty. The regulations also confirm that
it is lawful and ethical, as well as necessary, to conduct research involving
children where the research is, in the Court's terminology, nontherapeutic because
it "does not hold out the prospect of direct benefit for the individual
subject." /
The HHS regulations recognize that research may not benefit the particular
research subjects, but that the absence of benefit to each participant does
not make the research unlawful. If the legal standard is that the research must
be therapeutic for each and every individual involved who faces any risk, a
great deal of health research involving children and other persons under legal
disability (e.g., persons with Alzheimer's disease), including research regarding
the causes, progression, prevention, and treatment of conditions of high morbidity
and mortality, could never be conducted.
B. Risk is an inevitable consequence of medical research.
The Court held that no one can consent to nontherapeutic research involving
"a child or other person under legal disability" where "there
is any risk of injury or damage to the health of the subject." (Emphasis
added.) This "any risk" standard is inconsistent with medical research.
The blunt fact is that there is almost no research without risk. The Court should
modify its prohibition of nontherapeutic research where there is "any risk"
because that standard is unrealistic, unworkable, and unwise.
Rather than an "any risk" standard, the HHS regulations authorize
federally funded research where the IRB finds "that more than minimal risk
to children is presented." See 45 C.F.R. §§ 46.405, 46.406. The
IRB may approve such research where the IRB finds, among other things, "[t]he
risk represents a minor increase over minimal risk" and "[a]dequate
provisions are made for soliciting the assent of the children and permission
of their parents or guardians . . . ." See 45 C.F.R. § 46.406. "Minimal
risk" is defined as "the probability and magnitude of harm or discomfort
anticipated in the research are not greater in and of themselves than those
ordinarily encountered in daily life or during the performance of routine physical
or psychological examinations or tests." See 45 C.F.R. § 46.102(i).
Where the IRB cannot make the findings set forth in § 46.406, HHS will
conduct or fund research involving children only if the Secretary of HHS approves
the research and other conditions are satisfied. See 45 C.F.R. § 46.407.
As these HHS regulations recognize, research may be appropriate, ethical, and
lawful where there is "more than minimal risk" and the research is
nontherapeutic.
Unless narrowed, the Court's "any risk" holding would prohibit critically
important and potentially promising cutting edge research. For example, a great
deal of research is being done in early detection of adult diseases. Completely
normal children whose parents have Type I diabetes are being screened for antibodies
to pancreatic islet cells. There is some risk associated with these tests and
the findings from these blood tests will not benefit these normal children since,
at present, the significance of having the antibody (or not) is unknown. Opportunities
to do many types of genetic research would also be prohibited by the Court's
"any risk" standard. The ability to do skin biopsies, for example,
of disease-affected children and their non-affected siblings is necessary to
determine the association of abnormal genes with disease. Again, these biopsies
are not risk free, and they are nontherapeutic for the non-affected siblings.
The plaintiffs/appellants in Case No. 129 (Higgins) acknowledge that some risk
is inherent in the research enterprise. See supplemental brief of appellants
in no. 129 (September Term, 2000) at 13 (arguing for "a duty to protect
research subjects from unreasonable harm"); id. at 14 ("Researchers
are already required by professional ethical standards and federal regulations
to prevent unreasonable harm to [research] participants . . . .") (emphases
added). Appellants in Higgins also expressly stated that they were "not
seeking to impose a standard of care beyond that which Kennedy [KKI] should
already be complying." See id. at 14-15 (emphasis added).
Thus, the Court's "any risk" standard far exceeds both the standard
established in the federal regulations and the standard for which the appellants
in Higgins contended. Similarly, the Court's "any risk" standard exceeds
the standard with which KKI or any similar medical or health research organization
has been expected to comply, again contrary to the position of appellants in
Higgins.
In sum, amici urge the Court to reconsider and narrow substantially its holding in these cases. The Court's broad holding is unnecessary to the conclusion that the judgments below should be reversed. The Court should strike or modify its broad prohibitory holding because to fail to do so would cripple the pursuit of critical medical and public health research.
CONCLUSION
For the reasons stated, KKI's motion for reconsideration should be granted.
Respectfully submitted,
Ralph S. Tyler
Joseph H. Young
Hogan & Hartson, LLP
111 S. Calvert St., Suite 1600
September 17, 2001 Baltimore, MD 21202
This brief was typed in 13 point Century Schoolbook.
CERTIFICATE OF SERVICE
I HEREBY CERTIFY that on this 17th day of September, 2001, two copies of the
foregoing brief of amici curiae were served on each of the following by first-class
mail, postage prepaid:
Suzanne C. Shapiro, Esquire
Saul E. Kerpelman & Associates, P.A.
10 N. Calvert Street, Suite 600
Baltimore, MD 21202
Attorneys for Appellant Myron Higgins
Kenneth W. Strong, Esquire
11 E. Chase Street, Suite 4B
Baltimore, MD 21202
Attorneys for Appellant Ericka Grimes
S. Allan Adelman, Esquire
Michael I. Joseph, Esquire
Goddard, West, Adelman, Sheff & Smith, LLC
200A Monroe St., Suite 310
Rockville, MD 20850
Shale D. Stiller, Esquire
George A. Nilson, Esquire
Piper Marbury Rudnick & Wolfe, LLP
6225 Smith Ave.
Baltimore, MD 21209-3600
Attorneys for Appellee
Deborah Thompson Eisenberg, Esquire
Marc E. Steinberg, Esquire
Tara Andrews, Esquire
Public Justice Center
500 E. Lexington Street, Suite 200
Baltimore, MD 21202
Attorneys for Amici Curiae The Public Justice Center, the National Health Law Program and East Harbor Village Center
Angus R. Everton, Esquire
Morgan Shelsby Carlo Downs & Everton, P.A.
4 North Park Drive, Suite 404
Hunt Valley, MD 21030
Attorneys for Amicus Curiae The National Center for Lead-Safe Housing
_____________________________
Ralph S. Tyler